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Physiology and Pathophysiology of Heat-Related Illness

1. NORMAL THERMOREGULATION — THE BASICS

Heat Generation

The Central Thermostat

• Central thermoreceptors (in the hypothalamus and spinal cord)
• Peripheral thermoreceptors (in skin)

1. Cutaneous vasodilation — skin blood flow can increase 25–30 times the basal rate, making the skin surface the principal radiator of heat
2. Diaphoresis (sweating) — evaporative cooling

Four Mechanisms of Heat Dissipation

Key point: At high ambient temperatures and high humidity, all four mechanisms can be simultaneously impaired, creating a perfect storm for heat illness.

Cardiovascular Adaptations to Heat

• Cardiac output increases markedly
• There is compensatory vasoconstriction of the splanchnic and renal vascular beds
• This splanchnic diversion is critical to pathophysiology later

Acclimatization

• Lowered sweating threshold (sweating begins earlier)
• Increased sweat volume (1–2 L/h), but with lower salt concentration
• Plasma volume expansion → improved cutaneous vascular flow
• Lower heart rate with higher stroke volume

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2. ENVIRONMENTAL HEAT LOAD MEASUREMENT

• Air temperature
• Humidity
• Radiant heat
• Wind speed

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3. PATHOPHYSIOLOGY — OVERVIEW

• Magnitude and duration of temperature elevation
• Whether thermoregulation remains intact
• Vulnerability of the individual

The Critical Threshold

• Multiorgan dysfunction occurs rapidly at core temperatures >40.5°C (104.9°F)
• Above 42°C (107.6°F), direct cellular injury occurs:
  • Thermosensitive enzymes become nonfunctional
  • Irreversible uncoupling of oxidative phosphorylation
  • Heat-shock proteins increase (protective response, but overwhelmed)
  • Cytokines mediate a systemic inflammatory response

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4. THE SPECTRUM OF HEAT-RELATED ILLNESS

A. Heat Edema

• Cutaneous vasodilation → pooling of interstitial fluid in dependent areas (hands, feet, ankles)
• Heat stimulates ADH and aldosterone secretion → sodium and water retention
• Result: mild pitting edema in first few days of heat exposure

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B. Prickly Heat (Miliaria Rubra)

• Prolonged sweating in clothed areas → maceration of stratum corneum
• Debris blocks sweat pores → inflammation in sweat ducts
• Ducts dilate → rupture → superficial vesicles
• Presents as maculopapular, pruritic, erythematous rash

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C. Heat Syncope (Exercise-Associated Collapse)

1. Heat stress → cutaneous vasodilation → peripheral blood pooling
2. Relative hypovolemia (volume redistribution to skin)
3. Decreased venous return → decreased cardiac output
4. Simultaneously: decreased vasomotor tone from heat
5. Net result: postural hypotension → syncope

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D. Hyperventilation Tetany

• Heat exposure → stimulates hyperventilation
• → respiratory alkalosis
• → Decrease in ionized calcium (alkalosis shifts albumin binding)
• → paresthesias, carpopedal spasm

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E. Heat Cramps

1. Profuse sweating during exertion → large sodium losses
2. Fluid replaced with hypotonic solutions (plain water) → dilutional hyponatremia + hypochloremia
3. Relative intracellular sodium and potassium deficiency
4. Impaired calcium-dependent muscle relaxation → involuntary spasmodic contractions
5. Total-body potassium depletion may compound this during acclimatization

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F. Heat Exhaustion

Water-Depletion Heat Exhaustion

• Most common in laborers, athletes, elderly during exertion
• Inadequate fluid intake despite large sweat losses
• Workers voluntarily consume only ~2/3 of actual fluid losses → voluntary dehydration
• → Hypovolemia → reduced cardiac output → impaired heat dissipation

Sodium-Depletion Heat Exhaustion

• Develops more slowly
• Typically in unacclimated persons replacing losses with large quantities of hypotonic solutions
• Results in hyponatremia and hypochloremia
• Slower onset than water-depletion type

• Progressive dehydration reduces plasma volume
• Cardiovascular system struggles to maintain both mean arterial pressure and adequate skin perfusion simultaneously
• Orthostatic hypotension, tachycardia, influenza-like symptoms (headache, vertigo, ataxia, malaise, nausea, muscle cramps)
• Hepatic aminotransferases mildly elevated in both types
• Urinary Na⁺ and Cl⁻ concentrations usually low (renal conservation)

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G. Heatstroke — The Critical Emergency

1. Exposure to heat stress
2. CNS dysfunction
3. Core temperature >40.5°C (104.9°F)

The Precipitating Mechanism

• Cutaneous radiation of heat ceases
• Core temperature rises dramatically and rapidly
• A vicious cycle ensues: rising temperature → more cellular damage → more cardiovascular failure → less cooling

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5. CELLULAR AND MOLECULAR PATHOPHYSIOLOGY OF HEATSTROKE

Direct Thermal Injury (>42°C)

• Enzyme denaturation — thermosensitive enzymes become nonfunctional
• Uncoupling of oxidative phosphorylation — ATP synthesis fails, cellular energy collapse
• Protein unfolding — heat-shock proteins (HSPs) are upregulated as a protective response, but overwhelmed at extreme temperatures

Systemic Inflammatory Response Syndrome (SIRS)

• Direct thermal injury to cells releases damage-associated molecular patterns (DAMPs)
• Cytokine storm: IL-1, IL-6, TNF-α and others are released
• This creates a state clinically indistinguishable from sepsis

Vascular Endothelial Injury

• Heat directly damages the vascular endothelium
• Endothelial injury → activation of the coagulation cascade → DIC
• Increased vascular permeability → interstitial edema

Splanchnic Ischemia and Gut Barrier Failure

• During heat stress, splanchnic blood flow is already reduced (compensatory)
• In heatstroke, this becomes severe gastrointestinal ischemia
• Gut mucosal barrier disrupts → bacterial translocation → endotoxemia
• Endotoxins further impair thermoregulation (a feedback loop worsening the condition)

Multiorgan Dysfunction

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6. TWO FORMS OF HEATSTROKE

Why is EHS more severe metabolically?

• Active muscle exertion generates far more heat
• Profound lactic acidosis from anaerobic metabolism
• Rhabdomyolysis releases: K⁺ (hyperkalemia), myoglobin (renal tubular toxicity), phosphate (reciprocal hypocalcemia)
• Hypoglycemia from depletion of muscle and hepatic glycogen stores

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7. CARDIOVASCULAR PATHOPHYSIOLOGY IN HEATSTROKE

• Initially: hyperdynamic circulation — high cardiac output, low peripheral vascular resistance, wide pulse pressure (from maximal cutaneous vasodilation)
• Then: As core temp rises → thermal cardiomyopathy → right-sided heart failure → elevated CVP despite hypovolemia (deceptively elevated filling pressures)
• Simultaneously: Noncardiogenic pulmonary edema and basilar rales, despite the patient being significantly hypovolemic
• ECG: tachyarrhythmias, non-specific ST-T changes, heat-related ischemia/infarction
• Oxyhemoglobin dissociation curve shifts right (increased O₂ delivery to tissues, but also impaired loading)

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8. PREDISPOSING FACTORS (Mechanistic Basis)

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9. WHY ANTIPYRETICS DON'T WORK IN HEATSTROKE

• Fever = elevated hypothalamic set-point driven by pyrogens → antipyretics (NSAIDs, acetaminophen) work by blocking pyrogen action at the hypothalamic receptor
• Heatstroke = thermoregulatory system has collapsed entirely; the hypothalamic set-point is NOT elevated — the body simply cannot dissipate the heat load

• NSAIDs (salicylates) are harmful — they further uncouple oxidative phosphorylation and worsen coagulopathies
• Acetaminophen is harmful — further stresses an already failing liver
• Dantrolene is ineffective unless the mechanism is malignant hyperthermia (which involves abnormal ryanodine receptor-mediated calcium release)

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10. SUMMARY: THE PATHOPHYSIOLOGIC CONTINUUM

Environmental/Exertional Heat Load
           ↓
Compensatory response:
• Hypothalamic activation
• Cutaneous vasodilation (skin blood flow ↑25-30×)
• Diaphoresis
• Splanchnic/renal vasoconstriction
           ↓
If overwhelmed:
• Dehydration → ↓plasma volume
• ↓Venous return → ↓cardiac output
           ↓
HEAT EXHAUSTION
(thermoregulation intact, CNS intact, temp <40.5°C)
           ↓
Critical point: Peripheral vasoconstriction to maintain BP
→ Cutaneous radiation ceases
→ Core temp rises dramatically
           ↓
HEATSTROKE (>40.5°C, CNS dysfunction)
           ↓
Direct thermal cellular injury (>42°C)
+ SIRS + Endothelial damage + Splanchnic ischemia/endotoxemia
           ↓
Multiorgan Failure:
Liver failure | DIC | AKI | ARDS | Rhabdomyolysis | CNS injury

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• The thermoregulation section (preoptic nucleus, four mechanisms of heat loss, acclimatization) — from the "Thermoregulation" section of the chapter
• The predisposing factors and drug mechanisms — from the "Predisposing Factors and Differential Diagnosis" section + Table 478-1
• The heat edema, prickly heat, syncope, cramps, exhaustion — from the "Minor Heat-Emergency Syndromes" and dedicated sections
• The heatstroke pathophysiology (cellular injury, SIRS, DIC, organ failure) — from the "Heatstroke" section
• The Classic vs. Exertional heatstroke comparison — directly from Table 478-2
• The why antipyretics don't work reasoning — from the "Resuscitation" section