Which emergency medication may cause cerebral hemorrhage atropine dopamine epinephrine vasopressin

There are many kinds of medical shock.

Hypovolemic shock occurs when the body begins to shut down due to the loss of large amounts of blood or fluid. When hypovolemic shock is caused by blood loss, it’s known as hemorrhagic shock.

People with injuries that involve heavy bleeding may go into hemorrhagic shock if the bleeding isn’t stopped immediately.

According to a 2019 study, hemorrhagic shock as a result of injury is the leading cause of death in people ages 1 to 46 years old in the United States.

Common causes of hemorrhagic shock include:

• severe burns
• deep cuts
• gunshot wounds
• trauma
• amputations

Blood carries oxygen and other essential substances to your organs and tissues. When heavy bleeding occurs, these substances are lost more quickly than they can be replaced. There’s not enough blood flow to the organs in your body, and they begin to shut down.

As your heart shuts down and fails to circulate an adequate amount of blood through your body, symptoms of shock occur. Blood pressure plummets and there’s a massive drop in body temperature, which can be life threatening.

The American College of Surgeon’s Advanced Trauma Life Support program divides hemorrhagic shock into four classes. The classifications are based on the amount of expected blood loss in a healthy person weighing 154 pounds:

• People with class 1 shock have lost up to 15 percent of their total blood volume.
• People with class 2 shock have lost 15 to 30 percent of their total blood volume.
• People with class 3 shock have lost 30 to 40 percent of their total blood volume.
• People with class 4 shock have lost over 40 percent of their total blood volume.

Call 911 or your local emergency services if someone is bleeding heavily or has symptoms of shock. Also, follow the steps below:

1. If the person doesn’t have a head injury, neck injury, or spine injury, lay them on their back with their legs elevated 12 inches from the ground. Don’t elevate their head.
2. Remove any visible dirt or debris from the injury site. DO NOT remove embedded glass, a knife, a stick, an arrow, or any other object stuck in the wound.
3. If the area is clear of debris and no visible object is protruding from it, tie fabric such as a shirt, towel, or blanket around the injury to minimize blood loss. Apply pressure to the area. If you can, tie or tape the fabric to the injury.
4. Wait for emergency personnel to arrive.

There are often no advance warnings of shock. Instead, symptoms tend to arise only when you’re already experiencing shock.

A physical examination can reveal signs of shock, such as low blood pressure and a rapid heart rate. Someone in shock may also be less responsive when asked questions by an emergency room doctor.

While heavy bleeding is immediately recognizable, internal bleeding sometimes isn’t found until someone shows signs of hemorrhagic shock. Shock requires immediate attention, so treatment may begin before diagnosis.

If the reason for shock is not obvious, or it’s internal, various tests may be used to diagnose the cause, including:

• X-rays
• blood tests
• ultrasound
• CT scan
• MRI

Your doctor may order a complete blood count (CBC) after addressing the site of the bleeding. The results of this test will let them know whether a blood transfusion is necessary.

Your doctor may also order a blood transfusion without doing a CBC if there’s a large amount of blood loss from the injury. A blood transfusion is given by transferring donor blood into your body intravenously.

The standard treatment for hemorrhagic shock is intravenous (IV) fluid and resuscitation via the administration of blood products.

In some cases, you may be given medications that increase your blood pressure, such as norepinephrine or vasopressin. These are known as vasopressors. People who also have heart dysfunction may be prescribed the vasopressors dobutamine or epinephrine, according to a 2017 study.

Common complications of hemorrhagic shock include kidney damage, other organ damage, and death.

Some people may also develop gangrene due to decreased circulation to the limbs. This infection may result in amputation of the affected limbs.

The outlook will depend on the amount of blood loss and the type of injury. The outlook is best in people with no preexisting health conditions who haven’t had severe blood loss.

Seeking medical help as soon as you notice symptoms of shock will help improve your outlook overall.

by James Lamberg, DO

Case Study: Cardiac Arrest After Intubation

Paramedic Unit 44 is dispatched to a nursing home for a patient in severe respiratory distress. You, serving as the medic on that unit, gather your equipment and head into the building with EMT Mukherjee. You are directed into the patient’s room and find an elderly female gasping for air. She is barely conscious. You ask for a brief medical history and prepare for intubation using your institutional protocol. Oxygen is applied by bag-valve-mask with assistance of respirations to pre-oxygenate.
The nursing assistant reads the patient’s chart: history of stroke, can’t move her right side, been bedbound for months, requires assistance for all activities, hypertension…you’ve heard a similar story before. Yep, you say to yourself, she’s really sick and needs a breathing tube. EMT Mukherjee has obtained IV access and baseline vital signs: SpO2 85%, HR 120, BP 145/75, RR 24. You direct him to give 20mg IV etomidate and 100mg IV succinylcholine. After fasciculations you put the laryngoscope in the mouth and almost immediately see vocal cords.
Tube passed, bag squeezed, chest rises bilaterally. You look at the monitor and see no end-tidal CO2 tracing. EMT Mukherjee tries to troubleshoot, assuming it’s faulty equipment. Heart rate remains stable, SpO2 is 80%, then the BP cuff cycles and times out, saying “unable to read.” You check a carotid pulse – absent. You check the other carotid, hoping the worst hasn’t happened. But it has; you direct EMT Mukherjee to start CPR and you begin ACLS protocol. After several rounds of epinephrine and CPR, the patient remains in asystole.

Critical Thinking Questions

1. Why do you think the patient went into cardiac arrest?
2. What could have been done differently?
3. What are your institutional protocols for medication-assisted endotracheal intubation?

Education Standard
Integrates comprehensive knowledge of pharmacology to formulate a treatment plan intended to mitigate emergencies and improve the overall health of the patient.

Learning Objectives

1. Identify common intravenous fluids and which are preferred for large volume resuscitation.
2. Discuss medications used for respiratory emergencies and options for a patient presenting with a severe asthma exacerbation.
3. Discuss medications for treatment of tachycardia and bradycardia.
4. Discuss medications for treatments of life-threatening ventricular arrhythmias.
5. Discuss medications for management of ischemic heart disease and acute coronary syndrome.
6. Explain the difference between a vasopressor and an inotrope, including indications for use.
7. Identify drugs for the management of neurologic and behavioral emergencies.
8. List the mechanisms of nausea and medications that target these receptors.
9. Describe medications used for diabetes mellitus and contraindications to their use.
10. Explain how to manage an anaphylactic reaction, including appropriate drug dosing and route of administration.
11. List drugs used in the management of common toxidromes.
12. Describe medications used for analgesia and anesthesia, as well as medications used to cause muscle relaxation (paralysis).

Key Terms
Alkaline solution

Anticholinergic

Anuria

Black box warning

Catecholamine

Depolarizing muscle relaxant

Diuresis

Dromotropic agent

Dysgeusia

Effective dose

Enantiomer

Extravasation

Hypersensitivity reaction

Isotonic

Nondepolarizing muscle relaxant

Off-label use

Racemic mixture

Tachyphylaxis

Tocolytic

Toxidrome

Introduction

Medications give paramedics the power to make drastic changes to a patient’s physiology within seconds. But, with great power comes great responsibility. Administration of a medication always comes at a cost. That cost could be a minor side effect, like headache, or a serious life-threatening side effect, like cardiac arrhythmias. This is why it is important to understand not only the indications for a drugs use, but also the contraindications and adverse effects.
The management of most medical emergencies involves administration of medications by the paramedic. Some of these emergencies may be the direct result of drugs that the patient intentionally or unintentionally ingested. As you will see, the route of administration can have major effects on how the drug works. This emphasizes the point that drug dosing is dependent on route of administration (Vanden Hoek et al, 2010). Epinephrine is one example where the intramuscular and subcutaneous doses are about the same and are administered in a 1:1000 concentration (1mg/mL). For intravenous administration, the dose is significantly less than other routes and the concentration is 1:10,000 (0.1mg/mL). Accidental administration of the wrong epinephrine concentration would be ten-times more epinephrine than planned!
The goal of this chapter is to provide you with a detailed overview of the common medications used for paramedic emergencies. It is not as important to memorize the exact onset time of a drug, for instance, as it is to know in general how fast the drug will work. Understanding the drug’s mechanism of action can help you remember the scenarios where it will be the most effective. Most importantly, contraindications to the use of each drug need to be remembered as administration of these drugs in the wrong circumstance can have dire consequences.
The Institute for Safe Medication Practices (ISMP) has a list of high-alert medications for the acute care setting. These medications have the potential for serious patient harm if used in error. Mistakes with these medications are not necessarily more common than with other drugs, but the consequences can be devastating. The majority of the medications discussed in this chapter are considered high alert. Please check all medications with an up-to-date resources or drug reference. The ISMP has several error-reducing strategies for managing these medications.

Table 15-1: High Alert Medications

That’s Not True … or Is it? You Can’t Give That By The Intraosseous Route
Every medication that is listed as IV administration can also be given via the intraosseous (IO) route. The IO route is equivalent to IV in both functionality and drug delivery. In 2014, Dr. Anson wrote a review article on intraosseous access and drug administration. He further outlined the safety of drug administration into the medullary space and emphasized the American Heart Association guidelines that all emergency medications can be given IO in their standard IV dosing. Fluid administration is typically limited to 5L/hr by the medullary space.
IO dosing will not be discussed in this chapter because it can be assumed that any medication that can be given IV can also be given IO in the same dose.

Intravenous Fluids

Intravenous access is indicated for fluid replacement, for blood replacement, for drug administration, and for obtaining blood specimens. There are several intravenous fluid solutions that can be used for large volume fluid replacement during resuscitation or for management of specific emergency situations. Crystalloids are the primary out-of-hospital fluid solution and are described as being hypotonic, isotonic, or hypertonic. The tonicity of a solution is a comparison of that solution’s concentration to the concentration in the patient. A hypotonic solution has a concentration less than the patient’s blood and a hypertonic solution has a concentration greater than the patient’s blood. Isotonic solutions are similar in concentration to the patient and thus do not cause a fluid shift into or out of the intravascular space after they are administered. These solutions are therefore preferred for volume resuscitation. Colloid solutions, such as albumin or volume-expanding starches, have larger molecules that a meant to remain in circulation for a longer period of time.

Dextrose 5% in Water

Class: hypotonic crystalloid solution.

Indications: hypoglycemia, as a solution for diluting medications like bicarbonate.

Contraindications: hyponatremia, hyperglycemia, large volume fluid resuscitation.

Adverse Effects: hyponatremia, peripheral edema, pulmonary edema, cerebral edema.

Dextrose 5% in water (D5W) is a slightly hypotonic solution that is used for medical conditions, particularly hypoglycemia. A 5% dextrose solution means there are 50mg of dextrose in each mL of fluid. A 1-liter bag of D5W would contain 50 grams of dextrose. For comparison, a D50 (dextrose 50% in 100mL) bolus syringe also contains 50 grams of dextrose. D10 (dextrose 10% in 50mL) contains 5 grams of dextrose. All three of these options (D5W, D10, D50) can be used to treat hypoglycemia in adults, however D5W is the least preferred. Some authors recommend D10 as a better choice than D50 for adult hypoglycemia (Moore et al, 2005). D10 may also be used for hypoglycemia in infants and children.
So why is D5W a poor choice for hypoglycemia? A soda can of Mountain Dew® contains 46 grams of glucose per 12 ounces (355mL). As mentioned, D5W contains 50 grams in the entire 1000mL bag. Depending on the size of the peripheral IV catheter placed, this could take some time to administer and is not very useful during a hypoglycemic emergency. D5W may be useful as a maintenance infusion to prevent hypoglycemia from reoccurring after it has been appropriately treated.
D5W is almost isotonic when it is administered, however the liver quickly metabolizes the glucose in the solution. This leaves water alone, which is hypotonic and distributes out of the intravascular space. Only about 75mL of the 1000mL originally given will remain in the vascular space (Doherty et al, 2012). This means D5W is a very poor choice for large volume fluid resuscitation. As a comparison, 1000mL of 0.9% normal saline will distribute as 250mL in the intravascular space. Complications that result from giving a large amount of water are low sodium (hyponatremia) in the blood and edema. Hyponatremia occurs from diluting out the salt in the body with water. Edema can occur in all parts of the body including the periphery (e.g. feet), lungs (pulmonary edema), and brain (cerebral edema/swelling). Cerebral edema can cause neurologic injury and can worsen any form of brain injury by increasing intracranial pressure. Signs of cerebral edema include confusion, seizures, and coma. The increase in intracranial pressure can lead to brainstem herniation and death.
D5W is more commonly used as a solution for diluting other medications. One example is creating an alkaline solution to manage certain drug overdoses. An alkaline solution, or basic solution, is one that has a pH greater than 7. An acidic solution would have a pH less than 7. A common mixture for creating an alkaline solution is 150mEq (3 amps) of bicarbonate mixed into 1 liter of D5W. Overall, D5W has limited useful applications in the out-of-hospital environment. It can be used to prevent hypoglycemia and as a solution for diluting medications. It has several negative side effects, especially if given in a large volume.

Lactated Ringer Solution

Class: isotonic crystalloid solution.

Indications: large volume fluid resuscitation, standard IV infusion fluid.

Contraindications: hyperkalemia, hypercalcemia, renal failure.

Adverse Effects: volume overload.

Lactated Ringer (LR) is crystalloid solution that is isotonic with blood. It can be used for large volume fluid resuscitation and as a standard intravenous fluid solution for infusion. Knowing the composition of crystalloid solutions can help you determine when they would be inappropriate to use. LR contains the following mixture of electrolytes: 130 mEq of sodium, 109 mEq of chloride, 28 mEq of lactate, 4 mEq of potassium, and 3 mEq of calcium. See Table 15-2 for normal electrolyte levels in the blood. Comparing LR to normal blood values, you can see that the crystalloid solution is relatively similar. This allows for LR to be given in large volumes without significant changes in body electrolytes.
There are few contraindications to the use of lactated Ringer solution, all of which are related to the electrolyte composition. Patients who have high potassium levels (hyperkalemia) or high calcium levels (hypercalcemia) should not receive LR. Renal failure patients are unable to excrete potassium effectively, thus this solution would not be preferred in those patients. All resuscitation fluids can cause volume overload if too much is given. Due to the risk of volume overload, these solutions should be used cautiously in patients with congestive heart failure.
That’s Not True … or Is it? Can Lactated Ringer solution be given with blood?
There has been debate about the use of Ringer’s lactate solution combined with blood products. Citrate is an anticoagulant used in many blood products. This can combine with calcium solutions to form clots. It has been suggested that LR should be avoided when using blood products. However, studies have shown that this is not an issue as long as the infusion rate is fast (Lorenzo et al, 1998).

Multi-Electrolyte Solutions

Class: isotonic crystalloid solution.

Indications: large volume fluid resuscitation, standard IV infusion fluid.

Contraindications: hyperkalemia, hypermagnesemia, renal failure.

Adverse Effects: volume overload.

Multi-electrolyte solutions are isotonic crystalloids used for large volume fluid resuscitation and as a standard intravenous fluid solution for infusion. Two common brands are Plasma-lyte (PLASMA-LYTE® 148 Injection from Baxter) and Isolyte (Isolyte®S pH 7.4 from B Braun), both with very similar electrolyte compositions (Table 15-2). Comparing these solutions to normal blood values reveals that they are very similar. Like LR, this allows for Plasma-lyte and Isolyte to be given in large volumes without major changes to body electrolytes.
There are few contraindications to the use of these multi-electrolyte solution. Patients who have high magnesium levels (hypermagnesemia) or high potassium levels (hyperkalemia), including renal failure patients, should not receive Plasma-lyte or Isolyte. As with other resuscitation fluids, care should be taken in patients who have congestive heart failure. These multi-electrolyte solutions contain no calcium so they can be used freely with blood products.

Normal Saline Solution

Class: isotonic crystalloid solution.

Indications: standard IV infusion fluid, initial fluid resuscitation, head injury.

Contraindications: hypernatremia, possibly large volume fluid resuscitation.

Adverse Effects: hypernatremia, hyperchloremic acidosis in large volumes, volume overload.

Normal saline (NS) is an isotonic crystalloid solution used for initial volume fluid resuscitation and as a standard intravenous fluid solution for infusion. Normal saline typically comes as 0.9%, meaning there are 9mg of sodium chloride per mL of fluid. This is much different from the blood composition (Table 15-2). Despite being called “normal”, saline solution is far from physiologic. In particular, there is a higher amount of sodium and a much higher amount of chloride than in the blood. If large volumes of NS are given, a significant increase in the patient’s sodium and chloride levels can occur. On the other hand, increasing a patient’s sodium can reduce swelling in the brain. For this reason, normal saline may be a good fluid choice for a patient with a brain injury.
Large volume administration of normal saline can lead to high blood levels of chloride, known as hyperchloremia. The compensatory mechanism in the body for this leads to acidosis, a condition where there is increased acidity of the blood. Several diseases lead to acidosis, so there is a perception that the acidosis caused by normal saline is a major issue and should be avoided. Despite this, there is little evidence that significant patient injury has occurred from using normal saline for resuscitation (Handy et al 2008). However, lactated Ringer solution has been shown to be superior to normal saline for management of massive hemorrhage and resuscitation (Healey et al, 1998). Several other studies have shown increased risk if kidney injury and even mortality when normal saline is used in the hospital setting (Yunos et al, 2012; Shaw et al, 2012). As you would expect, normal saline should be avoided in patients with high sodium levels (hypernatremia) or high chloride levels (hyperchloremia).

Virtual Mentor: Which Fluid Bag?

Multi-electrolyte solutions, as well as Lactated Ringer solution, are the fluids of choice for nearly every out-of-hospital scenario. These solutions are more physiologic than D5W and normal saline, especially for large volume fluid resuscitation. As a practical point, it is unlikely that you will know a patient’s blood electrolytes during out-of-hospital management so you may choose whichever of these fluid solutions your service has in stock.

Table 15-2: Comparison of Crystalloid Solutions

Albumin

Class: colloid solution.

Indications: in-hospital for specific liver and kidney disorders, burns after the first 24-hours.

Contraindications: fluid resuscitation instead of crystalloids, congestive heart failure.

Adverse Effects: allergic type reaction, congestive heart failure, infectious disease (rare).

Albumin is a colloid solution, which means it is a larger insoluble molecule. The idea is that these larger molecules cannot cross the vessel wall easily, unlike cystalloids, thus they will increase intravascular volume for a longer period of time. Although this sounds like a good idea in theory, randomized clinical trials have not shown albumin to be any better than crystalloids (SAFE Study, 2004). Colloid solutions are generally much more expensive than crystalloids solutions. Although albumin is pasteurized during manufacturing to eliminate viral diseases, albumin comes from human donors and the risk of disease transmission is not zero.
Albumin typically comes in 5% (large bottle) and 25% (small concentrated bottle) solutions. Indications for use are mainly related to in-hospital patients with certain liver diseases and kidney diseases. Albumin can be used in burns after the first 24-hours. Albumin is not the first line therapy for resuscitation, but may be appropriate as a second line solution (Liumbruno et al, 2009). Given that albumin has some minor risks and is no better than crystalloids for resuscitation, the cost of use is likely not worth any patient benefit in the prehospital setting.
Side effects and adverse reactions have been reported with albumin. Allergic-type reactions can occur (Laxenaire et al, 1994). Rapid infusion can paradoxically drop blood pressure and lead to congestive heart failure, especially in elderly patients or those with pre-existing heart failure. As with other solutions, albumin should not be administered if the solution appears cloudy or turbid.

Starches

Class: colloid solution.

Indications: very few.

Contraindications: fluid resuscitation instead of crystalloids, heart failure, renal failure.

Adverse Effects: allergic type reaction, congestive heart failure, infectious disease (rare).

Black box warning: renal failure, increased risk of bleeding (coagulopathy).

Starches are colloid solutions that were created to be volume expanders. The idea is that these solutions contain large molecules that will remain in the vessel, similar to albumin but without the risk of blood borne disease. Since they do not require a human donor, starch solutions are aimed at also being cheaper than albumin. Brand names for different products include: Hespan 6%, Voluven 6%, and Gelatin 4%, although there are others.
Unfortunately, several studies have shown these products to be detrimental and their use is falling out of favor. Renal failure has been associated with the use of starch volume expanders (Schortgen et al 2001; 6S trial, 2005). The U.S. Food and Drug Administration (FDA) released a black box warning that these solutions can increase the risk of bleeding. A boxed warning, sometimes called a black box warning, is found on the package insert for certain drugs and is the strongest warning that the FDA requires, indicating that life-threatening adverse effects can occur if the drug is used in these circumstances. Starch solutions have little value and can cause significant patient harm if used for large volume resuscitation in the prehospital setting.
Virtual Mentor: Mobile References
Technology has advanced significantly over the past decade to the point where our mobile phones have more powerful technology than the Apollo Guidance Computer that landed astronauts mission to the moon. Creating software applications for mobile devices has become easier as well and there are countless medical applications available. Since drug indications, dosing, and adverse effects can change with time, it is useful to have an up-to-date medical reference. But with the number of applications available, how do you choose the right one? Look for applications that: are used by a large number of providers, allow for updates to be downloaded, and are written by clinicians. Two examples are Medscape and UpToDate. Medscape is a web-based free medical reference, available for most mobile devices (“point-of-care”), that can provide current information on drugs and illnesses. UpToDate is an evidence-based clinical decision support resource that requires a subscription. The drug information in this chapter is by no means all inclusive. Mobile references can provide complete details about drug indications, adverse effects, and drug interactions.

Medications Used for Respiratory Emergencies

Oxygen

Class: medical gas.

Indications: hypoxia, pre-oxygenation prior to apnea.

Contraindications: open flame, respiratory insufficiency if ventilation related (hypercarbia), high-flow use in certain situations such as preterm infants

Adverse Effects: drying of skin, absorption atelectasis, masking of hypercarbia.

No drug is used more commonly in emergency medical services than oxygen. The indications to use oxygen therapy are too numerous to list here. Major indications for the use of oxygen focus on hypoxia, which is low oxygen levels in the tissues. Hypoxia can be split into several categories, all of which can be managed with oxygen therapy:
1) Low oxygen in the blood (hypoxemia), examples include: pulmonary embolism, pneumonia, COPD, hypoventilation from medications (e.g. opioids) or neurologic issues (e.g. stroke).
2) Hemoglobin problems, examples include: anemia, methemoglobinemia, carbon monoxide poisoning.
3) Cellular-level problems, examples include: cyanide poisoning.
4) Tissue ischemia, examples include: myocardial infarction, stroke, gangrene.
In general, a pulse oximeter reading of 90% or below should be managed with oxygen therapy. Below 90% SpO2, the oxygen-hemoglobin dissociation curve plummets (Figure 15-1) and less oxygen in the blood is transferred to tissues. At the same time, a saturation of 100%, called hyperoxia, is associated with potential harm. The American Heart Association (AHA) guidelines for recommend avoiding hyperoxia during resuscitation (Field et al, 2010). Their guidelines aim for SpO2 ≥ 94% during resuscitation efforts, which is a reasonable goal for emergency situations in general. In patients with chest pain but no hypoxia, the AHA guidelines do not recommend giving supplemental oxygen. Oxygen in this situation can reduce coronary blood flow and make vasodilating medications less effective.
In infants, titration of oxygen therapy is even more critical. As with adults, providing insufficient of excessive oxygen therapy can lead to problems. Preterm infants are at risk for retinal injury with excessive oxygen use. The AHA recommends managing term babies with room air, not 100% oxygen, and then titrating oxygen therapy with a blender device (Kattwinkel et al, 2010). Pulmonary oxygen toxicity has been described in adults, but typically requires high oxygen administration over many hours (Clark et al, 1985). This is not an issue with prehospital care; aim for an SpO2 of 94-99% in most patients.
Some other issues with high flow oxygen are absorption atelectasis, drying of mucous membranes, and combustion. Absorption atelectasis occurs when nitrogen, from air, in the lungs is washed out by oxygen. The alveoli in the lungs are held open by nitrogen during normal air breathing. When nitrogen is not present, oxygen can cross into the blood resulting in collapse of the alveoli. This typically only occurs once the fractional inspired concentration of oxygen (FiO2) is greater than 50%. Drying of the mucous membrane is a minor worry as it can cause pain and potentially increase the risk of membrane bleeding. Oxygen is combustible and poses significant risk for fire when near an ignition source. There are several cases of patients who suffered burns secondary to smoking with nasal cannula oxygen in place (Lindford et al, 2006)
That’s Not True … or Is it? Can oxygen be used in COPD patients?
A commonly taught dogma in medicine is that COPD patients have a primary hypoxic drive and giving them oxygen will result in hypoventilation and increased CO2 retention (hypercapnia). This has been shown to be false (Abdo et al, 2012). There is no need to withhold oxygen therapy from COPD patients for fear of worsening their respiratory status. The review article also found that titrating oxygen to an SpO2 of 88-92%, as oppose to higher values, resulted in better outcome for COPD patients.

One of the most worrisome issues with oxygen administration is the masking of hypercarbia. Respiratory failure is typically divided into two types: Type 1, also known as hypoxemic, and Type 2, also known as hypercarbic. Assessment of hypoxemia is typically done by SpO2 and assessment of hypercarbia is typically done by ETCO2. Hypoxemia respiratory failure is improved with oxygen therapy. Hypercarbic respiratory failure may by masked by oxygen therapy. This is the reason the American Society of Anesthesiologists (ASA) requires both pulse oximetry and end-tidal CO2 monitoring for all patients receiving sedation (ASA, 2002).
To illustrate this issue, let us examine a case by Ayas et al. A 75-year-old woman was in the post-anesthesia care unit after hip surgery. Her endotracheal tube was left in place due to inadequate respirations. An oxygen-delivery device was connected to her endotracheal tube that delivery 100% oxygen down the tube but did not assist her respirations. After 3.5 hours, an arterial blood gas was drawn and showed a pH of 6.65, pO2 of 213, and pCO2 of 265. This demonstrated that her oxygenation was adequate but her ventilation was so poor that her CO2 level rose to an astounding 265 mmHg in her blood. A pH below 7 is severely acidotic and a pH below 6.8 is not typically compatible with life. Again, assessment of respiratory status requires both oxygenation (SpO2) and ventilation (ETCO2); administering oxygen can fool the provider into thinking there is no respiratory issue if only SpO2 is monitored.
The above case also highlights apneic oxygenation. Apneic oxygenation is the diffusion of oxygen into the alveoli without ventilation. In a classic study by Frumin et al, SpO2 was maintained at 100% in volunteer at for an hour without them taking a single breath. Weigard and Levitan more recently reviewed methods to prevent desaturation during emergency airway management, with a focus on appropriate oxygen therapy. Their recommendations for preoxygenation include high-flow facemask oxygen if SpO2 > 95% or bag-valve-mask ventilation with high-flow oxygen otherwise. During the apneic period with tracheal intubation attempts, they recommend applying nasal oxygen at 15LPM to assist with apneic oxygenation.
Virtual Mentor: When Should You Consider Using Oxygen?
“When in doubt, whip it out.”

Anticholinergic Agents

Anticholinergic medications act by blocking the neurotransmitter acetylcholine in the peripheral nervous system. This causes inhibition of the parasympathetic nervous system and are therefore also referred to as parasympatholytic medications. A toxidrome is a syndrome (collection of signs and symptoms) seen with drug toxicity from a specific class of medications. Anticholinergic syndrome (ACS) can occur with inadvertent overdose or intentional overdose of anticholinergic medications. The signs and symptoms associated with this syndrome are the same, though to a lesser degree, as the signs and symptoms seen with use of anticholinergic medications. They include skin flushing, dry skin, dry mucous membranes, mydriasis (dilated pupils), altered mental status, and fever. These signs are recalled with the mnemonic “red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare.” Tachycardia may be seen as well as hypertension and urinary retention. Bronchodilator effects can occur and are exploited to cause bronchial smooth muscle relaxation in patients with asthma and other bronchospastic disease.

Ipratropium [Atrovent]

Route & Dosage: 2 actuations inhaled, 2.5mL (500 mcg) nebulized.

Onset & Duration: onset 15min, peak 1-3hr, duration 3-4hr.

Pharmacokinetics: liver metabolism, urine elimination, half-life 2hr.

Indications: chronic obstructive pulmonary disease, acute asthma exacerbation (off-label).

Contraindications: hypersensitivity to ipratropium or atropine or similar anticholinergics.

Adverse Effects: paradoxical bronchospasm, dry mouth, hypersensitivity, urinary retention, bronchospasm in myasthenia gravis, worsening of glaucoma.
Drug Interaction: none contraindicated, anticholinergics.

Ipratropium is an anticholinergic medication used for patients with chronic obstructive pulmonary disease and during acute asthma exacerbation. In COPD, the inhaler dose is 2 actuations, 4 times per day, to a maximum of 12 actuations per day. In asthma exacerbation this is changed to 8 actuations every 20 minutes, to a maximum of 3 hours. In the setting of asthma, ipratropium should be given in combination with a short-acting beta-adrenergic (SABA) agonist medication like albuterol. The brands Duoneb and Combivent are available combinations of ipratropium with albuterol. The nebulized solution is 500mcg in 2.5mL and is given as a single 2.5mL dose. For COPD, nebulized ipratropium can be given 3-4 times per day spaced 6-8 hours apart. In asthma exacerbation, nebulization dose is 500mcg every 20 minutes for three doses, then as needed.
It is worth noting that ipratropium for asthma exacerbation is an off-label use. The drug label on FDA-approved medications explains the medical conditions for which it was approved. If the drug is not used for the indicated condition, or is used differently (dose or route), the use is said to be off-label. Medical evidence typically supports the off-label use of these drugs but the manufacturer of that drug has not done formal testing that is required by the FDA. In the case of ipratropium, there is sufficient medical evidence to warrant its use in the emergency setting (NAEPP, 2007). However, it is not first-line therapy alone and should be used after SABA therapy or in addition to SABA therapy (NAEPP, 2007).
Caution should be taken when using ipratropium in the setting of other anticholinergics, such as atropine, since side effects can increase. Common side effects follow with anticholinergic symptoms: dry mouth and urinary retention. Hypersensitivity immune reactions are rare. A hypersensitivity reaction is any of the types of immune reactions, which can range from a mild rash to life-threatening anaphylaxis. These can occur with most drugs and previous hypersensitivity reaction is a contraindication to the use of any medication. There have been cases of patients with myasthenia gravis who had worsening of their pulmonary status with the use of ipratropium. The mydriasis effect of anticholinergic medications, such as ipratropium, can worsen angle-closure glaucoma and should be avoided in these patients. No major drug interactions warrant avoiding ipratropium in the emergency setting.

Beta Agonists

Beta agonist therapy for respiratory refers to agonists of the adrenergic beta-2 (ß2) receptors, which results in bronchial smooth muscle relaxation and decreased secretions. Beta-1 agonists affect the heart. To differentiate ß1 and ß2, remember that you have 1 heart and 2 lungs. Beta-2 agonists also result in peripheral vasodilation, which can lead to tachycardia. Tachycardia with beta agonists can also be secondary to direct cardiac stimulation. This tachycardia can lead to myocardial ischemia and arrhythmias in susceptible individuals, such as those with underlying coronary artery disease. Other side effects include tremors, sweating, anxiety, and agitation. Hyperglycemia can occur with beta-2 agonists due to breakdown of glucose in the liver and release of glucagon from the pancreas. Reduction in serum potassium occurs by moving the potassium into cells from the bloodstream. Beta-2 agonists for pulmonary conditions include albuterol, epinephrine, levalbuterol, racemic epinephrine, and terbutaline.

Albuterol [AccuNeb, ProAir, Proventil, Ventolin, VoSpire]

Route & Dosage: 1-2 puffs inhaled, 2.5-5mg nebulized.
Onset & Duration: onset 3-10min, peak 30min, duration 3-4hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 4hr.
Indications: bronchospasm, asthma exacerbation, hyperkalemia.
Contraindications: hypersensitivity to albuterol, severe coronary artery disease, severe aortic stenosis.
Adverse Effects: tachycardia, hypokalemia, hyperglycemia, seizures, worsening of glaucoma.
Drug Interaction: none contraindicated, sotalol.
Albuterol is a ß2-agonist used very commonly for patients with bronchospasm, wheezing, and/or acute asthma exacerbations (NAEPP, 2007). Bronchospasm can be triggered by asthma, anaphylaxis, or tracheal stimulation such as during the placement of an endotracheal tube. Adult dosing for bronchospasm is 1-2 puffs every 4-6 hours as needed. Typical inhaler concentration is 90mcg per puff. Albuterol can also be administered into an endotracheal tube via an adapter device or using a 60mL syringe (see Figure 15-2). For acute severe asthma, the dose is 4-8 puffs every 20 minutes for up to 4 hours. These metered inhaler doses are the same for pediatric patients.
Nebulized albuterol can be given as a single dose or as a continuous infusion. Maximum doses are different for adults and children. For bronchospasm in adults the dose is 2.5mg, 3-4 times per day. In children 2-12 years old the dose is 1.25mg, 3-4 times per day. For children older than 12 years old, the dose is 2.5mg, 3-4 times per day. Higher doses are used for acute severe asthma exacerbation. In adults with asthma, the dose is 2.5-5mg every 20 minutes for up to 3 doses. Continuous nebulization dosing is 10-15mg per hour, though symptoms such as tremors may limit dosing. For children under 12 years old, the dose is 0.15mg/kg every 20 minutes for up to 3 doses or 0.5mg/kg/hour by continuous nebulization, to a maximum of 10mg per hour. Dosing for children over 12 years old with acute asthma is the same as adults.
Albuterol can also be used in the treatment of hyperkalemia (Allon et al, 1989). Although prehospital laboratory assessment may not be available, clues such as renal failure on dialysis or peaked T-waves on the ECG can suggest hyperkalemia. The typical dose in this situation is 20mg of albuterol nebulized as a single adult dose. This can decrease serum potassium levels by 1.0mEq/L within 30 minutes with an effect lasting two hours. This does not remove potassium from the body, however. It only temporarily moves potassium into cells, which reduces the risk of cardiac arrhythmias.
Patients with severe coronary artery disease are at risk for myocardial ischemia if they become tachycardic. The coronary arteries are primarily perfused during cardiac diastole, which is shortened as the heart rate increases. For this reason, albuterol should be used with caution in these patients. Patients with severe aortic stenosis are also at risk for cardiac ischemia if they become tachycardic. Hypokalemia (low potassium) can occur with albuterol, especially during continuous nebulization. Hyperglycemia can occur as well, thus caution should be taken in diabetic patients at risk for hyperglycemia. If continuous nebulization is used in diabetic patients, it would be prudent to assess glucose levels intermittently. Beta-agonists can cause central nervous system stimulation, which can precipitate seizures in patients with seizure disorders. They can also increase intraocular pressure, thus should be used with caution in patients with glaucoma. Using albuterol in patients who are taking sotalol may lead to atrial fibrillation (Vader et al, 2002). An oral version of albuterol exists but is not preferred for use in emergencies.

Epinephrine 1:1000 (SQ/IM)

Route & Dosage: 0.01mg/kg subcutaneous, 0.01mg/kg IM.
Onset & Duration: onset 5-10min, duration 20min.
Pharmacokinetics: liver metabolism, urine elimination, short half-life.
Indications: acute severe asthma (off-label).
Contraindications: severe coronary artery disease, severe aortic stenosis.
Adverse Effects: tachycardia, hypertension, hypokalemia, hyperglycemia, pallor.
Drug Interaction: none contraindicated, cocaine, sodium bicarbonate.
Epinephrine is a commonly used emergency medication that is a ß1-agoist, ß2-agonist, and alpha-1 (α1) agonist. The α1-agonist properties cause vasoconstriction, resulting in an increase in blood pressure. So aside from the ß2-agonists effects of bronchial smooth muscle relaxation, tachycardia and hypertension are to be expected. In patients with acute severe asthma who are unresponsive to inhaled beta-agonist therapy, epinephrine may be used. This is considered an off-label use, but is part of the AHA guidelines (Vanden Hoek et al, 2010). Dosing is 0.01mg/kg subcutaneous, divided into three doses of approximately 0.3mg/dose, given in 20-minute intervals. Subcutaneous dosing is with the 1:1000 concentration (1mg/mL). There is no evidence that subcutaneous epinephrine has advantages over inhaled beta-agonist therapy. Epinephrine has been used intravenously for asthma as a continuous infusion starting at 0.25mcg/min and up to 1mcg/min, however this also has not been shown to improve outcomes compared with inhaled therapy. For status asthmaticus, the dose is 0.01mg/kg IM of the 1:1000 (1mg/mL) concentration. This dose is the same for children and adults, with a maximum single dose of 0.3mg IM.
Critical Concepts: Epinephrine Dosing
Epinephrine is a fantastic, life-saving medication. Unfortunately, dosing comes in different concentrations and is dependent on route of administration. Choosing the wrong concentration can have devastating consequences. There have been numerous reports of patient harm, including death, from the misuse of epinephrine (PA PSRS, 2006). Some of the confusion seems to be related to expressing epinephrine as a ratio strength (e.g. 1:1,000) instead of a metric per volume concentration (e.g. mg per mL). For this reason, you must memorize that 1mg/mL of a drug is the same as a 1:1,000 concentration. When referring to medications, the standard is to state the concentration (e.g. milligrams) not the volume.
Figure 15-3 shows different concentrations of epinephrine. The common concentrations used in prehospital emergency care are 1mg/mL and 100mcg/mL (0.1mg/mL). The concentrated 1mg/mL version is only used for subcutaneous and intramuscular injection. The diluted 0.1mg/mL version is used for intravenous or intraosseous administration. Lammers et al did a study involving a simulated pediatric anaphylaxis scenario. They found that less than half of prehospital providers gave the correct epinephrine dose via the correct route. Over 20% of providers gave an epinephrine dose that was ≥ 5 times too strong; an error that could result in cardiac arrest. In Image 15-3, the prefilled syringe is shown as an example concentration that is used by anesthesiologists for patients undergoing cardiac surgery. An intravenous bolus dose of 10mcg can sufficiently increase blood pressure and heart rate during peri-arrest situations for those patients. That is 100 times smaller of a dose than the 1mg/mL vial!
As a rule, intravenous epinephrine should only be used in a 1:10,000 concentration (1mg in 10mL) for patients in cardiac arrest. If the patient has a pulse, the intramuscular or subcutaneous route and dosing should be used. Never administer the 1:1,000 (1mg per mL) concentration into a vessel.

As with other ß-adrenergic agonists, epinephrine should be used with caution in patients with severe coronary artery disease or severe aortic stenosis. The provider should weight the risks of causing myocardial ischemia in these patients versus the benefit of treating their underlying disorder (e.g. acute severe asthma). Side effects include hypertension, tachycardia, hypokalemia, and hyperglycemia. Pallor can occur with systemic use secondary to the α1 effects. Life-threatening hypertension and tachycardia can occur in patients who have recently used cocaine. Epinephrine should not be mixed with sodium bicarbonate.

Levalbuterol [Xopenex]

Route & Dosage: 2-8 puffs inhaled, 0.63mg nebulized.
Onset & Duration: onset 3-10min, peak 90min, duration 6-8hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 3-4hr.
Indications: bronchospasm, asthma exacerbation (off-label).
Contraindications: hypersensitivity to albuterol, severe coronary artery disease, severe aortic stenosis.
Adverse Effects: tachycardia, hypokalemia, hyperglycemia, seizures, worsening of glaucoma.
Drug Interaction: none contraindicated, sotalol.
Levalbuterol is a short-acting ß2-agonists (SABA) used in similar situations to albuterol. Albuterol is a racemic mixture, meaning it contains both the (R) and (S) enantiomers of the drug. An enantiomer is a chemical, containing the same elemental components, but is a mirror-image when the chemical structure is drawn out. Drugs that are racemic mixtures are sometimes divided into their two enantiomer components, (R) and (S), because one of the components has a more favorable response when administered. Levalbuterol is the (R)-enantiomer of racemic albuterol, which was created because of possible negative effects from the (S)-enantiomer. Some studies have shown that levalbuterol has more efficacy than racemic albuterol, while other studies have shown no difference (NAEPP, 2007).
Levalbuterol dosing for bronchospasm is 2 puffs every 4-6 hours as needed. The nebulized solution dosing is 0.63mg three times daily every 6-8 hours, to a maximum of 1.25mg three times daily. In children, the dosing is same for the metered dose inhaler (MDI) but the child should be at least 4 years old. Levalbuterol has off-label evidence for the use in acute severe asthma, where adult dosing is 4-8 puffs every 20 minutes for up to 4 hours with the inhaler or nebulized as 1.25-2.5mg every 20 minutes for up to 3 doses. For children with asthma, the inhaler dose is the same and the nebulized dose is 0.075mg/kg every 20 minutes for three doses in children under the age of 12, up to a maximum of 5mg. Adverse effects are the same as albuterol.

Racemic epinephrine (generic)

Route & Dosage: 0.05-0.1mL/kg of 2.25% solution nebulized.
Onset & Duration: onset within 1 minute, duration 20min to maximum of 2hr.
Pharmacokinetics: liver metabolism, urine elimination, short half-life.
Indications: laryngotracheobronchitis (croup).
Contraindications: severe coronary artery disease, severe aortic stenosis.
Adverse Effects: worsening of epiglottitis, rebound phenomenon.
Drug Interaction: none contraindicated.
Racemic epinephrine comes in a 2.25% inhalational solution, which is 22.5mg/mL of epinephrine. Racemic epinephrine 10mg is equivalent to 5mg of (R)-epinephrine, which is the standard available epinephrine that comes in a 1:1000 (1mg/mL) mixture. Therefore, the racemic epinephrine for nebulization is approximately equivalent to a 1:100 (10mg/mL) mixture of the standard (R)-epinephrine used for other emergencies. This is yet another potentially dangerous concentration of epinephrine that should only be given as an inhaled solution.
Dosing for racemic epinephrine in croup patients is 0.05-0.1mL/kg with a maximum dose of 0.5mL. This solution is then diluted in 2mL of normal saline before administration. This dosing is for infants and children. Although some advocate for using a fixed 0.5mL dosing in all patients, the lower-end of dosing is recommended in younger infants (Hegenbarth et al, 2008). The dose may be repeated every 20 minutes as needed. The potent vasoconstricting effects of epinephrine on the airway mucosa limits the systemic absorption. In children, heart rate may be slightly increased or even reduced during administration. However, the potential for cardiac stimulation exists and inhaled epinephrine is not recommended for lower airway issues, such as bronchospasm or asthma exacerbation (NAEPP, 2007). Adverse effects are rare and are similar to those seen with subcutaneous epinephrine administration, though to a lesser degree. There has been a case of myocardial infarction in a child with croup who received racemic epinephrine (Butte et al, 1999), thus cardiac monitoring may be warranted.
This recommendation against racemic epinephrine for lower airway problems highlights that it is a treatment for upper airway issues. The exception is epiglottitis, where cases have been reported where children rapidly deteriorated after racemic epinephrine (Kissoon et al, 1985). A rebound phenomenon can occur after croup treatment. Nebulized epinephrine lasts up to two hours, at which point the effect goes away and symptoms can return to baseline. Although long transport times are not common in EMS, this information is useful at handoff communication. A study by Waisman et al found no difference in croup for patients receiving racemic epinephrine or (R)-epinephrine, which is more widely available and often less costly. The dose when using (R)-epinephrine is 0.5mL/kg of the 1:1000 (1mg/mL) solution, to a maximum of 5mL. The dose should be diluted in normal saline up to 5mL and may be repeated every 20 minutes as needed.

Terbutaline (generic)

Route & Dosage: 0.25mg subcutaneous.
Onset & Duration: onset 6-15min, peak 15-60min, duration 6hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 11-16hr.
Indications: asthma, bronchoconstriction.
Contraindications: prolonged management of labor.
Adverse Effects: tachycardia, hypokalemia, hyperglycemia, tremors, nervousness.
Drug Interaction: none contraindicated, sotalol.
Black box warning: prolonged tocolysis.
Terbutaline is a ß2-agonist that can be used for asthma, but is also used as a tocolytic during pregnancy. A tocolytic medication is one that suppresses uterine contractions in an effort to prevent preterm labor. All ß2-agonists have tocolytic properties but should not be used for that purpose in the prehospital setting. Oral and inhalational formulations exist, but the subcutaneous route is preferred for terbutaline in the management of asthma or bronchoconstriction. Adult dosing is 0.25mg subcutaneously, repeated once in 15-30 minutes if needed, to a maximum of 0.5mg in a 4hr period. The NAEPP guidelines extend this dosing to a maximum of 3 doses, with a 20-minute period between doses, for a maximum of 0.75mg in a 1hr period. For children less than 12 years old, dosing is 0.005-0.01mg/kg/dose to a maximum of 0.4mg/dose given every 15-30 minutes, for a maximum of 3 doses. This dose could also be written as 5-10mcg/kg/dose.
Nebulized or inhaler SABA medications are first line therapy for asthma and bronchospasm. If unavailable or failed, subcutaneous terbutaline is an option. It is worth noting that terbutaline typically comes in a 1mg/mL vial, thus dosing is only a portion of the vial. As a general rule, medication vials for non-oral administration are single patient dose. Meaning, you should not usually need to draw up more than one vial of any medication for a standard dose. If you are drawing up more than one vial, or multiple vials, you should second guess the accuracy of your drug dosing.
The side effects of terbutaline are the same as other ß2-agonist medications. Terbutaline in particular has a black box warning for the use in early labor. Prolonged use in these situations has led to adverse effects to the mother: tachycardia, hyperglycemia, hypokalemia with cardiac arrhythmias, and myocardial ischemia. Maternal hyperglycemia can lead to neonatal hypoglycemia after the child is born. In the uterus, the fetus will release extra insulin to maintain its glucose level while getting glucose-rich blood from the mother/placenta. After birth, this glucose infusion stops but the child still has a high level of insulin, resulting in hypoglycemia.

Corticosteroids

Asthma is a disease that has three effects on the airway: bronchospasm, mucus production, and inflammation. Corticosteroids act to reduce systemic inflammation and cause immunosuppression. The major acute complications of steroid therapy are hyperglycemia, increased intraocular pressure, and mania. Steroids have a slow onset of action and therefore are not first line therapy for pulmonary emergencies. Daily inhaled steroids are used in inflammatory pulmonary conditions as part of maintenance therapy. Oral dosing for steroids is common in the clinic and hospital setting. For patients with acute issues, intravenous dosing is more appropriate as it avoids the need for the patient to swallow while dyspneic. Intravenous formulations also have a quicker onset of action. Corticosteroids used in asthma include dexamethasone, hydrocortisone, methylprednisolone. Other corticosteroid options include prednisolone and prednisone. Steroid dosing can be converted between types by using the following equipotent dosing chart. As an example, 4mg of IV dexamethasone would be equivalent to about 100mg IV hydrocortisone or about 20mg IV methylprednisolone.

Table 15-3: Equipotent Dosing of Corticosteroids

Dexamethasone [Decadron]

Route & Dosage: 0.6 mg/kg IV, 0.5-2 mg/kg/day IV/IM.
Onset & Duration: onset rapid, peak 5-10min, duration 36-72hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 1-5hr.
Indications: laryngotracheobronchitis (croup), airway edema.
Contraindications: systemic fungal infection.
Adverse Effects: worsening of psychiatric disturbances, worsening of glaucoma, fluid retention, hyperglycemia.
Drug Interaction: none contraindicated.
Dexamethasone is a corticosteroid with a wide range of uses. We will focus on the respiratory indications in this section. Dexamethasone is not indicated for use in asthma (NAEPP, 2007). Pulmonary indications are airway edema and for children with croup. Several routes of administration are available, but IM or IV are preferred for respiratory emergencies. Intravenous onset is more rapid than IM and peak effect is shorter for IV (5-10min versus 30-120min). Dosing for airway edema is 0.5-2mg/kg/day divided into 4 doses. This regimen is typically used in-hospital for extubation management. For croup, dosing is 0.6mg/kg given once by IV or IM, to a maximum dose of 16mg.
The duration of drug action or effect depends on several factors. Elimination half-life is only one of many factors. Half-life typically refers to the elimination half-life which is the time it takes for the body to remove half of the drug concentration. Steroids are one example of medication in which the elimination half-life is much different from the duration of drug effect. For dexamethasone, the half-life is less than 6 hours but the duration of action is up to 3 days. The half-life of aspirin in the plasma is 20 minutes but the duration of action is 7-10 days. Most sedation induction agents, like propofol and etomidate, have a half-life that is significantly longer than the duration of effect. Duration of action is more important clinically for the EMS provider.
Corticosteroids unfortunately have a large number of side effects. The severe side effects of chronic steroid use, such as adrenal insufficiency, will not be discussed. Corticosteroids should not be given if the patient has a known systemic fungal infection. In the acute setting, steroids oppose the action of insulin and cause an increase in glucose output from the liver. This leads to hyperglycemia, which can lead to diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS). Steroids increase intraocular pressure and should be used with caution in patients who have glaucoma. Steroids can also worsen psychiatric conditions, such as bipolar disorder or mania. Steroids can also trigger mania in patients without a previous psychiatric diagnosis. Fluid retention can be seen with steroid use; thus, caution should be taken in patients in congestive heart failure. There is debate and confusion about the use of steroids in patients with active infection, as the immunosuppression could make it difficult for the body to fight infection. However, steroids are used in a variety of infectious diseases and have mortality benefit in certain circumstances (Prasad, 2011).

Hydrocortisone [A-Hydrocort, Cortef, Solu-CORTEF]

Route & Dosage: 1-2 mg/kg IV.
Onset & Duration: onset rapid, peak 1hr, duration 8-12hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 100min.
Indications: status asthmaticus.
Contraindications: systemic fungal infection.
Adverse Effects: worsening of psychiatric disturbances, worsening of glaucoma, fluid retention, hyperglycemia.
Drug Interaction: none contraindicated.
Hydrocortisone is a corticosteroid that is indicated for the management of status asthmaticus. Dosing is 1-2 mg/kg/dose IV every 6 hours for 24 hours in both adults and children. Oral and IM dosing is used for anti-inflammatory indications, but not typically for status asthmaticus. Adverse effects are the same as other corticosteroids (see dexamethasone).

Methylprednisolone [A-Methapred, Medrol, Solu-MEDROL]

Route & Dosage: 40-80mg IV, 1-2 mg/kg IV.
Onset & Duration: onset rapid, peak 1hr, duration 12-16hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 3hr.
Indications: asthma exacerbation including status asthmaticus, COPD exacerbation (off-label).
Contraindications: systemic fungal infection, premature infants.
Adverse Effects: worsening of psychiatric disturbances, worsening of glaucoma, fluid retention, hyperglycemia.
Drug Interaction: none contraindicated.
Methylprednisolone is a corticosteroid that is indicated for the management of asthma exacerbation. Adult dosing for asthma exacerbation is 40-80 mg/day in 1 to 2 divided doses, either IV or PO. Children under the age of 12 may receive 1-2 mg/kg/day in 2 divided doses, to a maximum of 60mg/day. NAEPP dosing for asthma is 7.5mg/kg IM if 0-4 years old and 240mg IM if 5-11 years old. Adverse effects are the same as other corticosteroids (see dexamethasone). Some formulations of methylprednisolone contain benzyl alcohol as a preservative, which is contraindicated for use in premature infants.

Xanthines

Xanthines are chemical compounds with bronchodilating effects. They also oppose the action of adenosine, which leads to alertness and stimulant effects. The most widely used xanthine derivative is caffeine. Other xanthine derivatives include aminophylline and theophylline.

Aminophylline (generic)

Route & Dosage: not applicable.
Onset & Duration: onset rapid, peak 30min, duration 4-8hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 6hr in adults.
Indications: no pulmonary indications – do not use for asthma.
Contraindications: severe coronary artery disease, severe aortic stenosis.
Adverse Effects: arrhythmias, tachycardia, hypertension.
Drug Interaction: none contraindicated.
Aminophylline is a xanthine-derivative that relaxes bronchial smooth muscle, resulting in bronchodilation. There is Category A evidence recommending against the use of aminophylline for asthma (NAEPP, 2007). Evidence Category A is the highest level and means that randomized controlled trials have been performed and there is a rich body of data supporting the recommendation. In an emergency department study, aminophylline was found to provide no additional benefit over SABA therapy and increased the number of adverse effects (Parameswaran et al, 2000). For every 100 patients that got aminophylline in that study, 20 vomited and 15 had arrhythmias or palpitations. The stimulant side effects of xanthines can lead to tachycardia, hypertension, and arrhythmias. They should not be used in patients with severe coronary artery disease or severe aortic stenosis due to the risk of myocardial ischemia.
Case Study: Bronchospasm
You are called to the home of a 35-year-old woman with a history of severe asthma. On arrival, you find her in severe respiratory distress with audible wheezing. Initial vital signs show hypertension, tachycardia, and an SpO2 of 85%. She is barely able to speak and oxygen therapy is ineffective. You prepare an albuterol nebulizer and the patient attempts to use it, but SpO2 decreases. You prepare for endotracheal intubation. The patient received 200mg IV propofol and 100mg IV succinylcholine. The endotracheal tube is passed without issue and you begin to provide positive pressure ventilation.
As you ventilate, you notice it is very difficult to squeeze the bag and move the chest. You place the patient on a transport ventilator and it begins alarming “high airway pressure.” Your EMT partner suggests a muscle relaxant and you administer 10mg IV vecuronium, which has no effect on the airway pressures. SpO2 remains at 85% and tidal volumes are around 50mL per breath. You spray 10 puffs of albuterol into the endotracheal tube, which is minimal effect. You draw 0.3mg of 1:1000 epinephrine, give it subcutaneously, and begin to see increased tidal volumes with decreased airway pressures over the next five minutes. Albuterol is given again with excellent effect.
Critical Thinking Questions
1. Why do you think vecuronium did not help this patient in bronchospasm?
2. Why was epinephrine effective in this situation?
3. Why was albuterol ineffective initially, but effective the second time?

Medications Used for Cardiovascular Emergencies

Angiotensin Converting Enzyme (ACE) Inhibitors

The renin-angiotensin-aldosterone system (RAAS), also known as the renin-angiotensin system (RAS), is a mechanism in the body for maintaining blood pressure. The kidneys sense a low blood pressure then release renin, which begins the complex pathway toward increased blood pressure. ACE inhibitor (ACE-I) agents block this pathway, which makes them useful agents for hypertension. Their primary indication in the acute setting is for patients after myocardial infarction (Hazinski et al, 2010).
ACE inhibitors reduce mortality and improve left ventricular dysfunction in patients who have had a myocardial infarction. They are indicated, in oral form, within 24 hours after AMI. They are also indicated for clinical signs of AMI with left ventricular dysfunction and for left ventricular ejection fraction < 40%. Therapy should start with low-dose oral administration, though IV doses are available in some preparations. Generally, they are not started by EMS or in the ED, but instead are started after coronary reperfusion therapy has been completed and blood pressure is stable. Since PO dosing is preferred and no more than a single dose would be given by an EMS provider, pharmacokinetics will not be discussed.

Table 15-4: ACE Inhibitors Post-Myocardial Infarction

Contraindications for ACE inhibitors is are the same for each of the drugs listed. They should not be used in pregnant patients due to the risk of fetal injury or death (black-box warning). They can cause angioedema and thus are contraindicated in this setting. Hypotensive patients, especially if volume depleted, should not receive ACE-I agents. Hypotension in this setting is defined as systolic blood pressure < 100 mmHg or a drop > 30 mmHg from baseline. They may worsen renal failure and should be avoided in these patients. They can also lead to hyperkalemia and thus are contraindicated if potassium levels are high. Caution should be taken in patients with aortic stenosis since ACE-I agents can reduce coronary perfusion leading to ischemia. The reduction in afterload (drop in SVR) can worsen symptoms for HOCM patients. Common side effects include hypotension, chest pain, palpitations, tachycardia, hyperkalemia, skin rash, and worsening of renal dysfunction. Intravenous enalapril at 1.25mg should be given over 5 minutes and this formulation is contraindicated in STEMI due to the risk of hypotension.

Adrenergic Antagonists

Beta-adrenergic antagonists are primarily used to reduce heart rate. Heart rate is mediated by ß1 adrenergic receptors. Some of the beta-adrenergic antagonists are specific to ß1 receptors. However, some are mixed blockers of both ß1 and ß2 receptors. These mixed medications can cause undesirable effects from ß2 blockade, such as bronchoconstriction and wheezing. As a general rule, beta blockers that start with the letter A-M are ß1-specific and those starting with N-Z are mixed ß1 and ß2. Labetalol, as well as carvedilol, are exceptions to the rule. These two-medication block ß1 receptors, ß2 receptors, and α1 receptors. Blockade of both ß1 and α1 receptors makes labetalol a useful medication for patients with severe hypertension.

Table 15-5: Commonly Used Beta Blockers

Beta blockers specifically block sympathetic action on the heart, depress SA and AV nodes, decrease cardiac conduction, and slow automaticity. Reduction in cardiac output typically results in a decreased blood pressure with these medications. Reducing heart rate leads to a decrease in myocardial oxygen demand and also an increase in myocardial oxygen supply. For this reason, beta-adrenergic antagonists have a role in angina management.

Atenolol [Tenormin]

Route & Dosage: 5mg IV.
Onset & Duration: onset and peak rapid, duration 12-24hr for oral form.
Pharmacokinetics: liver metabolism, urine and feces elimination, half-life 6-7hr.
Indications: supraventricular tachycardia, postmyocardial infarction, hypertension, angina, atrial fibrillation (off-label).
Contraindications: bradycardia, cardiogenic shock.
Adverse Effects: bronchospasm, bradycardia, hypotension, cardiogenic shock.
Drug Interaction: cocaine, epinephrine, calcium-channel blockers, digoxin.
Black box warning: avoid abrupt withdrawal.
Atenolol is a ß1-specific blocker available in oral and intravenous form. It is typically used in oral form for chronic management of hypertension, angina, and atrial fibrillation. Acute use is limited to supraventricular tachycardia and patients who recently had a myocardial infarction. American Heart Association guidelines recommend considering an oral beta-blocker for NSTEMI patients or those with high-risk unstable angina as use decreases mortality (O’Connor et al, 2010). However, this step is far enough down the algorithm that patients are typically at the hospital when the decision is made to start beta blockers.
In stable narrow-complex tachycardia, rate control is the primary goal. Uncontrolled tachycardia increases myocardial oxygen demand and decrease myocardial oxygen supply. Cardiac ischemia will occur sooner or later, which can lead to cardiac arrest. For patients in supraventricular tachycardia who are unresponsive to vagal maneuvers and adenosine, the next step is rate control with a beta block or calcium channel blocker (Neumar et al, 2010). For atenolol, the adult dose is 5mg IV given over 5 minutes. This dose can be repeated in 10 minutes if the arrhythmia persists or reoccurs. This dose can also be used in patients with atrial fibrillation or atrial flutter who have rapid ventricular response. This is also the regimen used for acute myocardial infarction, where oral dosing follows.
Use of oral atenolol for chronic conditions, such as hypertension and angina, is not uncommon. Oral dosing of atenolol for EMS providers is not particularly relevant. Patients may be on these medications at home, which puts them at risk for adverse effects and drug interactions while receiving emergency care. Since beta blockers slow heart rate, they should not be used in patients who are already bradycardic. Blockade of ß1 receptors reduces myocardial contractility. So, although beta blockers are used for patients after myocardial infarction this is only for those who are hemodynamically stable. For patients in cardiogenic shock, beta blockers are absolutely contraindicated and can lead to further deterioration of the condition.
Bronchospasm is unlikely given that atenolol is ß1 specific, however patients should still be monitored closely for respiratory changes after administration. Beta blockers should be used cautiously or even avoided in patients who are taking medications that decrease heart rate, such as digoxin. The use of beta blockers in patients on calcium channel blockers can lead to asystole. Epinephrine may have reduced effects in patients who are beta blocked, which has implications for management of anaphylaxis. Cocaine toxicity is associated with tachycardia, hypertension, and coronary vasoconstriction. These patients should not be given beta blockers as a resultant unopposed alpha agonist effect can occur, leading to severe hypertension. For patients with chest pain and recent cocaine use, beta blockers can worsen the condition (McCord et al, 2008). Beta blockers carry a black box warning with regard to abrupt withdrawal from chronic use, as this can lead to myocardial infarction and ventricular arrhythmias.

Esmolol [Brevibloc]

Route & Dosage: 0.5mg/kg IV then 0.05mg/kg/min.
Onset & Duration: onset and peak 2-10min, duration 10-30min.
Pharmacokinetics: red blood cell esterase metabolism, urine elimination, half-life 9min.
Indications: supraventricular tachycardia, hypertension, atrial fibrillation or flutter.
Contraindications: bradycardia, cardiogenic shock.
Adverse Effects: bronchospasm, bradycardia, hypotension, cardiogenic shock.
Drug Interaction: cocaine, epinephrine, calcium-channel blockers, digoxin.
Esmolol is a ß1-specific blocker that has a very short half-life. It is metabolized by red blood cell esterases, so its half-life is not prolonged in renal failure or liver failure. It is available in intravenous form and is typically given as a bolus dose followed by an infusion. Because of the short half-life, it is a very forgiving medication and can be used in bolus-only form to terminate arrhythmias. For ongoing arrhythmias and hypertension, an infusion is required, which necessitates having an infusion pump available.
Adult dosing for supraventricular tachycardia, including atrial fibrillation and flutter, is 0.5mg/kg IV bolus over 1 minute followed by an infusion of 0.05mg/kg/min. If the effect is inadequate, a second IV bolus dose of 0.5mg/kg can be given followed by a double infusion at 0.1mg/kg/min. This can be repeated up until a maximum infusion rate of 0.3mg/kg/min. For acute management of tachycardia and/or hypertension, the dose is 0.5-1.5mg/kg IV, given over 30 seconds, with a maximum single bolus dose of 100mg. Like atenolol, the ß1-specific properties make this medication much more suitable for tachycardia management than hypertension management. Esmolol is most likely to affect blood pressure if the hypertension is related to the tachycardia, versus low SVR for example. Recall that cardiac output is related to heart rate, stroke volume, mean arterial pressure, and systemic vascular resistance: CO ≈ HR * SV ≈ MAP / SVR. Since ß-adrenergic blockers do not affect α1-receptors, the body can compensate for changes in heart rate by changing SVR. Also, the need for an infusion pump makes this medication less desirable as an option for hypertension management.
Contraindications, side effects, and drug interactions are the same as for atenolol and other beta-blockers. Similar to atenolol, the ß1-specific effects make bronchospasm unlikely. Esmolol is not for chronic use thus there is no black box warning for abrupt withdrawal. Doses higher than 0.2mg/kg/min provide minimal effect for reduction of tachycardia. Doses larger than 0.3mg/kg/min have not been studied and are not indicated.

Labetalol [Trandate]

Route & Dosage: 10-20mg IV.
Onset & Duration: onset 2-5min, peak 5-15min, duration 2-18hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 6hr.
Indications: acute hypertension.
Contraindications: bradycardia, cardiogenic shock, asthma, hypotension.
Adverse Effects: bronchospasm, bradycardia, hypotension, cardiogenic shock.
Drug Interaction: cocaine, epinephrine, calcium-channel blockers, digoxin.
Black box warning: avoid abrupt withdrawal.
Labetalol is a beta-blocker available in oral and intravenous form that is different from most other beta blockers. It has ß1 blocking effects, ß2 blocking effects, and α1 blocking effects. The α1 effects make this drug more suitable for acute hypertension than tachycardia management. The alpha:beta ratio is 1:3 in oral form and 1:7 in intravenous form, meaning labetalol has 7 times more beta-blocking effect than alpha-blocking effect when given IV (MacCarthy et al, 1983). Labetalol is an option for oral hypertension management in adults, thus patients may present who are this therapy. In oral form, the half-life is about 8-12 hours. In IV form, the half-life is typically shorter but can be up to 18 hours depending on the dose and duration of infusion. Contrasting this with esmolol, one can see this is a much less forgiving medication as side effects can last significantly longer.
AHA guidelines for the management of adult stroke include measures to control arterial hypertension in acute ischemic stroke patients who are potential candidates for acute reperfusion therapy (e.g. rtPA). For patients who would otherwise be candidates for reperfusion, but have blood pressure higher than 185/100 mmHg, pharmacologic therapy is indicated. Labetalol dosing for these patients is 10-20mg IV given over 1-2 minutes, which may be repeated once (Jauch et al, 2010). If reperfusion therapy has started (e.g. rtPA administered) and either systolic pressure is 180-230 mmHg or diastolic pressure is 105-120 mmHg, then labetalol can be used. Dosing for hypertension after rtPA or other acute reperfusion therapy is 10mg IV followed by a continuous infusion of 2-8mg/min. Another option is nicardipine, discussed later in this chapter. If blood pressure is still not controlled and diastolic pressure is > 140 mmHg, sodium nitroprusside may be considered. For acute ischemic stroke, if reperfusion therapy is not planned than there is little evidence to suggest hypertension should be treated unless systolic is > 220 mmHg or diastolic is > 120 mmHg.
For acute hemorrhagic stroke, expert opinion suggests managing hypertension if systolic pressure is > 180 mmHg or mean pressure is > 130 mmHg (Aiyagari et al, 2009). A target blood pressure of 160/90 mmHg or MAP of 110 mmHg can help maintain cerebral perfusion pressure in these patients. Small studies have found that a reduction in blood pressure by 15% or less will maintain cerebral perfusion pressure, while a drop in blood pressure > 20% will not. Thus, avoid decreasing blood pressure more than 20%; incremental doses at the lower end of the dosing range (e.g. 5-10mg IV) may be more appropriate than a large bolus at the higher end of the dosing range (e.g. 20mg or more IV). For hypertensive emergency or urgency, manufacturer dosing is a more aggressive. They recommend an initial 20mg IV bolus over 2 minutes, which may be increased to 40-80mg given in 10 minute intervals, to a maximum of 300mg. If an infusion is needed, dosing is 2mg/min (not weight based) titrated to a maximum of 300mg. Pediatric dosing is off-label, but intermittent boluses of 0.3-1mg/kg have been described. For pediatric hypertensive emergency, dosing is 0.4-1mg/kg/hour to a maximum of 3mg/kg/hour.
Contraindications, side effects, and drug interactions are the same as for other beta-blockers. The ß2-blocking properties makes bronchospasm more likely, thus patients with bronchospastic disease should not receive labetalol. The α1-blocking properties mean hypotension is more likely and this hypotension can be profound if the drug is administered inappropriately. Because labetalol blocks both ß1 and α1 receptors, hypotension after administration is difficult to treat as inotropes (ß1 agonists) and vasopressors (α1 agonists) are less effective. Patients who are hypovolemic are at risk for significant hypotension with labetalol since they have limited ability to improve cardiac output. Cardiac output is increased by increasing heart rate (ß1 agonist), increasing inotropy (ß1 agonist), and increasing preload (sufficient volume in circulation). A compensatory mechanism for hypovolemia is increasing systemic vascular resistance (α1 agonist), which would be blocked by labetalol.
Epinephrine is less effective in a patient taking labetalol, thus increased doses may be needed for emergency situations such as anaphylaxis. Using the standard dosing regimen first is appropriate, but one should keep in mind that additional dosing may be needed in these patients. Labetalol would seem like an attractive choice for hypertension and tachycardia associated with cocaine intoxication, since unopposed alpha effects are less likely when compared with the beta-specific blockers. Unfortunately, labetalol does not appear to offer any advantages in acute cocaine intoxication (McCord et al, 2008). In animal studies, labetalol increased the risk of seizures and death with cocaine toxicity. In adult studies, labetalol did not reverse coronary artery vasoconstriction with cocaine toxicity.

Metoprolol [Lopressor, Toprol]

Route & Dosage: 2.5-5mg IV.
Onset & Duration: onset rapid, peak 20min, duration 5-8hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 3-4hr.
Indications: supraventricular tachycardia, postmyocardial infarction, hypertension, angina, atrial fibrillation, atrial flutter.
Contraindications: bradycardia, cardiogenic shock.
Adverse Effects: bronchospasm, bradycardia, hypotension, cardiogenic shock.
Drug Interaction: cocaine, epinephrine, calcium-channel blockers, digoxin.
Black box warning: avoid abrupt withdrawal.
Metoprolol is a ß1-specific blocker available in oral and intravenous form. Oral use is typically for chronic conditions including angina, heart failure, atrial fibrillation, hypertension, and after myocardial infarction. Acute conditions where the intravenous form can be used include supraventricular, hypertension, and after acute myocardial infarction. For supraventricular tachycardia unresponsive to vagal maneuvers and adenosine, dosing is 5mg over 1-2min, which can be repeated every 5 minutes to a maximum of 15mg. For hypertension or ventricular rate control (e.g. atrial fibrillation with rapid ventricular response), dosing is 1.25-5mg IV initially. In acute myocardial infarction, without cardiogenic shock, metoprolol 5mg IV may be given every 5 minutes up to 3 doses in hypertensive patients who have ongoing ischemia.
Similar to atenolol and esmolol, ß1-specificity means ß2 effects (bronchospasm) are uncommon. Contraindications, side effects, and drug interactions are the same as for other beta-blockers. As with other beta-blockers, caution is needed in heart failure as reducing contractility can worsen the condition. Acute supraventricular tachycardia in patients who have beta-blocker contraindications, such as heart failure, can be managed with cardioversion (January et al, 2014). The same black box warning applies for metoprolol as it does for other oral beta-blockers, where abrupt withdrawal can lead to myocardial infarction.

Propranolol [Inderal, InnoPran]

Route & Dosage: 0.5-1mg IV.
Onset & Duration: onset rapid, peak 1min, duration 4-6hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 4hr.
Indications: supraventricular tachycardia, postmyocardial infarction, hypertension.
Contraindications: bradycardia, cardiogenic shock, asthma.
Adverse Effects: bronchospasm, bradycardia, hypotension, cardiogenic shock.
Drug Interaction: cocaine, epinephrine, calcium-channel blockers, digoxin.
Black box warning: avoid abrupt withdrawal.
Propranolol is a non-specific ß1 and ß2-blocking agent. Oral formulation has similar indications are previously mentioned beta-blockers plus several other indications for chronic condition such as essential tremor, migraine prophylaxis, and esophageal bleeding prophylaxis for liver patients. IV dosing for adult supraventricular tachycardia is 0.5-1mg over 1 minute, repeated up to a total of 0.1mg/kg if needed. For children, use for tachycardia is off-label and dosing range is 0.01-0.1mg/kg/dose over 10 minutes, to a maximum of 1mg for infants and 3mg for children. Contraindications, side effects, drug interactions, and black box warning are the same as for other beta-blockers. The ß2-blocking properties increases the risk of bronchospasm and propranolol should be avoided in patients with asthma or bronchospastic disease. This makes propranolol a less desirable choice for tachycardia management when compared with atenolol, esmolol, or metoprolol. The lack of α1-blocking properties makes propranolol a less desirable choice for hypertension management when compared to labetalol.

Analgesic Agents

Pain during acute coronary syndrome is secondary to the supply-demand mismatch of the heart, where oxygen supply cannot reach myocardial demand. Medications that improve this mismatch will help relieve chest pain symptoms. Examples are antianginal agents like nitroglycerin and beta-blockers, as they reduce heart rate which improve supply and decreases demand. Opioid analgesics may have a role in the management of pain during cardiovascular emergencies, but caution should be taken. Opioids effect the sensation of pain but do not always improve the cause of the pain. There is potential for false reassurance that the underlying disorder is improved just because the patient is in less pain.

Morphine (generic)

Route & Dosage: 2-4mg IV.
Onset & Duration: onset 5-10min, peak 20min, duration 4-5hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 90min.
Indications: chest pain with acute coronary syndrome.
Contraindications: altered mental status, severe respiratory depression, acute or severe asthma, known paralytic ileus.
Adverse Effects: apnea, sedation, confusion, hypotension, flushing, bradycardia, histamine release, anticholinergic effects, constipation, nausea, miosis, itching, muscle rigidity, potential for abuse, worsening of hypotension with right ventricular infarction, worsening of hypotension in volume-depleted patients.
Drug Interaction: sedatives and analgesics including ethanol.
Black box warning: respiratory depression.
Morphine is an opioid analgesic first discovered in the year 1804. It is widely available in generic format for PO and IV use, however there are several name brand formulations for other routes of administration. Morphine is the prototypical opioid used for comparison to other opioids. For patients with chest pain that is not responsive to nitrates, intravenous morphine may be administered (O’Connor et al, 2010). Morphine is the preferred analgesic agent for patients with STEMI, but there is some uncertainty about use in patients with unstable angina (UA) or NSTEMI. For this reason, the AHA reduced their recommendation from Class I to Class IIa in patients with NSTEMI or UA. Morphine for chest pain in STEMI remains a Class I recommendation, where the benefit definitely outweighs the risk.
For ACS patients unresponsive to nitrates or in acute cardiogenic pulmonary edema with adequate blood pressure, dosing is 2-4mg IV. Additional doses of 2-8mg IV may be given at 5-15 minute intervals, noting that the onset takes at least 5 minutes. For NSTEMI/UA, dosing is 1-5mg IV only if symptoms are unrelieved by nitrates or if they reoccur, and morphine should be used with caution in these patients.
Opioids have many effects on different parts of the body. They relieve pain by several mechanisms and have both supraspinal (brain) and spinal analgesic effects. They can lead to sedation and euphoria, but generally do not cause loss of consciousness. They have cough suppressant effects and are used widely for this purpose in the outpatient setting. Their cardiovascular effects include bradycardia and some vasodilation. Pruritus (itching) is common as is nausea/vomiting. Histamine release is associated with the vasodilation and pruritus. They cause miosis, delayed gastric emptying, ileus with constipation, and urinary retention. If a patient is known to have severe constipation, opioids should be avoided or used cautiously. Most importantly, they depress ventilation and can lead to apnea. For this reason, they should be avoided or at least used cautiously in patients with severe respiratory depression, including severe asthma, as well as patients with altered mental status.
Morphine has several black box warnings, but most of the warnings are for specialty formulations of the drug. Addiction potential exists for all formulations of morphine and there is a black box warning discussing chronic use/misuse. The most important black box warning, which applies to all morphine formulations, is respiratory depression. Respiratory depression is the leading cause of death from overdose of morphine and other opioid medications. Providers must be prepared to manage the airway of any patient receiving sedatives and analgesics. Opioids should be used with caution when the patient has taken or received other analgesics or sedatives, including ethanol. These substances are additive (i.e. 1 + 1 = 2) in their effect on sedation and respiratory depression. Some combinations are synergistic, meaning their combined effect is higher than each drug would cause alone (i.e. 1 + 1 = 3), which further increases the likelihood of severe respiratory depression.

Antianginal Agents

Initial EMS care for acute coronary syndrome is remembered by the mnemonic MONA: morphine, oxygen, nitroglycerin, aspirin. Although this is a standard regimen, one must know about the contraindications and details of each of these medications. Morphine has some contraindications and cautions, as previously mentioned. Oxygen is used in acute coronary syndrome only if the patient is dyspneic, has signs of heart failure, or has SpO2 < 94%. Aspirin contraindications will be discussed later in this chapter. However, aspirin should always be used when appropriate as it can reduce mortality by 25% in AMI and by 50% in unstable angina. Some add a B to the MONA mnemonic (MONA-B) to recall that ß-blockers are useful in the management of acute coronary syndrome, especially since beta-blockers can reduce mortality.
Several antianginal agents exist and are typically divided into nitrates, beta blockers, and calcium channel blockers. Nitrates, such as nitroglycerin, have the largest effect on preload thus should be used cautiously in patients who depend on their cardiac preload (e.g. hypovolemia, right ventricular injury). Patients at risk for cardiac ischemia may be on nitrates at home and are typically instructed to call for EMS if their pain is either unrelieved or increased after a single rescue dose.

Table 15-6: Commonly Used Antianginal Agents

Nitroglycerin (generic)

Route & Dosage: 0.3-0.4mg sublingual, 12.5-25mcg IV then 10mcg/min infusion.
Onset & Duration: depends on formulation – onset 1-3min, peak 1-60min, duration 5min to 7hr.
Pharmacokinetics: liver metabolism (extensive first pass), urine elimination, half-life 1-4min.
Indications: ischemic chest pain, hypertension, uterine relaxation (off-label).
Contraindications: hypotension especially with tachycardia, severe bradycardia, right ventricular infarction, use with phosphodiesterase inhibitors.
Adverse Effects: hypotension, increased intracranial pressure, paradoxical bradycardia, tachycardia, hypertrophic cardiomyopathy, methemoglobinemia (rare).
Drug Interaction: phosphodiesterase inhibitors.
Nitroglycerin is the initial antianginal of choice for suspected ischemic chest pain. It is available in several formulations including sublingual tablets, aerosol spray, topical paste, transdermal patch, and intravenous fluid. Nitroglycerin relaxes vascular smooth muscle, causing more venous dilation than arterial dilation. The mechanism is similar to nitroprusside in that it metabolizes to nitric oxide, which causes vasodilation. Nitroglycerin dilates coronary vessels, but despite this there is no conclusive evidence that it should be used routinely in AMI. Nitrates can be given for ischemic chest pain in up to 3 doses, given 3-5min apart. Dosing is 0.3-0.4mg sublingual in either tablet or spray form, as this route skips first pass metabolism in the liver. Topical nitrates (e.g. nitroglycerin paste applied to the chest) are an acceptable alternative.
In patients with obvious acute coronary syndrome or ongoing ischemia, an intravenous infusion may be used. Dosing is 12.5-25mcg IV then an infusion of 10mcg/min. Titration of the infusion to effect involves increasing by 10mcg/min every 3-5min, with a max dose of 200mcg/min. This is considered the route of choice for emergencies. Onset of action for the sublingual tablet/spray is 1-3min with peak effect in 5min and duration lasting 25min. Topical formulations typically take 15-30min for onset, 60min for peak, and last about 7 hours. Patients may present wearing transdermal patches, which should be left on unless they are causing undesired effects (e.g. hypotension) or they are in the way of defibrillation pads. Intravenous onset is immediate with immediate peak, but duration of action is 3-5min so effects quickly stop after stopping the infusion.
Preload reduction makes nitroglycerin a good choice for cardiogenic pulmonary edema. Nitroglycerin improves myocardial oxygen supply and reduces demand through several mechanisms including reduced venous return, reduced preload, and relief of coronary vasospasm. Nitroglycerin can cause significant hypotension and therefore is contraindicated if systolic pressure is < 90 mmHg or has dropped ≥ 30 mmHg from baseline. Hypotension is a side effect that can preclude the use of other beneficial agents, such as angiotensin converting enzyme (ACE) inhibitors. Patients taking phosphodiesterase inhibitors, such as sildenafil for erectile dysfunction, should not receive nitrates due to risk for severe hypotension. Compensatory tachycardia may be seen with the drop in preload and SVR, thus caution should be taken in patients who are already tachycardic as further tachycardia will reduce myocardial oxygen supply and increase demand. There have been reports of paradoxical bradycardia with nitroglycerin, thus it should be avoided in patients with HR < 50 bpm. Patients with hypertrophic cardiomyopathy (HOCM) have cardiac outflow tract obstruction and thus depend on adequate preload to reduce this obstruction. Giving nitroglycerin to these patients worsens their obstruction by reducing preload. If tachycardia occurs, this further reduces the time for the heart to fill and can lead to cardiac arrest in HOCM patients. One of nitroglycerin’s metabolic products is nitrite, which can convert hemoglobin to methemoglobin. Fortunately, methemoglobinemia is rare with nitroglycerin use but should be suspected if SpO2 reading remains at 85% despite oxygen therapy. Uterine relaxation is a side effect of nitroglycerin, thus it should be avoided in patients with significant vaginal bleeding especially if they are pregnant.
Case Study: Chest Pain And Severe Hypotension
You receive a call for a 67-year-old man who is having severe chest pain at home. On arrival you find a large diaphoretic man who is gripping his chest. Your partner EMT Yoo obtains vital signs: HR 68 bpm, BP 104/76 mmHg, SpO2 96%, and RR 22/min. You have your partner obtain an ECG as you obtain a medical history. The patient has known coronary disease and is taking a beta blocker for hypertension. You direct EMT Yoo to administer aspirin and you review the ECG, shown in Figure 15-4. A 22-gauge IV is started and a 1L bag of PlasmaLyte is hung.
You determine that the patient is not taking any medications for erectile dysfunction then administer 0.4mg sublingual spray of nitroglycerin. The patient reports no relief and remains uncomfortable with crushing chest pain. You ask EMT Yoo to obtain vital signs, but she is busy talking with dispatch to have the hospital activate their cardiac catheterization team. Heart rate and SpO2 are unchanged. You administer 5mg IV morphine for the ongoing chest pain. The patient begins to feel dizzy and you cycle the blood pressure cuff: 78/44 mmHg. You act quickly to obtain another IV, this time larger gauge, and hang fluids wide open. After 10 minutes the blood pressure is > 90 mmHg systolic and you are on the way to the hospital.

Nitrates and morphine are contraindicated in patients with right ventricular infarction. The right ventricle needs adequate preload to pump, and preload is reduced with these medications. In inferior wall STEMI, a right-sided ECG should be obtained to evaluate for RV infarction (V4R most sensitive lead). RV infarction or ischemia may occur in up to 50% of patients who present with an inferior wall MI. It should be suspected in any patient with hypotension and an inferior wall infarction on ECG. Hypotension in this setting should be initially treated with IV fluids. Diuretics and other vasodilators, such as ACE inhibitors, should also be avoided due to the risk for severe hypotension.

Antiarrhythmic Agents

Antiarrhythmic agents are commonly used as part of the Advanced Cardiac Life Support (ACLS) guidelines and the Pediatric Advanced Life Support (PALS) guidelines. Arrhythmias are treated in three different ways: mechanically (e.g. surgery), electrically (e.g. pacemaker, cardioversion), or pharmacologically. Ventricular arrhythmias and more serious arrhythmias typically require immediate electrical therapy. Pharmacologic therapy can both improve arrhythmias and prevent their reoccurrence. These drugs work by modifying ion channels and the Singh-Vaughan Williams Classification divides them this way (Table 15-7).

Table 15-7: Antiarrhythmic Agents

Class I medications block sodium channels, which has led them to be termed “membrane stabilizing.” Sodium channels affect myocardial cell depolarization, so these agents work to reduce cellular excitability. Class II medications are beta blockers, which as previously discussed reduce the effects of the sympathetic nervous system on the heart. This makes them the most common treatment for supraventricular tachycardia and ventricular tachycardia. Class III agents block potassium channels, which increases cardiac action potential duration and the refractory period of the heart. Amiodarone and dronedarone have activity in Class III, as well as Class II and I. Class IV agent primarily slow AV node conduction by blocking calcium channels. This makes them the most common treatment for idiopathic rhythms and ectopic atrial tachycardia.

Adenosine [Adenocard]

Route & Dosage: 6mg IV rapid push, 0.1mg/kg IV rapid push.
Onset & Duration: rapid onset and peak, duration very brief.
Pharmacokinetics: blood and tissue metabolism, half-life < 10 seconds.
Indications: supraventricular tachycardia.
Contraindications: symptomatic bradycardia, second- or third-degree AV block, asthma, poison-induced tachycardia, irregular polymorphic wide-complex tachycardia.
Adverse Effects: chest pain, lightheadedness, flushing, nausea, headache, apprehension, bradycardia, cardiac arrest, hypertension, seizures.
Drug Interaction: xanthines, carbamazepine, dipyridamole.
Adenosine is an antiarrhythmic medication that acts by activating adenosine receptors. It significantly decreases conduction through the AV node and depresses sinus node rate. Due to rapid metabolism in the body, the half-life is less than 10 seconds. Adenosine should be given as a rapid bolus through a peripheral IV as close to the trunk as possible (i.e. not the hand or foot). It should be followed with a flush of 5mL for infants or 20mL for adults, then extremity elevation. It is recommended that a T-connector or stopcock be used with both syringes attached so that the drug can be quickly administered and followed immediately by a flush. Placing the patient in Trendelenburg position can help prevent side effects related to reduced blood flow to the brain. Obtain a continuous rhythm strip during drug administration.
Adenosine is indicated as the first drug for stable narrow-complex SVR unresponsive to vagal maneuvers. It can be considered or unstable SVT while preparations are being made for cardioversion. Adenosine will not convert atrial fibrillation, atrial flutter, or ventricular tachycardia. However, it is used as a diagnostic maneuver to cause a transient AV-nodal block and uncover the underlying arrhythmia (e.g. atrial fibrillation or flutter). Dosing for stable SVT is 6mg IV rapid flush. A second dose of 12mg can be given in 1-2 minutes if needed. A third dose is no longer recommended (Neumar et al, 2010). For children, the initial dose is 0.1mg/kg to a max of 6mg. A second dose may be given 1-2minutes later, at 0.2mg/kg to a max of 12mg (Kleinman et al, 2010).
Adenosine should not be used in patients with symptomatic bradycardia or high-degree AV node block as worsened block, and even asystole, can occur. Bronchoconstriction has occurred during use thus adenosine should be avoided in asthmatics. Drug- or poison-induced tachycardia should not be managed with adenosine. Adenosine given in the setting of irregular or polymorphic wide-complex tachycardia can lead to ventricular fibrillation. Due to the risk of significant bradycardia, an external pacemaker should be available. Common side effects include chest pressure, flushing, headache, nausea, apprehension (feeling of doom), and transient hypertension. Xanthines medications interact with adenosine. Seizures have been reported and the risk may be higher in patients taking aminophylline. Larger adenosine doses may be needed in patients taking caffeine or theophylline. Initial adenosine dosing should be decreased to 3mg IV bolus in patients taking dipyridamole or carbamazepine. The 3mg IV bolus dose is also recommended if administered through a central line.

Amiodarone [Cordarone, Nexterone, Pacerone]

Route & Dosage: 300mg IV, 5mg/kg IV.
Onset & Duration: onset minutes, peak within 1hr, duration 1-3hr.
Pharmacokinetics: liver metabolism, urine and feces elimination, half-life 3-80hr.
Indications: ventricular fibrillation or pulseless ventricular tachycardia unresponsive to defibrillation, recurrent hemodynamically unstable ventricular tachycardia.
Contraindications: Wolff-Parkinson-White (WPW) syndrome, prior iodine reaction.
Adverse Effects: bradycardia, hypotension, nausea, tremor, prolonged QT, widened QRS, severe toxicity with long-term use.
Drug Interaction: multiple but most serious interactions related to QT prolongation.
Black box warning: “Amiodarone is intended for use only in patients with indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity.”
Amiodarone is a complex drug with several different effect sites, multiple drug interactions, and multiple serious side effects. It works on sodium channels, potassium channels, and calcium channels. It has ß-adrenergic blocking properties as well as α-adrenergic blocking properties. Amiodarone slows AV conduction, prolongs the AV refractory period, prolongs the QT interval, and slows ventricular conduction (widens the QRS). IV dosing is indicated for life-threatening arrhythmias only. PO dosing is used for long-term arrhythmia management and is associated with multiple potentially fatal toxicities. In IV form, onset is quick and duration can last up to 3 hours. In PO form, pharmacokinetics are significantly different. The oral onset of action is 2 days to 3 weeks, peak occurs in 1 week to 5 months, and half-life is 26-107 days. There is little correlation between the plasma concentration of amiodarone, or its major active metabolite, and drug efficacy or toxicity.
Management of VF/VT involves CPR, defibrillation, and the administration of a vasopressor. In patients who are unresponsive to this therapy but remain in VF/VT, amiodarone is indicated. The dose is 300mg IV push and a second dose may be given at 150mg IV after a round of CPR with attempted defibrillation. Recurrent, hemodynamically unstable VT fits the criteria for life-threatening arrhythmia. In this circumstance, dosing is 150mg IV over 10 minutes (15mg/min), considered a rapid infusion, followed by a maintenance infusion of 540mg IV over 18 hours (0.5mg/min). Rapid infusion may lead to hypotension, so a slow infusion is an alternative, which is dosed as 360mg IV over 6 hours (1mg/min). Maximum cumulative dose is 2.2 grams (2200mg) IV over 24 hours. For children, the dose is 5mg/kg IV, which may be repeated twice up to 15mg/kg, with maximum single dose of 300mg. In cardiac arrest, amiodarone may be pushed rapidly in children but should be given over 20-60min in perfusing rhythm. Expert consultation is strongly recommended prior to administration to a child with a perfusing rhythm.
Amiodarone has been shown to improve return of spontaneous circulation (ROSC) and survival to hospital admission, where lidocaine has not. However, both amiodarone and lidocaine have not been shown to improve survival to hospital discharge. This emphasizes the point that good ACLS starts with excellent BLS, as CPR and defibrillation have been shown to improve survival. Amiodarone can be useful in terminating SVT, however the slower onset of action, toxicity, and possible proarrhythmic effects make it a less desirable choice compared to adenosine. Combinations of medications (“cocktails”) are not recommended and can cause patient harm because of proarrhythmic effects. Do not alternate amiodarone with lidocaine. Interruption of CPR to assess rhythm and administer antiarrhythmic agents is discouraged.
Amiodarone can prolong the QT interval, leading to torsade de pointes. Therefore, it should not be given with drugs that also prolong the QT interval, such as procainamide. Other QT prolonging drugs include: citalopram, clarithromycin, droperidol, erythromycin, flecainide, haloperidol, ibutilide, methadone, moxifloxacin, ondansetron, pentamidine, quinidine, and sotalol. Amiodarone affects the pharmacokinetics of warfarin, digoxin, quinidine, and procainamide. It also affects the pharmacodynamics of beta-blockers and calcium-channel blockers, thus should be used with caution in patients on these medications. In patients with WPW syndrome who have pre-excitation atrial fibrillation/flutter, the use of amiodarone can lead to ventricular fibrillation. The ECG would appear irregular, wide-complex, and “chaotic” with slurred upstroke of the QRS (delta waves). Amiodarone should be used with caution or avoided in patients with a prior iodine reaction.
Hypotension can occur with amiodarone use and may be refractory to treatment in some cases. Other common effects include bradycardia, nausea, and tremor. Severe, and even fatal, toxicity can occur with amiodarone but this is more typical of long-term PO dosing than single bolus IV dosing. However, it is important to know about these toxicities as patients may present with them. The most important amiodarone toxicity is pulmonary, which is fatal 10% of the time. Amiodarone is also toxic to the liver and the thyroid. This is remembered by “PFTs, LFTs, TFTs” as amiodarone affects pulmonary function tests, liver function tests, and thyroid function tests. Corneal deposits occur in the majority of patients which can cause visual disturbance. A light-sensitive blue-grey discoloration of the skin can occur as well.
That’s Not True … or Is it? Shellfish Allergy And Iodine
No one is allergic to iodine; it is an element found in everyone’s body (Beaty et al, 2008). The mechanism of iodine reactions is not likely to be immune related and should not be classified as an “allergy.” Local skin reactions to iodine-solutions are due to other substances in the cleaning solutions. Patients and providers may report that a shellfish allergy makes them allergic to iodine-containing substances, such as amiodarone. However, this is a myth (Schabelman et al, 2010). There is no link between shellfish allergy and iodine reactions.

Diltiazem [Cardizem]

Route & Dosage: 15-20 IV.
Onset & Duration: onset 3min, peak 5min, duration 1-3hr.
Pharmacokinetics: liver metabolism, urine and feces elimination, half-life 4hr.
Indications: supraventricular tachycardia (off-label), rate control with atrial fibrillation or flutter (off-label), hypertension, angina, coronary vasospasm.
Contraindications: symptomatic bradycardia, second- or third-degree AV block, poison-induced tachycardia, irregular polymorphic wide-complex tachycardia, Wolff-Parkinson-White syndrome, cardiogenic shock.
Adverse Effects: bradycardia, edema, headache, vasodilation, cardiogenic shock.
Drug Interaction: beta-blockers, digoxin, midazolam.
Diltiazem is a calcium-channel blocker used in the acute care setting to control tachycardia by reducing conduction through the AV node (negative dromotropic effect). A dromotropic agent is a drug that affects conduction speed through the AV node. Diltiazem also relaxes coronary vascular smooth muscle and dilates coronary arteries, thus it is used as a treatment for coronary vasospasm. It is indicated for use in SVT after adenosine has been attempted, however it should not be used in patients with WPW. It is also indicated to control ventricular rate with atrial fibrillation or atrial flutter (e.g. atrial fibrillation with rapid ventricular response). Dosing is 15-20mg IV (0.25mg/kg) over 2 minutes. A second dose may be used in 15 minutes at 20-25mg (0.35mg/kg) given over 2 minutes. Maintenance infusion, if needed, is 5-15mg/hr titrated to physiologically appropriate heart rate. An initial infusion rate of 10mg/hr is appropriate for adults. Minimal data is available for children, though adolescents may use the adult dosing. In younger children, there is not enough data to support use of diltiazem in IV form.
Contraindications are similar to beta-blockers due to risk of complete AV blockade. They can also precipitate heart failure and should be avoided in cardiogenic shock. Wide QRS tachycardias of uncertain origin should prompt expert consultation and not be managed with calcium channel blockers or beta blockers, as they may be ventricular in origin. Drugs that block the AV node (e.g. adenosine, calcium channel blocker) should be avoided in WPW due to the risk for rapid ventricular response/tachycardia secondary to the unblocked accessory pathway in rapid atrial arrhythmias. Beta blockers block slow AV node conduction and the SA node, but despite SA node slowing they do not typically terminate tachycardia with WPW and should not be used (Prystowsky et al, 1987).
Side effects are similar to beta blockers in that they cause bradycardia, hypotension, and can precipitate heart failure. Peripheral vasodilation is greater with verapamil than with diltiazem, but hypotension can still occur. Headache from vasodilation is common and peripheral edema can occur, most commonly with long-term dosing. As discussed before, calcium-channel blockers should not be used with beta-blockers due to the risk of complete AV blockade. These medications have other indications in the chronic outpatient setting, so the provider should ask specifically about them before administering another AV nodal blocking agent. Digoxin can decrease heart rate, so the use of calcium channel blockers in this setting can cause serious bradycardia. In patients taking oral diltiazem or verapamil, one study showed peak concentrations of midazolam were doubled and duration of action was prolonged (Backman et al, 1994). The dose of midazolam should be decreased in this setting.

Lidocaine [Xylocaine]

Route & Dosage: 1-1.5mg/kg IV.
Onset & Duration: onset rapid, peak 45-90sec, duration 10-20min.
Pharmacokinetics: liver metabolism, urine elimination, half-life 7-30min.
Indications: ventricular fibrillation or pulseless ventricular tachycardia unresponsive to defibrillation, stable monomorphic or polymorphic ventricular tachycardia, rapid sequence induction and intubation.
Contraindications: acute myocardial infarction, severe hepatic dysfunction, premature infants, high degree AV block, Wolff-Parkinson-White syndrome.
Adverse Effects: arrhythmias, increased defibrillation threshold, flushing, hypotension, anxiety, seizure, coma, metallic taste, perioral numbness, tinnitus, bronchospasm, methemoglobinemia.
Drug Interaction: amiodarone, dronedarone.
Lidocaine is a Class Ib antiarrhythmic and a local anesthetic with actions on sodium channels. It is frequency dependent with significantly more action at higher heart rates. It has good efficacy in the ischemic myocardium. Both lidocaine and amiodarone do not improve survival to hospital discharge, however amiodarone improves survival to hospital admission after recurrent VF/VT. For this reason, lidocaine is only appropriate for cardiac arrest with VF/VT if amiodarone is not available. It is also indicated for stable monomorphic or polymorphic VT with a normal baseline QT interval and preserved left ventricular dysfunction, though this indication is more typical for in-hospital use and required correction of electrolyte abnormalities.
Dosing for adults in cardiac arrest from VT/FT is 1-1.5mg/kg IV. For refractory VF, an additional 0.5-0.75mg/kg IV may be given then repeated in 5-10minutes to a maximum of 3 doses or 3mg/kg. Although a much less desirable route, endotracheal administration is possible at 2-2.5x the typical dose, so 2-3.75mg/kg ETT diluted in 5-10mL of sterile water. For children, dosing is 1mg/kg IV to a maximum of 100mg. A second bolus of 0.5-1mg/kg may be given 15 minutes later. Endotracheal dosing in children is 2-3mg/kg diluted in 5mL of saline. For perfusing arrhythmias, such as stable VT or wide complex tachycardia, adult dosing is 0.5-0.75mg/kg and up to 1-1.5mg/kg may be used. Repeat dosing every 5-10 minutes is 0.5-0.5mg/kg up to a maximum of 3mg/kg. Maintenance infusion rate is 1-4mg/min (30-50mcg/kg/min). In children, the maintenance infusion rate is 20-50mcg/kg/min.
Lidocaine can be used during rapid sequence induction and intubation (RSII) to blunt the effects of laryngoscopy and endotracheal intubation. This can help reduce the increase in ICP and the cough reflex, which may be useful in head trauma patients. There is controversy however given the lack of evidence for benefit and because of the risk of hypotension with administration (El-Orbany et al, 2010). Also, the optimal time for lidocaine premedication effect is 3 minutes, which may not be practical in an emergency situation (Tam et al, 1987). PALS guidelines recommend 1-2mg/kg IV for RSII, however several studies have shown that a dose of 1.5mg/kg is the most appropriate (Salhi et al, 2007). Multiple randomized trials have shown that lidocaine 1.5mg/kg IV suppresses the cough reflex when given before intubation.
In the past, lidocaine was used to suppress ectopy seen on the ECG rhythm strip. Current AHA guidelines recommend against the use of lidocaine to suppress isolated ventricular premature beats, couplets, runs of accelerated idioventricular rhythm, and nonsustained ventricular tachycardia (O’Gara et al, 2013). Lidocaine should not be used in high-degree AV block or in patients with WPW. Lidocaine can cause flushing, hypotension, and increase the defibrillation threshold (i.e. make defibrillation less effective). There are case reports of methemoglobinemia with lidocaine. Patients with severe hepatic dysfunction are at high risk for lidocaine toxicity secondary to poor hepatic metabolism of the drug. For in-hospital patients, hypokalemia and hypomagnesemia should be corrected before use as an antiarrhythmic. Some formulations of lidocaine contain benzyl alcohol as a preservative, which is contraindicated for use in premature infants. Most of the drug interactions with lidocaine result in an increased serum lidocaine concentration, however providers only need to monitor therapy for signs of toxicity. Signs of lidocaine toxicity are shown in Figure 15-5.

Magnesium (generic)

Route & Dosage: 1-2g IV.
Onset & Duration: onset immediate, peak rapid, duration 30min.
Pharmacokinetics: bone distribution, urine elimination, half-life not applicable.
Indications: cardiac arrest with torsades de pointes, life-threatening arrhythmias due to digitalis toxicity, asthma (off-label), pre-eclampsia, hypomagnesemia, calcium toxicity.
Contraindications: routine administration in hospitalized patients with AMI, routine use during ACLS, neuromuscular disease.
Adverse Effects: hypotension, muscle weakness, muscle twitching, seizures, flushing, blurred vision, loss of deep tendon reflexes, respiratory arrest, AV block, bradycardia, cardiac arrest.
Drug Interaction: calcium, non-depolarizing muscle relaxants.
Magnesium is available in several formulations (citrate, oxide, acetate, chloride, sulfate). Magnesium sulfate is the formulation for IV injection. It has a wide-range of actions and a number of indications. It is an essential modulator of electrical activity in the cardiac cell. Magnesium is second only to potassium as the most abundant cation in cells and both of these play an important role in arrhythmias. In the hospital setting, hypokalemia and hypomagnesemia are avoided in patients with arrhythmias (Boyd et al, 1984). A typical goal of K+ = 4.0 and Mg2+ = 2.0 has been suggested in an effort to reduce depletion of potassium and magnesium.
Magnesium causes relaxation of bronchial smooth muscle and can be used in asthma and bronchospasm. It causes relaxation of the uterus and is used to prevent preterm labor. It is also used in pregnant women with preeclampsia to prevent seizures (eclampsia). It affects NMDA receptors and is used in some settings for analgesia. Importantly, magnesium is an antagonist to calcium and is used in the treatment of calcium toxicity. Because of the effects of magnesium on calcium and potassium (Specter et al, 1975), it is a treatment option for life-threatening ventricular arrhythmias due to digitalis toxicity.
Magnesium is indicated for cardiac arrest only if torsades de pointes is occurring or suspected. The dosing for this indication is 1-2g IV (1000-2000mg) given over 15 minutes. This use follows AHA guidelines but is considered off-label by the manufacturer. The manufacturer’s indication is treatment of cardiac arrest due to known hypomagnesemia. After gathering evidence from studies, investigators concluded that magnesium has no particular positive effect in cardiac arrest and therefore should not be used routinely (Neumar et al, 2010).
Magnesium is also indicated for torsades de pointes with a pulse or in AMI patients with known hypomagnesemia. Dosing is 1-2g IV given over 5-60 minutes followed by 0.5-1g/hr IV titrated to control of torsades. Hypotension limits the rate of administration when titrating. It is worth noting that the AHA recommends against the routine use of magnesium in patients with AMI (e.g. hospitalized patients who do not have hypomagnesemia). Magnesium is not likely to be effective for irregular polymorphic VT in patients with a normal QT interval. So, in the prehospital setting, the primary indication is torsades de pointes and use of magnesium for other arrhythmias is not recommended and can be harmful.
Magnesium causes muscle weakness and should be used with caution in patients that have neuromuscular disease, such as myasthenic gravis. It also prolongs the duration of action for non-depolarizing muscle relaxants (e.g. rocuronium, vecuronium). Renal failure results in increased levels of magnesium after administration, which can lead to toxicity. Systemic effects of magnesium are related to serum concentrations. At 3-4mEq/L, flushing can occur and occasionally an increase in the PR and QRS intervals. At 5-6mEq/L, blood pressure begins to decline, heart rate slightly increases, breathing function becomes slightly impaired, blurred vision occurs, and lethargy can occur. At 10mEq/L, deep tendon reflexes are lost, which makes this a good physical exam marker for toxicity if laboratory assessment is not available. At 20mEq/L there is progressive QRS widening, bradycardia, and AV conduction block. Cardiac arrest occurs at levels > 25mEq/L, which is over 10 times higher than the normal range and would probably require repeated infusions in the setting of renal failure.
Virtual Mentor: What If CPR and Epinephrine Doesn’t Work?
Not all patients will recover from cardiac arrest and the AHA algorithms may give providers a false sense of confidence. If AHA guidelines do not work, providers may feel helpless. They may even consider other medications that are not part of the algorithm (e.g. bicarbonate) in a last ditch attempt at resuscitation. This is strongly discouraged and may lead to irreversible harm, removing any potential for recovery if the guidelines had continued to be followed. Magnesium, calcium, and sodium bicarbonate are not recommended for routine use in cardiac arrest. These medications should only be used in the special circumstances for which they are indicated. The routine use of bicarbonate has intentionally been removed from the AHA guidelines. Other drugs that have been removed for routine use include: procainamide, lidocaine, atropine, amiodarone, hormones, and fibrinolytics (Hazinski et al, 2010). Again, each of these medications should only be used for specific indications and not used outside of those indications as they may cause more harm.

Procainamide (generic)

Route & Dosage: 20mg/min IV.
Onset & Duration: onset rapid, peak 10-30min, duration 8hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 3-4hr.
Indications: atrial fibrillation with rapid rate in Wolff-Parkinson-White syndrome (off-label), stable monomorphic ventricular tachycardia, stable wide-complex tachycardia.
Contraindications: QT prolongation, high-degree heart block.
Adverse Effects: hypotension, arrhythmias, QRS widening, QT prolongation, torsades de pointes, may worsen heart failure, may worsen myasthenic gravis, dosage reduction for renal failure.
Drug Interaction: tricyclic antidepressants, QT prolonging drugs.
Black box warning: mortality.
Procainamide is a Class Ia antiarrhythmic that blocks sodium channels and potassium channels. It is specifically indicated for life-threatening ventricular arrhythmias. Additionally, it may be used for atrial fibrillation with rapid ventricular rate in patients with Wolff-Parkinson-White syndrome as it reduces conduction through the accessory electrical pathway (January et al, 2014). Procainamide, like amiodarone, has vasodilatory effects and can cause hemodynamic instability secondary to hypotension. Procainamide is typically less tolerated than amiodarone (AHA, 2000) with regard to hemodynamic stability. In patients with stable wide-complex tachycardia, with QRS ≥ 0.12 seconds, expert consultation is recommended. The provider may also consider an antiarrhythmic infusion, choosing from procainamide, amiodarone, or sotalol. However, sotalol should be used with expert consultation only. The use of procainamide in cardiac arrest is limited by the infusion rate and uncertain efficacy.
Adult dosing for recurrent VF/VT is 20mg/min IV infusion to a total of 17mg/kg. In urgent situations the dose may be increased up to 50mg/min IV with the same total dosing, but hypotension may limit the infusion rate. Dosing for other indications, including atrial fibrillation with rapid rate in WPW, is 20mg/min IV until one of the following occurs: 1) arrhythmia suppression, 2) hypotension, 3) QRS widens by 50%, or 4) total dose of 17mg/kg is reached. In patients with renal dysfunction or cardiac dysfunction, maximum total dosing should be reduced to 12mg/kg. Maintenance infusion is 1-4mg/min, which should be reduced to 1-2mg/min if the patient has renal dysfunction.
Expert consultation is recommended for procainamide in children. In children, it is used for supraventricular tachycardia, atrial flutter, and ventricular tachycardia with pulses. Loading dose in this setting is 15mg/kg IV over 30-60 minutes. Dosing should be reduced in patients with poor renal or cardiac function. The vasodilatory and negative inotropy effects of procainamide can lead to hemodynamic instability, which can limit infusion rates.
Procainamide is contraindicated in patients with high-degree heart block due to risk of complete heart block. It is also contraindicated in patients with QT prolongation as it can lead to torsade de pointes. Medications that prolong the QT interval on the ECG should not be used with procainamide. A list of some of the QT prolonging drugs can be found under Amiodarone in this chapter. QRS widening occurs with procainamide and it should not be used with tricyclic antidepressants as they can further widen the QRS complex (Thornton, 1979). Examples of some tricyclic antidepressants are: amitriptyline, desipramine, doxepin, imipramine, and nortriptyline. The sodium-channel blocking properties of tricyclic antidepressants is responsible for the high mortality rate in overdose for these patients (Harrigan et al, 1999). The negative inotropic effects of procainamide can worsen heart failure, so caution is advised. There are some reports that procainamide can worsen myasthenia gravis, thus respiratory status should be followed in these patients. For in-hospital patients, hypokalemia and hypomagnesemia should be corrected before use as an antiarrhythmic.
There are several black box warnings associated with this medication. The most applicable to EMS providers is “mortality”, which relates to the CAST study. Procainamide has pro-arrhythmic effects and has not been shown to improve mortality in patients without life-threatening arrhythmias. The Cardiac Arrhythmia Suppression Trial results tell providers that procainamide should be reserved for patients with life-threatening ventricular arrhythmias. Prolonged administration of procainamide can cause a lupus-like syndrome as well as blood disorders, but these are not particularly relevant to EMS providers.

Verapamil [Calan, Covera, Isoptin, Verelan]

Route & Dosage: 2-.5-5mg IV.
Onset & Duration: onset 1-5min, peak 5min, duration 10-20min.
Pharmacokinetics: liver metabolism, urine and feces elimination, half-life 4min.
Indications: supraventricular tachycardia (off-label), rate control with atrial fibrillation or flutter (off-label), hypertension, angina, coronary vasospasm.
Contraindications: symptomatic bradycardia, second- or third-degree AV block, poison-induced tachycardia, irregular polymorphic wide-complex tachycardia, Wolff-Parkinson-White syndrome, cardiogenic shock.
Adverse Effects: bradycardia, edema, headache, vasodilation, cardiogenic shock.
Drug Interaction: beta-blockers, digoxin, midazolam.
Verapamil is a calcium-channel blocker that is an alternative option to beta-blockers and diltiazem for control of rapid AV node conduction. Similar to diltiazem, it is a negative dromotropic agent that causes coronary dilation and peripheral vasodilation. It is indicated for use in SVT after adenosine has been attempted, however it should not be used in patients with WPW. It is also indicated to control ventricular rate with atrial fibrillation or atrial flutter (e.g. atrial fibrillation with rapid ventricular response). Dosing is 2.5-5 IV over 2 minutes in adults and over 3 minutes in elderly patients. A second dose may be used in 15-30 minutes at 5-10mg, then repeated as needed to a maximum total dose of 20mg. Alternatively, 5mg IV may be bolused very 15 minutes to a total dose of 30mg. Verapamil is no longer included in the PALS guidelines.
Contraindications for verapamil are similar to contraindications for diltiazem. Calcium channel blockers can precipitate heart failure and should be avoided in cardiogenic shock. Wide QRS tachycardias of uncertain origin should prompt expert consultation and not be managed with calcium channel blockers or beta blockers, as they may be ventricular in origin. Drugs that block the AV node (e.g. adenosine, calcium channel blocker) should be avoided in WPW due to the risk for rapid ventricular response/tachycardia secondary to the unblocked accessory pathway in rapid atrial arrhythmias.
Side effects include bradycardia, hypotension, headache, and heart failure. Peripheral vasodilation is greater with verapamil than with diltiazem, but hypotension can still occur. Calcium-channel blockers should not be used with beta-blockers or digoxin due to the risk of complete AV blockade. These medications have other indications in the chronic outpatient setting, so the provider should ask specifically about them before administering another AV nodal blocking agent. As with diltiazem, the dose of midazolam should be decreased in patients receiving verapamil.

Antihypertensive Agents

Antihypertensive agents typically fall into three categories: diuretics, sympatholytics (e.g. beta-blockers), and vasodilators. Most of these vasodilators cause an arteriolar dilation. Nitroglycerin, however, primarily causes venodilation. Nitroprusside leads to both arteriolar and venous dilation. The mechanism of vasodilators is usually though α1-antagonism, through smooth muscle relaxation (e.g. calcium channel blockers), through the kidneys (ACE inhibitors), or through conversion to the potent vasodilator nitric oxide. Nitroglycerin and nitroprusside metabolize to nitric oxide, causing intense vasodilation. Hydralazine causes arterial dilation via α1-adrenergic blockade. Nicardipine and nifedipine are calcium-channel blockers that cause more vascular smooth muscle relaxation than diltiazem or verapamil.

Hydralazine (generic)

Route & Dosage: 5-10mg IV/IM.
Onset & Duration: onset 5min, peak 20min, duration 1-4hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 3-7hr.
Indications: hypertensive emergency including during pregnancy (off-label).
Contraindications: severe coronary artery disease, severe aortic stenosis, mitral valve rheumatic heart disease.
Adverse Effects: tachycardia, flushing, severe hypotension, dizziness, rash.
Drug Interaction: NSAIDs may decrease the effectiveness of hydralazine.
Hydralazine is an α1-adrenergic antagonist that causes arterial dilation, which significantly reduces cardiac afterload. It has minimal effects on cardiac preload as it does not dilate veins. A reflex tachycardia is typically seen with administration of hydralazine, with a heart rate increase greater than would be seen with nitroprusside or nitroglycerin. The baroreceptor reflex mediates this response. As blood pressure falls, decreased activation is seen in baroreceptors in the aortic arch and carotid sinuses in the neck. The brainstem receives this signal and triggers an increase in heart rate in an effort to restore blood pressure.
Dosing for hypertensive emergency is 10-20mg IV/IM every 4-6 hours as needed. Unfortunately, hydralazine action is unpredictable and can have prolonged antihypertensive effects. Some experts do not recommend using IV hydralazine for hypertensive emergencies (Marik et al, 2007). Dosing for pregnant patients with SBP ≥ 160 mmHg or DBP ≥ 110 mmHg is 5-10mg IV/IM every 20-40 minutes to a maximum dose of 20mg IV or 30mg IM (Magee et al, 2014). Alternatively, an infusion may be started after the first dose, run at 0.5-10mg/hr. Dosing for children is 0.1-0.2mg/kg IV/IM every 4-6 hours as needed, with a single dose not to exceed 20mg.
Advantages of hydralazine are intramuscular dosing as an option, usefulness in patients with bradycardia, and prolonged effect from a single dose. Prolonged effect reduces the need for an infusion, but is a disadvantage in cases where severe hypotension results. The tachycardic response to hydralazine makes it a poor choice in patients who cannot tolerate tachycardia, such as severe coronary artery disease of severe aortic stenosis. The manufacturer added rheumatic heart disease affecting the mitral valve as a contraindication due to worsening of this condition with tachycardia, however this is an uncommonly encountered condition for EMS providers. The primary disadvantage of hydralazine, aside from the tachycardia, is the long duration of action.
Given that the amount of hypotension after a dose is not very predictable, a provider could potentially be left with severe hypotension and a duration of action lasting hours. Similarly, labetalol has a relatively long duration of action and could cause the same issue. Unlike hydralazine, labetalol does have several useful indications such as reduction of blood pressure in acute stroke patients. If you are unsure about how a patient may respond to hydralazine or labetalol, or you are concerned about the ability to manage severe hypotension in these patients if it occurs, consider shorter acting agents (e.g. esmolol, nicardipine).

Nicardipine [Cardene]

Route & Dosage: 5mg/hr IV.
Onset & Duration: onset 10min, peak 20min, duration 15-40min.
Pharmacokinetics: liver metabolism, urine elimination, half-life 45min.
Indications: hypertensive emergency, acute hypertension, acute hypertension in ischemic stroke (off-label).
Contraindications: severe coronary artery disease, severe aortic stenosis.
Adverse Effects: hypotension, tachycardia, palpitations, edema, headache, nausea, pain at injection site, may worsen heart failure.
Drug Interaction: sodium bicarbonate, lactated Ringer solution.
Nicardipine is a calcium-channel blocker that primarily effects resistance vessels (arterial) with little effect on capacitance vessels (venous). It is indicated for acute hypertension and hypertensive emergencies. It is also an option for reducing blood pressure to allow for the administration of fibrinolytic therapy. In patients with hypertension and end-organ damage, nicardipine was more effective than labetalol in reaching blood pressure goals (Cannon et al, 2013). Nicardipine does not have a negative inotropic effect, as compared with diltiazem and verapamil. Because nicardipine does not block calcium receptors in the heart it has no effect on contractility or AV conduction. Nicardipine was compared with sodium nitroprusside in patients with subarachnoid hemorrhage and found to be superior. In that setting, efficacy was the same but nicardipine avoided problems with toxic metabolites, frequent dose adjustments, and was less likely to increase intracranial pressure (Aronson et al, 2014). These two studies, the CLUE trial and the ECLIPSE trial, further strengthen the safe and effective role of nicardipine in the management of acute hypertension.
Dosing for nicardipine is by infusion and bolus dosing is not typically used. Initial infusion rate is 5mg/hr and may be increased by 2.5mg/hr every 5-15 minutes, to a maximum of 15mg/hr. Infusion rate should be decreased to 3mg/hr once desire blood pressure is obtained. This is also the recommended dosing in acute stroke patients with hypertension who would otherwise be eligible for reperfusion (fibrinolytic) therapy. After administration of a fibrinolytic, if refractory hypertension occurs such that DBP > 140 mmHg, one should consider other IV agents such as nitroprusside. Limited data is currently available for use in children.
Tachycardia is an expected side effect with nicardipine given the peripheral arterial dilation and unaffected AV node conduction. Therefore, caution should be used in patients who cannot tolerate tachycardia (severe aortic stenosis or severe coronary artery disease). Other adverse effects include palpitations, peripheral edema, headache, nausea, and pain at the injection site. Caution should be used in patients with liver or kidney impairment and dosing may need to be decreased in these patients. Mixing nicardipine with sodium bicarbonate will result in immediate precipitation. Mixing of nicardipine with lactated Ringer solution will cause precipitation over time and also a loss in drug efficacy (Baaske et al, 1996). These mixtures should be avoided.

Nifedipine [Adalat, Afeditab, Nifediac, Nifedical, Procardia]

Route & Dosage: 10-30mg sublingual/buccal/PO.
Onset & Duration: onset 10-30min, peak 30-60min duration 4-6hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2-5hr.
Indications: chronic hypertension, chronic angina, high altitude pulmonary edema (off-label).
Contraindications: severe coronary artery disease, severe aortic stenosis, hypertensive emergency, heart failure, hypertrophic cardiomyopathy, STEMI.
Adverse Effects: tachycardia, flushing, pulmonary edema, headache, dizziness, palpitations.
Drug Interaction: cocaine.
Nifedipine is a calcium-channel blocker that showed early promise in the prehospital management of hypertension. Unfortunately, most recent data shows it is not a useful agent in prehospital care and can increase mortality in some cases. In particular, nifedipine is contraindicated in patients with STEMI (O’Gara et al, 2013). In UA/NSTEMI patients, it should be used very cautiously and not without beta-blockade (Anderson et al, 2013). Nifedipine, oral and sublingual dosing, has been shown to be potentially dangerous in patients with hypertensive crisis and is not recommended (Varon et al, 2003). The manufacturer warns that the use of immediate-release nifedipine in hypertensive emergencies is neither safe nor effective. Use in this situation has resulted in serious adverse effects (e.g. death, stroke, myocardial infarction).
Nifedipine has been studies as a treatment option for high altitude pulmonary edema (HAPE), however this is an off-label use. Management of HAPE is primarily oxygen therapy, however nifedipine has been suggested if oxygen is not available. Dosing is 10mg initially then 30mg every 12-24hr. Onset of action is 10-15 minutes for buccal application, with peak in 30 minutes. Oral onset is 30-45 minutes, with peak in 60 minutes. Duration of action is 4-6hr regardless of route and half-life can be up to 7hr in the elderly or in patients with liver cirrhosis. Nimodipine, a drug similar to nifedipine, is used in-hospital to prevent cerebral artery vasospasm after subarachnoid hemorrhage.
Tachycardia after administration can lead to serious consequences for patients with severe coronary artery disease or severe aortic stenosis. Heart failure can be exacerbated and thus nifedipine is contraindicated in these patients. Nifedpine should not be used in cocaine intoxication (Furburg et al, 1995). Overall, nifedipine currently has very limited usefulness for the prehospital provider.

Nitroprusside [Nipride, Nitropress]

Route & Dosage: 0.3-0.5mcg/kg/min IV.
Onset & Duration: onset 30 seconds, peak 1min, duration 1-2min possibly up to 10min.
Pharmacokinetics: combines with hemoglobin to produce cyanide and cyanmethemoglobin, urine elimination (thiocyanate), half-life 2min.
Indications: acute hypertension, acute decompensated heart failure.
Contraindications: increased intracranial pressure, renal failure, hypovolemia, sepsis, anaphylaxis, severe coronary artery disease, severe aortic stenosis.
Adverse Effects: tachycardia, ECG changes, flushing, severe hypotension, palpitations, paradoxical bradycardia, methemoglobinemia, thiocyanate toxicity, cyanide toxicity.
Drug Interaction: methemoglobin-causing agents, phosphodiesterase inhibitors.
Black box warning: reconstitution/dilution, precipitous hypotension, cyanide toxicity.
Sodium nitroprusside, often abbreviated SNP, is an effective vasodilator that works on both arterial and venous vessels. Like nitroglycerin, nitroprusside is a nitric oxide donor and causes direct smooth muscle relaxation. It has been reliably used for over 30 years and is effective for significant arterial hypertension (Friederich et al, 1995). Nitroprusside typically results in a reflex tachycardia which is more severe than with nitroglycerin. Cardiac preload is reduced, but not quite as much as with nitroglycerin. Afterload reduction (decreased SVR) is significant and on par with hydralazine. Similar to hydralazine and nitroglycerin, SNP will increase intracranial pressure. The effects of SNP are rapid and profound. Onset is in 30-40 seconds after starting an infusion and peak effect is rapid. Offset, or duration of action, is also rapid and rarely lasts longer then 10 minutes.
Nitroprusside is indicated for acute severe hypertension and acute decompensated heart failure where dyspnea relief is the goal. Generally, it is not a first-line agent in these cases. In acute stroke patients who would otherwise be candidates for reperfusion, nitroprusside is suggested if initial anti-hypertensive therapy does not work or if diastolic blood pressure is > 140 mmHg (Jauch et al, 2010). Dosing is 0.3-0.5mcg/kg/min and may be titrated by 0.5mcg/kg/min every few minutes to achieve the desired effect. Dosing should be limited to 2mcg/kg/min to reduce the likelihood of toxicity, however a maximum dose of 10mcg/kg/min has been reported for acute use (Marik et al, 2007). For heart failure, initial starting dose is 5-10mcg/min with usual range between 5-300mcg/min. Doses > 400mcg/min are not recommended due to minimal benefit and increased risk of toxicity.
A Look Inside: Nitroprusside Metabolism
Many of the reports of serious adverse effects occurred with providers who were unfamiliar with the potency and metabolic pathways of nitroprusside. It should be emphasized how extremely potent nitroprusside is and accidental free-free flow of an infusion rate (e.g. pump disconnect) can have dire consequences. SNP is broken down in red cells and causes a release of nitric oxide and cyanide. It interacts with oxyhemoglobin to form cyan-methemoglobin and cyanide. Cyanide is converted to thiocyanate by the liver enzyme rhodanese. Toxicity with nitroprusside can be caused by any or all of these three metabolic byproducts (methemoglobin, thiocyanate, cyanide). Signs of cyanide toxicity are typically seen with blood testing in the hospital and include metabolic acidosis and hyperoxemia, which is high oxygen in the venous blood as the tissues are not using the oxygen. Symptoms of thiocyanate toxicity are increased tendon reflexes (hyperreflexia), pinpoint pupils (miosis), and ringing in the ears (tinnitus).
Methemoglobinemia is more common when other methemoglobinemia-causing agents, such as local anesthetics, are also used. Thiocyanate is excreted through the kidneys, so renal failure significantly increases the risk of toxicity. The half-life elimination of nitroprusside is rapid, however the half-life elimination of thiocyanate is about 3 days and may be doubled or tripled in renal failure. Rhodanese couples cyanide with a sulfur group from a sulfur donor (e.g. thiosulfate), but this process has limited capacity to couple cyanide. Cyanide toxicity is typical of high-doses over a period of time when the cyanide-sulfur coupling mechanism becomes overwhelmed. Prolonged infusions can lead to tachyphylaxis, which is a decreased body response to the medication. Increasing doses of SNP would be needed to achieve the same effect, which increases the risk of cyanide toxicity.

SNP is associated with tachycardia, ECG changes, flushing, and palpitations. Tachycardia can be significant thus SNP should not be used in patients with severe coronary artery disease or severe aortic stenosis. The reduction in afterload secondary to arterial dilation will lead to increased cardiac output. Therefore, SNP should not be used in patients with low SVR and high cardiac output, which defines distributive shock (e.g. sepsis, anaphylaxis). Hypovolemic patients are unlikely to tolerate the effects of nitroprusside; hypertension in the setting of hypovolemia may simply be compensatory. Paradoxical bradycardia has been described with nitroprusside, which could significantly increase the hypotensive effects of the drug (Lukacsko, 1982). Fortunately, the rapid half-life of nitroprusside means these effects are short lived when the infusion is stopped. Nitroprusside should not be used in patients at risk for elevated intracranial pressure, such as traumatic brain injury (Cottrell et al, 1978).
There are several black box warnings for nitroprusside. Nitroprusside is extremely potent and is not suitable for injection after reconstituting the powder. The reconstituted liquid must be further diluted prior to infusion. Because nitroprusside can cause rapid hypotension, patients must be monitored very closely. Failure to monitor can result in irreversible ischemic injury or death secondary to profound hypotension. Patients taking phosphodiesterase inhibitors may have enhanced hypotensive effects with nitroprusside. The medication is light-sensitive and must be covered to prevent exposure; some vials include a dark bag to cover the diluted infusion.
Virtual Mentor: Hypertension
Hypertension is one of the most common medical conditions encountered by EMS personnel. But, when should you treat it? Hypertensive urgency is defined as a systolic pressure > 180 mmHg or a diastolic pressure > 110 mmHg. Associated symptoms may include headache, shortness of breath, anxiety, and nosebleed. These patients typically do not need immediate treatment with an antihypertensive agent and should instead by managed in the hospital. Hypertensive emergency is defined as the same high blood pressure reading but with organ damage (Varon et al, 2003). In the hospital, tests can be done to determine if organs are being damaged. These tests are typically not available or useful in the prehospital environment. Instead, treatment should be considered if a patient has an acute medical condition that can be worsened by the hypertension. Specific examples are chest pain, heart attack, stroke, pulmonary edema, and suspected aortic dissection.
The American Heart Association guidelines for acute hemorrhagic stroke suggest starting an antihypertensive agent if systolic blood pressure is > 180 mmHg or mean pressure is > 130 mmHg (Aiyagari et al, 2009). The target blood pressure in these patients is 160/90 mmHg or a mean pressure of 110 mmHg, meaning a large drop in blood pressure is not needed. A decrease of up to 15% will maintain cerebral perfusion pressure, while a decrease of 20% or greater will not. Incremental boluses of labetalol or an infusion of nicardipine is appropriate for most situations requiring immediate blood pressure control. AHA hemorrhagic stroke guidelines recommend bolus doses on the lower range for labetalol (5-10mg IV) instead of 20mg IV or higher.
One should be cautious about dropping a patient’s blood pressure. As mentioned, hypertension alone is not typically an indication to start an antihypertensive agent. The patient should also have a serious condition that would be worsened by hypertension. This is an important point as several conditions have hypertension as a presenting sign or as a compensatory response. For example, in severe head injury with impending brain herniation the Cushing reflex may be seen. With insufficient blood flow to the brain and high intracranial pressure, the body causes peripheral vasoconstriction to drive mean arterial pressure high in an attempt to overcome the increased intracranial pressure. Hypertension in this setting does not need to be managed with antihypertensive agents; instead the patient needs immediate management of their increased intracranial pressure.
Patients with aortic coarctation may have blood pressure that is significantly higher in their upper body than their lower body. Again, this does not mean they should receive antihypertensive agents in the ambulance on their way to the hospital. Hypovolemia is another condition where compensatory hypertension may be seen (Cohn, 1966). This hypertension is seen in the earlier stages of hypovolemia and represents an increased sympathetic release with the body secreting epinephrine and norepinephrine. Additional of an antihypertensive agent in these patients can lead to profound hypotension.

Vasopressor Agents

Vasoactive agents are drugs that affect the diameter of blood vessels, and therefore affect the blood pressure. These agents typically work on the alpha-1 (α1) receptors, with antihypertensive agents causing α1-antagonism and vasopressors causing α1-agonism. Commonly used vasopressors include norepinephrine, phenylephrine, and vasopressin. Norepinephrine has some ß1 activity as well, making it an inotrope. However, the α1 activity is so strong that this drug is most often used as a vasopressor to increase blood pressure.
Epinephrine has some dose-dependent specificity for ß1 and α1 receptors. At lower doses, the drug is primarily an inotropic agent (ß1-agonist) and at higher doses (e.g. 1mg) it is primarily a vasopressor. This is the reason why such a large dose is used during cardiac arrest, since the goal of epinephrine and vasopressin during cardiac arrest is to significantly increase systemic blood pressure and coronary perfusion pressure (Yakaitis et al, 1978). So, if the goal is to give a small bolus dose of drug to increase blood pressure then the common options are norepinephrine, phenylephrine, or vasopressin. Since these three drugs significantly increase systemic vascular resistance, a reflex decrease in heart rate may be seen.

Norepinephrine [Levophed]

Route & Dosage: 0.1-0.5 mcg/kg/min IV.
Onset & Duration: onset immediate, peak rapid, duration 1-2min.
Pharmacokinetics: metabolism via catechol-o-methyltransferase (COMT) and monoamine oxidase (MAO), urine elimination, half-life 1min.
Indications: hypotension, septic shock.
Contraindications: hypovolemia, trauma, mesenteric or peripheral vascular thrombosis.
Adverse Effects: arrhythmia, bradycardia, digital ischemia, headache, dyspnea.
Drug Interaction: monoamine oxidase inhibitors (MAO-I), tricyclic antidepressants (TCA).
Black box warning: extravasation.
Norepinephrine is a sympathomimetic drug with both α1 and ß1 activity. Sympathomimetic drugs mimic the effects of sympathetic activation on the heart and circulation. Norepinephrine is one of the naturally occurring neurotransmitters in the body that gets released during sympathetic stimulation. It has no significant effect on ß2 receptors thus is not useful in the management of asthma or bronchospasm. The α1-agonist effects of norepinephrine are significantly stronger than the ß1 effects, so tachycardia is not typically seen with norepinephrine. Typically, heart rate will stay the same or decrease slightly. However, heart rate will not decrease as significantly as would be seen with a pure α1-agonist, such as phenylephrine.
Norepinephrine is used primarily for hypotension and shock, particularly septic shock. It is an option for poison-induced and drug-induced hypotension. It can be used in the post cardiac arrest period for patients with severe cardiogenic shock. However, it is considered an agent of last resort for the management of ischemic heart disease with shock (Peberdy et al, 2010). In the management of prehospital cardiac arrest, norepinephrine was not shown to have benefit and actually trended towards a worse outcome (Callaham et al, 1992). Reviewing the physiology of different types of shock and how norepinephrine works, it becomes clear why the drug is useful in septic shock but not so useful in cardiogenic shock. Septic shock is highlighted by high cardiac output with low systemic vascular resistance. Norepinephrine increases the systemic vascular resistance back towards normal and reduces cardiac output, which reduces cardiac demand. In cardiogenic shock, cardiac output is low and systemic vascular resistance is typically high to compensate. Adding a drug that further increases SVR without much improvement in cardiac output will not significantly improve the problem. Also, norepinephrine can increase myocardial oxygen requirements, further worsening cardiogenic shock.
Dosing for severe hypotension or septic shock starts at 0.1-0.5mcg/kg/min. Doses up to 3mcg/kg/min can be used in septic shock, however 0.5mcg/kg/min is the high end dosing recommended by the AHA for post cardiac arrest. A typical treatment goal is to achieve a mean arterial pressure of at least 65 mmHg or higher. Norepinephrine should not be used in hypovolemic shock, with the exception that it can be used temporarily to maintain blood pressure while rapid fluid administration is taking place. In hypovolemia, increased SVR is seen and further increasing SVR with norepinephrine can lead to ischemia of the fingers and bowel (mesentery). Since hypotension in trauma is typically due to hypovolemia, norepinephrine should be avoided in trauma patients. If a patient has a known mesenteric vascular thrombosis or peripheral vascular thrombosis, norepinephrine can lead to worsening ischemia.
Monamine oxidase (MAO) contributes to the metabolism of norepinephrine. Thus, patients taking MAO inhibitors an have exaggerated hypertension with norepinephrine. Tricyclic antidepressant (TCA) drugs inhibit the reuptake of norepinephrine, which can also lead to exaggerated hypertension in patients taking these medications. Similar reactions can be seen with other vasoactive agents including epinephrine, dopamine, phenylephrine, ephedrine, and vasopressin. The potent vasoconstricting effects of norepinephrine make it a worrisome medication if it is extravasated into the soft tissue. Extravasation is the accidental administration of IV medications into the tissue around infusion sites. Ideally, norepinephrine should infuse through a central line. If a peripheral line must be used, the provider should assess the patency of the line often to ensure the drug is not extravasating. If norepinephrine is extravasated, wrap the location with a warm compress and elevate the limb above the heart. Definitive treatment with phentolamine may be needed upon arrival to the hospital.

Phenylephrine [Neo-Synephrine]

Route & Dosage: 100mcg IV, 0.5-2 mcg/kg/min IV.
Onset & Duration: onset immediate, peak rapid, duration 15-20min.
Pharmacokinetics: liver metabolism, urine elimination, half-life 5min.
Indications: hypotension.
Contraindications: hypovolemia, trauma, heart failure, mesenteric thrombosis, bradycardia.
Adverse Effects: bradycardia, reduced cardiac output, reduced renal blood flow.
Drug Interaction: monoamine oxidase inhibitors (MAO-I), tricyclic antidepressants (TCA).
Black box warning: extravasation.
Phenylephrine is a synthetic α1-agonist that causes dose-dependent vasoconstriction. It is synthetic in that it is created/synthesized in a lab as the body does not produce phenylephrine, unlike norepinephrine and epinephrine. Vasoconstriction is also seen in the visceral organs (splanchnic circulation), intestinal tract (mesenteric circulation), kidneys, muscles, and skin. There is no ß activity with phenylephrine, thus a reflex bradycardia is typically seen secondary to the pure α1 effects. Bradycardia may be severe and even lead to brief asystole, though this is uncommon. Although not recommended for routine use, phenylephrine has been used for hypotension with supraventricular tachycardia as the reflex heart rate reduction may break the arrhythmia.
Approved indications are hypotension with low systemic vascular resistance and drug-induced hypotension. Although briefly mentioned by the AHA (Peberdy et al, 2010), other inotropes and vasopressors are recommended in the management of post cardiac arrest patients. The primary role of phenylephrine is in the management of drug-induced hypotension, such as during sedation or in the peri-intubation period (Hemmings et al, 2013). Most of the sedative-hypnotic medications used for intubation and post-intubation sedation cause peripheral vasodilation without significant effects on cardiac contractility. Phenylephrine acts to directly counteract this dilation via pure α1-agonism. Also, slowing of the heart rate in this setting both reduces myocardial oxygen demand and increases myocardial oxygen supply.
Dosing for drug-induced hypotension is 100mcg IV bolus, repeated every 10-15 minutes as needed. If an infusion is needed, typical dosing is 0.5-2mcg/kg/min with a goal mean blood pressure of > 65 mmHg. Bolus dosing can range from 50mcg (1mcg/kg) to 500mcg, though 100mcg is a common starting dose. Phenylephrine may be available in prefilled syringes or as a vial requiring dilution. A vial with 10mg of phenylephrine would need to be diluted into 100mL of fluid to create 100mcg/mL for bolus dosing. Therefore, caution should be taken with this medication as administration of a 1mL vial would be 100 times the standard bolus dose, which could lead to hypertensive stroke, heart failure, or asystole. Use of prefilled syringes at a standard dose (e.g. 100mcg/mL) can improve the safety of this medication. An example of this is seen in Figure 15-6.
Phenylephrine is not recommended for septic shock and, like norepinephrine, should be used cautiously in hypovolemic patients. It should be avoided in trauma patients as hypovolemia is typically the cause of hypotension. However, it may be used temporarily in patients with severe hypotension to maintain blood pressure while rapid fluid administration is taking place. Phenylephrine should be avoided in patients with bradycardia. Unlike norepinephrine, phenylephrine has no ß effects thus cardiac output is expected to remain the same with administration. However, in patients with ischemic heart disease cardiac output may decrease. For this reason, it should be avoided in patients with heart failure as it can worsen the already low cardiac output. Drug interactions exist with MAO-I and TCA agents, which can lead to exaggerated hypertension. Extravasation should be managed similar to norepinephrine.
Communication: Norepinephrine and Phenylephrine
Brand names for drugs are often easier to remember and spell. The brand names Levophed and Neo-Synephrine may be used by some providers. Some may even shorten these to “levo” or “neo”. This is not recommended and should be strongly discouraged. The Institute for Safe Medication Practices does not recommend using these brand names. They also released a Medication Safety Alert in 2013 for these two medications warning providers not to truncate, stem, or shorten drug names. The shortened name “neo” was also listed as an error-prone medication in the book Avoiding Common ICU Errors.
The reason for avoiding “neo” is that there are other drugs that start with this stem, including the parasympathomimetic drug neostigmine. The same goes for “levo”, with the antibiotic levofloxacin being an example. Yet another reason for avoiding these brand names is confusion over the generic drug being discussed. One example is Neo-Synephrine, which is surprisingly the brand name for two different nasal spray medications: phenylephrine or oxymetazoline. Intravenous adrenergic agonists are considered High Alert medications with the potential for serious harm if administered inappropriately. It is important to communicate and document these medications appropriate to avoid errors in administration and errors with patient handoff.
Recommended Terminology: phenylephrine, norepinephrine.
Do Not Use/Say: neo, levo, Neo-Synephrine, Levophed.

Vasopressin [Pitressin, Vasostrict]

Route & Dosage: 40units IV, 0.02-0.04units/min IV.
Onset & Duration: onset rapid, peak < 15min, duration 20min.
Pharmacokinetics: liver metabolism, urine elimination, half-life 10-20min.
Indications: cardiac arrest, vasodilatory shock.
Contraindications: severe coronary artery disease, extravasation.
Adverse Effects: bradycardia, angina, cardiac ischemia, reduced cardiac output, water intoxication.
Drug Interaction: lithium, demeclocycline.
Vasopressin, or arginine vasopressin, is a hormone made in the brain that gets released to retain water and constrict blood vessels. It regulates water, glucose, and salts in the blood. A synthetic version is available for injection. Vasopressin binds two V1 and V2 receptors. V2 receptor activation increase blood volume via fluid reabsorption in the kidneys. V1 receptor activation increases systemic blood pressure through vasoconstriction, similar to α1-receptor agonists. Importantly, there are no V1 receptors in the pulmonary circulation thus vasopressin can increase systemic blood pressure without increasing pulmonary blood pressure, which makes it a useful medication in patients with pulmonary hypertension. The vasoconstricting properties of vasopressin are extremely potent to that point that increased peripheral vascular resistance can provoke angina.
Common indications for vasopressin are cardiac arrest and vasodilatory shock. In cardiac arrest, vasopressin can be used as an alternative to epinephrine for either the first or second dose-cycle. Dosing is 40units IV given only once though a known working IV line (Neumar et al, 2010). Several randomized controlled trials have been performed comparing epinephrine to vasopressin, including combination dosing (epinephrine plus vasopressin), and repeated dosing (vasopressin twice). The effects of vasopressin have not been shown to differ from epinephrine and both combination and repeated dosing have not been shown to be beneficial. This is the reason why vasopressin may be substituted for epinephrine only once during cardiac arrest management. Of note, other vasopressors such as phenylephrine and norepinephrine have not been shown to improve survival compared to epinephrine.
Vasopressin may be given via the endotracheal route, though this is much less desirable especially with the easy of intraosseous access. Endotracheal dosing is 2-2.5x the typical dose, so 80-100units ETT diluted in 5-10mL of sterile water. There is very little literature on this route of administration for vasopressin. Another indication for vasopressin is vasodilatory shock, such as septic shock. Dosing range is 0.02-0.04units/min, with the typical dose for septic shock being 0.03units/min IV (Dellinger et al, 2013). This indication is much more common in the intensive care unit and less commonly seen in the prehospital setting. What is worth noting is the dosing for a continuous infusion. Continuous infusions are generally given though central lines due to the risk of local tissue necrosis if the medication were extravasated. A bolus dose of 40units if 1000 times larger than a 0.04units/min infusion, and many hospital providers would not administer that infusion through a peripheral IV line. So, caution should be taken to ensure a properly working IV line prior to administration of a bolus dose of vasopressin. Of course, this may be difficult in the setting of cardiac arrest.
Because of the potent vasodilating properties and drug side effects, vasopressin should not be used as a routine vasopressor. A significant rise in peripheral vascular resistance can lead to angina and cardiac ischemia, thus it should not be used in responsive patients with coronary artery disease. Side effects of bradycardia and reduced cardiac output can occur, similar to phenylephrine. Additionally, water intoxication is an uncommon but serious complication of vasopressin use due to V2-receptor action. Early signs or water intoxication include drowsiness, listlessness, and headache. This mechanism is also why vasopressin should be avoided in patients taking lithium or demeclocycline. Extravasation should be managed similar to norepinephrine.
From a practical standpoint, vasopressin is typically only used in the prehospital setting for cardiac arrest as an alternative to epinephrine. Many of the side effects and complications have less patient risk than the benefit of giving vasopressin. Providers should focus on following the American Heart Association guidelines during emergency cardiovascular care and not get caught up in the details and side effects. However, these side effects are much more important in responsive patients and in situations that are not life-threatening emergencies (e.g. sepsis with hypotension).

Cardiac Glycosides

Cardiac glycosides are drugs that act by increasing the contractile force of cardiac muscle. They disrupt cardiac function to the point that most are very toxic. In the distant past, glycosides from plants were used to for coating hunting arrows, for rat poison, and for intentional overdose (Norn et al, 2004). Digoxin, derived from the foxglove plant, is the only cardiac glycoside routinely used in clinical practice. Digoxin has been used for hundreds of years, however it has largely been replaced by medications with fewer side effects. Toxic effects are common and can include serious arrhythmias. This limits the usefulness of digoxin in the prehospital setting, however providers may encounter patients on this medication.

Digoxin [Digitek, Digox, Lanoxin]

Route & Dosage: 4-6mcg/kg IV.
Onset & Duration: onset 5-60min, peak 1-6hr, duration 3-4day.
Pharmacokinetics: liver metabolism, urine elimination, half-life 36-48hr.
Indications: supraventricular tachycardia.
Contraindications: ventricular fibrillation, extravasation, poison-induced tachycardia, Wolff-Parkinson-White syndrome, hypertrophic cardiomyopathy, hypokalemia, hypomagnesemia.
Adverse Effects: junctional rhythm, asystole, AV block including complete heart block, PR prolongation, premature ventricular contractions, ventricular tachycardia, ventricular fibrillation, facial edema.
Drug Interaction: calcium-channel blockers, beta blockers, amiodarone, calcium, succinylcholine.
Digoxin inhibits the sodium/potassium ATPase pump in myocardial cells, which temporarily increases the sodium level in these cells. This causes calcium to move into cells via the sodium-calcium exchange pump. Calcium within myocardial cells leads to increase contractility. Digoxin also directly depresses AV node conduction which decreases electrical conduction velocity. This decreases the ventricular rate, which can be useful for rapid atrial arrhythmias especially in patients with decreased heart function. Digoxin has a slow onset and relatively low potency. This, combined with the drug’s toxicity, make it a less useful choice in the management of acute arrhythmias. Digoxin is used in the hospital setting and outpatient setting for heart failure, thus providers may encounter patients taking this medication. This is important due to drug toxicity and interactions during emergency cardiovascular care.
Digoxin is indicated as a second- or third-line drug for supraventricular tachycardia to control ventricular rate. The loading dose is 4-6mcg/kg IV over 5 minutes. A second and third bolus dose, given at 4-8 hour intervals, is 2-3mcg/kg IV over 5 minutes. This initial loading is referred to as “digitizing”. The total digitizing dose (TDD) is 8-12mcg/kg divided over 8-16 hours (Neumar et al, 2010). Patients should have continuous heart rate and rhythm monitoring while being digitized. IM administration at the same IV dose is an option, however it is not recommended due to severe injection site pain.
The list of side effects and interactions with digoxin is long. Arrhythmias are common with digoxin and can be life-threatening. Premature ventricular contractions are the most common arrhythmia seen, though many other arrhythmias can be seen including: bradycardia, AV nodal blockade, ventricular bigeminy, asystole, ventricular fibrillation, and ventricular tachycardia. Digoxin should be avoided in patients with WPW or HOCM. Due to the mechanism of action, there are several electrolyte interactions that occur with digoxin. Patients with hypokalemia or hypomagnesemia are at increased risk for digoxin toxicity. The use of calcium or succinylcholine in patients on digoxin can lead to serious arrhythmias. Electrical cardioversion should be avoided in patients receiving digoxin unless the arrhythmias is life-threatening. If needed, cardioversion dosing should be decreased and started at 10-20J (Hazinski et al, 2010). The use of beta-blocker and calcium-channel blockers with digoxin can enhance the bradycardia effect. Amiodarone can increase the serum concentration of digoxin, so dosing should be reduced by 50% in patients taking amiodarone. Extravasation can lead to tissue necrosis. Digoxin toxicity is treated with digoxin immune Fab, an antidote that binds to digoxin rendering it inactive.

Diuretics

Diuretics are commonly used medications that act by preventing sodium from being reabsorbed at different points in the kidney. This results in increased sodium and water loss in the urine. This mechanism makes these medications useful in the management of hypertension and edematous states, such as pulmonary edema. Diuretics are divided into four categories: loop diuretics (e.g. furosemide), thiazide diuretics (e.g. hydrochlorothiazide), potassium sparing diuretics (e.g. spironolactone), and proximal tubule diuretics (e.g. mannitol, acetazolamide).
Acetazolamide is used for altitude illness and some specialized edematous states. Mannitol, an osmotic diuretic typically used for increased intracranial pressure, will be discussed later. Potassium sparing diuretics are used for heart failure, hypertension, and ascites from cirrhosis. Thiazide diuretics are one of the most commonly used medications in the management of hypertension and providers are likely to encounter patients on these medications. Thiazide diuretics are more effective in patients with normal renal function and have less adverse effects, while loop diuretics are more effective in patients with impaired renal function (Wile, 2012). Loop diuretics have a short duration of action, thus they are not typically used as initial treatment for hypertension. Loop diuretics, in particular, are useful in the management of acute heart failure and acute pulmonary edema.

Furosemide [Lasix]

Route & Dosage: 0.5-1mg/kg IV.
Onset & Duration: onset 5min, peak 30min, duration 6hr.
Pharmacokinetics: minimal liver metabolism, urine elimination, half-life 0.5-2hr.
Indications: acute pulmonary edema, acute heart failure, hypertensive emergencies.
Contraindications: complete renal failure, hypovolemia, hypotension.
Adverse Effects: hypovolemia, hypotension, hypokalemia, hypomagnesemia, hypocalcemia, ototoxicity, nephrotoxicity, sulfa allergy reaction.
Drug Interaction: gentamycin, streptomycin, lithium.
Black box warning: fluid and electrolyte loss.
Furosemide is a loop diuretic that inhibits the reabsorption of sodium and chloride in the kidney. The site of action is the ascending loop of Henle of the kidney nephron, hence the name loop diuretic. This action leads to a loss of sodium and chloride in the urine, which leads to the loss of water and can create a negative overall fluid balance. Additionally, potassium, magnesium, and calcium are excreted. Loop diuretics are potent in their action and can lead to significant fluid loss if given in high doses. The loss of fluid makes furosemide useful in pulmonary edema secondary to heart failure. Intravenous furosemide has a rapid onset of action. Symptomatic improvement with acute pulmonary edema occurs in 15-20 minutes, which is prior to the diuretic effect. This effect is thought to occur secondary to venodilation with reduction of cardiac preload by the increased vascular capacitance (Dormans TP et al, 1996). With large doses, up 20-25% of filtered sodium can be excreted, making furosemide a potent diuretic. Half-life for patients with normal renal function is 0.5-2hr, but it can be up to 9 hours in patients with end stage renal disease.
The primary indication for prehospital use is acute pulmonary edema in patients with heart failure (Yancy et al, 2013). Furosemide may be used in these patients as adjuvant therapy if systolic blood pressure is > 90mmHg and there are no signs or symptoms of shock. Dosing is 0.5-1mg/kg IV given over 1-2 minutes. If there is no response, a double dose may be given up to 2mg/kg IV, administered slowly over 1-2 minutes. For patients with new-onset pulmonary edema and hypovolemia, dosing should be < 0.5mg/kg IV. Oral formulations are available but not typically used in the prehospital setting. Furosemide can be used for hypertension that is associated with volume overload or hypertensive emergencies in general, however it is not a first line agent and should be used with caution in this setting. There are several other indications for use, which are typically reserved for a hospital setting. They include hyperkalemia, hypercalcemia, acute renal failure, ascites from liver disease, and volume overload.
The black box warning for furosemide wants that large doses can lead to profound diuresis (high urine output) with water and electrolyte depletion. Therefore, caution should be used in patients who are hypovolemic and in patients who are hypotensive. Some guidelines consider hypovolemia a contraindication to furosemide use. Further, complete renal failure with anuria (no urine output) is a contraindication. In anuria, the drug can accumulate and lead to toxicity and adverse effects. Several electrolytes are lost including sodium, chloride, potassium, magnesium, and calcium. Thus, furosemide should be used with caution in patients who are known to have low serum levels of any of these electrolytes. Furosemide can lead to ototoxicity (i.e. hearing loss), but this is primarily with high doses > 240mg/hr. Nephrotoxicity (i.e. kidney injury) can also occur. Both ototoxicity and nephrotoxicity are enhanced by aminoglycoside antibiotics including gentamycin and streptomycin. The renal clearance of lithium is altered by furosemide, which makes lithium toxicity more likely. Furosemide can cause hypersensitivity reactions, particularly in patients with sulfa allergy. In patients who did not have a life threatening sulfa reaction, the risk is low that they would have a reaction with furosemide. Thus, it appears safe to use furosemide for emergency situations in patients with sulfa allergy (Sullivan et al, 1991).

Fibrinolytic Agents

Clots form secondary to a complex coagulation cascade involving over a dozen coagulation (clotting) factors. The final factor in the pathway is fibrin, also known as factor Ia, which leads to a fibrin clot. Clot formation is a generally beneficial process to prevent hemorrhage. However, clot formation in an important vessel can lead to catastrophic consequences such as myocardial infarction or stroke. A blood clot is known as a thrombus, thus thrombolytic medications are aimed at breaking (lysing) the thrombus. Thrombolytic medications work by activating plasminogen, which leads to the breakdown of fibrin cross links. These fibrin cross links give clots structural integrity. Since thrombolytic medications act to break fibrin, they can also be called fibrinolytics. Fibrinolytics are indicated for certain myocardial infarctions and certain ischemic strokes. Because of the risk of life threatening bleeding from other body sites, a “Fibrinolytic Checklist” is typically performed prior to administration. The three major classes of fibrinolytics are tissue plasminogen activator (tPA), streptokinase (SK), and urokinase (UK). Tissue plasminogen activators include alteplase, reteplase, and tenecteplase. For these agents, a separate IV line should be started and one line used exclusively for fibrinolytic administration.

Alteplase rtPA [Activase]

Route & Dosage: 15mg IV bolus for STEMI, 0.9mg/kg for stroke.
Onset & Duration: onset immediate, peak 5-10min, duration 1-3hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 26min.
Indications: ST elevation myocardial infarction, acute ischemic stroke, acute large pulmonary embolism.
Contraindications: history of stroke, ischemic stroke within 3 months, recent intracranial or intraspinal surgery or trauma, intracranial tumor, prior intracranial hemorrhage, arteriovenous malformation or aneurysm, active bleeding (excluding menses), known bleeding or clotting problem, severe uncontrolled hypertension, suspected aortic dissection, significant closed head or facial trauma within 3 months, pregnant female, serious systemic disease (e.g. severe liver or kidney disease), routine use in cardiac arrest.
Adverse Effects: reperfusion arrhythmias, hemorrhage including hemorrhagic stroke, hypotension, cerebral edema, cerebral herniation, seizure.
Drug Interaction: nearly all antithrombotics.
Alteplase is a recombinant form of tissue plasminogen activator (tPA) used to dissolve blood clots. It is indicated for STEMI, acute ischemic stroke, and acute massive pulmonary embolism. It also has other indications, in lower doses, for non-life threatening problems such as central venous catheter clotting. Side effects from the use of tPA mainly include bleeding and these may be severe enough to cause death. For that reason, the ACLS guidelines for STEMI and ischemic stroke include fibrinolytic checklists that providers must complete prior to administration of tPA. Acute massive pulmonary embolism requiring tPA is not typically diagnosed in the prehospital setting. Acute stroke must be defined as ischemic, instead of hemorrhagic, prior to the administration of tPA (Jauch et al, 2013). This typically requires a computed tomography (CT) scan of the head so use of tPA for stroke in the prehospital setting is not common. Interestingly, the PHANTOM-S trial from Berlin, German involved the use of prehospital tPA where prehospital providers had a small CT scanner in the ambulance (Weber et al, 2013). Alteplase is the only fibrinolytic agent approved for use with acute ischemic stroke. On the other hand, STEMI determination needs symptoms with specific ECG changes thus tPA could be use in the prehospital setting for this indication. As with ischemic stroke, a fibrinolytic checklist must be completed prior to administration.
Dosing for STEMI involves an accelerated infusion over 1.5 hours administered through a dedicated peripheral IV line (O’Gara et al, 2013). Dosing starts at 15mg IV bolus followed by a 0.75mg/kg infusion over 30 minutes, with maximum dose of 50mg. After that, a 0.5mg/kg infusion continues for 60 minutes (90 minutes total infusion time) with maximum dose of 35mg. The maximum total dose of alteplase rtPA for NSTEMI is 100mg. To review STEMI, the patient should have signs and symptoms of acute myocardial infarction with ECG changes. ECG changes consistent with STEMI are ST elevation > 1mm in 2 or more continuous leads, or a new (or presumably new) left bundle branch block. Primary percutaneous coronary intervention (PCI) should be considered first in these patients, especially if there are contraindications to the use of fibrinolytics. If PCI is not available or > 90 minutes away, then fibrinolytic therapy should be considered. Timing goals are door-to-balloon inflation (PCI) of < 90 minutes or door-to-needle (fibrinolysis) of < 30 minutes.
Dosing for acute ischemic stroke is 0.9mg/kg IV given over 60 minutes, with maximum dose of 90mg. An initial bolus dose of 10% total dose should be given IV over 1 minute, with the remaining dose over 60 minutes. As an example, a 100kg patient would require a total dose of 90mg. They should receive 9mg (10%) IV over 1 minute followed by 81mg (remainder) over 60 minutes. Life threatening pulmonary embolism dosing is 10mg IV bolus followed by 90mg IV infusion given over 2 hours, for a total dose of 100mg.
Contraindications and complications center on the risk of bleeding with administration of tPA. The American Heart Association has fibrinolytic checklists for both NSTEMI and acute ischemic stroke. Fibrinolytics should not be used in patients with: head trauma, prior stroke in the past 3 months, symptoms of subarachnoid hemorrhage, history of any previous intracranial hemorrhage, severe uncontrolled hypertension with systolic > 185mmHg or diastolic > 110mmHg, evidence of active bleeding, acute bleeding disorder, intracranial tumor, suspected aortic dissection, recent major surgery including laser eye surgery, pregnancy, and serious systemic disease such as severe liver disease, advanced cancer, or severe kidney disease. There are other relative contraindications listed on the fibrinolytic checklists which require the provider to weight the risks of bleeding with the benefit of tPA therapy. There is insufficient evidence to recommend the routine use of tPA in cardiac arrest patients.
Adverse effects are common with tPA. Over 15% of patient will have bleeding at the IV insertion site. Gastrointestinal hemorrhage (blood in stool) and genitourinary hemorrhage (blood in urine) occur in about 5% of patients. Minor bleeding occurs in about 7% of patients with major bleeding occurring in about 0.5% (GUSTO trials). Reperfusion arrhythmias can occur with use for STEMI and include nearly the entire gamut of possible arrhythmias as well as cardiac arrest. Use in ischemic stroke has resulted in hemorrhagic stroke, cerebral edema, cerebral herniation, and seizures. Hypotension is a common adverse effect regardless of the indication. Although these adverse effects are serious, the success rate of tPA for NSTEMI and acute ischemic stroke shows there is more benefit than harm as long as providers follow the fibrinolytic checklist prior to administration. Fibrinolytics have few direct drug-to-drug interactions, however caution should be used in any patient taking antithrombotic medications due to an increased risk of hemorrhage. Antithrombotic agents encompass the antiplatelet drugs (e.g. aspirin), anticoagulant drugs (e.g. warfarin), and the other thrombolytic agents.

Reteplase rtPA [Retavase]

Route & Dosage: 10unit IV bolus then 10unit after 30 minutes.
Onset & Duration: onset 30min, peak 30-90min, duration 48hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 13-16min.
Indications: ST elevation myocardial infarction.
Contraindications: similar to alteplase.
Adverse Effects: similar to alteplase.
Drug Interaction: nearly all anticoagulants and antithrombotics.
Reteplase, like alteplase, is a recombinant tissue plasminogen activator used to dissolve blood clots. It is only indicated for acute myocardial infarction. Although it is much easier to administer than alteplase, the GUSTO III trial showed it did not have any additional survival benefit over alteplase. Dosing is 10unit IV bolus given over 2 minutes, followed 30 minutes later by another 10unit IV bolus over 2 minutes. Contraindications, adverse effects, and drug interactions are essentially similar to alteplase.

Streptokinase [Streptase]

Route & Dosage: 1,500,000unit IV over 1hr.
Onset & Duration: onset immediate, peak 20-120min, duration 4hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 18-83min.
Indications: ST elevation myocardial infarction.
Contraindications: similar to alteplase, previous streptokinase use.
Adverse Effects: similar to alteplase, allergic reactions, diminished efficacy after streptococcal infection.
Drug Interaction: nearly all anticoagulants and antithrombotics.
Alteplase is relatively specific for clot-associated fibrin, which can lead to undesirable bleeding. Streptokinase, on the other hand, binds to both non-circulating fibrin (clot-associated) and circulating fibrin. This makes it a less desirable drug when compared to alteplase. The GUSTO I trial showed alteplase to be superior to streptokinase. The INJECT study showed that reteplase is no better than streptokinase. However, streptokinase is the most widely used fibrinolytic in the world because of low cost and a reasonable efficacy to safety ratio. While less effective than alteplase, it has a lower risk of intracranial hemorrhage. Dosing is 1.5 million units IV administered over 1 hour. Contraindications, adverse effects, and drug interactions are similar to alteplase with some minor differences. Streptokinase is antigenic, meaning it prompts an immune response. This can result in allergic reactions, especially with repeat administration. Antibodies that form can be elevated for up to 7.5 years, thus use of streptokinase should be avoided in patients who have received it previously due to the risk of allergic reactions. Streptokinase is made from streptococci bacteria. Patients who have had a recent streptococcus infection will create antibodies against streptococci. The use of streptokinase in these patients may be less effective due to antibodies, thus higher doses may be needed to achieve fibrinolysis.

Tenecteplase [TNKase]

Route & Dosage: 30-50mg IV.
Onset & Duration: onset rapid, peak 60-90min, duration unknown.
Pharmacokinetics: liver metabolism, urine elimination, half-life 20-24min then 90-130min.
Indications: ST elevation myocardial infarction.
Contraindications: similar to alteplase.
Adverse Effects: similar to alteplase.
Drug Interaction: nearly all anticoagulants and antithrombotics, dextrose solutions.
Tenecteplase, like alteplase, is a recombinant tissue plasminogen activator used to dissolve blood clots. It is only indicated for acute myocardial infarction and has a longer half-life than alteplase with greater binding affinity. The ASSENT-2 trial showed tenecteplase was similar to alteplase for reducing mortality, however tenecteplase was found to have less major bleeding. Tenecteplase has become the fibrinolytic agent of choice in many countries due to similar efficacy, less major bleeding, ease of administration, and lack of antigenic activity. Dosing for STEMI is weight-based as a single IV bolus between 30-50mg given over 5 seconds. Weight-based dosing is: 30mg for < 60kg, 35mg for 60-69kg, 40mg for 70-79kg, 45mg for 80-89kg, and 50mg for ≥ 90kg. Contraindications, adverse effects, and drug interactions are similar to alteplase with less bleeding overall. Tenecteplase is not compatible with dextrose containing solutions.

Mineral Supplements

Electrolytes are minerals that are dissolved in body fluid and have a wide range of physiologic importance. They regulate blood acid-base balance, are critical for muscle function, and are critical for nerve function. Electrolytes include sodium, potassium, calcium, magnesium, bicarbonate, chloride, phosphate, and others. They play an important role in cardiac arrhythmias and the administration of certain electrolytes can be helpful during cardiac emergencies. In particular, calcium, magnesium, and bicarbonate have specific roles in cardiac life support. However, none of these three medications is recommended for routine use during cardiac arrest (Sinz et al, 2013).
In cardiac arrest, magnesium is only indicated for torsade de pointes. It may be considered in patients with known low magnesium levels who have acute myocardial infarction. However, it has no particular positive effects in routine cardiac arrest and can lead to worsening hypotension and respiratory insufficiency. Similarly, calcium is not indicated for routine use and no trial has shown benefit to survival either in-hospital or out-of-hospital. Additionally, magnesium and calcium have opposing effects; calcium is a treatment option for hypermagnesemia. Thus, these two medications should not be used together and especially not during cardiac arrest. Lastly, sodium bicarbonate has specific indications and routine use can worsen outcome. It is not useful of effective in cardiac arrest without a definitive airway (e.g. intubation). Most studies no sodium bicarbonate have shown no benefit or have found a relationship with worse outcome.

Calcium Chloride (generic)

Route & Dosage: 500-1000mg IV, 20mg/kg IV.
Onset & Duration: onset 5-15min, peak unknown, duration up to 4hr.
Pharmacokinetics: urine and feces elimination, half-life unknown.
Indications: ionized hypocalcemia, suspected hyperkalemia, severe hypermagnesemia, calcium channel blocker overdose (off-label), beta blocker overdose (off-label).
Contraindications: routine use in cardiac arrest, digoxin toxicity.
Adverse Effects: transient hypertension, hypotension, bradycardia, vasodilation, arrhythmias, cardiac arrest, dysgeusia, tingling sensation.
Drug Interaction: magnesium, sodium bicarbonate, ceftriaxone, blood products.
Calcium is the most abundant mineral in the body. It plays an important role in the blood clotting cascade, smooth muscle contraction, skeletal and cardiac muscle contraction, and nerve function. The most obvious indication for calcium use is low calcium in the blood, known as ionized hypocalcemia. The distinction between total serum calcium and free (ionized) serum calcium is important, since total calcium is dependent on the serum albumin concentration. It has been shown that “corrected” calcium levels, using an equation for total serum calcium with albumin, are inaccurate (Dickerson et al, 2004). Therefore, only ionized calcium levels should be used to guide treatment. Ionized hypocalcemia is common after blood product transfusions as the blood preservative citrate binds to calcium. This can lead to serious life-threatening hypocalcemia if not managed appropriately.
Calcium is also used in the treatment of severe hypermagnesemia since these two electrolytes have opposing actions. Hypermagnesemia is not common in the prehospital setting but may be seen in obstetrical patients who are on magnesium infusions. Hyperkalemia, however, is more common especially in renal failure patients. Calcium is indicated for known or suspected hyperkalemia (e.g. peaked T-waves on ECG with known renal failure). Calcium does not directly affect the potassium level; it acts by protecting the myocardium against unwanted depolarization. In calcium channel blocker overdose, administering calcium theoretically increases the calcium concentration gradient in an attempt to overcome the channel blockade. In beta blocker overdose, high doses of beta blockers (e.g. propranolol) can block calcium channels leading to AV conduction block, myocardial depression, and asystole.
Dosing for calcium chloride is 500-1000mg IV of a 10% solution, given by slow injection. This dose may be repeated as necessary, particularly for beta blocker or calcium channel blocker overdose. Calcium gluconate is another option for the administration of calcium, with calcium chloride being roughly 3 times more potent. Thus, 5mL of 10% calcium chloride would be similar to 15mL of 10% calcium gluconate. Further, a dose of 1000mg IV calcium chloride would be comparable to 30mL of 10% calcium gluconate. An example of these medications is seen in Figure 15-7. Pediatric dosing for calcium chloride is 20mg/kg IV.
As previously mentioned, calcium should not be given routinely in cardiac arrest. In patients who are taking digoxin, calcium can precipitate cardiac arrhythmias. Calcium should not be given in known or suspected digoxin toxicity. Typically, calcium injection results in a transient increase in blood pressure. This can be followed by vasodilation and hypotension. Bradycardia and other cardiac arrhythmias can occur, especially with rapid injection. Dysgeusia is an abnormal taste, such as a metallic taste after injection of lidocaine. Calcium injection is associated with a chalky taste. Rapid injection in particular can cause a tingling sensation. Calcium should not be administered with magnesium due to opposing effects. Calcium should not be mixed with sodium bicarbonate as they may precipitate (create a solid in solution). Similarly, the antibiotic ceftriaxone can precipitate with calcium. Blood products that contain the anticoagulant citrate should not be mixed with calcium as the calcium will bind to citrate. Citrate toxicity leading to hypocalcemia is one of the major complications of blood transfusion.

Parasympatholytics

A parasympatholytic agent is one that reduces activity of the parasympathetic nervous system. They are typically anticholinergic agents, which reduce the neurotransmitter acetylcholine in the central and peripheral nervous system. Acetylcholine receptors are either nicotinic (nAChR) or muscarinic (mAChR). Some anti-nicotinic agents are used for muscle relaxation, such as rocuronium and vecuronium. Some anti-muscarinic agents are used to block cardiac vagal tone, which can increase heart rate. Commonly used anti-muscarinic drugs include atropine, glycopyrrolate, and scopolamine. Each of these medications affects the central nervous system, oral secretions, and heart rate at different degrees. Scopolamine is typically used for nausea and motion sickness. It crosses the blood brain barrier thus can cause amnesia, drowsiness, and fatigue. It has little effect on heart rate. Glycopyrrolate is used to increase heart rate and dry secretions, with a longer duration of action than atropine. Also, it does not cross the blood brain barrier thus has no central nervous system effects. Of the three, atropine has the most profound heart rate effects which makes it the most useful for bradycardia. Atropine does cross the blood brain barrier thus can cause anticholinergic symptoms (“red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare”).

Atropine [AtroPen]

Route & Dosage: 0.5mg IV, 0.02mg/kg IV.
Onset & Duration: onset 45-60sec, peak 2min, duration 1-2hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2-3hr.
Indications: symptomatic bradycardia, organophosphate poisoning, prior to intubation in infants.
Contraindications: narrow-angle glaucoma, prostate hyperplasia, tachyarrhythmias, thyrotoxicosis, routine use during asystole or pulseless electrical activity, hypothermic bradycardia, severe coronary artery disease, severe aortic stenosis.
Adverse Effects: tachycardia, palpitation, flushing, drowsiness, dizziness, skin rash, nausea, dry mouth, urinary retention, angle-closure glaucoma, blurred vision, pupil dilation, increased intraocular pressure, blockade of bradycardic response to hypoxia.
Drug Interaction: oral potassium.
Atropine is an anti-muscarinic agent and therefore is also and anticholinergic and parasympatholytic. It is a naturally occurring chemical that is extracted from the belladonna (i.e. deadly nightshade) plant. It is primarily used to reduce cardiac vagal tone, thereby increasing heart rate. For adults, it is the first drug for symptomatic sinus bradycardia and may be beneficial for second degree Mobitz type I (Wenckebach) AV nodal blockade. It will not be effective for infranodal blockade, which includes Mobitz type II and complete AV (3rd degree) block. It is also unlikely to have therapeutic benefit in asystole or pulseless electrical activity (PEA), thus was removed from this portion of the ACLS algorithm. Atropine is the primary treatment for organophosphate poisoning.
Dosing for symptomatic bradycardia is 0.5mg IV every 3-5 minutes as needed, up to a maximum total dose of 3mg. A shorter dosing interval may be used in severe clinical conditions. For children, the dose is 0.02mg/kg IV with a minimum dose of 0.1mg and a maximum single dose of 0.5mg (adult dose). The maximum total dose of a child is 1mg and maximum total dose for an adolescent is 3mg (adult maximum). Although a much less desirable route, endotracheal administration is possible at 2-2.5x the typical dose, so 0.04-0.06mg/kg ETT diluted in 5-10mL of sterile water. Dosing prior to intubation for children < 1 year of age is 0.01-0.02mg/kg IV with a minimum dose of 0.1mg and a maximum single dose of 0.5mg. Alternatively, a dose of 0.02mg/kg IM may be given, which has a rapid onset and peaks in about 3 minutes.
Organophosphate poisoning may require extremely large doses, such as 2-4mg or higher in adults. This may require starting an atropine infusion, though this is less commonly seen in the prehospital setting. For children < 12 years old, organophosphate toxicity is treated with atropine 0.02-0.05mg/kg IV repeated every 20-30 minutes until muscarinic symptoms reverse. For children > 12 years old, dosing is 1-2mg IV every 20-30 minutes. There are several mnemonics for the cholinergic toxidrome, which is a toxidrome that generally involves fluid coming from most orifices. SLUDGE-Mi, said as “Sludge Me”, is one such mnemonic and stands for salivation, lacrimation, urination, defecation, gastrointestinal upset, emesis, and miosis (pinpoint pupils). This can help differentiate miosis from mydriasis (dilated pupils). Mydriasis would therefore be seen in the opposing toxidrome, anticholinergic toxicity, and is a common side effect of atropine.
Pupil dilation in patients with narrow-angle glaucoma and lead to blindness from increase intraocular pressure. Urinary retention can be worsened in patients with enlarged prostates. Patients with tachyarrhythmias or thyrotoxicosis are at risk for worsened arrhythmias after administration of atropine. Patients who cannot tolerate tachycardia, including severe aortic stenosis and severe coronary artery disease, should only receive atropine for life-threatening emergencies. Atropine has minimal to no effect on the heart in patients who are hypothermic (Wüst et al, 1976). Adverse effects can be remembered by the anticholinergic toxidrome. They include tachycardia, palpitations, flushing, drowsiness, nausea, dry mouth, urinary retention, and increased intraocular pressure. A paradoxical bradycardic response can occur with low doses of atropine, which is why the minimum pediatric dose is 0.1mg IV and the minimum adult dose is 0.5mg IV. The cardiac response to hypoxemia starts with a sympathetic burst, which increases heart rate. It is then followed by bradycardia as the myocardium is starved for oxygen. Bradycardia in children, in particular, is an ominous sign and should prompt the provider to consider hypoxemia as the primary cause. This bradycardic response is blocked by atropine, so pulse oximetry monitoring is strongly encouraged. Although not common in the prehospital setting, atropine can prolong gastrointestinal transit time which can lead to ulcers from oral potassium pills.
That’s Not True … or Is it? LOAD For Rapid Sequence Induction
LOAD is a commonly seen mnemonic for premedication prior to rapid sequence induction and intubation (RSII). It stands for lidocaine, opioid, atropine, and defasciculating agent. The idea is to prevent side effects that are associated with succinylcholine, laryngoscopy, and endotracheal intubation. These undesired effects include bradycardia, tachycardia, hypertension, and increase intracranial pressure. Fortunately, several studies have been done on these medications and their ability to reduce the side effects. Unfortunately, many of them do not work but this mnemonic continues to be taught. Some of the studies that have shown these drugs ineffective are decades old, yet the mnemonic still persists.
Lidocaine has been proposed to decrease intracranial pressure and hemodynamic response during rapid sequence intubation. Lidocaine 1.5mg/kg IV has been shown to decrease anesthetic requirements during intubation (Himes et al, 1977). Reductions in hemodynamic response are seen with lidocaine 3mg/kg IV (Kasten et al, 1986), which is a higher dose than typically recommended for RSII. Lidocaine at 1.5mg/kg IV has been shown to be ineffective at reducing the hemodynamic response to laryngoscopy and intubation (Miller et al, 1990; Splinter, 1990). Only a single human study ever showed that lidocaine reduced intracranial pressure for intubation and that study involved only 20 patients. A systemic review of the literature has not been able to show any evidence of reduced ICP with lidocaine prior to RSII and also showed no positive effect on neurologic outcome (Robinson et al, 2001). So, the evidence suggests that lidocaine has no role in decreasing ICP or preventing a hemodynamic response to intubation during RSII.
Atropine has been proposed for preventing bradycardia in children due to laryngoscopy and also for preventing bradycardia associated with succinylcholine. Children under 1 year of age have predominant parasympathetic nervous systems with immature sympathetic nervous systems. This puts them at risk for bradycardia with vagal stimulation, such as during laryngoscopy. It is reasonable to use atropine pretreatment in this patient population (Guyton et al, 1996). A study of children > 1 month old in the critical care setting showed atropine reduced the incidence of new arrhythmias during intubation (Jones et al, 2013). In children older than 1 year of age, the sympathetic nervous system has matured and bradycardia from laryngoscopy is less likely. The use of atropine pretreatment in adults is not recommended.
But what should we do about children > 1 year or those receiving succinylcholine? In children aged 1-12 years, atropine plus succinylcholine had a similar incidence of arrhythmias compared to succinylcholine alone (McAuliffe et al, 1995). Another literature search found no evidence to support the use of atropine in children prior to a single dose of succinylcholine (Fleming et al, 2005). Yet another study showed that atropine pretreatment did not prevent bradycardia associated with intubation or hypoxia (Fastle et al, 2004). However, PALS guidelines recommend using atropine for children 1-5 years old before succinylcholine or anyone > 5 years old receiving a second dose of succinylcholine. So which is it? This controversial topic is still being investigated and there is no definitive answer at this time (Shaffner, 2013). It would seem prudent to follow current PALS guidelines and use atropine prior to succinylcholine for children aged 1-5 years. Sinus bradycardia with succinylcholine is more common after a second dose (Stoelting et al, 1975), so administration of atropine in this setting is not unreasonable. The use of high dose rocuronium for RSII would avoid this issue entirely, with the exception to use atropine routinely for children < 1 year of age.
Opioids have been proposed to prevent the hemodynamic changes seen with laryngoscopy and intubation. Laryngoscopy in children is associated with bradycardia. In adults, a sympathetic response with tachycardia and hypertension is more common. The placement of an endotracheal tube (intubation) is more stimulating than laryngoscopy and is associated with hypertension and tachycardia in all age groups. The opioids most commonly used for blunting this response are the fentanyl derivatives. The drugs remifentanil and alfentanil have rapid onset of action and can blunt this response effectively. However, these medications are rarely outside of the operating room. Fentanyl is likely the most commonly used drug for RSII, but it requires important understanding of the onset and dose-dependent effects. The peak effects of fentanyl for blunting the hemodynamic response to intubation may take up to 10 minutes (Billard et al, 1994). This point along should bring into question the practicality of using fentanyl for RSII when it is unlikely that the provider can wait a full 10 minutes prior to intubation. Blunting of response is dose-dependent, with 2mcg/kg IV fentanyl only partially blocking hypertension and tachycardia. Fentanyl 6mcg/kg IV was shown to be much more effective (Kautto, 1982), however this is a much higher dose than is typically recommended for intubation. Even higher doses, between 11-75mcg/kg IV, have been described to prevent most responses to intubation although side effects may be serious. The typical time needed for fentanyl before intubation is 6.4 minutes (Mi et al, 1998) at a dose of 2mcg/kg and this only partially blunts the hemodynamic response. In the setting of emergency intubation, fentanyl may not achieve the desired response in time for RSII.
Defasciculation with a nondepolarizing muscle relaxant has been proposed to prevent side effects associated with succinylcholine. There is debate about whether succinylcholine increases ICP (Clancy et al, 2001) with most literature showing no association. For elective neurosurgery, succinylcholine may increase ICP and this can be blunted with a defasciculating dose (Minton et al, 1986). A defasciculating dose can also reduce other side effects of succinylcholine, such as myalgias. So, a defasciculating dose may be helpful when given before succinylcholine. The problem, however, is with the appropriate dose. The defasciculating dose for a nondepolarizing muscle relaxant is 10% of the ED95 (Donati, 2006). Unfortunately, this has been incorrectly interpreted at 10% of the intubating dose in several textbooks. A typical intubating dose is about 2 times ED95, so the appropriate defasciculating dose is 5% (1/20th) of the intubating dose. An unacceptably high incidence of symptoms is seen when the incorrect dose is used (Donati, 2006). These symptoms include blurred vision, heavy eyelids, voice changes, difficulty swallowing, and dyspnea. Given an intubating dose of rocuronium as 0.6mg/kg IV, the appropriate defasciculating dose would be 0.03mg/kg IV, or 3mg for a 100kg patients. Further, if a defasciculating dose is used then the dose of succinylcholine should be increased to 1.5-2mg/kg IV due to antagonism between these medications (Szalados et al, 1990). This issue can be avoided by using high dose rocuronium for RSII.
To summarize, lidocaine does not seem to have a role in RSII. Atropine is useful for children < 1 year of age and may be useful when succinylcholine is given. Atropine is not useful for adults, especially when succinylcholine is not given or is only given once. Fentanyl has only a small role in RSII and must be timed appropriately. Defasciculating with a nondepolarizing muscle relaxant requires using an appropriate dose (5% intubating dose) and increasing the subsequent dose of succinylcholine to 1.5-2mg/kg.

Platelet-Aggregation Inhibitors

Platelet aggregation is a complex process with multiple steps. Activation of the GP IIb/IIIa receptor starts the process and allows these receptors to bind von Willebrand factor (vWF) or fibrinogen. Platelets also interact with coagulation factors as part of the coagulation cascade to form a clot. Several drugs are available that target portions of the aggregation pathway in an effort to reduce clotting. Aspirin inhibits platelets by blocking thromboxane and is indicated for all patients with acute coronary syndrome. The adenosine diphosphate (ADP) antagonists block platelet aggregation by inhibiting the P2Y12 receptor on platelets. They include clopidogrel, prasugrel, and ticagrelor. Ticagrelor is a newer medication be investigated STEMI and NSTEMI. Prasugrel has no data to support use in the emergency department or prehospital settings (Hazinski et al, 2010).

Aspirin (generic)

Route & Dosage: 160-325mg PO.
Onset & Duration: onset rapid, peak 1-2hr, duration 10 days.
Pharmacokinetics: liver metabolism, urine elimination, half-life 15-20min.
Indications: acute coronary syndrome, stroke, primary cardiovascular prevention, coronary artery disease, anti-inflammatory, analgesic, antipyretic.
Contraindications: hypersensitivity to aspirin, active gastrointestinal hemorrhage.
Adverse Effects: exacerbation of asthma, gastrointestinal bleed, worsening of gastrointestinal ulcers, bleeding, tinnitus, Reye syndrome, several others with long term use.
Drug Interaction: NSAIDs including ketorolac, steroids.
Black box warning: pregnancy.
Aspirin is also known as acetylsalicylic acid or ASA. Aspirin blocks a portion of the arachidonic acid pathway; See Figure 15-8. This pathway is responsible for pain, inflammation, and hemostasis. Arachidonic acid is broken down by the enzyme lipooxygenase to leukotrienes, which mediate inflammation. Arachidonic acid is also broken down by cyclooxygenase (COX) to prostaglandins and thromboxane. There are several prostaglandins with functions that include vasodilation, bronchodilation, and gastric protection. Thromboxane functions in platelet aggregation. Aspirin inhibits the enzyme cyclooxygenase; it acts as a COX blocker. It irreversibly binds to platelets to prevent aggregation. So, even though the plasma half-life of aspirin is only 20 minutes the duration of effect is about 10 days because that is the life span of platelets (Awtry et al, 2000). Blockade of this pathway also leads to undesired side effects, including bronchoconstriction and gastric ulcers.
Aspirin has several indications for acute and chronic use, making it a very common medication. In the prehospital emergency setting, it is primarily indicated for all patients with acute coronary syndrome. This includes any patients with symptoms suggestive of ischemic chest pain, such as chest “pressure”, “heavy weight”, “squeezing”, or “crushing”. Aspirin has been shown to decrease mortality in these patients, reduce reinfarction rate, and reduce the incidence of nonfatal stroke. Dosing is 160-325mg PO (oral) of a non-enteric coated tablet. Enteric coating slows the absorption and onset of action. It is preferred that patients chew the tablet, which can be accomplished by giving 4 of the 81mg chewable tablets (324mg total). For patients who cannot take oral medications, a 300mg rectal suppository is an option. It is reasonable for emergency medical dispatchers to instruct patients to chew 160-325mg aspirin while waiting for emergency medical providers (O’Connor et al, 2010). It should only be withheld if the patient has a true aspirin allergy or an active gastrointestinal hemorrhage.
The blockade of COX pushes the arachidonic acid pathway towards leukotrienes. Overproduction of leukotrienes leads to asthma and allergy-like effects, which can be severe in patients with known asthma or reactive airway disease. Blockade of COX also reduces prostaglandins that protect the stomach, making upset stomach and gastric ulcers a side effect. Tinnitus (ringing in the ears) can be caused by aspirin and is a sign of aspirin toxicity. Reye syndrome is a potentially life-threatening syndrome that occurs in children with viral illness. It affects many organs, particularly the liver and brain. For this reason, aspirin should not be given to children who have a fever. Increased bleeding is an expected side effect of aspirin. Since NSAIDs block the arachidonic acid pathway at the same point, they can potentiate the side effects. Also, anti-inflammatory steroids block the arachidonic acid pathway before COX, which can also potentiate some of the side effects. There is a black box warning for pregnant patients taking over-the-counter pain medications, such as aspirin, as they can cause fetal issues such as low birth weight. However, low dose aspirin may have a role in some pregnant patients such as in the prevention of preeclampsia (ACOG, 2013). Either way, the decision to use aspirin in a pregnant patient should be made by the patient’s obstetrician unless it is a true emergency (e.g. acute coronary syndrome).

Clopidogrel [Plavix]

Route & Dosage: 300-600mg PO.
Onset & Duration: onset 2hr, peak 3-7day, duration 5day.
Pharmacokinetics: liver metabolism, urine and feces elimination, half-life 6hr.
Indications: acute coronary syndrome (adjunctive therapy), cardiovascular disease, atrial fibrillation (off-label).
Contraindications: pathologic bleeding (peptic ulcer, intracranial hemorrhage).
Adverse Effects: gastrointestinal bleed, bleeding, skin rash, pruritus, purpura, epistaxis.
Drug Interaction: antithrombotic drugs, CYP2C19 drugs.
Black box warning: diminished effectiveness in poor CYP2C19 metabolizers.
Clopidogrel is an adenosine diphosphate (ADP) antagonists, which bocks platelet aggregation. The pharmacokinetics are slightly confusing given that the drug is typically used in daily dosing. Serum peak after a loading dose occurs in about 1 hour, however typically dosing is a single loading dose followed by daily administration which results in a second peak around 3-7 days. A single dose causes inhibition of platelet aggregation (IPA) that tapers slowly and lasts about 5 days. Some sources may list the onset of IPA as 2 hours and the peak serum concentration of 1 hour, meaning that platelet inhibition does not occur before peak serum concentrations are reached. Half-life for the active metabolite is 30 minutes but the drug itself has a half-life of 6 hours. Unfortunately, several sources disagree regarding the pharmacokinetics of clopidogrel. Fortunately, the pharmacokinetics of clopidogrel are not particularly useful in the prehospital setting as the drug is given as a single oral bolus dose.
Clopidogrel is primarily indicated as adjunctive therapy for acute coronary syndrome. It is also used for cardiovascular disease (recent MI, stroke, peripheral arterial disease) and chronic atrial fibrillation. For ACS patients, it is indicated for STEMI or moderate- to high-risk NSTEMI, including in patients who receive fibrinolysis (CRUSADE trial, 2008; TARGET trial, 2003). There is limited evidence for clopidogrel in patients 75 or older, so recommendations limit use to patients under the age of 75. Clopidogrel is an alternative to aspirin for patients that have hypersensitivity to aspirin, including aspirin-induced bronchospasm and gastrointestinal intolerance to aspirin. Dosing is 300-600mg PO loading followed by a maintenance dose of 75mg PO daily, with the full drug effects occurring after several days. Dosing for patients with suspected acute coronary syndrome who are unable to take aspirin is 300mg PO once.
The CURE trial found an increased risk of bleeding with clopidogrel in patients undergoing coronary artery bypass grafting (CABG) surgery. The AHA recommends weighing the risks versus the benefits of clopidogrel in patients who have a high likelihood of needing CABG, as clopidogrel should be held for 5-7 days prior to this surgery. Clopidogrel should not be used in patients with current active bleeding. Adverse effects include bleeding such as epistaxis (nosebleed) or gastrointestinal hemorrhage, skin rash, itchiness (pruritus), and red/purple discoloration of the skin (purpura). The addition of other antithrombotic agents can increase the risk of bleeding. Clopidogrel has a black box warning regarding diminished effectiveness in patients who are poor CYP2C19 metabolizers. The cytochrome P450 (CYP) system in the liver has several enzymes, such as 2C19, that metabolize different drugs. Clopidogrel is metabolized by CYP-2C19, which means metabolism may change if other CYP-2C19 drugs are present or in patients with genetic defects to CYP-2C19. There are several drugs that fall into this category, however it is mostly irrelevant as clopidogrel is given as a single dose during emergencies in the prehospital setting.

Inotropic Agents

Inotropic agents are drugs that affect the contractility of the heart, and therefore increase cardiac output. These agents typically work on the beta-1 (ß1) receptor, with effects that oppose the beta-blockers. Commonly used inotropic agents include: dobutamine, dopamine, and epinephrine. Norepinephrine has some ß1 activity, however it is not used as an inotrope given its significant α1 activity. This makes norepinephrine a more potent vasopressor than an inotropic agent. Along the same line, epinephrine has some α1 activity, especially at higher doses. However, at lower doses and infusion doses epinephrine is primarily an inotropic agent. Dopamine can also cause significant α1 effects with higher doses. Since these agents primarily cause ß1-agonism, they will typically increase heart rate and cardiac output.
Catecholamines are organic compounds with an amine side-chain in their chemical structure. Several stimulant drugs are related to catecholamines including dobutamine, dopamine, epinephrine, and norepinephrine. The catecholamine pathway in the body starts with the amino acid tyrosine and creates dopamine, norepinephrine, and epinephrine (See Figure 15-9). As an example of this pathway, PNMT (phenylethanolamine N-methyltransferase) levels increase during stress which converts more norepinephrine to epinephrine, making the stress response more powerful. Dobutamine is not part of this pathway because it is a synthetic drug that is only present in the body when administered by a healthcare professional.

Dobutamine (generic)

Route & Dosage: 2-20mcg/kg/min IV.
Onset & Duration: onset 1-10min, peak 10-20min, duration minutes.
Pharmacokinetics: liver and tissue metabolism, urine elimination, half-life 2min.
Indications: cardiac decompensation including the post-cardiac arrest setting and congestive heart failure.
Contraindications: suspected poison/drug induced shock, SBP < 100mmHg with shock, severe coronary artery disease, severe aortic stenosis.
Adverse Effects: tachycardia, arrhythmias, hypotension, hypertension, myocardial ischemia, angina, chest pain, dyspnea.
Drug Interaction: sodium bicarbonate, monoamine oxidase inhibitors (MAO-I), tricyclic antidepressants (TCA).
Dobutamine is a direct-acting ß1-adrenergic agonist and a synthetic catecholamine. It has some effect on ß2-receptors and minimal alpha effects. Beta-adrenergic effects are ß1 > ß2 in a 3:1 ratio (Overgaard et al, 2008). The result is increased cardiac contractility, increased heart rate, and decreased central venous pressure. Dobutamine increases myocardial oxygen consumption and, because of this, is used for cardiac stress testing in patients who cannot exercise. Dobutamine is used primarily for “pump problems” like congestive heart failure or pulmonary edema in patients with low blood pressure. It is typically started for systolic blood pressure between 70-100mmHg in patients with no signs of shock, particularly in patients with acute myocardial infarction (Antman et al, 2004). Signs of cardiogenic shock include: acute altered mental status, cool clammy skin, cyanosis, and oliguria (low urine output). Dobutamine is usually preferred over dopamine in adults with chronic low cardiac output as there is a greater cardiac output increase with fewer side effects (Loeb et al, 1977).
The primary prehospital indication for dobutamine is SBP 70-100mmHg without signs of cardiogenic shock, particularly in patients with acute myocardial infarction or in the post-cardiac arrest period. Dosing is 2-20mcg/kg/min IV and should not be started with a bolus dose. This dose applies for adults and children, though dobutamine is less commonly indicated in children. Dosing for post-cardiac arrest is typically started at 5-10mcg/kg/min IV (Peberdy et al, 2010). Infusion should be titrated so heart rate does not increase more than 10% beyond baseline. Elderly patients have desensitization of beta receptors, thus will have significantly decreased response to beta-adrenergic inotropes like dobutamine.
Dobutamine is not typically used in hypotension with signs of cardiogenic shock due to the potential for worsening hypotension and hypoperfusion. Tachycardia is a side effect of beta1 stimulation, thus caution should be used in patients with coronary artery disease or aortic stenosis. Dobutamine should not be used for poison- or drug-induced shock. Premature ventricular contractions are common with dobutamine and are dose related. Increased ventricular rate can occur in patients with atrial fibrillation. Angina, chest pain, or palpitations are not uncommon. Hypotension can occur from beta2-adrenergic vasodilation and hypertension can occur from an increased cardiac output. Hypertension is more common in patients on nonselective beta-blockers (Oh et al, 2005). Drug interactions exist with MAO-I and TCA agents, which can lead to exaggerated hypertension. An alkaline pH will inactivate catecholamines, such as dobutamine, thus sodium bicarbonate should not be mixed with dobutamine.

Dopamine (generic)

Route & Dosage: 2-20mcg/kg/min IV.
Onset & Duration: onset 1-5min, peak about 5min, duration minutes.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2min.
Indications: symptomatic bradycardia, hypotension with signs of shock.
Contraindications: hypovolemia, severe coronary artery disease, severe aortic stenosis.
Adverse Effects: multiple adverse cardiac effects, headache, nausea, dyspnea, splanchnic ischemia.
Drug Interaction: sodium bicarbonate, monoamine oxidase inhibitors (MAO-I), tricyclic antidepressants (TCA), phenytoin.
Black box warning: skin necrosis with extravasation.
Dopamine is a naturally occurring catecholamine and the precursor to norepinephrine. It stimulates ß1 and α1 receptors, as well as vascular dopamine-1 (D1) receptors. At low plasma concentrations, dopamine primarily acts on D1 receptors causing vasodilation of renal, mesenteric, and coronary vasculature. Moderate doses, as are most commonly used, have ß1 and α1 effects. At high doses, the α1 effects (vasoconstriction) predominate. Dopamine also has ß2 effects, which are at most equal to the ß1 effects. Several sources disagree on the amount of ß2 activity, though most suggest there is at least some activity. Dopamine, similar to dobutamine, is used in the prehospital setting for patients with SBP 70-100mmHg. However, dopamine is indicated over dobutamine when there are signs and/or symptoms of cardiogenic shock. This relates to the α1 activity, which is much stronger with dopamine than with dobutamine. Dopamine is also used as a second-line drug, after atropine, for symptomatic bradycardia.
The primary prehospital indication for dopamine is SBP 70-100mmHg with signs of cardiogenic shock, particularly in patients with acute myocardial infarction or in the post-cardiac arrest period. Dosing is 2-20mcg/kg/min IV and should not be started with a bolus dose. To restate, dosing should be titrated to patient response and tapered slowly without bolus dosing. This dose applies for adults and children. Dosing for post-cardiac arrest is typically started at 5-10mcg/kg/min IV (Peberdy et al, 2010). In a study with healthy volunteers, a 10- to 75-fold variability was found between different volunteers with a weight-based dopamine infusion (MacGregor et al, 2000). Therefore, a bolus dose of dopamine could have wide-ranging and serious adverse effects, which is why slow titration is recommended. Dosing in the 3-10mcg/kg/min range primarily causes ß1 effects (increased heart rate) and dosing > 10mcg/kg/min primarily causes α1 effects (increased blood pressure). For this reason, dosing for symptomatic bradycardia is 2-10mcg/kg/min IV for adults. In children, symptomatic bradycardia is not typically managed with dopamine.
That’s Not True … or Is it? Dopamine Renal Dosing
At doses of 0.5-3mcg/kg/min, dopamine primarily stimulates D1 receptors (Goldberg et al, 1985). This results in vasodilation of several vascular beds, including those in the kidneys. This has been shown to increase renal blood flow, renal filtration rate, and urine output. For this reason, this was previously called “renal dosing” for dopamine. However, this concept has been shown to be false by several studies. Multiple studies have not shown a decreased incidence of renal failure when using low-dose dopamine (Kellum et al, 2001). Several authors recommend this practice be stopped and providers eliminate the phrase “renal dosing” from their vocabulary.

Hypovolemia should be corrected with volume replacement prior to starting a dopamine infusion. This relates to the α1 effects and is the same reason caution should be used in hypovolemia with phenylephrine and norepinephrine. Tachycardia from the ß1 effects can lead to myocardial infarction in patients with aortic stenosis or coronary artery disease. Dopamine has several serious cardiac adverse effects including atrial arrhythmias, ventricular arrhythmias, widened QRS, palpitations, and deterioration of tachyarrhythmias into cardiac arrest. Dopamine was compared to norepinephrine in septic shock and found to have worse outcomes (SOAP trial, 2006). Dopamine infusion is also associated with headache, nausea, and dyspnea. High doses (> 20mcg/kg/min) can cause splanchnic vasoconstriction and ischemia. Drug interactions exist with MAO-I and TCA agents, which can lead to exaggerated hypertension. Sodium bicarbonate can inactivate dopamine if infused through the same IV line. In patients taking phenytoin, there are reports of hypotension and bradycardia (Bivins et al, 1978). If dopamine is extravasated, wrap the location with a warm compress and elevate the limb above the heart. Definitive treatment with phentolamine may be needed upon arrival to the hospital
Critical Concepts: Dobutamine Versus Dopamine
Dobutamine and dopamine can cause some confusion. The FDA and ISMP lists these medications as having sound-alike/look-alike (SALA) issues. The tall man lettering scheme is seen with many drugs and is used to help differentiate medications with SALA problems (Filik et al, 2006). For these drugs, the tall man lettering is DOPamine and DOBUTamine. These two drugs have similar dosing, which is convenient. They are also used in similar situations. These features make dopamine and dobutamine seem very similar. However, they are different in their primary adrenergic activity.
For hypotension complicating AMI, dobutamine is the first line agent for SBP 70-100mmHg without signs of shock. If signs of shock are present, dopamine is recommended. However, there is not definitive outcome data supporting this decision (Antman et al, 2004); it is based primarily on the mechanism of these two drugs. When comparing these two drugs, dopamine has much more α1 activity and is therefore more useful as a vasopressor. Dobutamine has much more ß1 activity and is therefore more useful as an inotrope. This can be remembered with the mnemonic doPamine = Pressor and doButamine = Beta agonist. Recall that both of these medications have α1 and ß1 activity, but this mnemonic can help differentiate the two when comparing them side-by-side.

Epinephrine (generic)

Route & Dosage: 2-10mcg/min IV infusion, 1mg IV bolus.
Onset & Duration: onset 5-10min, duration 20min.
Pharmacokinetics: liver metabolism, urine elimination, short half-life.
Indications: cardiac arrest, symptomatic bradycardia, severe hypotension with bradycardia.
Contraindications: severe coronary artery disease, severe aortic stenosis.
Adverse Effects: tachycardia, hypertension, hypokalemia, hyperglycemia, pallor.
Drug Interaction: none contraindicated, cocaine, sodium bicarbonate.
Epinephrine was previously discussed in this chapter for treatment of acute severe asthma by taking advantage of the ß2-adrenergic effects. Epinephrine will be discussed later in the treatment of anaphylaxis, which takes advantage of both ß2- and α1-adrenergic effects. This section will focus on the use of epinephrine primarily for its ß1-adrenergic effects as an inotropic agent and in high-doses (cardiac arrest) for its α1-adrenergic effects as a vasopressor. Epinephrine is indicated for symptomatic bradycardia including severe hypotension with bradycardia. It is a second-line agent, after atropine, for symptomatic bradycardia. It is also the first-line agent for cardiac arrest.
The administration of vasopressor agents, including vasopressin or high-dose epinephrine, have not been shown to improve the rate of neurologically intact survival to hospital discharge (Neumar et al, 2010). There is evidence that these agents increase the rate of ROSC. It is essential to emphasize the importance of excellent basic life support, including effective cardiopulmonary resuscitation and chest compressions, in the setting of cardiac arrest. Basic life support measures have been shown to increase the rate of survival to hospital discharge (Berg et al, 2010). Epinephrine is used for its α1-adrenergic properties in cardiac arrest, which includes: VF, pulseless VT, asystole, and pulseless electrical activity (PEA).
Dosing for adult cardiac arrest is 1mg IV of the 1:10,000 (1mg/10mL) concentration, given every 3-5 minutes. The dose should be followed with a 20mL flush in adults and the limb elevated for 10-20 seconds. Pediatric cardiac arrest dosing is 0.01mg/kg IV of the 1:10,000 (1mg/10mL) concentration, given every 3-5 minutes, with a maximum single dose of 1mg. As mentioned previously, the general rule is that the 1:10,000 concentration should only be used for patients in cardiac arrest and is an IV dose. The 1:1000 (1mg/mL) concentration should not be used for IV administration without significant dilution.
Child, adult, and animal studies have shown several drugs can be absorbed via endotracheal administration. These medications include naloxone, atropine, vasopressin, epinephrine, and lidocaine (Neumar et al, 2010). The mnemonic NAVEL can be used to remember these medications. Unfortunately, the ETT dosing is different for adults and children, which can add to the dosing confusion with epinephrine. The concentration that should be used for ETT administration is the 1:1000 (1mg/mL). Adult cardiac arrest dosing is 2-2.5mg ETT of the 1:1000 (1mg/mL) concentration diluted in 5-10mL of sterile water. This is 2 to 2.5 times higher than the adult IV dose. For children in cardiac arrest, dosing is 0.1mg/kg ETT of the 1:1000 (1mg/mL) concentration diluted in 5mL of normal saline. This is 10 times higher than the pediatric IV dose. Endotracheal administration is a less desirable route and should only be used if IV and IO access cannot be obtained.
Epinephrine is an extremely potent medication. The high-end of dosing is used for cardiac arrest. So, to make the point again, the 1mg IV dosing is too large for patients who have a pulse. This mistake has cost patients their lives (APSF, 2012). No survival benefit has been shown when comparing typical-dose epinephrine in cardiac arrest with even higher-dose epinephrine (Neumar et al, 2010). This should emphasize the point that more epinephrine is not better and to follow appropriate guidelines for administration. Administering a dose every 3-5 minutes means epinephrine is not given at every pulse check pause during a 2 minute CPR cycle. Providers should maintain focus on measures that improve outcome, including CPR and defibrillation. Further, high doses may contribute to post-resuscitation myocardial dysfunction. The exception to the 1mg IV dose is beta-blocker and calcium-channel blocker overdose, where larger doses of epinephrine may be considered.
For symptomatic bradycardia, adult epinephrine dosing is 2-10mcg/min IV infusion. Pediatric bradycardia dosing is the same are pediatric cardiac arrest dosing; 0.01mg/kg IV bolus of the 1:10,000 (1mg/10mL) concentration. For profound hypotension, adult dosing is 0.1-0.5mcg/kg/min IV infusion and pediatric dosing is 0.1-1mcg/kg/min IV infusion. For epinephrine infusions, it is recommended that prehospital providers use prefilled epinephrine bags with a standard concentration. This concentration is typically 16mcg/mL, which can be created by adding 4mg into 250mL. Providers have enough to worry about when differentiating 1:1000 versus 1:10,000 and prefilled infusion bags can help reduce serious epinephrine errors. Table 15-8 is a summary of epinephrine dosing and route of administration for typical prehospital indications.
The pharmacokinetics are the same as previously discussed, with the exception that the onset and peak of IV epinephrine is much more rapid than with IM or subcutaneous dosing. Contraindications, adverse effects, and drug interactions are the same as previously discussed in the respiratory emergencies portion of this chapter.

Table 15-8: Epinephrine Dosing and Route

Vasopressors and Inotropes

Vasopressors and inotropes are very useful medications to manage hemodynamic emergencies in the prehospital setting. Table 15-9 is summary of these medications and their effects on alpha- and beta-adrenergic receptors. A similar table can be found in other textbooks, however it should be noted that not all sources agree on the level of activity at each receptor. Some sources group minimal receptor activity with no (zero) receptor activity, while other sources are more specific about the amount of receptor activity. Despite the differences among source, the majority agree with the primary receptors that is affected by each of the agents. The agents that are typically considered inotropes at usual doses are dobutamine, dopamine, and epinephrine. The agents that are typically considered vasopressors are usual doses are norepinephrine, phenylephrine, and vasopressin. The α1-adrenergic effects of dopamine and epinephrine are dose-dependent.

Table 15-9: Vasopressors and Inotropes

Case Study: Hypotension After Induction
You are working as stand-by EMS for a university sporting event. During the pole-vaulting competition, an athlete’s pole breaks mid vault. The athlete falls back, landing into the pole vault box with their head. You rush to their aid and find they are unconscious with snoring respirations. Vital signs are 200/100mmHg, 90bpm, SpO2 80%, and GCS 7. Suspecting a closed head injury with possible increased intracranial hypertension, you prepare propofol and rocuronium for intubation. Immediately after an uneventful intubation, BP is 88/46 and HR is 130. You open the IV fluid bag roller clamp and direct your partner to prepare a medication to treat the hypotension.
Critical Thinking Questions
1. Would phenylephrine be an appropriate choice of medication for this patient?
2. Would dobutamine be an appropriate choice of medication for this patient?

Table 15-10 below lists the common types of circulatory shock along with management examples. The type of shock will help you determine which agent, an inotrope or a vasopressor, is most beneficial. In some instances, such as obstructive or hypovolemic shock, pharmacologic agents can help temporize while the provider addresses the primary cause. Neurogenic shock is a distributive shock with loss of sympathetic tone, leading to massive vasodilation below the spinal cord lesion. This may be associated with a slow heart rate, depending on the level of the lesion. This combination causes profound hypotension that should be managed immediately with a vasopressor. The addition of an inotropic agent may be needed to increase heart rate.

Table 15-10: Types of Shock and Management Examples

Medications Used for Neurologic Emergencies

Anticonvulsants

Making the decision to administer anticonvulsant agents to a seizing patient requires taking into account the likely cause, the chance of recurrence, and the effects of the anticonvulsant medication. Seizures related to glucose control or hypoxemia, for example, may not require anticonvulsant medications. When presented with a seizure the tendency is to stop the event. This may mask the underlying cause and lead to complications related to the anticonvulsants. For a single seizure, observation is the key principle. Objects should not be placed in the patient’s mouth as they can obstruct the airway.
However, status epilepticus constitutes an emergency and should be managed with anticonvulsant medications. Seizures increase the cerebral metabolic rate, affecting the oxygen supply/demand relationship. They also increase cerebral blood flow, which can increase intracranial pressure. If a patient has a seizure lasting longer than five minutes, or two seizures within a five minute period, an anticonvulsant should be considered. First-line treatment includes the benzodiazepines and phenytoin. Refractory seizures can be managed with benzodiazepines, propofol, short-acting barbiturates, or phenobarbital. The benzodiazepines, such as lorazepam, are particularly effective for seizures. Phenytoin is less effective but is not associated with respiratory depression, which can be seen with the benzodiazepines.

Table 15-11: Benzodiazepines For Status Epilepticus

The depth of sedation is a continuum. Discrete points cannot be obtained with standard medication dosing. In an effort to formalize a definition, pharmacologic sedation is divided into four parts: minimal, moderate, deep, and general anesthesia (ASA, 2014). Minimal sedation, or anxiolysis, means the patient has a normal response to verbal stimulation (e.g. calling their name). Moderate sedation means the patient has a purposeful response to verbal or tactile stimulation (e.g. opens their eyes and responds to shaking their shoulder). These patients typically have adequate spontaneous ventilation and do not need assistance with their airway. Deeply sedated patients only respond to repeated or painful stimuli (e.g. sternal rub). Spontaneous ventilation in these patients may be inadequate and airway intervention may be required.
General anesthesia is defined as unconsciousness despite painful stimulation. This level of sedation is associated with impaired cardiovascular function, inadequate ventilation, and the need for airway intervention. It is important to recognize that, since sedation is a continuum, any sedative medication can lead inadequate ventilation and the need for airway management. Some medications, such as benzodiazepines, are commonly used for anxiolysis or moderate sedation. In higher doses, these can induce general anesthesia with inadequate ventilation and loss of airway reflexes. Proper patient monitoring is essential when administering sedatives and emergency airway equipment should be available.

Diazepam [Valium, Diastat]

Route & Dosage: 5-10mg IV/IM.
Onset & Duration: onset rapid IV and 15-30min IM, peak rapid IV and 1hr IM, duration 15-60min.
Pharmacokinetics: liver metabolism, urine elimination, half-life 40-100hr.
Indications: status epilepticus, acute alcohol withdrawal, severe agitation (tranquilization).
Contraindications: myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, sleep apnea syndrome.
Adverse Effects: anterograde amnesia, CNS depression, vesicant, paradoxical reactions, respiratory depression, pain on injection, hypotension, acute narrow-angle glaucoma.
Drug Interaction: CYP2C19 drugs, sedatives and opioids.
Diazepam is a benzodiazepine, which all potentiate the effects of the neurotransmitter gamma-aminobutyric acid (GABA). GABA is the major inhibitory neurotransmitter in the central nervous system and is the major target for benzodiazepines, barbiturates, and several anesthetic agents (e.g. propofol). Benzodiazepines are used for anxiety, hypnosis (sleep), muscle relaxation, and seizures. They are termed sedative-hypnotics in that they cause sedation (anti-anxiety) as well as unconsciousness, in larger doses. Onset and peak times are dependent on the route of administration, with effective duration being up to 1 hour. The drug half-life, however, is long lasting and particularly long lasting in patients with liver disease. In the prehospital setting, diazepam is most commonly used for agitation and for status epilepticus.
Dosing for status epilepticus is 5-10mg slow IV or IM in adults, with the IV route being preferred. Dosing may be repeated ever 10-15 minutes as needed to a maximum of 30mg. The Neurocritical Care Society recommends a dose of 0.15mg/kg with a maximum single dose of 10mg (Brophy et al, 2012). Diazepam is not the preferred benzodiazepine for IV or IM administration, though it is preferred for rectal administration. Rectal dosing is 10mg PR (per rectum) and the IV formulation may be used if diazepam gel is not available (Kälviäinen, 2007). For children, dosing is 0.15mg/kg IV/IM given over 2 minutes with repeat doses every 5-10 minutes as needed and a maximum single dose of 10mg. Rectal dosing in children is 0.5mg/kg with a maximum single dose of 20mg PR (Hegenbarth et al, 2008). The IV formulation may be used for rectal administration of diazepam gel is not available. Some recommend decreasing the dosing based on age, with 0.5mg/kg for younger children and 0.2mg/kg for adolescents.
Benzodiazepines can cause respiratory depression, especially in higher doses or if combined with opioids. For this reason, they are relatively contraindicated in patients at risk for respiratory failure including myasthenia gravis, sleep apnea, and respiratory insufficiency. Benzodiazepines can dilate pupils, which may worsen glaucoma. Benzodiazepines generally have minimal cardiovascular side effects but can cause hypotension in larger doses. Side effects include central nervous system (CNS) depression, anterograde amnesia (inability to create new memories), and unconsciousness. Pain on injection can be seen as well as blistering if extravasated (vesicant). Paradoxical reactions have been reported, particularly with children, which involves increased agitation after administration of the benzodiazepine. Some formulations of diazepam contain propylene glycol as a preservative, which is potentially toxic in large doses. Combination of sedatives with other sedatives or opioids increases the risk for respiratory depression. Similar to clopidogrel, diazepam and phenytoin have drug interactions with CYP2C19. However, these interactions are not particularly relevant in the prehospital setting.

Lorazepam [Ativan]

Route & Dosage: 4mg IV/IM.
Onset & Duration: onset rapid IV and 15-30min IM, peak ≤ 3hr IM, duration 6-8hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 13-18hr.
Indications: status epilepticus, acute alcohol withdrawal, severe agitation (tranquilization).
Contraindications: severe respiratory insufficiency, sleep apnea syndrome, intra-arterial injection.
Adverse Effects: anterograde amnesia, CNS depression, paradoxical reactions, respiratory depression, pain on injection, hypotension, acute narrow-angle glaucoma.
Drug Interaction: sedatives and opioids.
Lorazepam is a benzodiazepine with GABA potentiating effects. It has similar indications compared to diazepam. Onset is rapid with IV administration and it may be given IM if needed. However, lorazepam is a much longer acting benzodiazepines when compared to diazepam or midazolam. The duration of action is 6-8 hours in healthy individuals. This makes it a poor choice for procedural sedation but an excellent choice for seizures, as the goal is to stop the seizure and prevent recurrence. Lorazepam is generally considered the drug of choice for status epilepticus and is the preferred benzodiazepine for intravenous administration (Brophy et al, 2012).
Dosing for status epilepticus is 4mg slow IV or IM in adults, with the IV route being preferred. Dosing may be repeated ever 10-15 minutes as needed. The Neurocritical Care Society recommends a dose of 0.1mg/kg with a maximum single dose of 4mg (Brophy et al, 2012). The dosing is the same for children and may be repeated every 5-10 minutes as needed if seizure continues. Contraindications, adverse effects, and drug interactions are similar to diazepam. Some formulations of lorazepam contain propylene glycol as a preservative, which is potentially toxic in large doses. Some formulations of lorazepam contain benzyl alcohol as a preservative, which is contraindicated for use in premature infants.

Midazolam [Versed]

Route & Dosage: 10mg IV/IM.
Onset & Duration: onset 2-5min IV and 15min IM, peak 30-6min IM, duration ≤ 1hr IV and ≤ 6hr IM.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2-7hr.
Indications: status epilepticus, sedation, anesthesia, cocaine intoxication.
Contraindications: respiratory insufficiency.
Adverse Effects: anterograde amnesia, CNS depression, paradoxical reactions, respiratory depression, apnea, hypotension, acute narrow-angle glaucoma.
Drug Interaction: CYP3A4 drugs, calcium channel blockers, sedatives and opioids.
Black Box: respiratory arrest, decrease dosing in elderly, severe hypotension in neonates.
Midazolam as a versatile sedative, hence the brand name. Like other benzodiazepines, it potentiates GABA. It has rapid onset of action and a short duration of action, which separates it from many other sedatives. It is not associated with pain on IV injection and is the benzodiazepine of choice for IM administration in status epilepticus. It can be given via several routes including IV, IM, PR (rectal), PO (oral), intranasal, and buccal (gums). It has similar indications to diazepam and lorazepam, but is much more commonly used for sedation. The shorter duration of action makes midazolam less suited for alcohol withdrawal and agitation. It is an option for induction of anesthesia and endotracheal intubation as well
Dosing for status epilepticus is 10mg IM in adults, but it may also be given via IV. The Neurocritical Care Society recommends a dose of 0.2mg/kg IM with a maximum single dose of 10mg (Brophy et al, 2012). For refractory status epilepticus, repeat dosing is not used because of the shorter half-life. Instead, a loading dose of 10mg IV is used followed by an infusion at 0.05-2mg/kg/hour. This is not commonly used in the prehospital setting given the availability of other IV benzodiazepines (e.g. lorazepam) and the ease of IM administration of midazolam. For children, the dose is based on weight (Brophy et al, 2012). There is no data for children under 13kg. For children 13-40kg, the dose is 5mg IM once. For children > 40kg, the dose is 10mg IM once (adult dose). Intranasal administration in children is an option, with status epilepticus dosing being 0.2mg/kg intranasal. Buccal dosing is 0.5mg/kg, though this may be difficult to administer during a seizure. IM midazolam is at least as effective as IV lorazepam for status epilepticus in the prehospital setting.
Contraindications, adverse effects, and drug interactions are similar to diazepam and lorazepam. Midazolam has several black box warnings, mostly relating to respiratory depression. Midazolam given via any route has the potential for respiratory depression and apnea. Airway management equipment should be available when administering midazolam. Lower doses should be used for elderly patients, debilitated patients, or those who are also taking opioids. It is worth noting that status epilepticus dosing is on the high-end for benzodiazepines and sedation dosing is typically much lower. For example, sedation dosing for midazolam starts at 0.5-2mg IV in adults and no single dose should be greater than 2.5mg. When used for sedation, dosing should start small and be titrated appropriately. This may also be phrased “start low and go slow.” Neonatal patients should not be given midazolam by rapid injection due to the potential for profound hypotension, particularly in patients who are also receiving the opioid fentanyl. Some formulations of midazolam contain benzyl alcohol as a preservative, which is contraindicated for use in premature infants. Midazolam dosing should be decreased in patients on calcium channel blockers (Backman et al, 1994). Midazolam has interactions with CYP3A4 drugs, especially the antiviral agents used in HIV/AIDS. The drugs that interact with CYP3A4 are vast, but fortunately these interactions are not particularly relevant in the prehospital setting.
That’s Not True … or Is it? Benzodiazepines and Retrograde Amnesia
Benzodiazepines have been shown to cause anterograde amnesia, meaning memory formation is affected after the drug is given. The length of amnesia is dependent on the agent and dose. Amnesia can occur despite the patient being able to follow commands. For midazolam, a cumulative dose of at least 5mg is typically required before significant amnesia occurs (Bulach et al, 2005). Retrograde amnesia refers to memory loss of events that occurred before the administration of the drug. This could be a very useful property of benzodiazepines as it could block recent memory of a painful or traumatic event.
Unfortunately, the majority of studies on this topic show that benzodiazepines are not associated with retrograde amnesia (Bulach et al, 2005; Twersky et al, 1993; Ghoneim et al, 1990). There are rare case reports of retrograde amnesia (Koht et al, 1997), however the overwhelming majority of evidence suggests benzodiazepines do not cause retrograde amnesia (O’Boyle, 1988; Hupp et al, 1988).

Phenytoin [Dilantin, Phenytek]

Route & Dosage: 20 mg/kg IV.
Onset & Duration: onset 30-60min, peak 2-3hr, duration 12-24hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 7-42hr.
Indications: status epilepticus, anticonvulsant.
Contraindications: bradycardia or AV node dysfunction.
Adverse Effects: hypotension, cardiac arrhythmias, blood disorders, bone disorders, skin reactions, hepatic injury, hypothyroidism, porphyria, enlargement of facial features, gingival hyperplasia, hypertrichosis, blurred vision, confusion, constipation.
Drug Interaction: several minor, non-nucleoside reverse transcriptase inhibitors.
Black box warning: cardiovascular risk with rapid injection.
Phenytoin is an anticonvulsant medication that acts by blocking sodium channels. It is also a class Ib antiarrhythmic agent (see Table 15-7), though it is most commonly used for seizures. Phenytoin is indicated for status epilepticus but also used for non-emergency convulsions and for seizure prophylaxis. It was previously used to “load” patients for seizures prevention after head injury, however the newer medication levetiracetam is more commonly used for this indication. Rapid administration of the medication is associated with serious cardiovascular adverse effects, including cardiac arrest. Fosphenytoin is an alternative drug, which can be administered three times faster than phenytoin but does not necessarily achieve more rapid phenytoin levels in the body. Phenytoin is generally considered a second-line agent for status epilepticus, requires IV access, and has serious side effects if administered too quickly.
Dosing for status epilepticus is 20mg/kg IV administered at a maximum rate of 50mg/min (Brophy et al, 2012). An additional dose of 5-10mg/kg IV can be given 10 minutes after the loading dose if seizure persists. The dose is the same for children, with a maximum administration rate of 1mg/kg/min. Unlikely benzodiazepines, phenytoin lacks significant sedative and respiratory depressant effects. Phenytoin is not particularly useful for seizures related to alcohol withdrawal (Wilbur et al, 1981).
Phenytoin has a black box warning relating to rate of IV administration. Hypotension, bradycardia, AV block, and cardiac arrest rhythms are associated with rapid IV administration. Expert guidelines suggest a rate of 25-50mg/min in adults with an even slower rate of 10-20mg/min in the elderly or patients with cardiac disease. Pediatric infusion rates should be no faster than 1mg/kg/min and should be as low as 0.5mg/kg/min in neonates. Phenytoin levels are typically monitored in the hospital setting and liver function testing may be necessary due to the potential for liver toxicity. Patients with existing bradycardia or AV node dysfunction should not receive phenytoin due to the risk for cardiac arrest. There are several long term adverse effects with chronic phenytoin use including blood disorders, bone disorders, serious skin reactions, thyroid hormone alterations, issues with patients who have porphyria (a blood disease), enlargement of facial features, gingival hyperplasia (gum enlargement), hypertrichosis (excessive hair), and visual changes. Although the changes to facial features and gum are not acute, patients on chronic phenytoin may present with this which can complicate airway management. There are several minor drug interactions, such as CYP2C19, but these are not relevant in the prehospital setting. Phenytoin reduces the effectiveness of non-nucleoside reverse transcriptase inhibitors for HIV/AIDS, such as delavirdine. Although important for chronic administration, this is not particularly relevant in the prehospital setting for single-dose management of status epilepticus. Some formulations of phenytoin contain propylene glycol as a preservative, which is potentially toxic in large doses. Some formulations of phenytoin contain benzyl alcohol as a preservative, which is contraindicated for use in premature infants.

Osmotic Diuretics

Osmotic agents are pharmacologically inert, meaning they are not metabolized or used by the body. They act by increasing the solute concentration, which pulls water into that area. One example is sorbitol, a sweetener that can be used for constipation. The body cannot absorb sorbitol quickly through the gastrointestinal tract and the solute increase causes water to move into the gastrointestinal tract. Osmotic diuretics, such as mannitol, act by preventing the reabsorption of water and sodium in the kidney.
Mannitol increases the intravascular fluid volume by increasing solute concentration. This causes fluid outside the vessels to be pulled into the vessels. The increased intravascular fluid volume leads to increased kidney filtration, which inhibits the kidney’s ability to reabsorb water and electrolytes. Mannitol creates a gradient across the blood brain barrier, which makes it a useful agent for increased intracranial pressure. It is also thought that mannitol reduces blood viscosity (thickness), which can reduce intracranial pressure. However, the mechanism of action for mannitol with increased intracranial pressure is controversial (Brain Trauma Foundation, 2007). Mannitol has been shown to be useful in increased intracranial pressure, regardless of the exact mechanism.

Mannitol [Aridol, Osmitrol, Resectisol]

Route & Dosage: 1gm/kg IV.
Onset & Duration: onset 15-30min, duration 1.5-6hr.
Pharmacokinetics: liver metabolism (minimal), urine elimination, half-life 4.7hr
Indications: increased intracranial pressure (off-label), increased intraocular pressure, asthma testing.
Contraindications: severe renal disease, hypovolemia, congestive heart failure, pulmonary edema.
Adverse Effects: transient hypotension, vesicant, volume loss, electrolyte loss, kidney injury, headache, nausea, chest discomfort, cough, dyspnea, wheezing, precipitation, cerebral edema with prolonged use.
Drug Interaction: no major drug interactions, avoid mixing with other medications.
Black box warning: bronchospasm with powder form.
Mannitol is an osmotic diuretic when administered intravenously. It is used in the prehospital setting for head injury and increased intracranial pressure. Although this is an off-label use per the manufacturer, mannitol has been shown to decrease intracranial pressure (Brain Trauma Foundation, 2007). It is well accepted as a first line therapy option for patients with increased intracranial pressure in severe traumatic brain injury. The effectiveness of mannitol depends on an intact blood brain barrier. The larger the brain injury the more likely there is damage to the blood brain barrier. The onset of action for mannitol is 15-30 minutes to reduce intracranial pressure, but 1-3 hours to promote full diuresis (urine output). The reduction in intracranial pressure typically lasts 1.5-6 hours. Increased intracranial pressure is associated with pupil changes and the Cushing reflex of irregular respirations, hypertension, and bradycardia.
Dosing for mannitol in head injury is 0.25-2gm/kg IV, with a typical dose of 1gm/kg (1000mg/kg) given over 30-60 minutes. For children 12 years of age or older, the dose is 0.25-1gm/kg IV. Mannitol tends to precipitate if not handled appropriately or injected appropriately. A white flocculent precipitate occurs when it comes into contact with polyvinylchloride (PVC). For this reason, it should not be injected into an IV bag prior to administration. Premixed mannitol bags come in a flexible plastic container due to this issue. Before IV injection, the medication should be inspected for particulate matter and a filter is recommended, when possible, to prevent mannitol crystals from being injected. If crystals are present, they can be redissolved by warming the solution. A filter is particularly recommended for mannitol solutions of ≥ 20% (≥ 200mg/mL) and a blood filter set will suffice. Mixing mannitol with other solutions, including blood, can cause precipitation.
Mannitol is contraindicated in patients with severe renal disease, especially if they make little urine. These patients may be unable to filter the increased intravascular volume, which can cause congestive heart failure and pulmonary edema. Similarly, patients with current congestive heart failure or pulmonary edema may have worsening of these issues secondary to the increased intravascular volume. A loop diuretic, like furosemide, may be administered concurrently to help with removal of this excess fluid. Patients who are hypovolemic are unlikely to tolerate the additional loss of fluid caused by mannitol. In head trauma patients with multiple injuries, this is a common issue. Hypovolemia from blood loss combined with profound diuresis from mannitol results in severe hypotension. The damaged brain does not tolerate hypotension, which will worsened the brain injury. Intravenous fluids should be given in adequate amounts to restore intravascular volume. The manufacturer lists active intracranial bleeding as a contraindication to mannitol. However, no randomized trials support this and many head trauma protocols recommend the use of mannitol for suspected intracranial hypertension even in patients with hemorrhagic injury. Guidelines for intracerebral hemorrhage do not list this is a contraindication to mannitol use (Broderick et al, 2007).
The profound diuresis caused by mannitol can quickly fill the bladder. In patients who cannot actively empty their bladder, such as unconscious head trauma patients, a urinary catheter is useful. Bladder overdistension can lead to significant hypertension in these patients. Mannitol causes an initial transient hypotension with rapid administration, followed by an increase in blood volume. Electrolyte abnormalities are associated with mannitol, though these are typically not monitored in the prehospital setting. Common adverse effects include headache, nausea, chest discomfort, cough, dyspnea, and wheezing. Kidney injury can be worsened or cause by mannitol. In prolonged use, cerebral edema can occur. Mannitol is a vesicant that can cause tissue injury if extravasated. Management of extravasated mannitol is to apply a cold compress and elevate the limb. Definitive treatment with hyaluronidase may be needed upon arrival to the hospital. There is a black box warning for the powder form of mannitol, which can cause bronchospasm. This formulation is not used in the prehospital setting and is for asthma testing.
That’s Not True … or Is it? Hyperventilation and Head Injury
Hyperventilation causes a decrease in carbon dioxide levels in the blood (pCO2). This decreases cerebral blood flow, which decreases cerebral blood volume and thus decrease intracranial pressure. From a physiologic standpoint this makes sense and was the basis for the use of hyperventilation in head injury. However, several studies have shown no improvement in outcomes with hyperventilation and some have shown worse outcomes. The worse outcomes may be due to decreased cerebral blood flow to injured areas of the brain. The Brain Trauma Foundation has reviewed the evidence on this topic and routine hyperventilation is not recommended in patients with head injury (Badjatia et al, 2008). Providers should target an ETCO2 value of 35-40mmHg and avoid an ETCO2 < 35mmHg. Mild hyperventilation to 30-35mmHg is only indicated if there are signs of cerebral herniation, which include abnormal posturing and dilation or one or both pupils.

Medications Used for Gastrointestinal Emergencies

Antiemetic Agents

The nausea center of the brain is found in the chemoreceptor trigger zone (CTZ) of the area postrema, which is part of the brainstem. This portion of the brain is outside of the blood brain barrier, which allows it to detect toxins in the blood and induce vomiting. Opioids, for example, activate this area of the brainstem to cause nausea. The 5HT-3 antagonists are generally effective without significant side effects. The D2 antagonists and antihistamine agents, though useful, typically have more side effects. Droperidol is a first-generation antipsychotic that has been used for peri-operative nausea and vomiting, however concerns for QT prolongation have limited use of this medication.

Table 15-12: Nausea Receptors and Medications

Ondansetron [Zofran]

Route & Dosage: 4mg IV/IM, 8mg PO.
Onset & Duration: onset rapid, peak 10min IV and 40min IM, duration 4hr.
Pharmacokinetics: liver metabolism, urine and feces elimination, half-life 3-6hr.
Indications: nausea and vomiting.
Contraindications: apomorphine use, long QT interval.
Adverse Effects: headache, fatigue, malaise, constipation, drowsiness, anxiety, several others.
Drug Interaction: apomorphine, serotonergic agents.
Black box warning: maximum single dose, serotonin syndrome.
Ondansetron is a selective 5HT-3 receptor antagonist used for the management of nausea and vomiting. Ondansetron has anti-nausea effects as well as anti-vomiting effects, meaning it is useful for prevention of vomiting as well as treatment of vomiting. Its anti-vomiting effects are greater than its anti-nausea effects. Many consider ondansetron the current “gold standard” compared to other antiemetics. The NK1 antagonists may be more effective than the 5HT-3 antagonists, however the 5HT-3 antagonists are available in IV formulation as well as oral disintegrating tablet (ODT).
Dosing is 4mg IV given over 2-5 minutes or 8mg PO. These two doses are considered equivalent (Grover et al, 2009). For infants ≥ 1 month, the dose is 0.1mg/kg IV over 2-5 minutes with a maximum single dose of 4mg. Prolongation of the QT interval is a common side effect of all the 5HT-3 antagonists and is one of ondansetron’s black box warnings. The FDA released a statement in 2012 that a single dose of 32mg IV can prolong the QT interval and potentially cause torsades de pointes. The risk is higher for patients with congenital QT prolongation. However, there are currently no case reports of torsades de pointes in patients receiving a single dose of ondansetron. There have been rare case reports of dolasetron, a different 5HT-3 antagonist, causing torsades (Roberts et al, 2012). Regardless, the black box warning limits a single dose to 16mg IV (well above the 4mg IV standard dose) and to 8mg IV in patients ≥ 75 years old.
Ondansetron is associated with headache, fatigue, malaise, constipation, drowsiness, anxiety, and several other non-serious adverse effects. Apomorphine is a dopamine agonist that may be used for Parkinson disease, alcoholism, opioid addiction, and Alzheimer disease. It is a breakdown product of morphine, but does not contain morphine. The use of 5HT-3 antagonists is contraindicated in patients taking apomorphine due to the risk of profound hypotension with loss of consciousness. Ondansetron has the potential to cause serotonin syndrome when combined with other serotonergic agents, which patients may be taking for depression or chronic pain. Serotonergic agents include the cyclic antidepressants, serotonin specific reuptake inhibitors, and stimulant recreational drugs. Serotonin syndrome from ondansetron alone or in a single dose is unlikely. The risk increases in patients taking multiple serotonergic medications or in patients who took a large amount of one agent.

Prochlorperazine [Compazine, Compro]

Route & Dosage: 2.5-10 IV/IM/PO.
Onset & Duration: onset < 10min, peak 30-60min, duration 3-4hr.
Pharmacokinetics: liver metabolism, feces elimination, half-life 6-10hr.
Indications: nausea and vomiting, antipsychotic.
Contraindications: concurrent CNS depressants, children < 2 years old.
Adverse Effects: ECG changes, hypotension, cardiac arrest, agitation, sedation, coma, headache, restlessness, neuroleptic malignant syndrome, priapism, impotence, galactorrhea, liver injury.
Drug Interaction: CNS depressants.
Black box warning: dementia-related psychosis.
Prochlorperazine is a neuroleptic (antipsychotic) medication which acts on the dopaminergic D1 and D2 receptors in the brain, including in the chemoreceptor trigger zone. Aside from anti-nausea effects from blockade of dopamine receptors, there are several dopamine-related side effects. Prochlorperazine is in the same category as chlorpromazine, which will be discussed later. These two medications are noted as having potential for sound-alike/look-alike issues. Prochlorperazine and promethazine are primarily used for nausea; these can be differentiated from the other -azine antipsychotics by the starting “pro” in the name. Prochlorperazine also affects the reticular activating system (RAS) in the brainstem. The RAS is responsible for wakefulness and sleep-wake transition, which explains the drug’s sedative effects. The RAS is also involved in unconsciousness from traumatic injury, such as from a boxer’s knockout punch.
Dosing for nausea and vomiting is 2.5-10mg IV with a maximum single dose of 10mg in adults. Dosing can be repeated every 3-4 hours as needed. IM and PO dosing is 5-10mg with a daily maximum of 40mg. In children > 2 years old, the dose is 0.13mg/kg IM. Oral dosing is 2.5mg PO in children. There are no standard IV dosing guidelines for children. The preferred IM location is in the deep muscle of the outer quadrant of the buttocks. If one antiemetic fails, choosing an antiemetic with a different mechanism of action is much more effective than using the same antiemetic class. For example, if a 4mg IV dose of ondansetron does not alleviate nausea then a 5mg IV prochlorperazine dose will be more effective than a repeat 4mg IV ondansetron dose (Gan et al, 2014).
Because of the sedative effects, prochlorperazine should be used with caution in patients taking other CNS depressants including sedative-hypnotics and opioids. In elderly patients who have dementia-related psychosis, antipsychotic medications increase the risk of death. Side effects of prochlorperazine include ECG changes, hypotension, sedation, agitation, headache, and possible liver injury. Serious side effects are uncommon, but include coma and cardiac arrest. Blockade of the dopamine pathway can cause impotence, priapism (sustained erection), galactorrhea (spontaneous milk flow from breasts) in women and men, and extrapyramidal symptoms (EPS). Extrapyramidal symptoms include akathisia (inability to remain still), rigidity similar to Parkinson disease, irregular jerky movement (tardive dyskinesia), and dystonia (spasms and muscle contractions). Patients may report allergies to these medications after experiencing the uncomfortable, unrelenting akathisia sensation. Spasm of the neck to one side is termed torticollis. Spasm of the eyes, typically in an upward gaze, is termed oculogyric crisis. Neuroleptics can also induce neuroleptic malignant syndrome (NMS), especially when used in combination. NMS involves unstable blood pressure, confusion, muscle rigidity, and fever > 38ºC. NMS is considered a medical emergency and requires definitive treatment at a hospital. Do not use the abbreviation CPZ for Compazine, as this may be used for chlorpromazine. On that note, the ISMP does not recommend using any shorthand or abbreviations for medications.

Promethazine [Phenadoz, Phenergan, Promethegan]

Route & Dosage: 12.5-25mg IM.
Onset & Duration: onset 5min, duration 4-6hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 9-16hr.
Indications: nausea and vomiting.
Contraindications: children < 2 years old, intra-arterial injection, subcutaneous injection.
Adverse Effects: arrhythmia, confusion, neuroleptic malignant syndrome, tinnitus, seizure.
Drug Interaction: CNS depressants.
Black box warning: respiratory depression in children, tissue necrosis.
Promethazine is an antiemetic that works on dopaminergic receptors, histamine receptors, and muscarinic receptors. It is a strong histamine receptor antagonist and a moderate anticholinergic. It has weak dopaminergic effects and also has some effects on sodium channels, making it a local anesthetic as well. However, subcutaneous injection is contraindicated. The antihistamine effects can lead to CNS depression and enhance other CNS depressants, such as opioids. One particular prescription-strength cough syrup, containing the opioid codeine and promethazine, has been used illegally to enhance the euphoric effects of alcohol. This recreational concoction, popularized as “Purple Drank”, has led to several deaths. A different medication found in some cough syrups, dextromethorphan, has properties similar to ketamine and is also abused recreationally in a practice called “Robotripping” (named after the Robitussin brand). The FDA has had advisory panels to discuss prevention of adolescent abuse for both of these medications.
Dosing for nausea and vomiting 12.5-25mg IM, PO, or IV every 4-6 hours as needed. Deep IM injection is preferred over IV due to the risks of tissue necrosis with extravasation. PO and rectal dosing are the same, though PO dosing is potentially difficult in a nauseated patient. For children ≥ 2 years, dosing is 0.25-1mg/kg every 4-6 hours, with a single maximum dose of 25mg. If administering via IV, the solution should be diluted and given through a large bore vein. Preferred administration is into the IV port that is furthest from the patient while the IV fluid is flowing, which gives the drug more time to dilute before reaching the patient. If burning or pain occurs, the infusion should be stopped immediately and assessment made to ensure extravasation is not occurring.
Because of the sedative effects, promethazine should be used with caution in patients taking other CNS depressants including sedative-hypnotics and opioids. Side effects of prochlorperazine include ECG changes, hypotension, sedation, seizure, tinnitus, and agitation. Dopaminergic side effects can be seen, similar to prochlorperazine, but to a lesser degree given the mild effects at this receptor. A black box warning exists for children < 2 years old, who should not receive promethazine due to the potential for fatal respiratory depression. In children ≥ 2 years old, caution should be used and the lowest effective dose given. In 2009 a patient received an IV push injection of promethazine, which resulted gangrene and subsequent amputation of her arm. The injection was intended to be IV but was accidentally injected into her artery. This led to the black box warning that IM is the preferred route, with contraindication being intra-arterial injection and subcutaneous injection. If extravasation does occur, attempt to gently aspiration the solution, then remove the cannula. Elevate the extremity and apply a dry cold compress (Hurst et al, 2004).

Histamine-2 Receptor Antagonists

Histamine-2 receptor antagonists (H2RAs) inhibit gastric acid secretion by blocking the histamine-2 receptors in stomach parietal cells. There are several available including cimetidine, ranitidine, and famotidine. Many H2RAs can be obtained over-the-counter with uses in stomach ulcers and gastroesophageal reflux disease (GERD). Proton pump inhibitors (PPIs) cause more acid suppression and are also use for chronic management of GERD. For dyspepsia (i.e. heartburn, indigestion), H2 blockers have more rapid onset than PPIs. Histamine is released during allergic reactions, thus H2RAs have a role in the management of anaphylaxis as well.

Cimetidine [Tagamet]

Route & Dosage: 4mg/kg IV.
Onset & Duration: onset < 1hr, duration 4hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2hr.
Indications: anaphylaxis, dyspepsia.
Contraindications: no major contraindications.
Adverse Effects: confusion especially in the elderly, headache, dizziness.
Drug Interaction: P450 inhibitor.
Cimetidine is the first of the H2RAs developed for management of gastric acid secretion. It is still used for this purpose, but also has a role in the prehospital setting for allergic reaction management. Administration of H1 and H2 blockers together may be superior to H1 blockers alone (Tang, 2003). Cimetidine has been shown to be useful in anaphylaxis (Mayumi et al, 1987) as well as refractory anaphylaxis (Yarbrough et al, 1989). The other H2 blockers have less evidence for use in anaphylaxis.
Dosing for allergic reactions is 4mg/kg IV. This is in the range of typical oral dosing for dyspepsia, which is 200-400mg PO every 6 hours as needed. It is important to recall that the primary treatment for anaphylaxis is epinephrine and H1 blockers. Although the combination of H1 and H2 blockers may be more effective, it should not be given before or replace epinephrine. Recall that epinephrine is given IM for anaphylaxis, See Table 15-8. There are no major contraindications to the use of cimetidine. There are some P450 enzyme interactions, but none are clinically relevant in the prehospital setting with acute dosing. Dizziness and headache may be seen with cimetidine. Confusion after administration is more common in patients > 50 years old.

Medications Used for Metabolic Endocrine Emergencies

Carbohydrate Solutions

Carbohydrate solutions are used to increase blood glucose levels in hypoglycemia patients. Hypoglycemia is considered a medical emergency due to the risks from having an inadequate supply of glucose to the brain. Many of the manifestations of hypoglycemia are adrenergic, thus they would not be seen in a patient taking beta blockers. Sweating, however, is not prevented by beta-blockers thus this sign is useful in evaluating patients with suspected hypoglycemia. The mainstay of treatment is glucose. However, not all patients with hypoglycemia can swallow thus intravenous dextrose solutions exist.

Dextrose (50%, 25%, 10%)

Route & Dosage: 10-25g IV.
Onset & Duration: onset rapid, duration depends on degree of hypoglycemia.
Pharmacokinetics: liver metabolism, urine elimination, half-life 30 minutes.
Indications: hypoglycemia.
Contraindications: intracranial hemorrhage, hyperglycemic coma, dehydration, anuria, hepatic coma, thiamine deficiency.
Adverse Effects: vesicant if extravasated, hypokalemia, hyponatremia, hyperglycemia, hypotension.
Drug Interaction: no significant interactions.
As described early in this chapter, recall that dextrose solutions are very poor choices for fluid resuscitation and maintenance of IV patency. Intravenous dextrose comes in several concentrations: D5W (5%, 50mg/mL), D10W (10%, 100mg/mL), D25W (25%, 250mg/mL), and D50W (50%, 500mg/mL). D5W is isotonic alone but quickly becomes hypotonic with liver metabolism of the dextrose, leaving only water. D50 is hypertonic in solution, which can lead to venous irritation and hyperglycemia which can result in dehydration and coma. Hyperglycemia is associated with worse outcomes in myocardial infarction and neurologic injuries, including traumatic brain injury and stroke. Further, concentrated dextrose solutions like D50 may be difficult to administer in cold environments. Glucagon is a treatment option that may have benefits over D50 in prehospital patients (Carstens et al, 1998).
Dosing for intravenous dextrose depends on the level of hypoglycemia and also varies between institutions. For patients that are unable to swallow or those who do not respond to oral glucose treatment, a slow IV bolus of dextrose can be given. The bolus is 0.25g/kg up to a maximum single dose of 25g. Infants and children < 12 years old should receive 2.5mL/kg of D10W. Adults and adolescents can receive 1mL/kg of D25W or 0.5mL/kg of D50W. Alternatively, adults can receive D10W given in 50mL (5g) increments instead of D50. If IV access cannot be obtained, IM or subcutaneous glucagon is an option. After reversal of hypoglycemia, it is appropriate to start a D10W infusion at 6-9mg/kg/min to maintain a blood glucose level of 70-150mg/dL. This is especially important in patients with an unknown cause for hypoglycemia or those who ingested long-acting hypoglycemic medications.
Hypertonic solutions should not be used in patients with intracranial hemorrhage, thus D50W is not recommended in these circumstances. Concentrated solutions like D50 can lead to dehydration and hyperglycemic coma, thus monitoring of serum glucose levels is important. Dextrose IV solutions should not be used in patients who are dehydrated, do not make urine (anuria), or have coma associated with liver disease. In alcoholic patients with thiamine deficiency, Wernicke encephalopathy can develop. This involves confusion, abnormal gait, and abnormal eye movements. These patients should receive thiamine first, before dextrose. Giving dextrose first can worsen neurologic injury in these patients. Hypokalemia may be associated with concentrated solutions (e.g. D50) and hyponatremia with dilute solutions (e.g. D5). Hypotension may be seen after bolus dosing of D50 and other concentrated solutions. Hyperosmolar dextrose solutions (e.g. D50) are associated with significant tissue injury if extravasated. If extravasation occurs, gently aspirate from the catheter, remove the catheter, elevate the extremity, and apply a dry cold compress (Hurst, 2004). Additional treatment with hyaluronidase may be needed in the hospital setting.
So, why use D50 if it is associated with multiple side effects? Why not use D10 which has an osmolarity of 506mOsm/L and is within a safer range for peripheral administration? This question was investigated by Moore et al where D10 was found to be safer and just as effective as D50 when given in 5g increments. There are some criticisms of this study and debate on whether D50 or D10 is the best solution. Until further studies resolve this issue, it is best to stick with your institution’s protocols.

Glucose (generic)

Route & Dosage: 0.3g/kg PO.
Onset & Duration: onset 10 minutes, duration depends on degree of hypoglycemia.
Pharmacokinetics: liver metabolism, urine elimination, half-life 30 minutes.
Indications: hypoglycemia.
Contraindications: intracranial hemorrhage, hyperglycemic coma, dehydration, anuria, hepatic coma, thiamine deficiency.
Adverse Effects: hyperglycemia.
Drug Interaction: no significant interactions.
Oral glucose is associated with significantly fewer side effects when compared to intravenous dextrose. Onset is less rapid, but occurs within 10 minutes of administration. The oral route is preferred for hypoglycemia management and is only avoided if the patient is not alert or does not have an intact gag reflex. Dosing is 0.3g/kg (10-20g) PO of a rapidly absorbed carbohydrate. This could be 2-3 glucose tablets, a 15g tube of gel, 4oz (120mL) of sweetened fruit juice or non-diet soda, or a teaspoon (5mL) of honey or table sugar. The dose may be repeated in 10-15 minutes as needed. Contraindications are similar to intravenous dextrose. Patients who cannot maintain normal glucose levels with oral intake should be taken to the hospital. Hypoglycemia of unknown cause or after ingestion of long-acting hypoglycemic agents should prompt transport to the hospital. Further, patients who have additional hypoglycemic episodes during an observation period should also be brought to the hospital.

Hormones

As previously mentioned, glucagon is an option to increase serum glucose levels in patients who are hypoglycemic. Some diabetic patients carry emergency kits with glucagon for injection during hypoglycemic events. Glucagon also improved cardiac contractility via a non-adrenergic mechanism, thus it is useful in the management of beta-blocker overdose and calcium channel blocker overdose. Insulin is a hormone primarily used to decrease serum glucose levels. It comes in many different varieties with very different pharmacokinetic properties. These are typically divided into short-acting, intermediate-acting, and long-acting. Regular insulin is a short-acting formulation that can be used for intravenous infusion .

Glucagon [GlucaGen]

Route & Dosage: 1mg IM/subcutaneous/IV.
Onset & Duration: peak 5-20min IV and 30min IM, duration 60-90min.
Pharmacokinetics: liver metabolism, urine elimination, half-life < 45min.
Indications: hypoglycemia, beta blocker overdose (off-label), calcium channel blocker overdose (off-label).
Contraindications: pheochromocytoma, insulinoma.
Adverse Effects: hypertension, tachycardia, delayed hypotension, nausea, vomiting.
Drug Interaction: no significant interactions.
Glucagon is a hormone that stimulates adenylate cyclase to produce increased cyclic AMP. This leads to hepatic glycogenolysis and gluconeogenesis, which increases blood glucose levels. Glucagon will increase cardiac contractility, cardiac output, and systemic blood pressure (Murtagh et al, 1970). Inotropy and chronotropy (heart rate) are increased even in the presence of beta-adrenergic blockade (Parmley et al, 1968). However, use of glucagon to increase cardiac output is off-label and should be reserved for refractory hypotension in beta-blocker or calcium channel blocker overdose.
Dosing for hypoglycemia in adults is 1mg IM, subcutaneous, or IV. Dextrose IV should be available in the event that the patient fails to respond to glucagon. Dosing may be repeated every 15 minutes as needed. The dose and routes are the same for children down to 20kg. For children < 20kg, the dose is 0.5mg or 0.02-0.03mg/kg/dose every 15 minutes as needed. For beta-blocker overdose, the dose is 3-10mg IV (or 0.05-0.15mg/kg) followed by an infusion of 3-5mg/hr (or 0.05 to 0.1 mg/kg/hour), titrated to effect (Vanden Hoek et al, 2010). In children the dosing is 30-150mcg/kg IV followed by an infusion of 70mcg/kg/hour, with a maximum of 5mg/hr (Hegenbarth et al, 2008).
Glucagon is contraindicated in patients with known pheochromocytoma or known insulinoma. Fortunately, these hormone-secreting tumors are rare and not particularly relevant in the prehospital setting. Increased cardiac function including hypertension and tachycardia can be seen with glucagon use. Hypotension may occur after this effect wears off. Nausea and vomiting can occur secondary to smooth muscle relaxation in the gastrointestinal tract. The American Diabetes Association (ADA) recommends that family members and/or caregivers be trained in the administration of glucagon when caring for diabetic patients.

Insulin, regular [HumuLIN, NovoLIN]

Route & Dosage: 2-8units subcutaneous, 2-8units/hr IV.
Onset & Duration: onset immediate (IV), peak rapid (IV), duration 10min.
Pharmacokinetics: liver metabolism, urine elimination, half-life 0.5-1hr.
Indications: hyperglycemia, hyperkalemia (off-label).
Contraindications: hypoglycemia.
Adverse Effects: palpitations, tachycardia, confusion, diaphoresis, hypoglycemia, hypokalemia, nausea, tremor, temporary blurred vision.
Drug Interaction: beta blockers, hypoglycemics.
Insulin is a broad term for the peptide hormone produced in the pancreas beta cells. It promotes the absorption of glucose from blood into tissues. It is produced in proportion to glucose in the blood to remove the excess amount, which would otherwise lead to detrimental effects. Insulin, as a drug, comes in many different forms. Here are some examples:

Table 15-13: Insulin Preparations, Subcutaneous Administration

Insulin is typically administered subcutaneously. Regular insulin can be administered subcutaneously as well as intravenously, though the latter is an off-label use. However, IV regular insulin infusions are not uncommon and have been well studied. Mild to moderate hyperglycemia alone can be treated with subcutaneous insulin. For severe hyperglycemia, providers should try to determine if the patient is in diabetic ketoacidosis (DKA) or is in a hyperosmolar hyperglycemic state (HHS). The management of these two disorders involves insulin, but also includes fluid replacement and potassium replacement.
Dosing of insulin depends on several factors including the patient’s current glucose level and their typical insulin requirements. Several protocols are available for subcutaneous and intravenous dosing. For isolated hyperglycemia, a typical subcutaneous regimen is 2units regular insulin for every 50mg/dL glucose > 200mg/dL.

Table 15-14: Regular Insulin Example Subcutaneous Algorithm

Table 15-15: Regular Insulin Example Intravenous Algorithm

In this example intravenous algorithm, Level 1 is started once blood glucose levels are > 140mg/dL. This would be the typical starting level, particularly in patients who are insulin-naïve or at risk for hypoglycemia. For patients who fail Level 1 or have an initial glucose > 251mg/dL, Level 2 would be appropriate. Level 3 would be used for patients who fail Level 2 or have initial blood glucose levels > 400mg/dL. The infusion should be stopped when blood glucose levels are < 100mg/dL and treatment with dextrose is considered for glucose levels < 75mg/dL. Glucose levels < 50mg/dL during insulin infusion should always be treated.
Regular insulin may be given intravenously in the management of hyperkalemia. Dosing is 10units IV mixed with 25g of D50 (50mL) given over 15-30 minutes. The potassium-lowering effects are only temporary, so other measures should be taken to remove excess potassium (e.g. furosemide). Like many of the medications discussed in this chapter, unintentional overdose during administration can lead to serious morbidity and even death. Insulin may come in concentrated formulations (e.g. 100units/mL) that should be diluted prior to administration. Regular insulin can be found in 10mL vials that are 100units/mL. Bolus administration of this vial would be 1000units, enough to seriously harm any patient. A typical dilution would be 100units of regular insulin into a 100mL saline bag to make 1unit/mL concentration. This would be only 1mL of the 100units/mL concentrated regular insulin diluted into 100mL. Even free flow of this infusion bag (1unit/mL) could cause serious harm to a patient. For this reason, insulin infusions should always be on programmed infusion pumps.
Side effects of insulin administration include palpitations, tachycardia, confusion, diaphoresis, nausea, tremor, and temporary blurred vision. Insulin should be used with caution in patients who are on oral hypoglycemic medications as they can potentiate the effects, leading to rapid hypoglycemia. Beta blockers mask the adrenergic signs seen with hypoglycemia, thus they should be used with caution in patients on insulin infusions. Likewise, vigilance is needed when running insulin infusions in patients who are on beta blockers.

Vitamins

Vitamins are nutrients that humans need in limited amounts to function. They are easily obtained for an appropriate diet and even sunlight (i.e. vitamin D). Deficiency of a particular vitamin can have effects ranging from minor to life-threatening. Vitamin deficiencies are rarely emergencies, with the exception of thiamine deficiency as seen in alcoholic patients. Chronic alcoholism leads to thiamine deficiency via several mechanisms (Hoyumpa, 1980). First, alcoholics typically have inadequate intake of thiamine due to poor diet or malnutrition. Second, there may be reduced liver storage of thiamine and decreased conversion of thiamine to its active form. Third, ethanol inhibits intestinal thiamine transport. Eventually, this leads to Wernicke-Korsakoff syndrome (WKS).

Thiamine, Vitamin B1 (generic)

Route & Dosage: 100mg IV/IM.
Onset & Duration: onset rapid, duration depends on degree of deficiency.
Pharmacokinetics: urine elimination, half-life 9-18days.
Indications: alcohol withdrawal syndrome ,Wernicke encephalopathy.
Contraindications: no major contraindications.
Adverse Effects: cyanosis, restlessness, pruritus, nausea, throat tightness, GI bleed, weakness, pulmonary edema.
Drug Interaction: no significant interactions.
Thiamine, or vitamin B1, is an essential component in the metabolism of carbohydrates. It is found in oatmeal, brown rise, vegetables, eggs, pork, and liver. Chronic alcoholic patients may develop low levels of thiamine, which can lead to Wernicke encephalopathy. This is characterized by ocular disturbances, unsteady stance, and changes in mental state. Thiamine should be use for immediate treatment and can also be used in alcohol withdrawal syndrome. Dosing is 100mg IV or IM given once, followed by a daily dosing regimen.
Previously used “coma cocktails” included thiamine, glucose, and other medications. If glucose and thiamine are to be given, thiamine should be given first. Administration of glucose can potentiate neurologic injury in Wernicke encephalopathy if given first. However, the concept of a “coma cocktail” is considered to be a bad idea and should be abandoned (Bledsoe, 2002). Indiscriminate use of medications can lead to patient harm. Adverse effects are not common but can include cyanosis, restlessness, pruritus, nausea, throat tightness, GI bleed, weakness, and pulmonary edema. The benefit of thiamine, as well as dextrose, often outweigh the risk in patients with suspected alcohol-related or hypoglycemia-related coma. The same cannot be said about naloxone and flumazenil in patients with altered mental status of unknown origin.

Medications Used for Allergic Reaction

Antihistamines

Histamine is a neurotransmitter with functions in the gut and during immune responses. It is generated in mast cells and basophils within the body. During severe immune reactions, a large amount of histamine can be released. Some medications used in the pre-hospital setting can cause histamine release, such as morphine and succinylcholine. Certain antibiotics can cause histamine release, such as vancomycin (i.e. Red Man Syndrome). Eating spoiled fish can cause scombroid, a condition involving ingestion of a substance in the fish that converts to histamine and mimics an allergic reaction.
There are 4 main histamine receptors, with the H1 and H2 receptors being the most relevant. Histamine-1 receptor activation leads to bronchial smooth muscle contraction, pain, itching, vasodilation, runny nose, and motion sickness. Histamine-2 (H2) receptor activation leads to gastric acid secretion and vasodilation. Combined, this can lead to severe hypotension and difficulty breathing. The H2-receptor blockers were previously discussed, including cimetidine. Here we will discuss the Histamine-1 (H1) receptor blockers, in particular diphenhydramine.

Diphenhydramine [Benadryl]

Route & Dosage: 10-50mg IV/IM.
Onset & Duration: onset 2-3min IV and 20-30min IM, peak 2hr, duration 4-8hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 5-14hr.
Indications: allergic reactions, insomnia, cough, motion sickness, rhinitis, extrapyramidal symptoms.
Contraindications: neonates, children < 6 years old (for sleep).
Adverse Effects: CNS depression, urinary retention, blurred vision, chest tightness, nausea, constipation, diarrhea, angle-closure glaucoma.
Drug Interaction: sedatives and opioids.
Diphenhydramine is a first-generation H1 receptor antagonist. First-generation medications are non-selective for peripheral and central H1 receptors, thus they are associated with sedation. Second-generation and third-generation H1 antagonists are primarily used for seasonal allergy symptoms. These later generation blockers have significantly less sedation and side effects when compared to diphenhydramine. Other first-generation H1 antagonists include promethazine (for nausea), hydroxyzine (for anxiety), and meclizine (for motion sickness).
Due to the wide range of effect, diphenhydramine is used to treat many different conditions including cough, rhinitis (runny nose), motion sickness, and extrapyramidal symptoms. Extrapyramidal symptoms are associated with dopamine antagonist antiemetics droperidol, metoclopramide, and prochlorperazine. Due to the powerful hypnotic effects of diphenhydramine, it is approved as an over-the-counter sleep aid. The sedative effects could last a significant period though, since elimination half-life is about 5 hours in children, 9 hours in adults, and 14 hours in the elderly. Diphenhydramine can be found in many different over-the-counter cough suppressants and viral cold medications. Additionally, diphenhydramine has anti-cholinergic effects. In the pre-hospital setting, it is primarily used for allergic reactions.
Dosing for allergic reactions in adults is 10-50mg IV/IM with dosing being dependent on age. A typical adult dose would be 25-50mg with lower doses in the elderly. A single dose can be up to 100mg but no more than 400mg should be given in a 24 hour period. Most anaphylaxis protocols recommend giving diphenhydramine along with or shortly after epinephrine. For children ages 6-12, the dose is 12.5-25mg IV/IM to a maximum of 150mg per day. For children ages 2-6, dosing is 6.25mg IV/IM to a maximum of 37.5mg per day, but use is off-label for this age group. An alternative child dosing scheme is 1-2mg/kg/dose to a maximum of 50mg per dose (Hegenbarth et al, 2008).
Diphenhydramine should not be used in neonates and premature infants. It should also not be used to induce sleep in children < 6 years of age. The major side effect of diphenhydramine is sedation. Combination of sedatives with other sedatives or opioids increases the risk for respiratory depression. Other anti-histamine effects include bronchial relaxation, dry nose, and constipation. Anti-cholinergic effects are also seen, including urinary retention, blurred vision, and worsening of angle-closure glaucoma. Additional reported side effects include diarrhea and nausea, though these effects are less common given that anti-histamine and anti-cholinergic medications typically treat these symptoms.

Beta Agonists

Anaphylaxis is a serious, life-threatening condition that requires immediate treatment. Acute skin manifestations are the most common signs of anaphylaxis and include generalized urticaria (hives), angioedema (skin swelling), flushing, pruritus (itching). Approximately 10-20% of patients will not have cutaneous signs. The primary, and most important, therapy for anaphylaxis is epinephrine. There are no absolute contraindications to the use of epinephrine in anaphylaxis and it should be administered as soon as possible.
It is worth repeating that the 1:10,000 (1mg in10mL) concentration of epinephrine is for intravenous use and only used in patients who are in cardiac arrest. Epinephrine doses ≥ 0.5mg are not typically administered to patients who have a pulse. The 1:1,000 (1mg per mL) concentration is for intramuscular and subcutaneous injection, with typical doses < 0.5mg. Refer to table Table 15-8 for appropriate epinephrine dosing and route of administration.

Epinephrine 1:1000 (IM)

Route & Dosage: 0.3mg IM.
Onset & Duration: onset 5-10min, duration 20min.
Pharmacokinetics: liver metabolism, urine elimination, short half-life.
Indications: severe allergic reaction, anaphylaxis.
Contraindications: severe coronary artery disease, severe aortic stenosis.
Adverse Effects: tachycardia, hypertension, hypokalemia, hyperglycemia, pallor.
Drug Interaction: none contraindicated, cocaine, sodium bicarbonate.
Epinephrine has multiple beneficial effects during anaphylaxis. Alpha-1 receptor activation increases blood pressure through vasoconstriction and decreases mucosal edema in the larynx. Beta-1 receptor activation increases heart rate and cardiac contractility. Beta-2 receptor activation decreases mediator release from mast cells and basophils. It also leads to bronchodilation. Combined, these factors can alleviate the cardiac and pulmonary complications of anaphylaxis. For this reason, epinephrine should be used as soon as possible in patients with severe allergic reactions. For anaphylaxis, the preferred injection location is the outer thigh. Epinephrine injection into the anterolateral aspect of the middle third of the thigh provides the highest peak blood levels (Vanden Hoek et al, 2010).
Dosing is 0.3mg of the 1:1,000 (1mg/mL) concentration given IM. The preferred IM location is the mid-outer thigh. Administration can be repeated every 5-15 minutes as needed. Adult epinephrine auto-injectors come in 0.3mg per injection. If symptoms do not resolve, an epinephrine infusion may be started and titrated to response. For children, the dose is 0.01mg/kg IM into the mid-outer thigh with a maximum single dose of 0.3mg. Up to 0.5mg may be used in children and adults for a single dose (Vanden Hoek et al, 2010), however this is rarely necessary and the 0.3mg dose can be repeated in 5-15 minutes as needed. Epinephrine auto-injectors for children come in 0.15mg per injection.
The contraindications, side effects, and drug interactions of epinephrine have been previously discussed. Although there are situations where tachycardia can be seriously detrimental (e.g. severe coronary artery disease, severe aortic stenosis), epinephrine should still be administered in these patients if they are having an anaphylactic reaction.

Corticosteroids

Corticosteroids are steroid hormones that are subdivided into glucocorticoids and mineralocorticoids. Glucocorticoids, in particular, are used in the management of allergic reactions. They have anti-inflammatory effects and are intended to relieve symptoms of anaphylaxis that occur after the initial insult of histamine. Since the peak effect for these medications is delayed, they are much less important in the initial management of anaphylaxis and should not delay the use of epinephrine. Further, no randomized controlled trials have shown that glucocorticoids are effective in anaphylaxis (Choo et al, 2012). Despite this, some feel that the possible benefit outweighs any harm so many anaphylaxis protocols still include corticosteroids.
The glucocorticoids dexamethasone, hydrocortisone, and methylprednisolone have been previously discussed. For anaphylaxis, methylprednisolone is the steroid most commonly used. Dosing is 125mg IV for adults and 1mg/kg IV for children, to a maximum of 125mg.
To summarize the several of the medications discussed thus far, here is an example of an anaphylaxis protocol for adults and children.
1) Manage airway, including immediate intubation if impending respiratory obstruction from angioedema.
2) Administer epinephrine. Adults: 0.3mg IM. Children: 0.15mg IM.
3) Administer high flow oxygen as needed.
4) Administer fluid bolus to treat hypotension.
5) Consider albuterol. Adults: 2.5-5mg nebulized. Children: 0.15mg/kg nebulized.
6) Consider H1 antagonist. Adults: 25-50mg IV diphenhydramine. Children: 1mg/kg IV diphenhydramine.
7) Consider H2 antagonist. Adults/Children: cimetidine 4mg/kg IV.
8) Consider glucocorticoid. Adults: 125mg IV methylprednisolone. Children: 1mg/kg IV methylprednisolone.
9) For refractory symptoms, consider an epinephrine infusion. For refractory hypotension, consider a vasopressor such as norepinephrine. For patients on beta-blockers who poorly respond to epinephrine, consider glucagon.

Medications Used for Behavioral Emergencies

Antipsychotic Agents

Before the 1950s, treatment of patients with psychosis was mostly ineffective. Surgical therapy involved destruction or removal of brain tissue and was very controversial. Electroconvulsive therapy (ECT) was seen as brutal and a last resort. Today, ECT is still practice but in a more controlled manner and performed under general anesthesia. Then, chlorpromazine was discovered. This led to sweeping changes in the management of psychotic patients, particularly with regard to outpatient treatment. No longer did patients need to remain in psychiatric institutions.
Antipsychotic medications can be broken down into several groups: first-generation (typical antipsychotics), second-generation (atypical antipsychotics), mood stabilizers (e.g. lithium), and anticonvulsants (e.g. valproate). There are several other classes of psychiatric medications including psychostimulants, dopamine agonists, monoamine oxide inhibitors, and anticholinergics. Most of these medications are available in oral form and are for chronic management of psychiatric conditions. However, some are available as injections and can be useful in the management of acute psychiatric disorders. The first-generation antipsychotics chlorpromazine and haloperidol can be used for acute agitation, but are associated with extrapyramidal symptoms. Ziprasidone and olanzapine are second-generation antipsychotics that can be used for acute agitation in patients with schizophrenia. These medications are useful in situations where sedative and hypnotics (e.g. benzodiazepines) are not preferred.
For acute agitation that is undifferentiated, meaning not psychotic in nature, benzodiazepines such as lorazepam are the drugs of choice. Other options include haloperidol, ziprasidone, and olanzapine. For psychotic agitation, providers should differentiate acute substance intoxication from mental state disorders. For substance intoxication, benzodiazepines are preferred. After lorazepam, other options include haloperidol and ziprasidone.
Psychotic agitation without substance abuse can be divided into schizophrenia, psychotic depression, and mania. All of these can be treated acutely with olanzapine. Other options for schizophrenia and mania are ziprasidone, haloperidol, and lorazepam if needed. For psychotic depression, aside from olanzapine the atypical antipsychotic aripiprazole can be used. Chlorpromazine IM is not typically recommended due to side effects. Oral ziprasidone has not been well studied for acute agitation.

Table 15-16: Acute Agitation Treatment Options, Intramuscular

Table 15-17: Acute Agitation Treatment Options, Oral

Chlorpromazine [Thorazine]

Route & Dosage: 25-50mg PO.
Onset & Duration: onset 15min, peak 2-4hr, duration 4-6hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2hr initial and 30hr terminal.
Indications: psychotic disorders, nausea and vomiting, intractable hiccups.
Contraindications: use with CNS depressants.
Adverse Effects: QT changes, orthostatic hypotension, tachycardia, drowsiness, extrapyramidal symptoms, impotence, priapism, galactorrhea, blurred vision, parkinsonian-like syndrome, neuroleptic malignant syndrome, seizure.
Drug Interaction: CNS depressants.
Black box warning: increased mortality in elderly patients with dementia.
Blockade of the D2 dopamine receptors is the primary means to treat psychosis. Chlorpromazine is a first-generation antipsychotic that blocks these receptors, as well as alpha-adrenergic receptors. First-generation antipsychotics also affect histamine receptors, muscarinic cholinergic receptors, and some serotonin receptors. Chlorpromazine can be used for nausea and vomiting given its dopamine blocking effects, though the side effects of this medication make it an uncommon choice. It can be used for intractable hiccups. Its primary use, for both the in-hospital and out-of-hospital setting, is psychotic disorders. However, the oral form is preferred over the injection form. Several organizations do not recommend using chlorpromazine IM for acute agitation due to the risk of QT prolongation and hypotension (NICE, 2012).
Dosing is 25-50mg PO or IM for psychotic disorders without agitation, and 25-50mg PO for acute agitation. Dosing is similar for the nausea/vomiting and hiccups, though these are not typically managed with chlorpromazine by prehospital providers. Maximum dosing is 400mg IM total per day or 2000mg PO total per day. IM dosing can be repeated after 1 hour.
Side effects are similar to other medications that have dopamine-blocking action, such as droperidol, metoclopramide, and prochlorperazine. Because of the sedative effects, chlorpromazine should be used with caution in patients taking other CNS depressants including sedative-hypnotics and opioids. Use is contraindicated in patients taking large doses of CNS depressants. Dystonia, or painful sustained muscle contractions, is the first extrapyramidal symptom (EPS) typically seen. Treatment with diphenhydramine 25-50mg should be started to reduce the risk of worsening symptoms. Benztropine may also be used for treatment of extrapyramidal symptoms. EPS includes akathisia, tardive dyskinesia, torticollis, and oculogyric crisis. Recall that dopaminergic neuroleptics can induce neuroleptic malignant syndrome, which is a medical emergency. The seizure threshold may be lowered in patients with a history of seizure or in acute alcohol withdrawal. The ISMP does not recommend using any shorthand or abbreviations for medications, such as CPZ for chlorpromazine. The antiemetics that sound similar to chlorpromazine (promethazine, prochlorperazine) both start with “pro” while chlorpromazine does not. Elderly patients with dementia have an increased risk of death when on chronic chlorpromazine therapy.

Haloperidol [Haldol]

Route & Dosage: 5-10mg IM/PO/IV.
Onset & Duration: onset 20-40min, peak 1hr, duration 4-6hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 18hr.
Indications: psychoses, severe agitation (off-label), nausea (off-label).
Contraindications: Parkinson disease, severe CNS depression.
Adverse Effects: QT changes, orthostatic hypotension, tachycardia, drowsiness, extrapyramidal symptoms, impotence, priapism, galactorrhea, blurred vision, parkinsonian-like syndrome, neuroleptic malignant syndrome, bronchospasm, seizure.
Drug Interaction: CNS depressants.
Black box warning: increased mortality in elderly patients with dementia.
Haloperidol is a first-generation antipsychotic that blocks D1 and D2 receptors. It has similar effects to chlorpromazine, but with less side effects. Unlike chlorpromazine, it is appropriate to use in IM and IV form. The IM form is preferred for acute agitation and is a second line agent for psychotic agitation as well as undifferentiated agitation. Dosing is 5-10mg IM/PO/IV for acute agitation. Maximum dosing is 30mg IM total per day or 40mg PO total per day. IM dosing can be repeated after 30-60 minutes. Dosing is lower for psychosis without acute agitation, ranging from 0.5-5mg PO. For children ages 6-12, dosing is 1-3mg IM every 4-8hr to a maximum of 0.15mg/kg/day.
Neuroleptic malignant syndrome (NMS) is a potentially fatal condition that involves hyperthermia, muscle rigidity, and mental status changes. Any neuroleptic can trigger NMS, but the more potent first-generation agents are most associated. These include chlorpromazine, droperidol, and haloperidol. The treatment is fluid boluses, supportive care, and transport to the hospital so the patient can receive dantrolene. Extrapyramidal symptoms should be managed with diphenhydramine or benztropine.
Side effects are similar to chlorpromazine and caution should be taken in patients on CNS depressants. Patients with Parkinson disease should not receive haloperidol as it can cause acute Parkinson crisis (acute akinesia). The seizure threshold may be lowered in patients with a history of seizure or in acute alcohol withdrawal. Elderly patients with dementia have an increased risk of death when on chronic haloperidol therapy. Combinations of antipsychotic medications and benzodiazepines, such as haloperidol and lorazepam, have been shown to be superior to either agent alone. However, combinations can lead to excessive sedation thus providers should be prepared to manage this side effect.

Olanzapine [Zyprexa]

Route & Dosage: 10mg IM, 5-10mg PO.
Onset & Duration: onset 20-60min, peak 30min, duration unknown.
Pharmacokinetics: liver metabolism, urine elimination, half-life 21-54hr.
Indications: psychoses, severe agitation, depression, delirium (off-label).
Contraindications: no major contraindications.
Adverse Effects: drowsiness, extrapyramidal symptoms, increased appetite, dry mouth, weakness, increased liver enzymes, hyperglycemia, orthostatic hypotension, neuroleptic malignant syndrome, seizure.
Drug Interaction: no major drug interactions.
Black box warning: increased mortality in elderly patients with dementia.
Olanzapine is an atypical antipsychotic (second-generation) that is an antagonist at multiple receptors including serotonin, dopamine, histamine, alpha1-adrenergic, and muscarinic. It is used for chronic therapy in multiple conditions including schizophrenia, bipolar disorder, and depression. It has off-label use in delirium. Pre-hospital providers are most likely to use this medication for acute agitation. Olanzapine is considered a first line drug for all forms of acute psychotic agitation that are not substance related. These include schizophrenia, mania, and psychotic depression.
Dosing for acute agitation is 10mg IM or 5-10mg PO. Maximum dosing is 30mg IM or PO total per day. IM dosing can be repeated after 2-4 hours. A lower dose of 2.5mg should be used for debilitated patients. Unlike haloperidol, olanzapine should not be given intravenously. Offering oral medication first may help patients to feel more in control, which can help de-escalate the agitation. As with all drugs used to manage agitation, providers should rule out medical causes of agitation.
Side effects follow with other dopamine-blocking drugs (e.g. haloperidol) as well as anticholinergic effects (e.g. dry mouth, urinary retention). As with other dopamine antagonists, extrapyramidal symptoms and neuroleptic malignant syndrome are possible, though less commonly seen with the second-generation antipsychotics. Increased liver enzymes and hyperglycemia are additional side effects. The seizure threshold can be reduced and elderly patients on chronic therapy are at an increased risk of death.

Ziprasidone [Geodon]

Route & Dosage: 10-20mg IM, 20-40mg PO.
Onset & Duration: onset 15-30min, peak 30-45min, duration unknown.
Pharmacokinetics: liver metabolism, feces and urine elimination, half-life 2-5hr.
Indications: acute agitation, bipolar disorder, schizophrenia.
Contraindications: long QT interval, recent myocardial infarction, uncompensated heart failure, concurrent use of QT prolonging medications.
Adverse Effects: QT prolongation, drowsiness, extrapyramidal symptoms, increased appetite, dry mouth, weakness, orthostatic hypotension, chest pain, hypertension, bradycardia, hyperglycemia, neuroleptic malignant syndrome, seizure, rash.
Drug Interaction: class Ia antiarrhythmics, class III antiarrhythmics, QT prolonging medications.
Black box warning: DRESS syndrome, increased mortality in elderly patients with dementia.
Ziprasidone is a second-generation antipsychotic whose exact mechanism of action is unknown. It has been shown to have affinity for dopamine, serotonin, alpha1-adrenergic, and histamine receptors. The primary effects are likely similar to olanzapine, however there are more side effects and drug interactions with ziprasidone. Dosing for acute agitation 10-20mg IM. PO dosing is 20-40mg, however this route of administration has not been well studied for agitation. Maximum dosing is 40mg IM total per day or 240mg PO total per day. An IM dose may be repeated after 2 hours for the 10mg initial dose or after 4 hours for the 20mg initial dose.
Side effects follow with other dopamine-blocking drugs (e.g. haloperidol) as well as the second-generation antipsychotics (e.g. olanzapine). As with other dopamine antagonists, extrapyramidal symptoms and neuroleptic malignant syndrome are possible. The seizure threshold can be reduced and elderly patients on chronic therapy are at an increased risk of death. Additional side effects include QT interval prolongation, chest pain, hypertension, bradycardia, and rash. Ziprasidone should not be used in patients who have uncompensated heart failure or a recent myocardial infarction. It should also not be used if the patient has a long QT interval or is taking medications that prolong the QT interval. QT prolonging medications include the class Ia antiarrhythmics (e.g. disopyramide, quinidine, procainamide), the class III antiarrhythmics (e.g. amiodarone, dofetilide, ibutilide, sotalol), and multiple other medications: 5HT-3 antiemetics like ondansetron, droperidol, fluoroquinolone antibiotics like moxifloxacin, tacrolimus, and thioridazine. Ziprasidone can cause a drug reaction with eosinophilia and systemic symptoms (DRESS). This is a serious skin reaction that typically appears > 10 days after administering ziprasidone.

Medications Used for Toxicological Emergencies

Toxicology is a complex field where signs and symptoms can be vague and evidence for treatment may be controversial. Blanket use of reversal agents or antidotes in coma can lead to patient harm and is not recommended. Flumazenil, for example, should not be given to patients without sufficient suspicion for benzodiazepine overdose. Pralidoxime, an antidote for organophosphate poisoning, is not used as commonly in other countries that have a higher rate of poisoning. Naloxone administration is not without risk and can potentially cause serious pulmonary edema. Cyanide poisoning is difficult to determine in the pre-hospital setting and can be masked by carbon monoxide poisoning. As with all fields of medicine, toxicology continues to evolve.

Alkalizing Agents

Alkalizing agents are used to increase pH in the management of acidosis. They can also increase the pH of urine, promoting the excretion of acidotic substances. However, alkalization of urine does not always improve excretion as in the case of aspirin (Proudfoot et al, 2003). Further, there are situations where increasing blood pH will not improve acidosis and could potentially cause harm; this is why ACLS guidelines do not recommend the routine use of sodium bicarbonate during resuscitation. The sodium in sodium bicarbonate can be useful to treat overdose of sodium-blocking medications, such as tricyclic antidepressants.

Sodium Bicarbonate (generic)

Route & Dosage: 1mEq/kg IV.
Onset & Duration: onset rapid, peak 30min, duration 1-2hr.
Pharmacokinetics: dissociates in blood, urine elimination, half-life unknown.
Indications: hyperkalemia, metabolic acidosis, sodium channel blocker toxicity.
Contraindications: routine use during ACLS, hypernatremia, severe pulmonary edema, hypocalcemia.
Adverse Effects: vesicant if extravasated, cerebral hemorrhage, congestive heart failure, tetany (involuntary muscle contractions), hypernatremia, hypocalcemia, pulmonary edema, hypotension, increased carbon dioxide levels.
Drug Interaction: amphetamines, calcium solutions.
Sodium bicarbonate is a chemical compound with the equation NaHCO3. It is the main component found in baking soda. It dissociates into its individual parts, Na+ and HCO3-, after injection. The bicarbonate ions combine with hydrogen ions, reducing the amount of acid: HCO3- + H+ ==> H2CO3. This then dissociates into water and carbon dioxide: H2CO3 ==> H2O + CO2. So, the process of reducing acid (increasing pH) by administering sodium bicarbonate will lead to an increase in carbon dioxide. A transient CO2 increase of 1-3mmHg can be seen. This is not an issue for patients who can breathe on their own or for the prehospital provider who can increase minute ventilation in an intubated patient. However, this increase in CO2 can increase significantly and is detrimental for patients that cannot compensate like during cardiac arrest. Sodium bicarbonate should only be used in cardiac arrest caused by hyperkalemia (Neumar et al, 2010). Other indications include diabetic ketoacidosis, aspirin overdose, cocaine overdose, tricyclic antidepressant overdose, and diphenhydramine overdose.
Dosing is 1mEq/kg as a slow IV bolus in both adults in children. A typical adult dose starts at 50mEq IV slow bolus. The 8.4% concentration is typically used in adults but the 4.2% concentration is recommended in infants < 1 month of age. This dosing is used for severe metabolic acidosis, hyperkalemia-induced cardiac arrest, and sodium channel blocker toxicity (e.g. tricyclic antidepressant overdose). For urine alkalinization or sodium channel blocker toxicity, a bicarbonate infusion should be started and titrated to urine output. Once blood gas analysis is available, the goal is pH > 7.45 (7.50-7.55 for severe poisoning). A common mixture for creating an alkaline solution is 150mEq (3 amps) of bicarbonate mixed into 1 liter of D5W.
Sodium bicarbonate can cause a number of physiologic alterations including increased preload, decreased left ventricular contractility, increased hemoglobin affinity for oxygen, and intracranial hypertension. In patients with already compromised circulation or oxygen delivery, this further impairment in oxygen delivery can worsen hypoxia. Serum calcium concentration is decreased transiently, which depresses left ventricular contractility and can cause hypotension. The hypertonic solution of sodium bicarbonate expands intravascular volume, which will increase preload but can worsen heart failure and pulmonary edema. Rapid administration of > 1mEq/kg/min has been associated with intracranial hemorrhage, particularly in infants.
Hypernatremia can occur from the large sodium load when administered (Levin, 1983). Patients with known hypernatremia should not receive sodium bicarbonate; alternative alkalizing agents are available in the hospital setting, such as tromethamine. Hypocalcemia can lead to involuntary muscle contractions and tetany. Amphetamines have enhanced potency in an alkaline environment, which could affect children taking medications for attention deficit disorder or those taking illicit substances. Calcium solutions will precipitate into solid when combined with sodium bicarbonate; this could potentially block an IV line completely. If extravasation occurs, gently aspirate from the catheter, remove the catheter, elevate the extremity, and apply a dry cold compress (Hurst, 2004). Additional treatment with hyaluronidase may be needed in the hospital setting.

Benzodiazepine Antagonists

The discovery of a pharmacologic antagonists for benzodiazepines, flumazenil, was exciting. One of the first articles discussing this drug mentioned how it could be useful in coma of unknown origin, since benzodiazepine-induced coma cannot be easily distinguished from comas caused by other drugs or conditions (Votey et al, 1991). This line of thinking has changed significantly after multiple reports of seizures. It is now generally felt that flumazenil has risks that do not outweigh the benefits, except in very particular instances (Seger, 2004). Universal administration in coma patients is strongly discouraged (Bledsoe, 2002). The treatment of choice in benzodiazepine overdose is supportive care.

Flumazenil (generic)

Route & Dosage: 0.2mg IV.
Onset & Duration: onset 1-2min, peak 6-10min, duration 1hr.
Pharmacokinetics: liver metabolism, feces and urine elimination, half-life 40-80min.
Indications: benzodiazepine overdose.
Contraindications: increased intracranial pressure, status epilepticus, cyclic antidepressant overdose.
Adverse Effects: seizure, amnesia, CNS depression, re-sedation, respiratory depression.
Drug Interaction: cyclic antidepressants.
Black box warning: seizures.
Flumazenil is a drug that competitively binds to the benzodiazepine location on gamma-aminobutyric acid (GABA) receptors. This effectively pushes away any benzodiazepine that was previously bound to the receptor, which helps reverse the effects of the benzodiazepine. However, that benzodiazepine is still in the body and is being metabolized. Flumazenil has a shorter elimination half-life than midazolam, diazepam, and lorazepam. This means that flumazenil can wear off and the benzodiazepine can re-bind to the GABA receptor, leading to re-sedation. Flumazenil does not antagonize other GABA-binding drugs (e.g. anesthetics, ethanol) and does not reverse the effects of opioids. Flumazenil primarily reverses the sedative effects of benzodiazepines, but not necessarily the amnestic and respiratory depressant effects.
Flumazenil administration is associated with seizures, especially in patients on chronic benzodiazepines or those with mixed drug overdose. Flumazenil is most beneficial in patients who received an isolated benzodiazepine overdose, such as unintentional administration of a large dose during endotracheal intubation. Dosing is 0.2mg IV over 15 seconds in adults or 0.01mg/kg IV in children, to a maximum of 0.2mg. Repeat dosing is 0.3mg IV over 30 seconds. If response still is not adequate, a third dose of 0.5mg IV may be given over 30 seconds. Dosing can be repeated every minute to a maximum of 3mg. Providers should be prepared for possible seizure activity.
Flumazenil is contraindicated in patients receiving benzodiazepines for life-threatening conditions, such as increased intracranial pressure or status epilepticus. It should not be used in patients with unknown drug overdose or mixed drug overdose (e.g. cyclic antidepressants, cocaine, amphetamine). Caution should be used in patients who are ethanol-dependent, as these patients may be benzodiazepine-dependent as well. Patients should be monitored for re-sedation due to the short half-life of flumazenil. Amnesia is not reliably reversed with flumazenil nor is respiratory depression and hypoventilation. Airway management and supportive care are the mainstays of overdose management. Flumazenil has a black box warning for seizures, which are most common in chronic benzodiazepine users or patients with cyclic antidepressant overdose. Cyclic antidepressants include drugs ending in -triptyline or -ipramine.

Cholinesterase Reactivators

Cholinesterase reactivators are drugs that reverse the inactivation of acetylcholinesterase that is seen with organophosphate poisoning. Organophosphates are used to make different insecticides, herbicides, and nerve agents. Organophosphate poisoning from agriculture is less common in the United States, mainly due to the development of carbamates. Carbamates have similar toxicity but do not typically cause permanent binding with acetylcholinesterase, unlike organophosphates. Agricultural poisoning is more common outside the united states. Nerve agents inactivate acetylcholinesterase and could be used for biologic warfare in the future. Despite the reduction in overall poisonings there is still potential for a major event requiring the use of cholinesterase reactivators.

Pralidoxime [Protopam]

Route & Dosage: 600mg IM.
Onset & Duration: onset 5-15min, peak 45min, duration 1.5hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 3-4hr.
Indications: organophosphate poisoning.
Contraindications: no major contraindications.
Adverse Effects: myasthenia gravis crisis, tachycardia, hypertension, nausea, dizziness, skin rash, transient increase in liver enzymes, weakness, muscle fasciculations, blurred vision, hyperventilation, apnea, seizure, cardiac arrest.
Drug Interaction: no major drug interactions.
Pralidoxime, also known as 2-PAM, is an oxime compound that reactivates acetylcholinesterase. It is used for pesticide/herbicide poisoning as well as nerve agent poisoning. Various auto-injectors are available for military and civilian use. All of these injectors come with atropine, which should always be administered before pralidoxime. Recommendations for the use of atropine have strong evidence, while pralidoxime has weak evidence. Most organizations in the United States recommend the use of pralidoxime to all patients with signs of cholinergic toxicity, patients with neuromuscular dysfunction, and patients with known exposure to an agent that causes delayed neurotoxicity (Bird et al, 2014). Some data has shown that pralidoxime added to atropine does not seem to be beneficial over atropine alone (Syed et al, 2015). However, the addition of pralidoxime to atropine is still considered standard management of organophosphate poisoning in the United States. Pralidoxime is not indicated for carbamate poisoning because acetylcholinesterase is only weakly, not permanently, affected by carbamates.
Dosing is 600mg IM by auto-injector for mild symptoms and can be repeated every 15 minutes to a maximum of 1800mg (3 auto-injectors). For severe symptoms, doses may be given in rapid succession to a total of 1800mg. For persistent symptoms, the series can be repeated again after 1 hour. If the IV form is available, the World Health Organization (WHO) recommends a 30mg/kg IV bolus over 20 minutes followed by an 8mg/kg/hr infusion (Roberts et al, 2007).
There are no contraindications to the use of pralidoxime for organophosphate poisoning. Side effects include tachycardia, hypertension, hyperventilation, dizziness, nausea, skin rash, blurred vision, and weakness. Muscle fasciculations can be seen, though this may be related to the poisoning as well. There is potential for serious side effects including seizures, apnea, and cardiac arrest. However, these side effects are outweighed by the risk of not treating organophosphate poisoning. No major drug interactions exist. However, succinylcholine is degraded by acetylcholinesterase thus it should be avoided in patients with organophosphate poisoning because its effects can be prolonged. Myasthenia gravis is a condition where acetylcholine receptors are blocked, so treatment involves giving reversible acetylcholinesterase inhibitors like pyridostigmine. This increases the amount of acetylcholine to compensate for the blocked receptors. Pralidoxime would reverse this process, which would likely make myasthenia symptoms much worse. If needed in these patients, providers should be prepared to manage the airway in the event of respiratory distress.
Virtual Mentor: Cholinergic Syndrome
Organophosphates lead to a massive parasympathetic discharge. They block acetylcholinesterase, which breaks down acetylcholine in the neuromuscular junction. This leads to repeated stimulation of the muscarinic acetylcholine receptors in muscles and the organs innervated by the parasympathetic nervous system. Clinically, all the patient’s fluids inside their body find a way to make it outside.
There are several mnemonics used to remember this syndrome including DUMBBELLS, SLUDGE, and SLUDGEM. Here we will discuss another: SLUDGE-Mi. This mnemonic can be pronounced as “sludge me” to recall that miosis is seen with this syndrome. Eye manifestations, miosis (small pupils) versus mydriasis (large pupils), can help differentiate different toxidromes.
S: Salivation
L: Lacrimation
U: Urination
D: Diaphoresis
G: Gastrointestinal upset (diarrhea)
E: Emesis
Mi: Miosis
This mnemonic for cholinergic syndrome can also help you remember anticholinergic syndrome. The opposing symptoms would be seen when giving an anticholinergic medication (e.g. atropine, ipratropium, olanzepine, ziprasidone). Thus, mydriasis (large pupils) would be expected with atropine administration. Mydriasis is also seen with stimulants such as cocaine and amphetamine. Recall that anticholinergic syndrome involves patients who are “red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare.”

Cyanide Antagonists

Cyanide toxicity is usually not a result of attempted homicide or suicide. It is also not commonly seen as a result of medications, like sodium nitroprusside. Toxicity is most associated with smoke inhalation. Classically, providers are taught that carbon monoxide poisoning is the issue when patients present with smoke inhalation injuries. More recent information shows that cyanide is almost universally present in smoke inhalation (Eckstein, 2007). It comes from burning wool, cotton, silk, paper, plastics, and other polymers.
Both carbon monoxide poisoning and cyanide poisoning are difficult to determine. Co-oximetry has improved the recognition of carbon monoxide poisoning, but many hospitals may not have the capability of diagnosing cyanide poisoning by lab testing. A reasonable approach is to assume cyanide is present whenever a patient presents with smoke inhalation injury. Suspect cyanide poisoning when a patient has soot around their mouth, altered mental status, and hypotension.
For many years the standard treatment was amyl nitrite, sodium nitrite, and sodium thiosulfate. Hypotension as a presenting sign makes treatment more difficult, since nitrite medications will decrease blood pressure further. Fortunately, hydroxocobalamin is a treatment option that is not associated with hypotension. Thus, this option could be used universally in smoke inhalation victims.

Amyl Nitrite (generic)

Route & Dosage: 0.3mL inhaled.
Onset & Duration: onset rapid, duration 3-5min.
Pharmacokinetics: liver metabolism, urine elimination, half-life unknown.
Indications: cyanide toxicity, angina.
Contraindications: head injury, cerebral hemorrhage, pregnancy.
Adverse Effects: hypotension, cerebral ischemia, flushing, syncope, tachycardia, dizziness, headache, nausea, increased intraocular pressure, diaphoresis, methemoglobinemia.
Drug Interaction: phosphodiesterase inhibitors.
Amyl nitrite is a chemical that releases nitric oxide in the body, resulting in vasodilation. It also promotes the formation of methemoglobin, which has an affinity for cyanide ions. Cyanide binds with the cytochrome c oxidase enzyme in mitochondria. This enzyme functions in the electron transport chain to form energy, also known as ATP, in the cell. Cyanide effectively blocks this pathway, preventing cells from utilizing oxygen (aerobic metabolism) despite an adequate supply of oxygen. The cell must switch to a non-oxygen method, anaerobic metabolism, which is much less efficient and leads to systemic acidosis. When methemoglobin is present in the blood, it competes with the cytochrome c oxidase to pull the cyanide ion away. This frees the cytochrome c oxidase and allows aerobic metabolism to continue.
Unfortunately, amyl nitrite does not make much methemoglobin. The amount created has limited clinical value. However, it is an option when the patient has no IV access or while access is being obtained. Several different brand kits are available that contain the three medications amyl nitrite, sodium nitrite, and sodium thiosulfate. This combination may also be referred to as a cyanide antidote kit (CAK), not to be confused with the brand name Cyanokit that contains only hydroxocobalamin. Dosing of amyl nitrite is a 0.3mL ampule crushed into a gauze pad and placed in front of the patient’s mouth. This may be placed in front of an endotracheal tube as well, taking care not to drop glass pieces into the airway. The ampule is inhaled over a 15-30 second period and can be repeated every minute until IV access if available. The induced methemoglobinemia lasts about one hour (Horne et al, 1979).
Amyl nitrite should not be used in patients with head injury or cerebral hemorrhage, as it can worsen these conditions. It is also contraindicated in pregnancy due to hypoxia risk to the fetus. However, these situations would also be worsened with cyanide toxicity thus administration may be appropriate for these patients as the risk likely outweighs the benefit. Hypotension is expected with nitrite medications, which can cause flushing, syncope, dizziness, headache, tachycardia, and nausea. Phosphodiesterase inhibitors will potentiate the hypotensive effect, so care should be taken with these patients.

Hydroxocobalamin [Cyanokit]

Route & Dosage: 5g IV.
Onset & Duration: onset rapid, peak 8-01min, duration varies.
Pharmacokinetics: urine elimination, half-life 26-31hr.
Indications: cyanide toxicity.
Contraindications: no major contraindications.
Adverse Effects: hypertension, photosensitivity, headache, erythema, rash, nausea, chromaturia.
Drug Interaction: sodium thiosulfate, sodium nitrite, ascorbic acid, blood products.
Hydroxocobalamin (vitamin B12a) is a precursor to cyanocobalamin (vitamin B12), which is needed for numerous metabolic functions. Each hydroxocobalamin molecule binds to a cyanide ion, creating cyanocobalamin and effectively inactivating cyanide. The vitamin B12 is then excreted in the urine. This is in contrast to the three-drug combination previously used, which can cause hypotension and create methemoglobinemia. Hydroxocobalamin can cause hypertension, which is potentially useful in patients who present with hypotension. Overall it is a safe treatment for cyanide toxicity and some organizations give it universally to all smoke inhalation victims.
Dosing is 5g IV slow infusion for adults. Vials come as 5g and each should be diluted with 200mL of normal saline or another crystalloid fluid. The vial should then be inverted or rocked for 60 seconds without shaking. Infusion is over a 15 minutes period (15mL/min). A second dose can be given if needed for a total of 10g IV. Figure 15-10 demonstrates the administration steps of hydroxocobalamin. Dosing in children is off-label but has been calculated as 70mg/kg IV to a maximum of 5g given the same way (Shepherd et al, 2008).
The major side effect is hypertension, which is usually seen at the beginning of the infusion and can increase to > 180mmHg systolic of > 110mmHg diastolic. This tends to resolve within 4 hours of the infusion and may offset the hypotension induced by cyanide or nitrite therapy. There are no major contraindications if used for cyanide toxicity. Other side effects include photosensitivity, headache, erythema, rash, nausea, and chromaturia (discolored urine). Hydroxocobalamin should not be administered together with sodium thiosulfate, sodium nitrite, ascorbic acid (vitamin C), or blood products.

Sodium Nitrite (generic)

Route & Dosage: 300mg IV.
Onset & Duration: onset minutes, peak 30-60min, duration 55min.
Pharmacokinetics: liver metabolism, urine elimination, half-life 45min.
Indications: cyanide toxicity.
Contraindications: no major contraindications.
Adverse Effects: hypotension, flushing, syncope, tachycardia, dizziness, headache, nausea, diaphoresis, methemoglobinemia.
Drug Interaction: phosphodiesterase inhibitors.
Black box warning: hypotension, methemoglobinemia.
Like amyl nitrite, sodium nitrite promotes the formation of methemoglobin. Normally, methemoglobinemia is an unwanted condition that prevents the release of oxygen from hemoglobin, which starves tissues of their oxygen supply. In cyanide toxicity, methemoglobin is useful as it helps pull cyanide away from cytochrome c oxidase. So, the nitrites are useful in known or suspected cyanide toxicity but can lead to serious consequences if given otherwise. Namely, methemoglobinemia and hypotension, which are the listed black box warnings for sodium nitrite. Most cyanide toxicity protocols call for the use of hydroxocobalamin followed by sodium thiosulfate. In locations where hydroxocobalamin is not available, the nitrites may be given.
Dosing for sodium nitrite is 300mg IV (10mL of 3% solution). A second dose of 150mg IV may be given if symptoms return. The injection should be slow at 2.5-5mL/min and the infusion slowed or stopped if significant hypotension occurs. Dosing for children is 6mg/kg IV by slow infusion, to a maximum dose of 300mg. A second dose may be used in children at 3mg/kg IV, to a maximum of 150mg. In the hospital setting, methemoglobin levels are monitoring and sodium nitrite is stopped if levels exceed 30%. Additionally, sodium thiosulfate should be administered after sodium nitrite is given. Hypotension should be expected, which can cause flushing, syncope, dizziness, headache, tachycardia, and nausea. Phosphodiesterase inhibitors will potentiate the hypotensive effect, so care should be taken with these patients.

Sodium Thiosulfate (generic)

Route & Dosage: 12.5g IV.
Onset & Duration: unknown details.
Pharmacokinetics: liver metabolism, urine elimination, half-life 3hr (thiosulfate) and 3d (thiocyanate).
Indications: cyanide toxicity.
Contraindications: no major contraindications.
Adverse Effects: hypotension, headache, nausea, salty taste, warmth.
Drug Interaction: formal drug interaction studies have not been performed.
Sodium thiosulfate serves as a sulfur donor to form thiocyanate, which is far less toxic than cyanide. Cyanide is converted to thiocyanate by the liver enzyme rhodanese. In fire victims with significant carbon monoxide exposure, the nitrite medications can further worsen tissue hypoxia by inducing methemoglobinemia. Sodium thiosulfate does not have this issue and was previously used as the sole agent for suspected cyanide poisoning with significant carbon monoxide levels. Sources disagree on the onset, peak, and duration of sodium thiosulfate. Its use as a sole agent for cyanide toxicity is not well supported (Mégarbane et al, 2003; Gracia et al, 2004). Further, several authors feel the onset is delayed and its half-life too short to be an effective antidote (Gracia et al, 2004; Hall et al, 2007). Further, sodium thiosulfate does not distribute well to the brain where the effects of cyanide could be devastating. Hydroxocobalamin avoids all of these issues.
Dosing for sodium thiosulfate in adults is 12.5g IV (50mL of 25% solution) given over 10 minutes. Dosing for children is 400mg/kg IV (1.65mL/kg of 25% solution) given over 10 minutes. If symptoms return, one-half the original dose may be given. Side effects include hypotension, headache, warmth, nausea, and a salty taste. The half-life elimination of thiocyanate is about 3 days and may be doubled or tripled in renal failure. Symptoms of thiocyanate toxicity are increased tendon reflexes (hyperreflexia), pinpoint pupils (miosis), and ringing in the ears (tinnitus).
The combination of hydroxocobalamin and sodium thiosulfate has been shown to be effective in severe cyanide toxicity (Hall et al, 1987). The recommended treatment is: Hydroxocobalamin 70mg/kg IV up to 5g + Sodium thiosulfate 400mg/kg IV up to 12.5g
If hydroxocobalamin is not available, the combination of sodium nitrite and sodium thiosulfate can be given. If cyanide toxicity is possible but not certain and hydroxocobalamin is not available, then sodium thiosulfate can be given alone. The preferred treatment for acute cyanide toxicity is hydroxocobalamin.

Medical Adsorbents

Activated carbon, also known as activated charcoal, is a formulation of carbon that has a huge number of small pores on the surface. This increases surface area significantly and allows it to adsorb multiple substances. Activated charcoal has a wide number of applications outside of medicine including: water purification, air filters, coffee decaffeination, and gold purification.

Activated Charcoal [Actidose, Char-Flo, EZ Char, Kerr Insta-Char]

Route & Dosage: 25-100g PO/NG.
Onset & Duration: onset immediate, duration dependent on gastrointestinal transit time.
Pharmacokinetics: feces elimination.
Indications: acute poisoning.
Contraindications: intestinal obstruction, GI hemorrhage, GI perforation, unprotected airway.
Adverse Effects: abdominal distension, constipation, bowel obstruction, vomiting, aspiration, black stool, decline in mental status.
Drug Interaction: ipecac, cathartics.
Activated charcoal is an a adsorbent, meaning it causes other substances to bind to the surface. This prevents the gastrointestinal tract from absorbing (taking in) the substance. The gastrointestinal tract itself does not absorb activated charcoal, thus pharmacokinetics are not very important. Its use in indicated for a wide variety of poisonings, but it should not be used for alcohol, hydrocarbons, corrosives (e.g. strong acid, strong alkali), heavy metals (e.g. iron, lithium, arsenic), methanol, ethylene glycol, and cyanide. Timing is very important; administration within 1 hour of toxic substance ingestion is the most effective at reducing drug absorption. Administration has not been shown to delay transport to the hospital and complications are uncommon (Villarreal et al, 2015).
Dosing is 25-100g PO or nasogastric (NG) tube, with many toxicologists recommending a starting dose of 1g/kg. For adults, a dose of 50g PO is typical. Dosing for children ages 1-12 is 25-50g and infants < 1 year should receive 10-25g. Vomiting or gagging is the most common side effect seen, which occurs in < 10% of patients. Decline in mental status occurs in about 5% of patients, though in many cases this could be related to the toxin that was ingested.
Contraindications include gastrointestinal hemorrhage, gastrointestinal perforation, intestinal obstruction, and unprotected airway due to aspiration risk (Chyka et al, 2005). Side effects include abdominal distention, constipation, vomiting, aspiration, black stool, and decline in mental status. The addition of ipecac to induce vomiting or cathartics to induce defecation is not recommended. Some formulations contain propylene glycol as a preservative, which is potentially toxic in large doses. Some formulations contain benzyl alcohol as a preservative, which is contraindicated for use in premature infants

Opioid Antagonists

Naloxone and naltrexone are competitive antagonists at opioid receptors. They block the receptors so that the agonist medication cannot exert its effect. In effect, they are antidotes for opioid overdose. This can trigger acute withdrawal in some patients with severe, distressing symptoms. Additionally, there are some case reports of serious pulmonary edema after bolus administration of naloxone (Lassen et al, 2012; Johnson et al, 1995; Olsen, 1990), with some resulting in death (Wang et al, 1997). Dosing of naloxone should be titrated to effect.

Naloxone [Narcan]

Route & Dosage: 0.04-0.4mg IV.
Onset & Duration: onset 2-5min, peak 15min, duration 30-120min.
Pharmacokinetics: liver metabolism, urine elimination, half-life 30-90min.
Indications: opioid overdose.
Contraindications: no major contraindications.
Adverse Effects: acute withdrawal, arrhythmias, hypotension, pulmonary edema, seizures, cardiac arrest, agitation, diarrhea, nausea, tremor, diaphoresis, shivering.
Drug Interaction: no major drug interactions.
Naloxone is an opioid antagonist that competes with opioids, displacing them from their receptor and then binding to that receptor. It can be administered via multiple routers including IV, IM, subcutaneous, intranasal, and inhalational. Initiatives exist to distribute naloxone to family members who may be present during an opioid overdose, such as with known heroin users (Albert et al, 2011). The duration of action is longer in infants, but is about 30-120 minutes in adults. There are many opioids that have a duration of action longer than this, thus patients should be monitored and transport is recommended due to the risk of re-sedation. However, it may be comforting to know that the rate of death is very low in patients who use naloxone and refuse transport (Wampler et al, 2011).
Dosing to reverse respiratory depression in adults is 0.04-0.4mg IV, with the dose repeated every 2-3 minutes as needed. A 0.4mg/mL vial can be diluted with 9mL of fluid to make 0.04mg/mL, with 1mL administrations every 2-3 minutes until respiratory depression is reversed. This may help minimize the risk of pulmonary edema. For emergency situations, a dose of 0.4-2mg IV or IM can be used (Neumar et al, 2010). Dosing can be continued up to 10mg. Endotracheal administration is possible, but is off-label and not desirable. The dose is 2-2.5x, so 0.8-5mg ETT diluted in 5-10mL of sterile water. For children, dosing starts at 1-5mcg/kg IV and repeated every 2-3 minutes until respiratory depression is reversed (Hegenbarth et al, 2008). For emergency use in children, the dose is 0.1mg/kg to a maximum dose of 2mg, repeated every 2-3 minutes as needed. The intravenous route is the preferred route of administration.
Overall, the use of naloxone is safe. There are no major contraindications. Administration can trigger acute opioid withdrawal with associated symptoms (e.g. agitation, runny nose, sweats, yawning, nausea, diarrhea). Hypotension may be seen as well as various arrhythmias, including ventricular arrhythmias and cardiac arrest. Seizures have been reported. Although rare, pulmonary edema can occur and is potentially lethal. Many opioids have durations of action lasting hours, so patients should be monitored as the effects of naloxone may wear off.

Parasympatholytics

Atropine has two major roles in the management of toxicological emergencies. First, it is used in the event of severe bradycardia such as with toxicity from beta-blockers, calcium channel blockers, clonidine, or digoxin. Second, it serves as the primary treatment for the cholinergic syndrome seen with organophosphate poisoning.

Atropine [AtroPen]

Route & Dosage: 1-6mg IV.
Onset & Duration: onset 45-60sec, peak 2min, duration 1-2hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2-3hr.
Indications: symptomatic bradycardia, organophosphate poisoning.
Contraindications: narrow-angle glaucoma, prostate hyperplasia, tachyarrhythmias, thyrotoxicosis, routine use during asystole or pulseless electrical activity, hypothermic bradycardia, severe coronary artery disease, severe aortic stenosis.
Adverse Effects: tachycardia, palpitation, flushing, drowsiness, dizziness, skin rash, nausea, dry mouth, urinary retention, angle-closure glaucoma, blurred vision, pupil dilation, increased intraocular pressure, blockade of bradycardic response to hypoxia.
Drug Interaction: oral potassium.
Atropine is an anti-muscarinic agent and therefore is also and anticholinergic and parasympatholytic. The details of this medication were previously discussed. Symptomatic bradycardia secondary to toxicity can be treated with 0.5-1mg IV atropine every 2-3 minutes. Dosing for toxicity-induced symptomatic bradycardia in children is 0.02mg/kg IV every 2-3 minutes, with a minim dose of 0.1mg.
In organophosphate poisoning, significantly larger doses of atropine may be needed. Dosing starts at 1-6mg IV and may be repeated every 3-5 minutes (ATSDR, 2011). If the first dose does not provide adequate effect, the next dose may be doubled (Roberts et al, 2007). The goal is atropinization, which is marked by an increased heart rate and reversal of cholinergic effects. Pralidoxime may be given after atropinization is achieved. Once atropinization is achieved, the total loading dose required is divided by 5-10 to get a 10-20% calculation. An IV atropine infusion at 10-20% the loading dose per hour can be started. If an organophosphate antidote kit is being used, atropine should be administered prior to pralidoxime.

Medications Used for Obstetrical and Gynecological Emergencies

Hormones

Obstetric emergencies are particularly intimidating as both the mother and fetus are at risk. The primary goal is to manage the mother in these situations. Pre-eclampsia is a condition involving hypertension that can lead to maternal stroke, and thus is managed with antihypertensive medications such as labetalol. Eclampsia is the progression of that disorder to seizures, which is primarily managed with magnesium. Cardiac arrest in pregnancy is managed with minor modifications to technique, but the same medications can be used that would be used in a non-pregnant patient. Post-partum (after delivery) hemorrhage is a serious condition and major cause of death for these patients. The initial management of this is volume resuscitation and oxytocin therapy.

Oxytocin [Pitocin]

Route & Dosage: 10-40units IV infusion.
Onset & Duration: onset 1min, duration 1hr
Pharmacokinetics: liver metabolism, urine elimination, half-life 1-6min.
Indications: postpartum hemorrhage.
Contraindications: fetal distress, prior to delivery of the fetus, IV bolus injection.
Adverse Effects: uterine spasm, uterine rupture, water intoxication, hypertension, arrhythmias, ST changes, nausea, hypotension, subarachnoid hemorrhage, fetal death, maternal death.
Drug Interaction: beta2 agonists.
Black box warning: induction of labor.
Oxytocin is a serious medication that is used in pregnant women or immediately after childbirth. In the prehospital setting, oxytocin is rarely if ever indicated for use prior to delivery of the fetus. It is a uterotonic, meaning it stimulates uterine contraction by increasing the amount of calcium in uterine muscle cells. It also causes the release of prostaglandins, which further lead to uterine contraction. The primary indication in the prehospital setting is postpartum hemorrhage, which is a major cause of death in pregnant women. Postpartum hemorrhage is most often caused by uterine atony, which is loss of uterine muscle tone. Onset for IM injection is 2-3 minutes with a duration of 2-3 hours. Onset for IV injection is 1 minute with a duration of 1 hour after infusion.
Dosing is 10-40units mixed into 1000mL of crystalloid and run “at a rate necessary to control uterine atony.” The American Congress of Obstetricians and Gynecologists also follows this vague infusion recommendation, stating “rapid infusion of dilute IV oxytocin” (ACOG, 2006). From a practical standpoint, a typical infusion would be 20units into a 1L bag of fluid then run wide open through an intravenous line. The important point is that oxytocin should not be bolused in undiluted form through an IV. Bolus doses > 3 units has been associated with serious cardiovascular complications (Butwick et al, 2010). Further, the IV infusion method has been shown to be equally effective (Bhattacharya et al, 2013). Another option for dosing after delivery of the placenta is 10units IM, making sure to draw back before injection to prevent accidental IV injection.
Oxytocin should not be used in the prehospital setting prior to delivery of the fetus. It can lead to fetal distress and abortion. Side effects include hypertension, arrhythmias, ST changes, nausea, and uterine spasm. Uterine spasm can be severe enough to cause uterine rupture. Hypertension can lead to subarachnoid hemorrhage if not controlled. Oxytocin has an antidiuretic effect (prevents water removal), which can lead to water intoxication though this is more common with infusions over many hours. Arrhythmias including ST changes are most common with rapid infusion or bolus dosing and decreasing the infusion rate typically resolves these issues. Hypotension may occur, especially with bolus dosing, due to vasodilatory effects (Novartis, 2009) and release of natriuretic peptides (Madima, 2013). There have been cases of fetal death during early labor and maternal death secondary to hypertensive episodes. Beta2 adrenergic agonists, such as epinephrine, cause uterine relaxation and therefore could counteract the effects of oxytocin. However, these medications may be needed in resuscitation. Phenylephrine, on the other hand, is a pure α1-agonist and may be an appropriate choice for hypotension during administration of oxytocin. There is a black box warning for the use of oxytocin to induce labor, which is not particularly relevant in the prehospital setting.

Minerals

In the obstetrical setting, magnesium is primarily used for pre-eclampsia with severe features and eclampsia. Dosing for these indications is much higher than previously discussed indications, such as torsades de pointes. A significant level of hypermagnesemia is needed before life-threatening symptoms of toxicity occur, so these larger doses are not unsafe per se. Hypotension, however, is an expected side effect when given in larger doses.

Magnesium (generic)

Route & Dosage: 4-14g IV.
Onset & Duration: onset immediate, peak rapid, duration 30min.
Pharmacokinetics: bone distribution, urine elimination, half-life not applicable.
Indications: pre-eclampsia, eclampsia.
Contraindications: routine administration in hospitalized patients with AMI, routine use during ACLS, neuromuscular disease.
Adverse Effects: hypotension, muscle weakness, muscle twitching, seizures, flushing, blurred vision, loss of deep tendon reflexes, respiratory arrest, AV block, bradycardia, cardiac arrest.
Drug Interaction: calcium, non-depolarizing muscle relaxants.
The details of magnesium sulfate were previously discussed. Here we will focus on its indication in obstetric patients. Severe features of pre-eclampsia seen in the prehospital setting include pulmonary edema, new cerebral or visual disturbances, and a consistently elevated blood pressure. Seizures (eclampsia) is an absolute indication for magnesium therapy. Dosing is 10-14g given through a combination of IV and IM routes. A 4g IV infusion is started and simultaneous injections of 4-5g of IM magnesium are given into each buttock. After that, a 1-2g/hr IV magnesium infusion is started. Alternatively, a loading dose of 4-6g IV may be given followed by an infusion of 1-2g/hr (ACOG, 2013).
Contraindications, adverse effects, and drug interactions were previously discussed. Hypotension should be expected during infusion, which can be helpful if the patient is hypertensive secondary to pre-eclampsia. Fluids should be used primarily to help manage hypotension secondary to magnesium infusion.

Sedation and Pain Management Medications

Anesthetic Agents

General anesthesia is characterized by unconsciousness, loss of memory, lack of pain, and muscle relaxation. Nearly all sedative-hypnotic medications can induce general anesthesia in higher doses. Unfortunately, some physiologic reflexes are blunted by anesthesia and most anesthetic agents cause vasodilation. This leads to inevitable hypotension, which should be anticipated in any patient receiving an anesthetic. Inability for the patient to protect their airway should also be anticipated.
Anesthesia is a reversible coma that is different from sleep (Brown et al, 2010). It typically used in the prehospital setting to facilitate endotracheal intubation or to manage patients with extreme levels of pain secondary to injury or disease. Anesthetics are divided into the categories of inhalational or injectable. Inhalational volatile anesthetics are commonly used in the hospital setting for general anesthesia. Nitrous oxide is an inhalational anesthetic but is used primarily for analgesia in the pre-hospital setting. Intravenous anesthetics include: dexmedetomidine, etomidate, ketamine, propofol, barbiturates (e.g. methohexital), and benzodiazepines (e.g. midazolam). Each medication has benefits and unwanted side effects, which should be considered when deciding on an agent prior to endotracheal intubation.

Table 15-18: Common Intravenous Anesthetics, Induction

Therapeutic index (TI), also called the safety margin, is, defined as lethal dose in 50% of people over effective dose in 50% of people (LD50/ED50). Etomidate is a very safe medication in that doses can be increased by a significant amount before toxicity or serious side effects occur. About 25 times the standard intubating dose would be needed to cause lethal toxicity for etomidate. Propofol, on the other hand, has a narrow window of safety. Despite being nearly the ideal agent for induction and maintenance of anesthesia, toxic side effects prevent universal use in all patients. Further, dosage adjustments based on age and comorbidities are not commonly needed in etomidate or ketamine due to the safety margin. Propofol dosing should be adjusted is multiple circumstances, such as with the elderly or in multi-trauma patients, to reduce the risk of serious side effects.

Table 15-19: Common Intravenous Anesthetics, Infusion

Context-sensitive half-time (CSHT) defines the time needed for plasma concentrations of a drug to decrease a significant amount after stopping an infusion. Some drugs have negative side effects that prevent them from being used as an infusion, like etomidate. Other drugs accumulate in tissues significantly while they are being infused, like midazolam. This leads to a long period of time before awakening after stopping the infusion. For this reason, many recommend intermittent boluses of benzodiazepines for sedation instead of continuous infusions. Ketamine can be used for sedation and anesthesia, though it is not common because of propofol. Propofol is very useful for ongoing sedation and anesthesia as an infusion. Cessation of a propofol infusion typically results in rapid recovery even in cases of prolonged infusion.

Etomidate [Amidate]

Route & Dosage: 0.2-0.3mg/kg IV.
Onset & Duration: onset 30-60sec, peak 1min, duration 3-5min.
Pharmacokinetics: liver and plasma esterase metabolism, urine elimination, half-life 2.6hr.
Indications: sedation, anesthesia.
Contraindications: no major contraindications but not recommended in sepsis.
Adverse Effects: pain on injection, nausea, vomiting, myoclonus, hiccups, hypertension, hypotension, bradycardia, tachycardia, apnea, seizures, decreased cortisol synthesis.
Drug Interaction: sedatives and opioids.
Etomidate is an intravenous anesthetic that has sedative-hypnotic properties but not analgesic properties. Meaning, it causes sedation and can induce general anesthesia but does not relieve pain. Chemically, it is a carboxylated imidazole that has GABA-like effects. This is the same mechanism by which the benzodiazepines, barbiturates, and propofol work. Onset of anesthesia begins in 30 seconds and unconsciousness lasts approximately 5 minutes, which is similar to propofol and ketamine. The offset of effect (i.e. awakening) is due to redistribution of the drug out of the blood; it then takes a much longer period of time for the body to metabolize the drug. Repeated doses and infusions of etomidate are not recommended due to its powerful ability to block adrenal steroid production.
Dosing is 0.2-0.3mg/kg IV bolus and up to 0.6mg/kg is safe. Dosing adjustments do not need to be made for infants, elderly patients, debilitated patients, or severely hypotensive patients. Etomidate typically comes in a 20mg/10mL vial, which would be an appropriate dose for a 70kg (154lb) adult. Patients larger than this would then require a second vial or use of a 20mL vial to begin with. When used as part of a rapid sequence induction and intubation (RSII), anticipate patient emergence in 5 minutes. Additional sedation will likely be needed for the patient to tolerate the endotracheal tube. Also, use of depolarizing relaxants means the patient will regain consciousness in 5 minutes but be paralyzed; this also mandates the use of sedatives.
Etomidate is a very useful agent for induction of anesthesia and intubation. It has a wide safety profile and minimal cardiovascular effects. A slight decrease in blood pressure may be seen but this can be countered by a slight increase in heart rate. For patients that are have severe hemodynamic stability, etomidate represents one of the few appropriate options. Due to the adrenal suppressing effects, etomidate is not recommended in patients with sepsis (Chan et al, 2012). Some authors liken this to the “buy now, pay later” philosophy where the good hemodynamic stability during intubation is outweighed by the increase in mortality later for sepsis patients.
Etomidate is associated with pain on injection, thought this is seen less commonly than with propofol. Myoclonic muscle movements, jaw clenching, and an intact gag reflex can be seen after injection. These effects are not seen when muscle relaxants are co-administered (e.g. RSII). Trismus, or lock jaw, can be seen with etomidate injection (Bozeman et al, 2002). This can complicate airway management for prehospital organizations that do not allow muscle relaxants for intubation. Hiccups and vomiting can be seen with etomidate, particularly on emergence from anesthesia. Hypertension and tachycardia can occur, as can severe hypotension and bradycardia though these are less common. Etomidate can provoke seizures in patients with a history of seizures or in head injured patients.
That’s Not True … or Is it? Administering Steroids With Etomidate
The debate about the use of etomidate regarding adrenal suppression has gone on for years. At this point, no large studies have shown etomidate to increase mortality in the general population. Negative outcomes have been seen in septic patients and severe trauma patients (Warner et al, 2009). Debates continue since etomidate is one of the most cardio-stable medications for induction and intubation. Pharmacologists are trying to create a form of etomidate with less adrenal suppression.
So, if etomidate is such a great agent for intubation except for the adrenal suppression part, why not just give steroids? This should replace what the body will stop making over the next several hours. This sounds like a good theory, however it has not worked out in trials (Payen et al, 2012). Patients do not appear to benefit from steroids given after etomidate in an attempt to overcome the adrenal suppression.

Ketamine [Ketalar]

Route & Dosage: 1-2mg/kg IV, 4-10mg/kg IM.
Onset & Duration: onset 30sec IV and 3-4min IM, duration 5-10min IV and 12-25min IM.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2.5hr.
Indications: sedation, anesthesia, analgesic adjunct.
Contraindications: conditions where hypertension would be hazardous.
Adverse Effects: hypertension, tachycardia, possible increased intracranial pressure, hallucinations and emergence reactions, salivation, nausea, nystagmus, tonic-clonic movements, laryngospasm, respiratory depression (uncommon), bronchodilation.
Drug Interaction: sedatives and opioids.
Ketamine is an intravenous anesthetic that is both a sedative-hypnotic and an analgesic. It causes “dissociative anesthesia” where the patient’s eyes remain open but with slow nystagmus (repetitive eye movements). Unlike the mechanism of action for many other anesthetics, ketamine primarily inhibits the NMDA receptor. Amnesia occurs more often with benzodiazepines than with ketamine. Although patients tend to continue breathing and their airway reflexes tend to remain intact, patients may not be able to protect their upper airway. Onset of anesthesia begins in 30 seconds and unconsciousness lasts approximately 5 minutes for intravenous injection. IM injection is an option for uncooperative patients and those without IV access, but onset is slower (3-4 minutes until unconsciousness).
Dosing is 1-2mg/kg IV bolus in all age groups. For IM injection, 4-10mg/kg may be used but 4mg/kg is a more typical IM dose (Miller, 2011). Ketamine has a good therapeutic index so there is no reason to under dose. Also, ketamine is a sympathomimetic that tends to increase blood pressure and heart rate so cardiovascular stability can occur even in severely hypotensive patients. The cardio-depressant effects of ketamine are postulated to lead to hypotension in catecholamine depleted patients (e.g. intensive care unit patients), however the sympathomimetic effects usually overshadow this (White et al, 1996; Reich et al, 1989). Similar to etomidate and propofol, return of consciousness occurs after about 5 minutes so patients should receive ongoing sedation if non-depolarizing muscle relaxants were used. If needed for ongoing sedation, typical dosing is 5-20mcg/kg/min IV. If needed to maintain anesthesia (e.g. serious, painful injuries), typical dosing is 30-90mcg/kg/min IV.
Ketamine is an option for induction of anesthesia and intubation in most circumstances. The increase in blood pressure and heart rate make it the preferred choice for severe hypotension and hemodynamic instability. The unpleasant hallucinations, salivation, and maintenance of airway reflexes make it a less useful choice in routine intubation. The respiratory drive is minimally affected and ketamine has analgesic properties, making it a good choice for sedation and minor procedures. Ketamine should not be used in situations where tachycardia would be hazardous such as: severe coronary artery disease and severe aortic stenosis. It should also be avoided in situations where hypertension would be hazardous such as: cerebral aneurysm, aortic dissection, pre-induction uncontrolled hypertension, cocaine intoxication, and hyperthyroidism. Psychotic disorders can be potentially aggravated or triggered. Laryngospasm, or closure of the vocal cords, is possible with ketamine and may be caused by the excess salivation. Bronchodilation is a side effect, making ketamine and propofol useful choices for patients with bronchospasm (e.g. severe asthma attack). The manufacturer lists increased intraocular pressure as being possible but studies show ketamine significantly decreases intraocular pressure (Reich et al, 1989)
That’s Not True … or Is it? Ketamine In Head Injury
Studies decades ago showed that ketamine increases intracranial pressure (ICP), leading to a general recommendation to avoid ketamine in situations involving increased ICP (Shaprio et al, 1972). The recommendation still persists in many textbooks. However, most of the recent studies and meta-analyses show that ketamine does not increase intracranial pressure (Zeiler et al, 2014; Wang et al, 2014). The evidence is strong that ketamine either does not increase ICP or decreases ICP. The evidence is weak that ketamine could increase ICP.
An increase in cerebral blood flow (CBF) is seen with ketamine which may increase ICP. Maintaining normocapnia (normal ETCO2) blunts this effect (Albanèse et al, 1997). Also, there is no evidence that ketamine causes harm in traumatic brain injury. In fact, it may be helpful in these patients (Bar-Joseph et al, 2009). Further, ketamine has great hemodynamic stability which may be of benefit in patients with traumatic brain injury.
Both propofol and etomidate are good options for patients with increase intracranial pressure. Both of these medications decrease ICP and decrease CBF. Etomidate can cause seizures and emesis, while propofol does the opposite. Propofol seems to be the best induction agent for patients with increased intracranial pressure. For patients with traumatic brain injury, a single episode of hypotension can double mortality (Chesnut et al, 1993). This should be kept in mind when using propofol, which can decrease blood pressure significantly if overdosed or used in hypovolemic patients.

Midazolam [Versed]

Route & Dosage: 0.1-0.3mg/kg IV.
Onset & Duration: onset 2-5min, duration ≤ 1hr IV.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2-7hr.
Indications: sedation, induction of anesthesia, cocaine intoxication, seizures.
Contraindications: respiratory insufficiency.
Adverse Effects: anterograde amnesia, CNS depression, paradoxical reactions, respiratory depression, apnea, hypotension, acute narrow-angle glaucoma.
Drug Interaction: CYP3A4 drugs, calcium channel blockers, sedatives and opioids.
Black Box: respiratory arrest, decrease dosing in elderly, severe hypotension in neonates.
The details of midazolam were previously discussed for patients in status epilepticus. Benzodiazepines like midazolam are the treatment of choice for cocaine intoxication, especially if there is associated chest pain (McCord et al, 2008). For sedation and anesthesia, the IV route is preferred. Midazolam has an LD50 of about 50mg/kg (Lewis et al, 2004) and an ED50 of about 4.3 (Gross et al, 1985), making the therapeutic index > 10. Midazolam causes dose-dependent respiratory depression, hypotension, and amnesia. The lower end of doses does not typically cause any significant respiratory depression or hypotension.
Dosing for induction of anesthesia and intubation is 0.1-0.3mg/kg IV with a maximum single dose of 10mg. Onset can take 2-5 minutes, which makes midazolam a less desirable choice for RSII. For non-RSII, midazolam can be administered then a muscle relaxant given once the patient loses consciousness. Dosing should be toward the lower end (e.g. 0.15mg/kg IV) in elderly patients. For ongoing sedation, intermittent boluses are preferred. If this is not possible (e.g. neuromuscular blocker given), then an infusion of 0.25-1mcg/kg/min IV is typical. Like etomidate and propofol, midazolam has no analgesic properties. However, it has significant amnestic properties compared to other agents. Contraindications, adverse effects, and drug interactions were previously discussed. Hypotension is exacerbated when midazolam is combined with barbiturates or opioids. The dose needed to cause anesthesia can be reduced in the presence of fentanyl as the drugs are additive and slightly synergistic (Ben-Shlomo et al, 1990). In healthy adults, midazolam 0.15mg/kg IV (half dose) is all that is required if fentanyl 2mcg/kg IV is also administered.

Propofol [Diprivan, Propoven]

Route & Dosage: 1-2.5mg/kg IV.
Onset & Duration: onset 30, duration 5-10min.
Pharmacokinetics: liver metabolism, urine elimination, half-life 4-7hr.
Indications: sedation, induction of anesthesia.
Contraindications: egg/soy allergy.
Adverse Effects: hypotension, myoclonus, bradycardia, burning on injection, arrhythmia, tachycardia, bronchodilation, hypertriglyceridemia, propofol infusion syndrome, bacterial infection.
Drug Interaction: sedatives and opioids.
Propofol is likely the most commonly used drug for the induction of anesthesia for elective surgery in the hospital setting. It has a large number of useful properties for this patient population and has few drawbacks. It can also be used as an infusion for ongoing sedation or maintenance of anesthesia. Like many other anesthetics, the primary mechanism of action is through potentiation of GABA. Propofol is a sedative-hypnotic without clinically useful analgesic properties. It rapidly causes loss of consciousness and amnesia. It blunts airway reflexes which helps facilitate endotracheal intubation even if muscle relaxants are not given. It causes bronchodilation, making it useful for severe asthma attacks and other forms of bronchospasm. It has antiemetic properties, anticonvulsant properties, and decreases ICP which makes it useful in most neurologic injuries. It rapidly clears from the plasma, making for less of a “hangover” effect when compared with other agents.
Dosing, unfortunately, is very dependent on the clinical scenario and patient’s age. This is related to the hypotensive effects of the drug as well as the narrow safety margin (LD50/ED50). Typical dosing for intubation in an adult is 2mg/kg IV. Children require a larger dose for intubation, typically 3mg/kg IV. Elderly patients require a smaller dose for intubation, usually around 1mg/kg IV. Unstable patients should receive an even smaller dose.

Table 15-20: Propofol Dosing

Propofol has many useful effects, but like any drug there are drawbacks. Hypotension secondary to significant vasodilation is seen in up to 1 in 4 patients adults and 1 in 6 children. The effect on systemic blood pressure is more prominent in hypovolemic patients and the elderly. Rapid injection can lead to hypotension by itself. Unfortunately, propofol also blunts the baroreceptor reflex which would normally lead to an increased heart rate with hypotension. This prevents the body from compensating for the hypotension, as is seen with etomidate and midazolam. Vasopressors like phenylephrine may be needed temporarily if fluid boluses do not resolve hypotension. Burning on injection occurs in at least 1 in 10 patients. Bradycardia has been seen with propofol injection, but it is not common. Temporary myoclonic movements can be seen, but these are far less common than seen with etomidate or ketamine. Propofol is formulated in a solution containing soybean oil and lecithin (from egg yolks). Patients with egg or soy allergy may have reactions to propofol for this reason. Also, this makes propofol a medium for bacterial growth; once drawn into a syringe propofol should be used or discarded within 6 hours. High lipids in the blood (hypertriglyceridemia) can occur with prolonged infusions, as can propofol infusion syndrome (PRIS). PRIS should be suspected in patients on prolonged infusions who develop unexpected tachycardia.
Virtual Mentor: Induction & Intubation In Trauma Patients
Polytrauma patients with hypotension are usually assumed to be hypovolemic secondary to blood loss. Let’s consider the different induction agents we have discussed and see which agents may be appropriate. Midazolam has a slow onset when used for intubation. This would not be a very good choice for RSII since trauma patients are at risk for vomiting and aspiration. Administering midazolam and a relaxant together, then intubating 1 minute later, could result in a patient who is paralyzed and aware during intubation.
What about propofol? Propofol is an option, but appropriate dosing is 20% of normal (Shafer, 2004; Johnson et al, 2003). So, an adult hypotensive polytrauma patient could receive 0.4mg/kg IV propofol for induction. However, just because this is an option does not mean we should do it. Titrating a drug with a narrow margin of safety in a borderline patient requires expertise; there is little room for error here. Also, why give a medication that is known to cause vasodilation in a patient in hypovolemic shock – a condition where vasodilation could lead to serious consequences. Further, the use of vasopressors early in trauma resuscitation has been shown to increase mortality (Plurad et al, 2011; Sperry et al, 2008). So, can we use propofol to intubate very ill, hypotensive patients? Absolutely, but the appropriate dose matters so much so that it may best be avoided.
There are other agents with a wider therapeutic index, which have been shown to be safe to use in trauma. Etomidate has a wide safety margin, so why not use that for these patients? First, the dose required in hemodynamically unstable patients is actually higher than normal (Shafer, 2004). Second, etomidate has been associated with increased mortality in trauma patients (Warner et al, 2009; Ledingham et al, 1983; Watt et al, 1984). This has led to some authors recommending against the use of etomidate in trauma patients (Bernhard et al, 2011). Third, etomidate can drop blood pressure in shocked patients (Jung et al, 2012).
Ketamine is probably the safest anesthetic agent to use in trauma. No major changes in drug dosing are needed for ketamine, even in severe blood loss (Black et al, 2006). It increases tone and has analgesic effects, which are both beneficial for patients that are hemodynamically unstable. Multiple studies have shown ketamine to have good cardiovascular stability with induction even in very sick patients (Lippmann et al, 1983; Savege et al, 1976; Gelissen et al, 1996; Singbartl et al, 1976; Thangathurai et al, 1988). Opioids like fentanyl also have a wide margin of safety in patients with severe blood loss. Dosing for fentanyl can be reduced 50% in severe blood loss (Smith, 2008).

Neuromuscular Blocking Agents

Neuromuscular blocking drugs (NMBDs) interrupt nerve transmission in the neuromuscular junction. This leads to paralysis of the skeletal muscles, which makes improves first pass success rate for endotracheal intubation. Aside from intubation in the pre-hospital setting, they are used in the operating room to optimize surgical working conditions. There are some important things to remember about muscle relaxants in the pre-hospital setting:
1) They Are Not Analgesic: NMBDs do not provide analgesia of any kind. Patients may appear sedated due to lack of movement, but they could be awake and paralyzed.
2) They Are Not Sedating: Inadequate sedation while using NMBDs is the main cause of unwanted awareness. In the hospital setting, 93% of unintentional anesthesia awareness cases involved NMBDs (NAP 5, 2014).
3) Vital Signs Are Not Always Reliable. Patients may be taking medications (e.g. beta blockers) that can blunt the normal response that would be expected in an awake and paralyzed patient, such as tachycardia and hypertension. Awareness can occur despite normal vital signs. Tearing from the eyes suggestions the need for more sedation.
4) Everyone Is At Risk. All patients receiving NMBDs are at risk for awareness. Practice guidelines recommend the concurrent use of sedation for all patients who have received NMBDs (Murray, 2002).
Anesthesia providers rank patients death as their #1 concern and rank awareness under anesthesia as their #2 concern, right after death. Patients who had awareness with paralysis describe feelings of panic, helplessness, suffocation, being buried alive, and imminent death (Osterman et al, 2001). Over 95% of cases of anesthesia awareness were considered substandard care even with prompt recognition and management (Frakes et al, 2006). Awareness typically occurs after intubation has occurred and the anesthetic effect wears off. However, it can occur during intubation if a slow-onset induction agent is used (e.g. midazolam) or if poor techniques are used. Two techniques that are not recommended are the “priming” and the “timing” techniques (El-Orbany et al, 2010). The priming technique involves giving a small dose of a non-depolarizing muscle relaxant, waiting about 5 minutes, then giving the full dose along with an induction agent. The timing technique involves giving the full dose of a non-depolarizing muscle relaxant, waiting for the onset of symptoms, then giving the induction agent. Both of these techniques have the potential for the patient to be awake and paralyzed. They also both can lead to apnea, desaturation, and vomiting with aspiration. The timing technique has the potential for full paralysis if IV access is lost before the induction agent can be administered.
NMBDs are divided into depolarizing agents and non-depolarizing agents. Succinylcholine is a depolarizing agent with rapid onset and a short duration of action. Unfortunately, it has a huge list of side effects and contraindications. Non-depolarizing agents include pancuronium, rocuronium, and vecuronium. Of those, rocuronium is the only agent that can provide reliable intubating conditions during RSII.

Table 15-21: Muscle Relaxant Dosing

Succinylcholine [Anectine, Quelicin]

Route & Dosage: 1-1.5mg/kg IV, 3-4mg/kg IM.
Onset & Duration: onset 30-60sec IV and 2-3min IM, duration 4-6min IV and 10-30min IM.
Pharmacokinetics: pseudocholinesterase metabolism, urine elimination, half-life rapid.
Indications: endotracheal intubation.
Contraindications: malignant hyperthermia, hyperkalemia, conditions predisposing to exaggerated potassium release, intracranial hypertension, penetrating eye injuries.
Adverse Effects: tachycardia, bradycardia, arrhythmias, hyperkalemia, fasciculations, myalgia, sustained muscle contractions, malignant hyperthermia, masseter muscle rigidity, increased intraocular pressure, increased intracranial pressure, histamine release, increased intragastric pressure, anaphylaxis, cardiac arrest.
Drug Interaction: certain antibiotics, calcium channel blockers, lithium, magnesium.
Black box warning: death in male children.
Succinylcholine is a depolarizing relaxant that acts similar to acetylcholine. It causes widespread depolarization at the neuromuscular junction, resulting in flaccid paralysis. Onset of action is rapid, making it one of the two common medications used for RSII. Administration should be in conjunction with an anesthetic for intubation. Paralysis occurs within 60 seconds and fasciculations (muscle twitching) is often seen during this period. Duration of action is dose-dependent and, when used for RSII, critical desaturation will occur before the patient returns to an unparalyzed state even with adequate preoxygenation (Benumof et al, 1997).
Dosing is 1mg/kg IV for rapid sequence induction and intubation. In the non-RSII setting, dosing is typically around 0.6mg/kg IV and the effective dose for intubation is 0.3mg/kg (Miller, 2011). This means that 1mg/kg IV should be more than enough for RSII in the majority of patients. There are, of course, some rare exceptions. As a practical point, succinylcholine typically comes as 200mg/10mL. A 1mg/kg dose in a 70kg patient would be 3.5mL of this solution. Giving the entire syringe would be almost 3mg/kg, which is higher than any intubating dose described in the literature. IM dosing in children is 4-6mg/kg with a typical maximum dose of 150mg IM. Although ketamine and succinylcholine can be given IM, this induction sequence should be viewed with caution as no IV would be present in the event of a side effect (e.g. bradycardia, hypotension).
Of all the medications discussed in this chapter, succinylcholine has the longest list of side effects and contraindications. There is a black box warning for hyperkalemia-induced cardiac arrest in children who were later found to have undiagnosed neuromuscular disorders. These deaths typically involved males aged 8 and younger; some providers consider the use of succinylcholine in males ≤ 8 years old a contraindication. Succinylcholine is one of the few triggers of malignant hyperthermia (MH), a serious condition involving tachycardia, hypercapnia, muscle rigidity, and high fever. This condition needs immediate medical attention and mortality is high if not treated immediately in the hospital setting. Masseter muscle rigidity (MMR), also known as trismus or “jaws of steel”, can occur with succinylcholine administration and may last up to 30 minutes. Succinylcholine causes increased intracranial pressure and should be avoided in patients with head injury where intracranial hypertension would be detrimental. Succinylcholine increases intraocular pressure, thus it should be avoided in patients with penetrating eye injuries and those with glaucoma.
A small amount of hyperkalemia occurs with succinylcholine administration. This is not a problem for patients with normal potassium levels, but can cause cardiac arrest in those with hyperkalemia (e.g. renal failure patient who missed dialysis). Further, there are a large number of neuromuscular conditions that can lead to exaggerated hyperkalemia and potentially cardiac arrest. These are typically conditions involving loss of nerve function. The body compensates by creating more acetylcholine receptors and “upregulating” the ones that exist to make up for the limited nerve function. This does not happen immediately after injury and the timing depends on the disorder.

Table 15-22: Exaggerated Hyperkalemia With Succinylcholine

For acute conditions (e.g. stroke), risk increases after 24 hours
Myopathy
– Duchenne muscular dystrophy
– Becker muscular dystrophy
– Mitochondrial myopathy Immediate risk (e.g. Muscular myopathy)
Disuse atrophy/immobility After several days (≥ 16 days increases risk)
Prolonged relaxant use After several days of mechanical ventilation
From Miller, 2011; Kohlschütter et al, 1976; Jeevendra Martyn et al, 2006; Kopriva et al, 1971; Blanié et al, 2012.
Succinylcholine is also associated with histamine release which can cause hypotension and tachycardia. Bradycardia is more common in children and pre-treatment with atropine was previously discussed. Bradycardia is also seen with a repeated dose of succinylcholine in all patient populations. Muscle myalgias, which can be severe and temporarily debilitating, have been reported. Neuromuscular blocking agents, with succinylcholine in particular, are the most common cause of drug-induced anaphylaxis in the peri-intubation period (Ebo et al, 2007). Succinylcholine also has several drug interactions. Calcium channel blockers, lithium, and magnesium all prolong the effect of succinylcholine. Certain antibiotics have been implicated as well, including streptomycin, aminoglycosides, tetracycline, and clindamycin. An uncommon condition called pseudocholinesterase deficiency can lead to severely prolonged duration for succinylcholine (> 30 minutes). Although this condition is rare it should not be assumed that succinylcholine will wear off within 10 minutes after injection.
That’s Not True … or Is it? Succinylcholine: 1mg/kg? 1.5mg/kg? 2mg/kg?
If the RSII dose for succinylcholine is 1mg/kg, then why is it 1.5mg/kg or 2mg/kg in different books? Part of the answer is that there are exceptions where these doses are needed, and the other part is that incorrect dosing gets perpetuated from one resource to another. Here we’re discuss the exceptions where 1.5mg/kg or 2mg/kg are the preferred dosing.
Succinylcholine 1.5mg/kg IV is the appropriate dose when a non-depolarizing agent is used to defasciculate. So, if 0.03mg/kg IV rocuronium is given then 1.5mg/kg IV succinylcholine would be needed due to antagonism between the two drugs. Up to 2mg/kg IV can be used in this situation, but 1.5mg/kg IV is appropriate. Dosing related side effects increase as the dose increases. Succinylcholine 1mg/kg IV for RSII is associated with excellent intubating conditions 100% of the time (Prakash et al, 2012). In fact, several studies have shown that a dose of 0.6mg/kg IV succinylcholine can be used for RSII with excellent intubating conditions the majority of the time (Prakash et al, 2012; Luo et al, 2014; Naguib et al, 2003; El-Orbany et al, 2004; El-Orbany et al, 2005).
Succinylcholine 2mg/kg IV is only appropriate for infants. This is because infants have an increased volume of distribution. Children older than one year should receive 1mg/kg IV. Adults, elderly patients, patients in shock, trauma patients, and other typical pre-hospital patients should receive 1mg/kg IV for RSII. Studies have shown no advantage to using doses > 1.5mg/kg (Naguib et al, 2006).

Pancuronium (generic)

Route & Dosage: 0.1mg/kg IV.
Onset & Duration: onset 2-3min, duration 60-100min.
Pharmacokinetics: liver metabolism, urine elimination, half-life 110min.
Indications: endotracheal intubation.
Contraindications: no major contraindications.
Adverse Effects: tachycardia, hypertension, salivation, wheezing, bronchospasm, anaphylaxis, caution in liver disease, caution in renal disease.
Drug Interaction: certain antibiotics, calcium channel blockers, magnesium, anticonvulsants.
Black box warning: experience personnel required.
Pancuronium is a non-depolarizing muscle relaxants. It has a slow onset of action and a very long duration of action, making it a poor choice for endotracheal intubation. The duration of action makes pancuronium potentially useful for patients who require prolonged paralysis, however this is not common in the prehospital setting. This significantly increases the risk of awareness under anesthesia. With the arrival of relaxants that have less side effects (e.g. vecuronium and rocuronium), the use of pancuronium has decreased.
Dosing is 0.1mg/kg IV which results in a clinical duration of paralysis lasting 100 minutes. Due to the risk of awareness given the long duration of action, there is a black box warning that pancuronium should only be used by experienced personnel. Unlike succinylcholine, the non-depolarizing relaxants do not have major contraindications. An increase in heart rate is typically seen with pancuronium, but not as commonly with rocuronium or vecuronium. Hypertension, salivation, wheezing, and bronchospasm can be seen. Relaxants are associated with anaphylaxis, so this should be considered when hypotension, rash, and bronchospasm are seen after intubation. Malignant hyperthermia and potassium release are not seen with non-depolarizing relaxants. Renal failure and liver failure affect non-depolarizing relaxants – pancuronium in particular. Half-life elimination for pancuronium is doubled in these patients. There is also a pancuronium active metabolite that leads to further prolongation of action in renal failure. This is yet another reason to consider avoiding this medication. Like succinylcholine, non-depolarizing relaxants are potentiated with certain antibiotics, magnesium, and calcium channel blockers. Anticonvulsants like phenytoin reduce the effectiveness of non-depolarizing agents.

Rocuronium [Zemuron]

Route & Dosage: 0.6mg/kg IV for intubation or 1.2mg/kg IV for RSII.
Onset & Duration: onset 1-2min, peak 4min, duration 30min.
Pharmacokinetics: liver metabolism, urine elimination, half-life 66-144min.
Indications: endotracheal intubation.
Contraindications: no major contraindications.
Adverse Effects: tachycardia, hypertension, transient hypotension, anaphylaxis.
Drug Interaction: certain antibiotics, calcium channel blockers, magnesium, anticonvulsants.
Rocuronium is a non-depolarizing muscle relaxant that can be used almost every situation where relaxants are needed, including RSII. It has a fast onset and an intermediate duration of action. Since critical desaturation would occur regardless of the muscle relaxant used and due to all the side effects of succinylcholine, rocuronium would appear to be the agent of choice for RSII. This is slowly becoming the standard in many areas of medicine, with some authors touting the demise of succinylcholine (Lee, 2009).
Dosing is 0.6mg/kg IV which results in a clinical duration of paralysis lasting 36 minutes. Onset is about 90 seconds with this dose. For RSII, 1.2mg/kg IV can be used which gives intubating onset and conditions similar to succinylcholine. RSII dosing leads to paralysis for about 73 minutes. Although not commonly done, a dose of 2mg/kg IV rocuronium can be used to achieve ≥ 90% chance of perfect intubating conditions (Heier et al, 2000). This, of course, results in a significantly prolonged duration of action.
There are no black box warnings or major contraindications to the use of rocuronium. Hypertension can be seen as can transient hypotension, but these are not common. Tachycardia occurs in < 5% of cases, with the majority being in children. There really are no other common side effects seen with rocuronium. Like all non-depolarizing agents, anaphylaxis is possible. Drug interactions are the same as with pancuronium. Unlike pancuronium and vecuronium, there are no active metabolites. Thus, duration of action is only slightly prolonged in renal failure given that the majority of metabolism occurs in the liver.

Vecuronium (generic)

Route & Dosage: 0.1mg/kg IV.
Onset & Duration: onset 2.5-3min, peak 3-5min, duration 45-65min.
Pharmacokinetics: liver metabolism, feces and urine elimination, half-life 65-75min
Indications: endotracheal intubation.
Contraindications: no major contraindications.
Adverse Effects: bradycardia, flushing, anaphylaxis.
Drug Interaction: certain antibiotics, calcium channel blockers, magnesium, anticonvulsants.
Black box warning: experience personnel required.
Vecuronium is a non-depolarizing muscle relaxant that has a slow onset and an intermediate duration of action. Even with timing and priming techniques, which are not recommended, vecuronium still cannot achieve an onset similar to rocuronium or succinylcholine thus is not appropriate for RSII. Dosing is 0.1mg/kg IV which results in a clinical duration of paralysis lasting 44 minutes. There are no major contraindications and, like rocuronium, very few adverse effects. Bradycardia and flushing may occur, this this happens < 1% of the time. Drug interactions are the same as with pancuronium and rocuronium. A black box warning is present, which is the same as with pancuronium. Vecuronium does have some advantages for emergency medical service organizations in that the cost per minute of relaxation is cheaper than rocuronium. Also, it is available in power form (unlike rocuronium) and thus has a longer shelf life for storage.

Opioid Analgesic Agents

Analgesics are divided into opioids, non-opioids, and adjuvants. Adjuvants are most often used for chronic pain and not in the pre-hospital setting. Opioids bind to opioid receptors with action primarily at the mu subtype receptors. They cause supraspinal (brain-level) analgesia, spinal-level analgesia, ventilatory depression, gastrointestinal effects, itching, miosis, and sedation. Opioids are not only useful or painful conditions but can improve myocardial supply and demand (e.g. fentanyl), can alleviate angina (e.g. morphine), can reduce shivering (e.g. meperidine), and can reduce anesthetic requirements (e.g. fentanyl).
Opiate is the term used for the naturally occurring substance found in the poppy plant. Morphine was the first active ingredient purified from a plant and is still used today. Since it was the first, all other opioids are compared to morphine in terms of dose equivalency. Opioid is the broad term that includes both opiates and synthetic substances (e.g. fentanyl, hydromorphone, meperidine). Opioids are among the list of FDA controlled substances, along with the benzodiazepines, barbiturates, and ketamine.

Table 15-23: Opioid Equipotent Dosing

All opioids can cause apnea. These medications decrease the body’s ventilatory response to hypercarbia. This means that a higher PaCO2 (e.g. ETCO2) will be needed before the patient begins to breath. They decrease minute ventilation primarily be decreasing respiratory rate. This can be seen in Figure 15-11. Low PaCO2 levels in a normal adult result in low minute ventilation, but there is always some ventilation. When opioids are given, the curve shifts to the right and also extends down to zero (apnea). So, not only will a higher PaCO2 level be needed to increase spontaneous ventilation, but there is a point of apnea when PaCO2 decreases.

Fentanyl [Sublimaze]

Route & Dosage: 1-5mcg/kg IV.
Onset & Duration: onset immediate, peak rapid, duration 30-60min.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2-4hr.
Indications: analgesia, adjunct to anesthesia/intubation.
Contraindications: no major contraindications.
Adverse Effects: bradycardia, apnea, sedation, confusion, constipation, nausea, miosis, itching, muscle rigidity, potential for abuse.
Drug Interaction: CYP3A4 drugs, sedatives.
Black box warning: none for IV formulation.
Fentanyl is a synthetic opioid that is very commonly used in medicine. It is available in multiple forms and can be given via multiple routers including IV, IM, transdermal patch, buccal film, intranasal spray, sublingual tablet/spray, and buccal tablet. In the acute setting, it is almost exclusively administered via the intravenous route. Fentanyl has rapid onset and an intermediate duration of action. It has very little histamine release, thus is unlikely to cause hypotension even in large doses. A lowering of the heart rate can occur, which both increase myocardial oxygen supply and decreases myocardial oxygen demand for patients that are in pain. Fentanyl is considered one of the most hemodynamically stable opioids available.
Dosing for analgesia is 1mcg/kg IV in adult and children. Dosing should be lowered in the elderly (e.g. start at 25mcg). Dosing for induction and intubation is 2-5mcg/kg IV. Opioids do not reliably cause amnesia or unconsciousness, so they should be combined with an anesthetic agent for intubation. Huge doses are needed (> 30mcg/kg) to allow for intubation with fentanyl alone and even these doses do not reliably cause unconsciousness (Bailey et al, 1985). However, in patients who are obtunded and will not likely have recall of the intubation (e.g. unconscious), opioids like fentanyl may be used alone to provide analgesia and blunt the effects of laryngoscopy and intubation. For ongoing analgesia, an infusion of 0.033mcg/kg/min IV fentanyl is appropriate, which is in the range of 50-200mcg/hr.
There are no major contraindications to IV fentanyl and no black box warnings for the IV formulation. Common side effects of all opioids include sedation, nausea, miosis, constipation, and itching. Bradycardia is more commonly seen with fentanyl, especially with larger doses. All opioids have the potential for abuse, both by patients and providers. The drugs that interact with CYP3A4 are vast, but fortunately these interactions are not particularly relevant in the prehospital setting.
That’s Not True … or Is it? Opioids and Chest Wall Rigidity
Opioid-induced muscle rigidity with apnea has been shown to occur, especially with high doses (Streisand et al, 1993). This typically occurs with large bolus doses and also coincides with the onset of unconsciousness. This has also been termed opioid-induced chest wall rigidity, since mask ventilation can become extremely difficult or even impossible. Several studies have been done to try to understand the mechanism of the rigidity, but the precise mechanism is not well understood. However, several more recent studies have shown that the actual cause of difficulty with ventilation is related to the laryngeal musculature and vocal cords closing, not chest wall muscle rigidity.
Studies where providers visualized the upper airway and vocal cords during high-dose opioid infusion shed light on this topic. Vocal cord closure is likely the major cause of difficult ventilation after opioid bolus (Bennett et al, 1997). Chest wall rigidity is also not seen with patients who have a tracheostomy in place (Li et al, 2002), further suggestion the problem is with the upper airway. Placement of an endotracheal tube before a large bolus of opioid does not affect chest wall compliance (Abrams et al, 1996). So, the problem with a large bolus dose of fentanyl is that is can cause closure of the upper airway. This can be resolved by either giving a smaller bolus dose (e.g. 2mcg/kg instead of 5mcg/kg) or by administering a neuromuscular blocking agent.

Hydromorphone [Dilaudid, Exalgo]

Route & Dosage: 0.2-1mg IV.
Onset & Duration: onset 5min, peak 30-60min, duration 3-4hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2-3hr.
Indications: analgesia, adjunct to anesthesia/intubation.
Contraindications: no major contraindications.
Adverse Effects: apnea, sedation, confusion, hypotension, flushing, bradycardia, histamine release, anticholinergic effects, constipation, nausea, miosis, itching, muscle rigidity, potential for abuse.
Drug Interaction: sedatives.
Black box warning: errors with potent IV formulation.
Hydromorphone is an opioid analgesic with a quick onset of action and a duration longer than that of fentanyl. To compare these opioids, both fentanyl and hydromorphone have quick onset. Hydromorphone and morphine have longer durations of action and both release histamine. However, hydromorphone has less histamine release than morphine (i.e. less itching, less flushing, less hypotension). This makes hydromorphone a useful agent for analgesia because it has rapid onset, longer duration, and only a small amount of histamine release. It is less suited for the induction and intubation setting due to the potential for hypotension in higher doses. Further, it does not reduce the requirement for anesthetic agents to the degree seen with fentanyl.
Dosing is 0.2-1mg IV in adults. Hydromorphone is not commonly used in children. Continuous infusions are less common than fentanyl, but if needed the dose is 0.5-3mg/hr. The longer duration of action makes it, as well as morphine, less useful for continuous infusion when compared to fentanyl. Side effects are as expected for opioids in general. Anticholinergic-like effects can be seen. An inactive metabolite of hydromorphone can accumulate in renal failure, leading to neuroexcitation (e.g. myoclonus, agitation, seizures). Decreased heart rate is less commonly seen than with fentanyl. Muscle rigidity is less commonly seen when compared to fentanyl. A potent IV formulation (10mg/mL) is available in some settings so care should be taken to prevent inadvertent overdose.

Meperidine [Demerol]

Route & Dosage: 50-150mg IM (analgesia), 25-50mg IV (shivering).
Onset & Duration: onset 5-15min, duration erratic and variable.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2.5-4hr.
Indications: analgesia, shivering (off-label).
Contraindications: use with monoamine oxidase inhibitors (MAO-I).
Adverse Effects: apnea, sedation, confusion, hypotension, flushing, bradycardia, tachycardia, histamine release, anticholinergic effects, constipation, nausea, miosis, itching, muscle rigidity, potential for abuse.
Drug Interaction: sedatives, MAO-Is, serotonergic agents.
Meperidine is a synthetic opioid with a similar chemical structure to fentanyl. Decades ago it was the drug of choice for analgesia, but has now been mostly replaced by safer alternatives like fentanyl. Meperidine is an option for analgesia in patients without IV access because it can be given IM, however the duration of action is erratic. Dosing is 50-150mg IM, or about 1mg/kg IM, every 1-3 hours as needed. Intravenous dosing is also about 1mg/kg, but there are alternatives (e.g. fentanyl) with less side effects. Meperidine has good anti-shivering effects, where off-label dosing is 25-50mg IV.
Meperidine is contraindicated in patients on MAO inhibitors as well as other drugs that can cause serotonin syndrome (e.g. SSRIs). This is related to the famous Libby Zion case in 1984, where this patient received an MAO-I and meperidine, resulting in fatal serotonin syndrome. Side effects are as expected for opioids in general. Anticholinergic-like effects can be seen. With high doses, tachycardia can be seen which is thought to occur because atropine and meperidine have similar chemical structures. An active metabolite of meperidine can accumulate in renal failure, leading to seizures.

Morphine (generic)

Route & Dosage: 0.1mg/kg IV.
Onset & Duration: onset 5-10min, peak 20min, duration 4-5hr.

Pharmacokinetics: liver metabolism, urine elimination, half-life 90min.
Indications: analgesia, chest pain with acute coronary syndrome.
Contraindications: altered mental status, severe respiratory depression, acute or severe asthma, known paralytic ileus.
Adverse Effects: apnea, sedation, confusion, hypotension, flushing, bradycardia, histamine release, anticholinergic effects, constipation, nausea, miosis, itching, muscle rigidity, potential for abuse, worsening of hypotension with right ventricular infarction, worsening of hypotension in volume-depleted patients.
Drug Interaction: sedatives.
Black box warning: respiratory depression.
Morphine is an opiate that was previously discussed for use in the setting of chest pain. As an analgesic, it has a slower onset than fentanyl and hydromorphone, but is longer acting than fentanyl. It is more commonly used in children when compared to hydromorphone. It has more histamine release than most of the other opioids, which can result in hypotension. Dosing for analgesia is 0.1mg/kg IV up to 10mg for both children and adults. For acute severe pain, a dose of 2-3mg IV can be repeated every 5 minutes until either pain relief or respiratory depression. As an infusion in adults, dosing is 2-30mg/hr.
Side effects are as expected for opioids in general. Hypotension, especially with larger doses, is more common with morphine than other opioid analgesics. This is useful in patients with acute coronary artery disease, but not so useful in volume-depleted patients. Hypotension associated with right ventricular infarction can be worsened by morphine. Children tend to tolerate the hypotensive effects better than adult patients. An active metabolite of meperidine can accumulate in renal failure, leading to respiratory depression.

Mixed Opioid Agonist/Antagonists

Agonist-antagonist opioids are less commonly used when compared to the pure agonist opioids, like fentanyl. The mixed action opioids have respiratory depressant effects similar to morphine, but they have a ceiling effect where respiratory depression does not worsen even with higher doses. They are also less likely to be abused because they cause less euphoria (Miller, 2011). Cardiovascular effects vary between the mixed agonist-antagonists as do their actions at the mu and kappa opioid receptors. The mixed agonist-antagonists butorphanol and nalbuphine do not effectively attenuate the hemodynamic changes seen with laryngoscopy and endotracheal intubation. Fentanyl is preferred over these two medications for induction and intubation.

Table 15-24: Agonist-Antagonist Opioid Comparison

Butorphanol (generic)

Route & Dosage: 1-4mg IM/IV.
Onset & Duration: onset < 5min IV and < 15min IM peak 30-60min, duration 3-4hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2-9hr.
Indications: analgesia, labor pain.
Contraindications: no major contraindications.
Adverse Effects: apnea, sedation, confusion, hypotension, flushing, constipation, nausea, miosis, itching, muscle rigidity, intracranial hypertension, potential for abuse.
Drug Interaction: sedatives.
Butorphanol is a kappa opioid agonist and mu opioid agonist-antagonist. The kappa receptors are associated with the same side effects as the mu receptors, but without respiratory depression. It can be used for analgesia including labor pain. Butorphanol is a more effective analgesic in women than men (Gear et al, 1999), which may be due to kappa receptor effects. It was previously marketed under the brand name Stadol for this indication.
Dosing is 1-4mg IM or IV in adults. For labor pain, dosing is typically 1-2mg IM or IV and can be repeated every 4 hours. A typical analgesic dose for adults would be 1mg IV or 2mg IM. As with many opioids, dosing in the elderly should be cut in half (e.g. 0.5mg IV or 1mg IM). Butorphanol is not commonly used in children. Side effects are similar to other opioids, but respiratory depression has a ceiling effect after 30-60mcg/kg. Intracranial hypertension can be worsened with butorphanol. Drowsiness is the most common side effect, occurring in > 40% of patients.

Nalbuphine (generic)

Route & Dosage: 10mg/70kg (~0.15mg/kg) IM/IV/subcutaneous.
Onset & Duration: onset 2-3min IV and < 15min IM, duration 3-6hr.
Pharmacokinetics: liver metabolism, feces elimination, half-life 5hr.
Indications: analgesia.
Contraindications: no major contraindications.
Adverse Effects: apnea, sedation, confusion, clammy skin, dry mouth, hypotension, flushing, constipation, nausea, miosis, itching, muscle rigidity, intracranial hypertension, potential for abuse.
Drug Interaction: sedatives.
Nalbuphine has activity at the mu, kappa, and delta opioid receptors. It is a kappa agonist and a mu antagonist. It was previously marketed under the brand name Nubain. It has a ceiling effect for respiratory depression at 30mg. However, nalbuphine is not commonly used in the prehospital setting. Dosing is 10mg for every 70kg body weight with a maximum single dose of 20mg. Routes of administration include IM, IV, and subcutaneous. Side effects are similar to butorphanol.

Non-Opioid Analgesics

Non-opioid analgesics come in many varieties with many different mechanisms of action. These medications are typically used for mild to moderate pain, or in combination with opioids for severe pain. Aspirin and the nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX), resulting in decreased levels of prostaglandins. This mechanism is also responsible for the gastric side effects of aspirin and NSAIDs. The mechanism for acetaminophen is not fully understood, but is felt to block the synthesis of prostaglandins.
Nitrous oxide (N2O) is an inhalational anesthetic that is both a sedative-hypnotic and an analgesic. N2O interacts with the opioid system as well as NMDA receptors. Over 100% concentration would be needed to create general anesthesia with inhaled nitrous oxide, which is not only impossible but would provide 0% oxygen. N2O is self-administered in the prehospital setting, so patients must be alert, able to follow instructions, and able to place a mask against their intact face.

Acetaminophen [Ofirmev, Tylenol]

Route & Dosage: 325-1000mg PO/PR/IV.
Onset & Duration: onset < 5min IV and < 1hr oral, peak 1hr IV, duration 4-6hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2-3hr adults and 4-10hr neonates.
Indications: analgesia, fever.
Contraindications: liver disease.
Adverse Effects: nausea, hypertension, hypotension, tachycardia, constipation, electrolyte changes, dyspnea, serious skin reactions.
Drug Interaction: ethanol.
Black box warning: hepatotoxicity, 325mg max for combination products.
Acetaminophen (APAP) is one of the most common analgesic medications used around the world. It is effective for mild and moderate pain, as well as an antipyretic (anti-fever). Acetaminophen has a large number of brand names and comes combined opioids for analgesia as well as in many over-the-counter common cold medications. Unfortunately, acetaminophen toxicity has become the most common cause of acute liver failure in the United States and many other countries (Larson et al, 2005). The total daily dose in adults should not exceed 4000mg, though many organizations suggested the maximum daily limit be 3000mg.
Dosing in adults is typically 625mg PO/IV every 4 hours as needed or 1000mg PO/IV every 6 hours as needed. Dosing in children is 10-15mg/kg/dose every 4 to 6 hours as needed. Children aged 2-12 can received 15mg/kg IV as a single dose not to exceed 750mg. Rectal (PR) dosing for children is based on age: 6-12 year olds can receive 325mg, 3-6 year olds can receive 120mg, and 1-3 year olds can receive 80mg. Rectal dosing in adults and children > 12 years old is 650mg PR. Effects from rectal dosing is not as predictable when compared to PO or IV administration. These doses are the same for analgesia as they are for fever, with acetaminophen being one of the drugs of choice in fever.
Liver failure is the most worrisome side effect of acetaminophen use and has resulted in a black box warning. Combination opioid products should not contain more than 325mg acetaminophen due to the risk of toxicity. Acetaminophen is not recommended in standard doses for alcoholic patients; 2000mg/day maximum is appropriate in these patients. Nausea is the most common side effect. Hypertension and tachycardia can be seen, with hypotension being seen during rapid IV injection. Constipation can occur and is more common in children. Low electrolyte levels have been reported. Respiratory symptoms including dyspnea have been reported. Acetaminophen is associated with rare, serious/fatal skin reactions.

Ibuprofen [Advil, Caldolor, Motrin]

Route & Dosage: 400mg PO/IV.
Onset & Duration: onset 30-60min PO, peak 1-2hr, duration 6-8hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2hr adults and up to 75hr in premature infants.
Indications: analgesia, fever.
Contraindications: severe asthma, premature infants, bleeding disorders.
Adverse Effects: headache, bronchospasm, bleeding, drowsiness, hyperkalemia, blurred visions, serious skin reactions, epigastric pain, gastroesophageal reflux, tinnitus, kidney injury.
Drug Interaction: antithrombotics.
Black box warning: heart attack, stroke, gastrointestinal ulcer.
Ibuprofen is an NSAID that inhibits cyclooxygenase (i.e. COX blocker). Like acetaminophen, it is an analgesic for mild to moderate pain and an antipyretic. Acetaminophen side effects are benign, except for liver toxicity. NSAIDs, on the other hand, have multiple side effects. Dosing for ibuprofen in adults is 400mg PO or IV every 4-6 hours as needed. A single dose can be up to 800mg if needed. For children, dosing is 4-10mg/kg with a maximum single dose of 400mg. There are black box warnings that chronic ibuprofen can increase the risk of stroke, heart attack, and gastrointestinal ulcer. Ibuprofen is contraindicated in premature infants because NSAIDs can cause closure of a portion of the heart which may be needed if the child has congenital heart disease. Patients with severe asthma can have worsening of their disorder. NSAIDs inhibit platelets, which can lead to prolonged bleeding especially in patients who have bleeding disorders. Headache and drowsiness are potential side effects. Hyperkalemia has been seen in the elderly. Ringing in the ears (tinnitus) may be seen. Kidney injury is possible, especially with high doses in the elderly. Although rare, serious and fatal skin reactions can be caused by ibuprofen.

Ketorolac [Toradol]

Route & Dosage: 15-30mg IV or 30-60mg IM.
Onset & Duration: onset 30min, peak < 3hr, duration 4-6hr.
Pharmacokinetics: liver metabolism, urine elimination, half-life 2-6hr.
Indications: analgesia.
Contraindications: severe asthma, premature infants, bleeding disorders.
Adverse Effects: headache, bronchospasm, bleeding, drowsiness, hyperkalemia, blurred visions, serious skin reactions, epigastric pain, gastroesophageal reflux, tinnitus, kidney injury.
Drug Interaction: antithrombotics.
Black box warning: heart attack, gastrointestinal ulcer, short term use.
Ketorolac is a strong NSAID that is most commonly used by prehospital providers in the IV/IM formulation. It is indicated for mild to moderate pain, but can be helpful in severe pain as well. Unlike ibuprofen and acetaminophen, ketorolac is not commonly used as an antipyretic. Ketorolac parenteral (IM) is not considered to be more effective than oral ibuprofen (Arora et al, 2007). Dosing is 30mg IV or 60mg IM in adults. In the elderly, dosing is 15mg IV or 30mg IM. Dosing may be repeated every 6 hours as needed. For children, dosing is 0.5mg/kg IV or 1mg/kg IM with a single dose not to exceed the adult dose. Contraindications, adverse effects, drug interactions, and black box warnings are the same as with ibuprofen.

Nitrous Oxide (generic)

Route & Dosage: 25-50% inhaled.
Onset & Duration: onset rapid, duration 1-5min.
Pharmacokinetics: minimal metabolism, exhaled elimination, half-life 5min.
Indications: analgesia.
Contraindications: administration without oxygen, intraocular gas bubble.
Adverse Effects: hypotension, dizziness, apnea, pneumothorax, pneumocephalus, nausea, B12 deficiency, bone marrow suppression.
Drug Interaction: sedatives and opioids.
Nitrous oxide is one of the first inhalational anesthetics discovered. It has been used for decades and is still used for dental procedures and as an adjunct to general anesthesia. Nitrous oxide comes in blue cylinders in the United States, with oxygen coming in green cylinders by standard. N2O is administered by inhalational mask, has a rapid onset, and has a rapid duration of action. Concentrations higher than 50% can potentially cause general anesthesia if combined with other medications (e.g. opioids, sedatives). Analgesic effects are seen even at low doses. In the pre-hospital setting, N2O has been shown to be both safe and effective when compared with intravenous analgesics (Faddy et al, 2005). Studies in the 1970s found N2O may be useful in chest pain (Kerr et al, 1975; Thompson et al, 1976). However, the American Heart Association states that non-opioid analgesics do not have enough data to support their use in acute coronary syndrome (O’Connor et al, 2010).
Dosing is 25-50% nitrous oxide mixed with oxygen for inhalation, with a 50/50 mix being typical. Dosing is the same for adults, children, elderly, and laboring women. Patients who have had certain eye surgeries, such as for a detached retina, may have a gas bubble intentionally placed in their eye. N2O expands these spaces, which could lead to permanent vision loss in these patients. Patients who have had this surgery are usually asked to wear a medical alert bracelet for a certain period of time while they are at risk. Patients with the potential for pneumothorax, such as polytrauma patients, should not receive N2O as it can rapidly expand the pneumothorax. Open head injury can lead to pneumocephalus, which can also be worsened by N2O. Dizziness and hypotension are seen with administration. Nausea can occur with long periods of inhalation. Prolonged use (e.g. hours) can lead to B12 deficiency and bone marrow suppression, especially in elderly patients. As with all medications that cause sedation, the use of other sedatives or opioids can enhance the sedative effects.

References

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97. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Jneid H, Ettinger SM, Ganiats TG, Lincoff AM, Philippides GJ, Zidar JP; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Jun 11;127(23):e663-828. doi: 10.1161/CIR.0b013e31828478ac. Epub 2013 Apr 29.
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99. Nitroprusside. In: Lexicomp Online®. Topic 9707 Version 95.0. Retrieved 19-Feb-15 from http://www.uptodate.com/contents/nitroprusside-drug-information
100. Friederich JA, Butterworth JF 4th. Sodium nitroprusside: twenty years and counting. Anesth Analg. 1995 Jul;81(1):152-62.
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102. Cohn JN. Paroxysmal hypertension and hypovolemia. N Engl J Med. 1966 Sep 22;275(12):643-6.
103. Yakaitis RW, Otto CW, Blitt CD. Relative importance of alpha and beta adrenergic receptors during resuscitation. Crit Care Med. 1979;7:293–296.
104. Norepinephrine. In: Lexicomp Online®. Topic 9709 Version 98.0. Retrieved 03-Mar-15 from http://www.uptodate.com/contents/norepinephrine-noradrenaline-drug-information
105. Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, Gabrielli A, Silvers SM, Zaritsky AL, Merchant R, Vanden Hoek TL, Kronick SL; American Heart Association. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010 Nov 2;122(18 Suppl 3):S768-86. doi: 10.1161/CIRCULATIONAHA.110.971002.
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107. Phenylephrine. In: Lexicomp Online®. Topic 9900 Version 102.0. Retrieved 03-Mar-15 from http://www.uptodate.com/contents/phenylephrine-systemic-drug-information
108. Hemmings, Hugh. Pharmacology and Physiology for Anesthesia – Foundations and Clinical Application. Page 398. Elsevier, 2013. Print. ISBN: 1437716792.
109. Institute for Safe Medication Practices. ISMP Medication Safety Alert: Acute Care. 2013;18(3). Retrieved 03-Mar-15 from http://www.ismp.org/Newsletters/acutecare/issue.aspx?id=40
110. Marcucci, Lisa. Avoiding Common ICU Errors. Error #10. Philadelphia: Wolters Kluwer, 2007. Print. ISBN 0781767393.
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111. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af.
112. Norn S, Kruse PR. [Cardiac glycosides: From ancient history through Withering’s foxglove to endogeneous cardiac glycosides]. Dan Medicinhist Arbog. 2004:119-32.
113. Digoxin. In: Lexicomp Online®. Topic 9360 Version 148.0. Retrieved 18-Mar-15 from http://www.uptodate.com/contents/digoxin-drug-information
114. Wile D. Diuretics: a review. Ann Clin Biochem. 2012 Sep;49(Pt 5):419-31. doi: 10.1258/acb.2011.011281. Epub 2012 Jul 10.
115. Furosemide. In: Lexicomp Online®. Topic 8482 Version 144.0. Retrieved 23-Mar-15 from http://www.uptodate.com/contents/furosemide-drug-information
116. Dormans TP, Pickkers P, Russel FG, Smits P. Vascular effects of loop diuretics. Cardiovasc Res. 1996 Dec;32(6):988-97.
117. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK,
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124. Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. International Joint Efficacy Comparison of Thrombolytics. Lancet. 1995 Aug 5;346(8971):329-36.
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125. Tenecteplase. In: Lexicomp Online®. Topic 9955 Version 82.0. Retrieved 29-Mar-15 from http://www.uptodate.com/contents/tenecteplase-drug-information
126. Sinz E, American Heart Association. ACLS for Experienced Providers Manual and Resource Text, 1st Edition. 2013. Pages 91-92.
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127. Calcium Gluconate. In: Lexicomp Online®. Topic 9190 Version 111.0. Retrieved 29-Mar-15 from http://www.uptodate.com/contents/calcium-gluconate-drug-information
128. Dickerson RN, Alexander KH, Minard G, Croce MA, Brown RO. Accuracy of methods to estimate ionized and “corrected” serum calcium concentrations in critically ill multiple trauma patients receiving specialized nutrition support. JPEN J Parenter Enteral Nutr. 2004 May-Jun;28(3):133-41.
129. Atropine. In: Lexicomp Online®. Topic 8983 Version 112.0. Retrieved 29-Mar-15 from http://www.uptodate.com/contents/atropine-drug-information
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131. Himes RS Jr, DiFazio CA, Burney RG. Effects of lidocaine on the anesthetic requirements for nitrous oxide and halothane. Anesthesiology. 1977 Nov;47(5):437-40.
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133. Miller CD, Warren SJ. IV lignocaine fails to attenuate the cardiovascular response to laryngoscopy and tracheal intubation. Br J Anaesth. 1990 Aug;65(2):216-9.
134. Splinter WM. Intravenous lidocaine does not attenuate the haemodynamic response of children to laryngoscopy and tracheal intubation. Can J Anaesth. 1990 May;37(4 Pt 1):440-3.
135. Robinson N, Clancy M. In patients with head injury undergoing rapid sequence intubation, does pretreatment with intravenous lignocaine/lidocaine lead to an improved neurological outcome? A review of the literature. Emerg Med J. 2001 Nov;18(6):453-7.
136. Guyton DC, Scharf SM. Should atropine be routine in children? Can J Anaesth. 1996 Jul;43(7):754-5.
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145. Clancy M, Halford S, Walls R, Murphy M. In patients with head injuries who undergo rapid sequence intubation using succinylcholine, does pretreatment with a competitive neuromuscular blocking agent improve outcome? A literature review. Emerg Med J. 2001 Sep;18(5):373-5.
146. Minton MD, Grosslight K, Stirt JA, Bedford RF. Increases in intracranial pressure from succinylcholine: prevention by prior nondepolarizing blockade. Anesthesiology. 1986 Aug;65(2):165-9.
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148. Aspirin. In: Lexicomp Online®. Topic 8907 Version 136.0. Retrieved 30-Mar-15 from http://www.uptodate.com/contents/aspirin-drug-information
149. Awtry EH, Loscalzo J. Aspirin. Circulation. 2000 Mar 14;101(10):1206-18.
150. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013 Nov;122(5):1122-31. doi: 10.1097/01.AOG.0000437382.03963.88.
151. Clopidogrel. In: Lexicomp Online®. Topic 8921 Version 141.0. Retrieved 04-Apr-15 from http://www.uptodate.com/contents/clopidogrel-drug-information
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156. Dobutamine. In: Lexicomp Online®. Topic 9380 Version 103.0. Retrieved 05-Apr-15 from http://www.uptodate.com/contents/dobutamine-drug-information
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157. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ, Ornato JP, Pearle DL, Sloan MA, Smith SC Jr, Alpert JS, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Halperin JL, Hiratzka LF,
158. Hunt SA, Jacobs AK, Ornato JP. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004 Aug 4;44(3):E1-E211.
159. Loeb HS, Bredakis J, Gunner RM. Superiority of dobutamine over dopamine for augmentation of cardiac output in patients with chronic low output cardiac failure. Circulation. 1977 Feb;55(2):375-8.
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162. MacGregor DA, Smith TE, Prielipp RC, Butterworth JF, James RL, Scuderi PE. Pharmacokinetics of dopamine in healthy male subjects. Anesthesiology. 2000 Feb;92(2):338-46.
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164. Goldberg LI, Rajfer SI. Dopamine receptors: applications in clinical cardiology. Circulation. 1985 Aug;72(2):245-8.
165. Kellum JA, M Decker J. Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med. 2001 Aug;29(8):1526-31.
166. Filik R, Purdy K, Gale A, Gerrett D. Labeling of medicines and patient safety: evaluating methods of reducing drug name confusion. Hum Factors. 2006 Spring;48(1):39-47.
167. Berg RA, Hemphill R, Abella BS, Aufderheide TP, Cave DM, Hazinski MF, Lerner EB, Rea TD, Sayre MR, Swor RA. Part 5: adult basic life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010 Nov 2;122(18 Suppl 3):S685-705. doi: 10.1161/CIRCULATIONAHA.110.970939.
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169. Diazepam. In: Lexicomp Online®. Topic 9345 Version 141.0. Retrieved 06-Apr-15 from http://www.uptodate.com/contents/diazepam-drug-information
170. Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, Laroche SM, Riviello JJ Jr, Shutter L, Sperling MR, Treiman DM, Vespa PM; Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012 Aug;17(1):3-23. doi: 10.1007/s12028-012-9695-z.
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173. Midazolam. In: Lexicomp Online®. Topic 9650 Version 136.0. Retrieved 06-Apr-15 from http://www.uptodate.com/contents/midazolam-drug-information
174. Bulach R, Myles PS, Russnak M. Double-blind randomized controlled trial to determine extent of amnesia with midazolam given immediately before general anaesthesia. Br J Anaesth. 2005 Mar;94(3):300-5. Epub 2004 Nov 26.
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176. Ghoneim MM, Mewaldt SP. Benzodiazepines and human memory: a review. Anesthesiology. 1990 May;72(5):926-38.
177. Koht A, Moss JI. Does midazolam cause retrograde amnesia, and can flumazenil reverse that amnesia? Anesth Analg. 1997 Jul;85(1):211-2.
178. O’Boyle CA. Benzodiazepine-induced amnesia and anaesthetic practice: a review. Psychopharmacol Ser. 1988;6:146-65.
179. Hupp JR, Becker LE. Intensity and duration of amnesia from intravenous midazolam given for sedation. J Conn State Dent Assoc. 1988 Spring;62(2):80-5.
180. Phenytoin. In: Lexicomp Online®. Topic 9769 Version 152.0. Retrieved 06-Apr-15 from http://www.uptodate.com/contents/phenytoin-drug-information
181. Wilbur R, Kulik FA. Anticonvulsant drugs in alcohol withdrawal: use of phenytoin, primidone, carbamazepine, valproic acid, and the sedative anticonvulsants. Am J Hosp Pharm. 1981 Aug;38(8):1138-43.
182. Mannitol. In: Lexicomp Online®. Topic 9587 Version 101.0. Retrieved 07-Apr-15 from http://www.uptodate.com/contents/mannitol-drug-information
183. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS, Bratton SL, Chestnut RM,
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186. Broderick J, Connolly S, Feldmann E, Hanley D, Kase C, Krieger D, Mayberg M, Morgenstern L, Ogilvy CS, Vespa P, Zuccarello M; American Heart Association/American Stroke Association Stroke Council; American Heart Association/American Stroke Association High Blood Pressure Research Council; Quality of Care and Outcomes in Research Interdisciplinary Working Group. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Circulation. 2007 Oct 16;116(16):e391-413.
187. Badjatia N, Carney N, Crocco TJ, Fallat ME, Hennes HM, Jagoda AS, Jernigan S, Letarte PB, Lerner EB, Moriarty TM, Pons PT, Sasser S, Scalea T, Schleien CL, Wright DW; Brain Trauma Foundation; BTF Center for Guidelines Management. Guidelines for prehospital management of traumatic brain injury 2nd edition. Prehosp Emerg Care. 2008;12 Suppl 1:S1-52. doi: 10.1080/10903120701732052.
188. Ondansetron. In: Lexicomp Online®. Topic 9719 Version 145.0. Retrieved 07-Apr-15 from http://www.uptodate.com/contents/ondansetron-drug-information
189. Grover VK, Mathew PJ, Hegde H. Efficacy of orally disintegrating ondansetron in preventing postoperative nausea and vomiting after laparoscopic cholecystectomy: a randomised, double-blind placebo controlled study. Anaesthesia. 2009 Jun;64(6):595-600. doi: 10.1111/j.1365-2044.2008.05860.x.
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191. Prochlorperazine. In: Lexicomp Online®. Topic 9816 Version 139.0. Retrieved 08-Apr-15 from http://www.uptodate.com/contents/prochlorperazine-drug-information
192. Gan TJ, Diemunsch P, Habib AS, Kovac A, Kranke P, Meyer TA, Watcha M, Chung F, Angus S, Apfel CC, Bergese SD, Candiotti KA, Chan MT, Davis PJ, Hooper VD, Lagoo-Deenadayalan S, Myles P, Nezat G, Philip BK, Tramèr MR; Society for Ambulatory Anesthesia. Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2014 Jan;118(1):85-113. doi: 10.1213/ANE.0000000000000002.
193. Promethazine. In: Lexicomp Online®. Topic 9820 Version 149.0. Retrieved 11-May-15 from http://www.uptodate.com/contents/promethazine-drug-information
194. Hurst S, McMillan M. Innovative solutions in critical care units: extravasation guidelines. Dimens Crit Care Nurs. 2004 May-Jun;23(3):125-8.
195. Cimetidine. In: Lexicomp Online®. Topic 9265 Version 130.0. Retrieved 11-May-15 from http://www.uptodate.com/contents/cimetidine-drug-information
196. Tang AW. A practical guide to anaphylaxis. Am Fam Physician. 2003 Oct 1;68(7):1325-32.
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200. Glucose and dextrose. In: Lexicomp Online®. Topic 8711 Version 92.0. Retrieved 11-May-15 from http://www.uptodate.com/contents/instant-glucose-and-intravenous-dextrose-drug-information
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211. Choo KJ, Simons FE, Sheikh A. Glucocorticoids for the treatment of anaphylaxis. Cochrane Database Syst Rev. 2012 Apr 18;4:CD007596. doi: 10.1002/14651858.CD007596.pub3.
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213. Haloperidol. In: Lexicomp Online®. Topic 8516 Version 157.0. Retrieved 12-May-15 from http://www.uptodate.com/contents/haloperidol-drug-information
214. Olanzapine. In: Lexicomp Online®. Topic 9716 Version 163.0. Retrieved 12-May-15 from http://www.uptodate.com/contents/olanzapine-drug-information
215. Ziprasidone. In: Lexicomp Online®. Topic 10040 Version 131.0. Retrieved 13-May-15 from http://www.uptodate.com/contents/ziprasidone-drug-information
216. Sodium bicarbonate. In: Lexicomp Online®. Topic 9928 Version 113.0. Retrieved 13-May-15 from http://www.uptodate.com/contents/sodium-bicarbonate-drug-information
217. Proudfoot AT, Krenzelok EP, Brent J, Vale JA. Does urine alkalinization increase salicylate elimination? If so, why? Toxicol Rev. 2003;22(3):129-36.
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220. Pralidoxime. In: Lexicomp Online®. Topic 9802 Version 66.0. Retrieved 13-May-15 from http://www.uptodate.com/contents/pralidoxime-drug-information
221. Organophosphate and carbamate poisoning. Bird et al, In: UpToDate Online®. Topic 339 Version 15.0. Retrieved 13-May-15 from http://www.uptodate.com/contents/organophosphate-and-carbamate-poisoning
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225. Amyl nitrite. In: Lexicomp Online®. Topic 8767 Version 79.0. Retrieved 14-May-15 from http://www.uptodate.com/contents/amyl-nitrite-drug-information
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227. Hydroxocobalamin. In: Lexicomp Online®. Topic 8813 Version 75.0. Retrieved 14-May-15 from http://www.uptodate.com/contents/hydroxocobalamin-vitamin-b12-supplement-and-cyanide-antidote-drug-information
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229. Sodium nitrite. In: Lexicomp Online®. Topic 85782 Version 41.0. Retrieved 14-May-15 from http://www.uptodate.com/contents/sodium-nitrite-drug-information
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230. Hall AH, Dart R, Bogdan G. Sodium thiosulfate or hydroxocobalamin for the empiric treatment of cyanide poisoning? Ann Emerg Med. 2007 Jun;49(6):806-13. Epub 2006 Nov 13.
231. Santiago I. Gas poisoning. An Sist Sanit Navar. 2003;26(suppl 1):173-180.
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233. Hall AH, Rumack BH. Hydroxycobalamin/sodium thiosulfate as a cyanide antidote. J Emerg Med. 1987;5(2):115-21.
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235. Naloxone. In: Lexicomp Online®. Topic 9678 Version 103.0. Retrieved 15-May-15 from http://www.uptodate.com/contents/naloxone-drug-information
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238. Olsen KS. Naloxone administration and laryngospasm followed by pulmonary edema. Intensive Care Med. 1990;16(5):340-1.
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241. Agency for Toxic Substances and Disease Registry (ATSDR), “Nerve Agents,” 2011. Available at http://www.atsdr.cdc.gov/MHMI/mmg166.pdf
242. Oxytocin. In: Lexicomp Online®. Topic 9734 Version 80.0. Retrieved 15-May-15 from http://www.uptodate.com/contents/oxytocin-drug-information
243. American Congress of Obstetricians and Gynecologists (ACOG). Optimizing Protocols in Obstetrics. VOL. 108, NO. 4, OCTOBER 2006. Available at https://www.acog.org/~/media/Districts/District%20II/PDFs/Final_Hemorrhage_Web.pdf
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249. Miller, Ronald. Miller’s Anesthesia, 8th Edition. Page 829. Saunders, 2014. Print. ISBN: 0702052833
250. Etomidate. In: Lexicomp Online®. Topic 8428 Version 97.0. Retrieved 15-May-15 from http://www.uptodate.com/contents/etomidate-drug-information
251. Chan CM, Mitchell AL, Shorr AF. Etomidate is associated with mortality and adrenal insufficiency in sepsis: a meta-analysis. Crit Care Med. 2012 Nov;40(11):2945-53. doi: 10.1097/CCM.0b013e31825fec26.
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254. Warner KJ, Cuschieri J, Jurkovich GJ, Bulger EM. Single-dose etomidate for rapid sequence intubation may impact outcome after severe injury. J Trauma. 2009 Jul;67(1):45-50. doi: 10.1097/TA.0b013e3181a92a70.
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255. White JM, Ryan CF. Pharmacological properties of ketamine. Drug Alcohol Rev. 1996 Jun;15(2):145-55.
256. Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth. 1989 Mar;36(2):186-97.
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266. Ben-Shlomo I, abd-el-Khalim H, Ezry J, Zohar S, Tverskoy M. Midazolam acts synergistically with fentanyl for induction of anaesthesia. Br J Anaesth. 1990 Jan;64(1):45-7.
267. Barash, Paul. Clinical Anesthesia, 6th Edition. Lippincott Williams &amp; Wilkins, 2009. Print. ISBN: 1469805855.
268. Shafer SL. Shock values. Anesthesiology. 2004 Sep;101(3):567-8.
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269. Plurad DS, Talving P, Lam L, Inaba K, Green D, Demetriades D. Early vasopressor use in critical injury is associated with mortality independent from volume status. J Trauma. 2011 Sep;71(3):565-70; discussion 570-2. doi: 10.1097/TA.0b013e3182213d52.
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271. Warner KJ, Cuschieri J, Jurkovich GJ, Bulger EM. Single-dose etomidate for rapid sequence intubation may impact outcome after severe injury. J Trauma. 2009 Jul;67(1):45-50. doi: 10.1097/TA.0b013e3181a92a70.
272. Ledingham IM, Watt I. Influence of sedation on mortality in critically ill multiple trauma patients. Lancet. 1983 Jun 4;1(8336):1270.
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273. Bernhard M, Matthes G, Kanz KG, Waydhas C, Fischbacher M, Fischer M, Böttiger BW. [Emergency anesthesia, airway management and ventilation in major trauma. Background and key messages of the interdisciplinary S3 guidelines for major trauma patients]. Anaesthesist. 2011 Nov;60(11):1027-40. doi: 10.1007/s00101-011-1957-1.
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275. Black I, Grathwohl K, IB T, Martini W, Johnson K. The influence of hemorrhagic shock on ketamine: a pharmacokinetic analysis. Anesthesiology 2006; ASA Annual Meeting Abstracts A203.
276. Lippmann M, Appel PL, Mok MS, Shoemaker WC. Sequential cardiorespiratory patterns of anesthetic induction with ketamine in critically ill patients. Crit Care Med. 1983 Sep;11(9):730-4.
277. Savege TM, Colvin MP, Weaver EJ, Bond C, Drake J, Inniss R. A comparison of some cardiorespiratory effects of althesin and ketamine when used for induction of anaesthesia in patients with cardiac disease. Br J Anaesth. 1976 Nov;48(11):1071-81.
278. Gelissen HP, Epema AH, Henning RH, Krijnen HJ, Hennis PJ, den Hertog A. Inotropic effects of propofol, thiopental, midazolam, etomidate, and ketamine on isolated human atrial muscle. Anesthesiology. 1996 Feb;84(2):397-403.
279. Singbartl G, Langrehr D, Neuhaus R. [Cardiodepressive effects due to ketamine, etomidate, methohexitone and propanidid. A clinical study by means of the systolic-time-intervals (author’s transl)]. Prakt Anaesth. 1976 Dec;11(6):397-404.
280. Thangathurai D, Elder S, Rodriguez J, Allen HW, Chai M, Viljoen JF. Induction and maintenance of general anesthesia using ketamine-midazolam continuous infusion in cardiac surgical patients with low ejection fractions. Anesthesiology 1988;69(3a):A79
281. Smith, Charles. Trauma Anesthesia, 1st Edition. Chapter 8: Blood Loss: Does It Change My Intravenous Anesthetic? Cambridge University Press, 2008. Print. ISBN: 0521870585.
282. Pandit JJ, Andrade J, Bogod DG, Hitchman JM, Jonker WR, Lucas N, Mackay JH, Nimmo AF, O’Connor K, O’Sullivan EP, Paul RG, Palmer JH, Plaat F, Radcliffe JJ, Sury MR, Torevell HE, Wang M, Hainsworth J, Cook TM; Royal College of Anaesthetists; Association of Anaesthetists of Great Britain and Ireland. 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: summary of main findings and risk factors. Br J Anaesth. 2014 Oct;113(4):549-59. doi: 10.1093/bja/aeu313. Epub 2014 Sep 9.
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284. Osterman JE, Hopper J, Heran WJ, Keane TM, van der Kolk BA. Awareness under anesthesia and the development of posttraumatic stress disorder. Gen Hosp Psychiatry. 2001 Jul-Aug;23(4):198-204.
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285. Succinylcholine. In: Lexicomp Online®. Topic 9952 Version 78.0. Retrieved 17-May-15 from http://www.uptodate.com/contents/succinylcholine-suxamethonium-drug-information
286. Benumof JL, Dagg R, Benumof R. Critical hemoglobin desaturation will occur before return to an unparalyzed state following 1 mg/kg intravenous succinylcholine. Anesthesiology. 1997 Oct;87(4):979-82.
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287. Jeevendra Martyn JA, Fukushima Y, Chon JY, Yang HS. Muscle relaxants in burns, trauma, and critical illness. Int Anesthesiol Clin. 2006 Spring;44(2):123-43.
288. Kopriva C, Ratliff J, Fletcher JR, Van Tassel P, Stout R. Serum potassium changes after succinylcholine in patients with acute massive muscle trauma. Anesthesiology. 1971 Mar;34(3):246-9.
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289. Ebo DG, Fisher MM, Hagendorens MM, Bridts CH, Stevens WJ. Anaphylaxis during anaesthesia: diagnostic approach. Allergy. 2007 May;62(5):471-87.
290. Prakash S, Barde S, Thakur P, Gogia AR, Singh R. Intubating conditions following rapid sequence induction with three doses of succinylcholine. Indian J Anaesth. 2012 Mar;56(2):139-44. doi: 10.4103/0019-5049.96309.
291. Luo LL, Huang W, Zhou LX, Wang J, Xu L, Li P. Optimal dose of succinylcholine for tracheal intubation in patients during inhalation induction with sevoflurane: a randomized controlled trial. J Clin Anesth. 2014 Nov;26(7):557-62. doi: 10.1016/j.jclinane.2014.03.014. Epub 2014 Oct 16.
292. Naguib M, Samarkandi A, Riad W, Alharby SW. Optimal dose of succinylcholine revisited. Anesthesiology. 2003 Nov;99(5):1045-9.
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293. El-Orbany MI, Joseph NJ, Salem MR. Tracheal intubating conditions and apnoea time after small-dose succinylcholine are not modified by the choice of induction agent. Br J Anaesth. 2005 Nov;95(5):710-4. Epub 2005 Sep 16.
294. Naguib M, Samarkandi AH, El-Din ME, Abdullah K, Khaled M, Alharby SW. The dose of succinylcholine required for excellent endotracheal intubating conditions. Anesth Analg. 2006 Jan;102(1):151-5.
295. Pancuronium. In: Lexicomp Online®. Topic 9738 Version 79.0. Retrieved 17-May-15 from http://www.uptodate.com/contents/pancuronium-drug-information
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296. Lee C. Goodbye suxamethonium! Anaesthesia. 2009 Mar;64 Suppl 1:73-81. doi: 10.1111/j.1365-2044.2008.05873.x.
297. Heier T, Caldwell JE. Rapid tracheal intubation with large-dose rocuronium: a probability-based approach. Anesth Analg. 2000 Jan;90(1):175-9.
298. Vecuronium. In: Lexicomp Online®. Topic 10041 Version 88.0. Retrieved 17-May-15 from http://www.uptodate.com/contents/vecuronium-drug-information
299. Fentanyl. In: Lexicomp Online®. Topic 8441 Version 150.0. Retrieved 17-May-15 from http://www.uptodate.com/contents/fentanyl-drug-information
300. Bailey PL, Wilbrink J, Zwanikken P, Pace NL, Stanley TH. Anesthetic induction with fentanyl. Anesth Analg. 1985 Jan;64(1):48-53.
301. Streisand JB, Bailey PL, LeMaire L, Ashburn MA, Tarver SD, Varvel J, Stanley TH. Fentanyl-induced rigidity and unconsciousness in human volunteers. Incidence, duration, and plasma concentrations. Anesthesiology. 1993 Apr;78(4):629-34.
302. Bennett JA, Abrams JT, Van Riper DF, Horrow JC. Difficult or impossible ventilation after sufentanil-induced anesthesia is caused primarily by vocal cord closure. Anesthesiology. 1997 Nov;87(5):1070-4.
303. Li Y, Bjoraker D. Does chest wall rigidity after narcotic use cause difficult ventilation? Anesthesiology 2002; 96:A-1338
304. Hydromorphone. In: Lexicomp Online®. Topic 8538 Version 148.0. Retrieved 17-May-15 from http://www.uptodate.com/contents/hydromorphone-drug-information
305. Thwaites D, McCann S, Broderick P. Hydromorphone neuroexcitation. J Palliat Med. 2004 Aug;7(4):545-50.
306. Meperidine. In: Lexicomp Online®. Topic 9608 Version 118.0. Retrieved 17-May-15 from http://www.uptodate.com/contents/meperidine-pethidine-drug-information
307. Miller, Ronald. Miller’s Anesthesia, 8th Edition. Pages 903-905. Saunders, 2014. Print. ISBN: 0702052833
308. Butorphanol. In: Lexicomp Online®. Topic 9179 Version 110.0. Retrieved 18-May-15 from http://www.uptodate.com/contents/butorphanol-drug-information
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309. Nalbuphine. In: Lexicomp Online®. Topic 9676 Version 102.0. Retrieved 18-May-15 from http://www.uptodate.com/contents/nalbuphine-drug-information
310. Acetaminophen. In: Lexicomp Online®. Topic 9242 Version 136.0. Retrieved 18-May-15 from http://www.uptodate.com/contents/acetaminophen-paracetamol-drug-information
311. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiødt FV, Ostapowicz G, Shakil AO, Lee WM; Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005 Dec;42(6):1364-72.
312. Ibuprofen. In: Lexicomp Online®. Topic 8547 Version 173.0. Retrieved 18-May-15 from http://www.uptodate.com/contents/ibuprofen-drug-information
313. Ketorolac. In: Lexicomp Online®. Topic 9152 Version 138.0. Retrieved 18-May-15 from http://www.uptodate.com/contents/ketorolac-systemic-drug-information
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