Hyperthermia Case File

Hyperthermia Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 30

A confused 55-year-old female marathon runner presents to the emergency room (ER) complaining of a headache and muscle cramps. Her skin has turned red and is quite wet. After being asked to follow the nurse, the patient stands up, vomits, and subsequently faints. A nearby doctor immediately checks her pulse and temperature to find both elevated, with temperature reaching up to 39°C. The patient is immediately diagnosed with hyperthermia and treatment is started.

• What is the normal range for human body temperature?
• What region of the brain regulates body temperature?
• What are the treatment options available to her?

ANSWERS TO CASE 30: HYPERTHERMIA

Summary: A 55-year-old female marathon runner is complaining of headache and cramps, also experiencing confusion, nausea, elevated pulse, and red skin.

• Normal body temperature: 36°C–37°C.
• Brain region: Body temperature regulation is controlled primarily by the hypothalamus.
• Treatment options: Rehydration with water; rest in cool conditions.

CLINICAL CORRELATION

Hyperthermia is an acute condition that occurs when the body absorbs more heat than it can dissipate causing abnormally high body temperatures. Temperatures above 40°C are life threatening, and brain death begins at 41°C. Common signs include confusion, headache, muscle cramps, and nausea. Severe confusion may lead patients to become hostile and act intoxicated. High temperatures will cause excessive perspiration until dehydration occurs. Acute dehydration causes blood pressure to drop significantly, possibly leading to dizziness or even fainting, especially when standing suddenly. To counter the drop in blood pressure, increased heart rate (tachycardia) and respiration rate (tachypnea) occur to increase the oxygen supply to the body. Cutaneous blood vessels dilate to increase heat dissipation, resulting in a red skin color. As heat stroke progresses, blood vessels constrict to help increase blood pressure, then causing a paler, bluish skin color. Eventually body organs begin to fail until unconsciousness and coma result. Demographically, studies have shown that women and the elderly are at greater risk for heat stroke. Proper treatment of heat stroke includes immediate hospitalization. Patient’s body temperature must be lowered quickly. Methods include moving patient to cool areas with fans or air conditioning, removing patient’s clothes, and submerging patient in cold water bath. Additionally, rehydration is critical, and is achieved by drinking large amounts of water and isotonic beverages (eg, Gatorade).

APPROACH TO THERMOREGULATION

Objectives

1. Know the ways and means to prevent hypothermia.
2. Know the responses to temperature-increasing and temperaturedecreasing mechanisms.

Definitions

Homeotherm: An organism, such as a mammal or bird, having a body temperature that is constant and largely independent of the temperature of its surroundings; an endotherm; “warm-blooded.”

Poikilotherm: An organism, such as a fish or reptile, having a body temperature that varies with the temperature of its surroundings; an ectotherm; “cold-blooded.”

Preoptic area: A region of the brain that is situated immediately below the anterior commissure, above the optic chiasma, on the anterior side of the hypothalamus that regulates certain autonomic activities often with other portions of the hypothalamus.

Thermoreceptor: A sensory receptor that responds to heat and cold. Piloerection: Involuntary erection or bristling of hairs owing to a sympathetic reflex usually triggered by cold, shock, or fright or caused by a sympathomimetic agent.

Thyroxine (T4): An iodine-containing hormone, C15H11I4NO4, produced by the thyroid gland, that increases the rate of cell metabolism and regulates growth.

DISCUSSION

Thermoregulation is the ability of an organism to maintain its body temperature within certain boundaries, even when the environmental temperature is different. Like all mammals, humans are homeothermic, or “warm-blooded.” Human core temperature is about 37°C. Many nonmammals, such as reptiles and fish, are poikilotherms, or “cold-blooded” organisms.

Thermoregulation is controlled primarily by nervous feedback mechanisms operating through the hypothalamus. The thermostatic center is found in theanterior portion of the hypothalamus in the preoptic area. This area has a large number of heat-sensitive neurons (warm receptors) and about a third as many cold-sensitive neurons (cold receptors).

There are two general types of thermoreceptors: warm receptors and cold receptors. The axons of warm receptors are unmyelinated, slowly conducting C fibers, while the axons of cold receptors are lightly myelinated, faster conducting Aδ fibers. The receptive fields of thermoreceptors are small spots of approximately 1 mm in glabrous skin and 3-5 mm in hairy skin. About three to four spots are innervated by a single axon. At normal body temperature, both warm and cold spots discharge, but as temperatures increase, cold spots reduce their firing frequency while warm spots increase their firing. Activation of warm-sensitive receptors (temperatures above 37°C) results in activation of neurons in the paraventricular nucleus and lateral hypothalamus to increase parasympathetic outflow and increase heat dissipation. Warm-sensitive receptors have inhibitory connections on coldsensitive neurons. Increased discharge in cold-sensitive neurons results in activation of neurons in the paraventricular nucleus and the posterior hypothalamus to increase sympathetic outflow in order to generate and conserve heat. Cold-sensitive neurons do not have intrinsic temperature receptors, but instead increase their discharge by the decrease in the discharge rate of warm-sensitive neurons.

Unlike the preoptic area, the skin has far more cold receptors than warm receptors. This signifies that peripheral temperature detection is mainly concerned with distinguishing cool and cold rather than warm temperatures, probably in order to prevent hypothermia.

The temperature sensory signals from the peripheral thermoreceptors in the skin and mucous membranes and those from the internal central thermoreceptors in the hypothalamic preoptic area are transmitted bilaterally to a specific area in the posterior hypothalamus, at the level of the mamillary bodies. Here the signals are combined to control the heat-conserving and heat-producing mechanisms of the body.

The hypothalamus works together with higher cortical centers to keep core body temperature constant. Responses range from involuntary (mediated by the autonomic nervous system and neurohormones), to semivoluntary and voluntary behavioral responses.

Responses to Cold—Temperature-Increasing Mechanisms

Cold environments cool blood flowing into the skin and stimulate the skin’s cold receptors. When blood temperature drops below normal, the neurons stimulate regions in the caudal hypothalamus responsible for mechanisms of heat conservation, initiating a variety of responses to promote heat gain and inhibit heat loss. Involuntary responses, which involve activation of the sympathetic nervous system, include the following:

1. Vasoconstriction. Release of norepinephrine from the sympathetic fibers constricts cutaneous blood vessels, thereby reducing blood flow and heat loss to the cold air.
2. Piloerection. Contraction of the arrectores pilorum (stimulated by α1 adrenoreceptors) causes piloerection trapping warm air close to the skin.
3. Increased heat production. Sympathetic excitation and shivering allow for increased thermogenesis.

Cellular metabolism can be increased via sympathetic stimulation or circulating epinephrine and norepinephrine in the blood. This is called chemical thermogenesis. Epinephrine and norepinephrine have the ability to uncouple oxidative phosphorylation, allowing excess foodstuffs to be oxidized, releasing heat energy. The amount of brown fat, a type of fat that contains large numbers of special mitochondria where uncoupled oxidation occurs, is proportional to the amount of chemical thermogenesis in an organism. Infants, who have small amounts of brown fat, are able to use this process to double heat production. However adults, who have nearly no brown fat, are only able to increase heat production 10-15% via this process.

Another form of chemical thermogenesis involves increased cellular metabolism caused by thyroxine. Cooling the hypothalamic preoptic area causes an increase in production and secretion of thyrotropin-releasing hormone (TRH) by the hypothalamus. TRH travels through the portal veins to the anterior pituitary, where it stimulates secretion of thyroid-stimulating hormone (TSH). TSH then stimulates the thyroid to release thyroxine (T4), which increases the body’s metabolic rate.

Shivering is controlled by the primary motor center for shivering, found in the dorsomedial posterior hypothalamus. This center is usually excited by cold signals from the skin and spinal cord, and inhibited by warm signals from the hypothalamic preoptic area. When body temperatures fall too low, the center will transmit signals that cause shivering through bilateral tracts down the brain stem, the lateral columns of the spinal cord, and eventually to the anterior motor neurons, which stimulate an increase in the tone of skeletal muscles around the body. Shivering begins when muscle tone reaches and rises above a critical level, and can increase heat production up to four or five times that of normal.

More voluntary responses include increased physical activity, such as pacing and hand rubbing, and behavioral changes, such as wearing extra clothing and huddling in groups. These voluntary behaviors are activated mainly by the cerebral cortex and limbic system.

Responses to Heat—Temperature-Decreasing Mechanisms

Body temperature rises when the body is exposed to excess heat. The skin’s warm receptors and higher blood temperature signal the hypothalamus to inhibit adrenergic activity of the sympathetic nervous system, leading to metabolic rate reduction and cutaneous vasodilation. Responses to heat include the following:

1. Vasodilation. Inhibition of the sympathetic centers in the posterior hypothalamus causes cutaneous vasodilation, allowing for increased blood flow and greater heat loss via the skin.
2. Sweating. In particularly warm conditions, the hypothalamus signals the cholinergic sympathetic fibers to release acetylcholine in order to stimulate the muscarinic cholinergic receptors on the eccrine sweat glands to induce sweat. Eccrine sweat glands are found all around the body, but are most prevalent on the palms, soles, and forehead. Heat is then lost via the evaporation of sweat from the skin, at a rate of about 0.58 kcal/mL.
3. Decrease in heat production. All mechanisms involved in heat production and conservation are severely inhibited.

Voluntary behavioral responses to heat, such as resting, wearing less clothing, fanning, and drinking cold fluids help with heat loss as well.

Fever is a medical condition that describes a temporary increase in the body’s thermoregulatory set-point (usually by about 1°C-2°C). Fever differs from hyperthermia in that during a fever, the body’s thermoregulatory setpoint itself is elevated, whereas in hyperthermia, body temperature rises above the set-point. The increase in thermoregulatory set-point in the hypothalamus during a fever can be attributed to the activity of the cytokines IL-1, IL-6, and TNF-α. It is important to note that fever is not a medical condition itself, but rather a symptom of other pathology.

COMPREHENSION QUESTIONS

Refer to the following case scenario to answer questions 30.1-30.2:

A 28-year-old man in brought into the emergency department by EMS after having been found lying in the snow on the side of the road. He apparently had been walking along the road the night before and was struck by a car, which did not stop, and lay in the snow until someone noticed him this morning. His fingers and toes are blue and cool to the touch, and he is shivering uncontrollably.

[30.1] Stimulation of which receptors are primarily responsible for triggering these responses to cold?

A. Thermoreceptors in the skin

B. Thermoreceptors in the posterior hypothalamus

C. Thermoreceptors in the anterior hypothalamus

D. Thermoreceptors in the lateral hypothalamus

[30.2] What part of the hypothalamus receives input from cold-sensitive thermoreceptors and then generates signals that lead to conservation and generation of body heat?

A. Anterior hypothalamus

B. Posterior hypothalamus

C. Lateral hypothalamus

D. Medial hypothalamus

[30.3] A 44-year-old manual laborer is brought to the emergency department after collapsing on the job. He had been working outside, paving a city street, when, according to witnesses, he said he needed to sit down, and then collapsed. He did not lose consciousness at that time. His skin all over his body is red with very rapid capillary refill and he is sweating profusely. He is accurately diagnosed with heat exhaustion, and treatment is begun. Which hypothalamic nucleus is involved in generating heat-dissipating responses?

A. Medial hypothalamus

B. Lateral hypothalamus

C. Posterior hypothalamus

D. Anterior hypothalamus

Answers

[30.1] A. Thermoreceptors in the skin are responsible for responses to cold. There are two areas in the body in which thermoreceptors are located: the skin and the anterior hypothalamus, specifically the preoptic area. These areas do not behave the same, however. There are significantly more cold receptors than warm in the skin, and more warm receptors than cold in the hypothalamus. This meansthat skin based thermoreceptors are more important for detecting cold conditions and hypothermia, while hypothalamic receptors are more important for detecting warm conditions and hyperthermia. Of course in an extreme example such as this, both the skin and the hypothalamic thermoreceptors would be generating signals to conserve/ generate body heat.

[30.2] B. The posterior hypothalamus generates the signals that cause an increase in heat conserving and producing behaviors. The posterior hypothalamus is also involved in sympathetic outflow, which is

important in heat conservation. Sympathetic outflow is responsible for peripheral vasoconstriction and piloerection, both of which are heat conserving. Shivering, which is a heat-generating mechanism, is not mediated by the sympathetic system, but rather by the shivering center, found in the dorsomedial posterior hypothalamus. Posterior hypothalamic projections to the cortex are involved in the more complex behavioral responses to cold, such as putting on more clothing, pacing, and going inside. The anterior hypothalamus, while being the location of hypothalamic thermoreceptors, is more sensitive to heat than cold, and involved in heat-dissipating activities.

[30.3] D. The anterior hypothalamus is the area involved in heatdissipating activities. It receives warm signals primarily from the preoptic hypothalamus, but also from warm receptors located in the skin. Heat-dissipating activities include cutaneous vasodilation, achieved by sympathetic inhibition, which causes the skin to appear very red, and sweating. All heat-conserving activities are severely limited as well. There are also cortical responses to overheating, including fanning, removing clothing, and drinking cold drinks.

NEUROSCIENCE PEARLS ❖ Thermoregulation is controlled primarily by nervous feedback mechanisms operating through the hypothalamus, namely the preoptic area. ❖ Involuntary responses for heat conservation are initiated by the hypothalamus and include vasoconstriction, piloerection, and thermogenesis (ie, sympathetic excitation and shivering). ❖ Fever differs from hyperthermia in that during a fever, the body’s thermoregulatory set-point itself is elevated, whereas in hyperthermia, body temperature rises above the set-point.

REFERENCES

Bear MF, Connors BW, Paradiso MA, eds. Neuroscience: Exploring the Brain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006. 

Kandel E, Schwartz J, Jessell T, eds. Principles of Neural Science. 5th ed. New York, NY: McGraw-Hill; 2000. 

Zigmond MJ, Squire LR, Bloom FE, Landis SC, Roberts JL, eds. Fundamental Neuroscience. 2nd ed. San Diego, CA: Academic Press; 1999.

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