What happened when the body temperature rises up significantly beyond the normal temperature?

Abstract

When habitat temperature changes, body temperature follows in most fish. Thermal change can markedly shift the physical state of mitochondrial membranes, and may perturb the equilibrium among oxidative phosphorylation, proton leak, and ROS production. A fundamental response to thermal change occurs in mitochondrial phospholipids, with head groups and acyl chains changing to maintain membrane physical state. Mitochondrial enzyme levels and often mitochondrial abundance change, presumably to maintain capacity. This response sequence is common to many eurythermal temperate-zone fish, but gene-expression profiling shows suites of additional genes that change during thermal acclimation.

Maintaining Body Temperature

The potential of poisons to change body temperature should not be overlooked. Poisons may cause elevated body temperature (e.g., atropine, pentachlorophenol) or depressed body temperature (e.g., ethanol). Severe hyperthermia of small animals can be reversed by ice-water enema or, if an intravenous fluid line is in place, placing a loop of the tubing into a bowl of wet ice so that the fluid entering the body is chilled. Large animals, with the exception of sheep with more than minimal fleece, may be cooled by hosing or spraying, taking time to flatten the wet hair to the skin to remove the layer of dry air that would otherwise persist there. Shade and drinking water should be provided. Shearing will assist sheep, as well as long-haired goats or cattle, to cool. Warming of small animals can be promoted by hot water bottles, electric pads, or chemical hand-warmers. Large animals should be herded together to share body heat if possible. Woolen or reflective blankets help to conserve the animal’s own body heat and will lead to gradual warming.

3.8.1 Effect of levetiracetam

Low or high doses of levetiracetam mildly affected body temperature changes and stress symptoms after 4 h heat stress (Table 2 and Fig. 2). The physiological variables were also altered mildly after heat stress alone or intoxication with Ag or Cu NPs (Table 2 and Fig. 2). The BBB breakdown to EBA and radioiodine were slightly reduced (Fig. 2 and Table 1). However, the CBF, brain edema and cell changes were not much different from the heat stress alone or intoxicated with Ag or Cu NPs (Fig. 4 and Tables 1 and 2). The oxidative parameters also did not affect much following heat stress alone and associated with Cu or AG NPs intoxication (Figs. 5–9). Brain pathology in heat stress was also only slightly affected (Figs. 10–13). This suggests that levetiracetam has only limited protective effects on heat stress induced pathology exacerbated with Ag or Cu NPs treatment.

Therapeutic hypothermia

Although an exhaustive discussion of therapeutic hypothermia is beyond the scope of the present chapter, a discussion of body temperature changes in neurologic disorders would be incomplete without at least referring to this ever more popular form of treatment. The potential benefits of hypothermia as a neuroprotective strategy in patients with brain injury has been a subject of research for over two decades. The theoretical considerations of how hypothermia can lead to brain protection are numerous (Table 62.7) and have led to its study within the context of traumatic brain injury, ischemic stroke, increased intracranial pressure, and global brain ischemia resulting from cardiac arrest. At present, therapeutic hypothermia is being used in one or more of these clinical scenarios, the most frequent being following cardiac arrest (Eisenburger et al., 2001; Whitelaw and Thoresen, 2001; Darby, 2002; Gadkary et al., 2002; Marion, 2002; Feigin et al., 2003; Holzer and Sterz, 2003; Kochanek and Safar, 2003; McIntyre et al., 2003; Olsen et al., 2003; Bernard, 2004a, b, 2006; Moran and Solomon, 2004; Edwards and Azzopardi, 2006; Lyden et al., 2006).

Table 62.7. Proposed neuroprotective mechanisms of hypothermia

Thermoregulatory responses as a function of the sleep stage

Differences in thermoregulatory responses were first demonstrated in sleeping cats, whose body temperature regulation disappeared during REM sleep (Parmeggiani and Rabini, 1970). In contrast to REM sleep, the body temperature change during non-REM sleep is negatively correlated with environmental temperatures, suggesting that homeothermic regulation is still operative. A transition from a homeothermic state to a poikilothermic state occurs when switching from non-REM sleep to REM sleep. As a result, sleeping in a nonthermoneutral environment leads to a conflict between sleep pressure and maintenance of homeothermia. Alterations in sleep (and especially REM sleep deprivation) can thus be seen to prevent hypo- or hyperthermia in animals sleeping in a cold or warm environment, respectively (Parmeggiani, 1988).

The blockage of thermal responses during REM sleep has been interpreted as transient inactivation of the central controller. According to the model proposed by Parmeggiani (1988), the transition between the different sleep stages corresponds to a change in the hierarchical functional control of the central nervous structures involved in thermoregulation: the diencephalic structures (including the hypothalamus) are activated in SWS but not in REM sleep, during which autonomic responses are only controlled by the rhombencephalon. In REM sleep, the central controller may thus be disconnected from the spinal cord and the brainstem.

In humans sleeping in a cold environment, Haskell et al. (1981) did not find the marked decreases in oxygen consumption typically observed in animals during REM sleep. In the same way, during transient rises in air temperature, local sweating rates recorded from a sweat collection capsule stuck on the skin of the right pectoral region persisted in all sleep stages (Libert et al., 1982a). However, the sweat gland output was lower in REM sleep than in SWS, and the sweating onset was delayed. Sagot et al. (1987) and Amoros et al. (1986) pointed out that the greater sweating rate recorded during SWS was accounted for by a downshift in the hypothalamic set point for sweating when compared with sleep stages 1 and 2. In contrast, during REM sleep, the reduced thermal response was due to a decrease in the central controller's gain. Strikingly, repeated heat exposure during the day (for 7 days) triggered thermoregulatory adaptive mechanisms in SWS only (Di Nisi et al., 1989), highlighting an incompatibility between REM sleep and adaptive thermal processes. To our knowledge, this aspect has never been studied in the elderly.

In neonates, the linear relationship between thermal responses and body temperatures during AS episodes (in both cool and warm environments: Figure 14.1) demonstrates that closed-loop regulation operates during this sleep stage (Bach et al., 1994). The thermal response during AS is sometimes greater than that recorded during QS; QS is characterized by low energy utilization (Stothers and Warner, 1977, 1984; Darnall and Ariagno, 1982; Fleming et al., 1988; Azaz et al., 1992). However, this finding was not confirmed by other studies dealing with skin evaporative heat losses, either at thermoneutrality or in a warm environment (Azaz et al., 1992; Bach et al., 1994). Hence, in contrast to what is seen in adults during REM sleep, neonatal thermoregulatory responses are not depressed during AS – at least in the range of environmental temperatures usually studied. Thus, AS is a well-protected sleep stage (Bach et al., 1996). This may be important with regard to the duration of AS and its role in maturation of the neuronal network; the maintenance of thermoregulatory responses during AS protect the neonate from long periods of poikilothermy (Darnall and Ariagno, 1982).

The above-cited studies prompt the conclusion that thermoregulatory responses differ between sleep stages. However, in contrast to animals, thermoregulation in adults is not completely abolished during REM sleep but is merely impaired. In neonates, the AS response is at least as efficient as that measured during QS.

Generalisations Concerning Thermal Stress

For thermoconformers, the temperature of the ambient medium directly influences body temperature, and thereby modifies the rate of metabolic reactions and many other biological functions. That effect is reflected in the Arrhenius equation, which demonstrates the thermal dependence of most reactions, and the Q10 temperature coefficient, which provides a numerical solution for the impact of a given temperature change. For most animals, one finds a two- to three-fold elevation in biological reactions for a temperature change of 10°C. Mammals and birds also adhere to those principles, but as obligate thermal regulators, they have autonomically controlled organs that resist forced body temperature changes (Section Concepts of Mammalian Homeothermy). Instead, those species endeavor to defend body temperatures at levels that are generally higher than ambient temperature; for comfortably resting humans, the deep-body temperature will vary around 36.5–37.0°C (depending upon the site of measurement), and the average skin temperature will be about 33°C.37 While that thermoregulatory strategy is energetically expensive, it is advantageous due to the thermal dependence of most biological functions, which are held in a state of readiness for immediate activation.

Nevertheless, circumstances exist during which those mechanisms can become overwhelmed or disrupted (excessive heat storage, excessive heat loss and chemical disturbances), forcing body temperatures to move from a regulated to an apparently unregulated state.38 In other cases, temperature variations can be observed, but without regulation being lost. There are two general examples of this permissible or regulated variance. Firstly, when we are resting comfortably, body temperature changes over a range of about 0.6°C can be seen before either shivering (at one end) or sweating are activated. Secondly, during steady-state thermal exposures and exercise, body temperatures may rise (or fall) by as much a 1.5°C, resulting in the recruitment of sweating (or shivering). However, rather than that temperature change continuing unchecked, autonomically controlled structures are able to compensate for the elevated heat storage (or heat loss), resulting in the attainment of a stable body temperature, albeit above (or below) that which obtained when resting comfortably (the basal state). These regulated hyper- and hypothermic states are often misinterpreted as instances of regulatory failure.

Instead, they represent efficient accommodations that permit mild-moderate thermal stresses to be physiologically compensated (in the short term) without undue strain, and it is upon those conditions that the greatest emphasis of this contribution will be placed. In the first instance, thermal stresses are detected by sensors located just below the skin surface (thermoreceptors), giving rise to sensations we associate with high and low thermal energy states.39,40 Eventually, the deeper tissues may experience heating or cooling, the combined effect of that thermal feedback allows us to form an opinion concerning how comfortable we are with those thermal stresses, and in which set of conditions we prefer to reside (thermal preferendum); some prefer warmer, others prefer cooler temperatures. Nevertheless, depending upon one's place of residence and the use of air conditioning, thermal comfort is heavily influenced by past and concurrent experiences, and will vary seasonally,41 resulting in people reporting greater comfort with heat in the summer than during the winter months.

Safety Considerations with BMC Therapy

Although BMC therapy is considered safe for most patients, absolute contraindications include patients who have bone marrow-derived cancers, such as lymphoma, patients who use blood thinners, and those with systemic infections. Nonbone marrow-derived cancers are considered relative contraindications and caution should be used in patients with osteoporosis. Similarly to the way platelets can exhibit variability within the same patient when subjected to different environmental stresses, certain individual patient factors may produce variability in the quality and volume of BMC. Considerations include tobacco smoking, active menstrual cycle, body temperature changes, which may affect RBC distribution in the extremities, patient age, and endocrine hormone deficiency (estrogen, thyroid hormone, testosterone). Bay-Jensen et al. [85] recently reported a link between cartilage disease and metabolic syndrome, suggesting that patient deficiency in either estrogen or thyroid hormone may be an initiator, driver, or both of OA. Studies have evaluated the overall safety and complication rates of BMC therapy in orthopedic applications with encouraging outcomes [86,87]. Hendrich et al. [86] studied BMC, concluding that on-site preparation of BMC eliminates ex vivo cell proliferation and is safer in the use of autologous cell therapy. The authors additionally noted that bone marrow harvesting from the iliac crest yielded no patient infection, excessive bone formation, induction of tumor formation, or morbidity [86].

Centeno et al. [87] reported on 339 patients with degenerative joint disease of the knee who were treated with either cultured BMSC or surgery, with follow-up ranging from 3 months to 4 years. The authors concluded that significantly fewer complications occurred for patients in the cultured-BMSC treatment group compared with patients treated surgically [87].

Adjustment

The first level, short-term response of any organism to changes in its environment is adjustment, also referred to as acclimatization. All organisms have some degree of physiological, life-history, or behavioral plasticity that enables them to live in a variable environment. The degree of plasticity with regard to climatic and atmospheric conditions varies widely among different kinds of organisms. Therefore, some types of organisms will be able to adjust to relatively large changes in climate, whereas others will be unable to adjust to even apparently minor increases in temperature or slight variations in precipitation.

An example of climatic adjustment in animals involves thermoregulation in vertebrates. Endotherms such as mammals have built-in physiological mechanisms to cope with body temperature changes. Ectotherms such as reptiles have behavioral traits that help regulate body temperature. Because of traits such as these, initial increases in environmental temperature should be well within the tolerances of many vertebrates. In plants, the concurrent increase of atmospheric CO2 with surface temperature may augment the ability of some individuals, populations, and species to adjust to and flourish under anthropogenic climate change. Increases in CO2, especially for plants with the common C3 photosynthesis pathway (e.g., most trees and shrubs), can result, at least initially, in the CO2 fertilization effect mentioned above. Enhanced CO2 concentrations can increase the ability of these types of plants to tolerate water stress, higher temperatures, and lower light. Other kinds of plants, particularly those with the C4 photosynthesis pathway (e.g., many low-latitude and low-elevation grasses), have physiological mechanisms that enable them to withstand warm temperatures and low availability of water. Such mechanisms provide a means of adjustment to drought stress that may be associated with increased temperatures and evaporation.

While most biota will have at least some capacity to withstand, and in some cases benefit from, initial changes in climate, the rapid rate and large magnitude of climate change are likely to quickly surpass their capacity to adjust to new climate conditions within their prewarming habitats. Biota that cannot continue to adjust will have to respond through evolution, migration, or extinction.

Subjective effects

The authors of a meta-analyses searched for published articles that provided data on self-reported acute effects associated with use of ecstasy while intoxicated or within 24 hours after consumption [64]. The study criteria were met by 24 studies in 3074 ecstasy users. There was a slight preponderance of men; ages were 14–74, the largest proportion being 21–36 years.

Somatic effects were more frequent than any other effects, and 80% or more participants in one or more studies had bruxism/teeth problems, body temperature changes, fatigue or mental fatigue, accelerated heart rate or heartbeat, sweaty palms, dry mouth/thirst, and increased energy. A few subjects complained of stomach and/or intestinal pain, inability to urinate, shortness of breath, motor tics/shakiness, nausea and/or vomiting, headache, dizziness and/or vertigo, and muscle aches or tightness.

For emotional effects, 80% or more participants in three or more studies reported feeling tenderness/affection, peaceful/calm, euphoria or improved mood, and reduced defensiveness. A few subjects reported anxiety or nervousness, fear/paranoia, omnipotence, greater self-confidence or self-acceptance, and insecurity.

Cognitive effects reported in three or more investigations were confused thoughts (3–50%), loss of memory/forgetfulness (3–28%) and increased alertness/attention focused on the here-and-now (7–100%).

Sexual effects, especially arousal/increased sensual awareness (7–100% in 8 studies) and decreased sexual desire (3–45% in 4 studies) were also reported.

Sensory perceptions reported in three or more studies were visual effects/changes in visual perception (14–85%), sound hallucinations/altered sound perception (13–100%), enhanced sense of touch/tactile illusions (3–95%), and hallucinations not otherwise specified (2–60%).

Sleepiness was the only sleep effect recorded by more than one investigator (9–85%).

Reduced appetite was reported by 14–100% subjects in 9 studies.

Factors that affected ecstasy experience as reported in some studies were women having more negative physical and psychological effects than men. Larger doses were reported to be associated with more hallucinatory experiences, disorientation, loss of control, and increased adverse effects. Acute subjective experiences usually peaked at 45–90 minutes and lasted 4.5–9 hours. Desirable acute subjective experiences were experienced more often than non-desirable ones. The authors suggested that acute subjective experiences may motivate or restrain ecstasy use, and that educators and researchers could use these data to develop credible prevention messages.

The subjective experiences of ecstasy use have been explored in 305 unpaid volunteers (268 ecstasy users and 37 abstainers; mean age 26. range 18–72, years; 63% men) [65]. Lifetime use of ecstasy significantly correlated with estimated consumption of other drugs, including alcohol, cannabis, cocaine, and LSD; heavy use of ecstasy was associated with heavy use of all substances. Of the 262 individuals who specified their usual location of ecstasy use, 110 (41%) reported usually taking it at entertainment venues, 52% reported usually taking it in private houses, and 5% reported usually taking it outside. A heterogeneous sample of polysubstance misusers revealed six main components of acute ecstasy effects. These components were perceptual alterations, entactogenesis, pro-social effects, aesthetic and mood effects, negative intoxication effects, and sexual effects. More experienced ecstasy users reported fewer negative, perceptual, and aesthetic effects. Naive individuals expected greater perceptual alterations, aesthetic and mood effects, negative intoxication, and sexual effects than those who reported frequent use of ecstasy. Respondents reported using ecstasy for a variety of reasons, most often for raves, dancing, enjoyment of music, to be sociable, to produce altered states of consciousness, and for self-defined psychotherapy. There were no sex differences, in contrast to previous studies. The authors suggested that expectations may be primed by media reference to the negative effects of ecstasy and that those using the drug for other purposes, for example for spirituality, may adopt strategies to counteract negative effects or withdraw from social interactions as part of their drug use practice. They suggested that drug intervention strategies would be more effective if targeted to the particular user groups defined by the reasons given for substance use. Thus, people using ecstasy while dancing or to be social may be more interested in hearing harm reduction information focusing on ways to reduce negative effects. However, people who are not as attentive to negative effects, as those using ecstasy in self-defined therapeutic or spiritual context may be less interested in this information. A drawback of this study was that as many of the respondents were frequent polysubstance users, it would be difficult to differentiate the effects of ecstasy from those of other drugs.

It has been suggested that lowering of serotonin for a period after ecstasy use could account for increases in both self-rated and objective measures of aggression previously found in ecstasy users several days after taking the drug [66]. A total of 46 participants were tested, 19 were ecstasy users and 27 controls. They were compared on the night of drug use and 4 days later. On day 4, a task designed to tap cognitive bias toward material with aggressive content was administered. To investigate sex differences, another data set from a previous study with similar study design was combined, resulting in 107 participants. Ecstasy users recognized more aggressive sentences than controls. They rated themselves as being more aggressive and depressed than controls on day 4 but there were no sex differences on any measure of aggression in the combined data set.

Cardiovascular Responses

When the body has to counteract an increased heat load, it must direct enhanced blood flow to the skin, first to transport heat from the body core to the surface for dry heat loss (radiation, convection, conduction) and, second, to supply the water and electrolytes that are necessary for sweat formation. Cardiovascular adjustments to whole body heating in humans can be summarized as follows. During an aggressive heating of the whole body surface with water-perfused suits, the skin temperature rises from 35 to 40.5°C and the blood temperature increases from 36.7 to 39.1°C. These body temperature changes are accompanied by a continuous rise of cardiac output from 6.4 to 13 l/min. The doubling of cardiac output is, to a large degree, driven by an increased heart rate (rise of about 30 beats per minute per degree increase of core temperature), whereas stroke volume changes little. Increased cardiac output during heat stress is accompanied by a regional redistribution of blood. Despite the doubled cardiac output, splanchnic, renal, and muscle blood flows are reduced by 1.2 l/min during the heating period. Thus, skin blood flow can approach about 8 l/min during external heat stress (6.6 l/min additional cardiac output plus 1.2 l/min redistributed blood). The dramatic increase in skin blood flow during heat stress occurs over the entire body surface and is distributed between two general vessel types: capillaries and arteriovenous anastomoses (AVAs). AVAs are shunt vessels between arterioles and venoles. Opening AVAs accelerates blood flow and thereby heat flux substantially. AVAs are concentrated on the so-called acral sites of the skin (tips of extremities, nose, ears, tongue, and lips); there is a lack of AVAs in nonacral sites (torso, forearms, upper arms, and legs). The major mechanisms by which skin blood flow is increased during heat stress are (1) a reduced activity in sympathetic vasoconstrictor nerves, (2) an increased activity of a sympathetic active vasodilator system, and (3) direct local vasodilative effects of elevated skin temperature. Cardiac output and distribution/redistribution of blood under resting conditions and during heat stress are summarized in Figure 2.

It has to be noted that the increase of thermoregulatory skin blood flow is limited by the demands of the working muscles during hyperthermia induced by physical exercise.