Unit 7: Temperature Regulation

Learning Objectives

• Explain the mechanisms of body temperature regulation, including heat production and heat loss.
• Describe the role of the hypothalamus as the body's thermostat.
• Define fever and explain its pathophysiology, including the role of pyrogens.
• Define hypothermia and explain its pathophysiology and clinical stages.
• Understand the clinical and pharmaceutical relevance of temperature regulation (antipyretics, drug‑induced hyperthermia, malignant hyperthermia, heat stroke).

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Core Content

1. Introduction to Body Temperature Regulation

Thermoregulation is the homeostatic process that maintains core body temperature within a narrow, optimal range (~37 °C ± 0.5 °C) despite environmental fluctuations. It is essential for enzyme function, membrane fluidity, and overall metabolism.

A. Core vs. Shell Temperature

Measurement sites: oral (36.3–37.1 °C), rectal (36.7–37.5 °C – most accurate), tympanic, axillary, temporal artery.

B. Normal Variations

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2. Mechanisms of Body Temperature Regulation

Body temperature is determined by the balance between heat production (thermogenesis) and heat loss (thermolysis), controlled by the hypothalamus.

A. Heat Production (Thermogenesis)

• Thyroid hormones (T₃/T₄) enhance Na⁺/K⁺‑ATPase activity and mitochondrial enzymes, raising basal metabolic rate over days to weeks.
• Brown adipose tissue (BAT): Located in neck, supraclavicular, paravertebral regions; activated by cold exposure via sympathetic nerves.

B. Heat Loss (Thermolysis)

Sweating:

• Eccrine sweat glands innervated by sympathetic cholinergic fibres.
• Secretion is hypotonic (water, Na⁺, Cl⁻, K⁺, lactate).
• Up to 1–2 L/hour during heavy exercise; inefficient in high humidity.

Cutaneous blood flow:

• Vasodilation (active): NO, bradykinin, VIP release → increased skin blood flow (up to 8 L/min) → heat loss.
• Vasoconstriction (sympathetic α‑adrenergic): reduces skin blood flow near zero in cold.

Countercurrent heat exchange: In limbs, arteries and veins run parallel; warm arterial blood pre‑warms cool venous blood, reducing heat loss from extremities.

C. Thermal Balance Equation

Heat storage = Heat production – Heat loss

• If production > loss → temperature rises.
• If production < loss → temperature falls.
• At equilibrium, production = loss.

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3. The Hypothalamus: The Body’s Thermostat

The hypothalamus integrates thermal information and orchestrates efferent responses to maintain core temperature at the set point (~37 °C).

Temperature sensors:

• Peripheral: Cold receptors (Aδ fibres, peak ~25 °C) and warm receptors (C fibres, peak ~43 °C) in skin → spinothalamic tract → thalamus → POAH.
• Central: Warm‑sensitive neurons in POAH increase firing with heat; cold‑sensitive neurons increase firing with cooling.

Set point mechanism:

• Determined by balance of warm‑ and cold‑sensitive neurons in POAH.
• If actual temperature < set point → heat conservation/production activated.
• If actual temperature > set point → heat loss activated.

Efferent pathways:

Responses to cold:

• Cutaneous vasoconstriction, piloerection (minimal in humans), shivering, non‑shivering thermogenesis (BAT), increased thyroid hormone (chronic), behavioral (seek warmth, add clothing).

Responses to heat:

• Cutaneous vasodilation, sweating, behavioural (seek shade, reduce activity), inhibition of heat production.

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4. Pathophysiology of Fever

Fever is an elevation of body temperature resulting from a raised hypothalamic set point, usually due to infection or inflammation.

Distinction from hyperthermia:

A. Pyrogens

• Exogenous pyrogens: Microbial products (LPS from Gram‑negative bacteria, lipoteichoic acid, viral nucleic acids).
• Endogenous pyrogens (cytokines): IL‑1 (primary), IL‑6, TNF‑α, interferons – released by macrophages/monocytes.

B. Mechanism of Fever

1. Exogenous pyrogen binds TLRs on immune cells.
2. Release of endogenous pyrogens (IL‑1, IL‑6, TNF‑α).
3. Cytokines act on circumventricular organs (OVLT) → induce COX‑2 in hypothalamic endothelium → PGE₂ synthesis.
4. PGE₂ binds EP3 receptors on warm‑sensitive neurons in POAH → decreases their firing rate → set point rises.
5. Body perceives actual temperature as “cold” and activates heat conservation (vasoconstriction) and production (shivering, rigors).
6. Temperature rises to the new set point.
7. When pyrogenic stimulus ends, PGE₂ falls, set point returns to normal; heat loss mechanisms (vasodilation, sweating) cause defervescence.

Stages of fever:

• Prodrome: malaise, aches.
• Chill (rigor): shivering, vasoconstriction, feeling cold.
• Febrile plateau: temperature stable at elevated set point, flushed skin.
• Defervescence: sweating, vasodilation, temperature falls.

C. Benefits and Risks of Fever

• Benefits: enhanced immune function (leukocyte migration, phagocytosis, interferon), inhibition of pathogen growth.
• Risks: dehydration, increased metabolic demand (12% per °C), febrile seizures (children), exacerbation of pre‑existing conditions.

D. Antipyretic Drugs

Physical cooling (sponging, ice packs) is not recommended for fever because it induces shivering and discomfort, working against the raised set point. It is reserved for hyperthermia or extreme hyperpyrexia.

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5. Pathophysiology of Hypothermia

Hypothermia is a core temperature <35 °C (95 °F) due to excessive heat loss, insufficient heat production, or impaired thermoregulation.

A. Causes

B. Stages of Hypothermia

Cold diuresis: vasoconstriction increases central blood volume → suppression of ADH → diuresis → potential hypovolaemia.

Osborn (J) wave: positive deflection at J point (QRS‑ST junction), characteristic of moderate‑severe hypothermia.

C. Management

• Remove from cold environment, remove wet clothing.
• Mild: passive external rewarming (blankets, warm environment).
• Moderate: active external rewarming (forced‑air warming, warm water bottles).
• Severe: active internal rewarming (warmed IV fluids 40–42 °C, warm humidified O₂, peritoneal/pleural lavage, extracorporeal rewarming).
• CPR may be required; the adage “a patient is not dead until warm and dead” applies. Complications: afterdrop (core cooling during rewarming), rewarming shock (vasodilation → hypotension), arrhythmias.

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6. Clinical and Pharmaceutical Relevance

A. Drugs Affecting Thermoregulation

B. Malignant Hyperthermia (MH)

• Trigger: volatile anaesthetics (halothane, sevoflurane) or succinylcholine in genetically susceptible individuals (RYR1, CACNA1S mutations).
• Pathophysiology: uncontrolled Ca²⁺ release from SR via abnormal ryanodine receptor → sustained muscle contraction → massive heat production, rhabdomyolysis, hyperkalaemia, acidosis.
• Clinical: masseter rigidity, tachycardia, rapid temperature rise (up to 1 °C/5 min), metabolic acidosis, hyperkalaemia, elevated CK.
• Treatment: dantrolene (inhibits RyR, reduces Ca²⁺ release), stop triggering agent, hyperventilate with 100% O₂, active cooling, treat complications.

C. Heat Stroke

• Definition: core temperature >40 °C with neurological dysfunction, due to overwhelmed thermoregulation.
• Types:
  • Classic (non‑exertional): elderly, chronic illness, medications; gradual onset, anhidrotic skin.
  • Exertional: young individuals during strenuous exercise; rapid onset, sweating may persist.
• Pathophysiology: direct cellular toxicity, SIRS, endothelial injury, DIC, multi‑organ failure.
• Clinical: hyperthermia, CNS dysfunction (confusion, seizures, coma), cardiovascular collapse, hepatic necrosis, acute kidney injury.
• Treatment: rapid cooling (ice water immersion, evaporative cooling, cold IV fluids), supportive care.

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Tables

Table 1: Heat Production vs. Heat Loss Mechanisms

Table 2: Thermoregulatory Responses to Heat and Cold

Table 3: Fever vs. Hyperthermia

Table 4: Stages of Hypothermia

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Exam Angle

Short Answer Questions

• Differentiate between fever and hyperthermia.
• How does the hypothalamus regulate body temperature?
• What are endogenous pyrogens? Give examples.
• List the mechanisms of heat loss from the body.
• Define hypothermia and list its stages.

Essay Questions

• Explain the pathophysiology of fever, including the role of pyrogens, prostaglandins, and the hypothalamic set point.
• Describe the mechanisms of body temperature regulation, including heat production and heat loss.
• Discuss the pathophysiology and clinical management of hypothermia.

Viva / Short Notes

• Role of the hypothalamus as thermostat.
• Endogenous pyrogens (IL‑1, IL‑6, TNF‑α).
• Shivering thermogenesis.
• Cutaneous vasodilation and vasoconstriction.
• Mechanism of action of antipyretic drugs.
• Malignant hyperthermia.
• Heat stroke.

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Summary Box

• Body temperature is maintained by a balance between heat production (basal metabolism, shivering, non‑shivering thermogenesis, chemical thermogenesis) and heat loss (radiation, convection, conduction, evaporation).
• The hypothalamus (POAH) acts as the thermostat, comparing actual temperature to a set point (~37 °C) and initiating appropriate responses via autonomic, somatic, and endocrine pathways.
• Fever results from an increased set point driven by pyrogens (exogenous → endogenous cytokines → PGE₂ synthesis via COX‑2). Antipyretics (NSAIDs, paracetamol) lower the set point by inhibiting COX.
• Hyperthermia differs from fever: the set point is normal, but thermoregulation is overwhelmed (e.g., heat stroke, malignant hyperthermia).
• Hypothermia is a core temperature <35 °C, staged from mild to severe, and is managed by passive/active rewarming. Severe cases require internal rewarming and prolonged CPR.
• Pharmacy relevance: many drugs affect thermoregulation (antipyretics, antipsychotics, anaesthetics, sympathomimetics, anticholinergics). Malignant hyperthermia is a life‑threatening pharmacogenetic emergency treated with dantrolene.

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References

1. Hall, J. E. (2021). Guyton and Hall Textbook of Medical Physiology (14th ed.). Elsevier. (Chapter 74: Body Temperature Regulation and Fever)
2. Barrett, K. E., et al. (2019). Ganong’s Review of Medical Physiology (26th ed.). McGraw‑Hill.
3. Costanzo, L. S. (2024). BRS Physiology (7th ed.). Wolters Kluwer.
4. Widmaier, E. P., et al. (2023). Vander’s Human Physiology (16th ed.). McGraw‑Hill.
5. Bouchama, A., & Knochel, J. P. (2002). Heat stroke. N Engl J Med, 346(25), 1978‑1988.
6. Brown, D. J., & Brugger, H. (2012). Accidental hypothermia. N Engl J Med, 367(20), 1930‑1938.
7. Rosenberg, H., et al. (2015). Malignant hyperthermia: a review. Orphanet J Rare Dis, 10, 93.