How does lactic acidosis cause hyperpyrexia?

How Lactic Acidosis Causes Hyperpyrexia

Lactic acidosis can cause hyperpyrexia through increased metabolic rate, excessive muscle contractile activity, and mitochondrial dysfunction, leading to heat generation that overwhelms normal thermoregulatory mechanisms. 1, 2

Pathophysiological Mechanisms

• Lactic acidosis drives increased intermediary metabolism in skeletal muscle cells as they attempt to maintain ATP requirements, resulting in increased oxygen consumption and carbon dioxide production that generates heat 3
• When calcium homeostasis mechanisms within skeletal muscle cells fail during severe lactic acidosis, there is progressive increase in intracellular calcium that activates myofilaments, leading to muscle contractile activity that is thermally inefficient (30-60% of energy is released as heat) 3, 2
• The chemical reaction between hydrogen ions (from lactate) and bicarbonate (H⁺ + HCO₃⁻ ↔ H₂CO₃ ↔ CO₂ + H₂O) drives excess CO₂ production, increasing metabolic rate and heat generation 3
• Mitochondrial dysfunction during lactic acidosis impairs normal oxidative phosphorylation, causing energy to be released as heat rather than being captured as ATP 1, 4

Clinical Manifestations

• Early signs of hyperpyrexia due to lactic acidosis include tachycardia from increased sympathetic nervous system outflow triggered by rising CO₂ levels 3, 2
• Increased end-tidal CO₂ (in ventilated patients) or tachypnea (in spontaneously breathing patients) occurs as the body attempts to eliminate excess CO₂ produced during lactic acidosis 2
• As hyperpyrexia progresses, exposed areas of skin become hot, flushed and sweaty, while mottling of the skin appears more commonly in young children 3
• Severe cases can progress to rhabdomyolysis with muscle swelling, compartment syndrome, and acute renal injury 3, 1

Specific Clinical Scenarios

• In malignant hyperthermia, a genetic disorder triggered by certain anesthetics, lactic acidosis contributes to hyperpyrexia through excessive calcium release from the sarcoplasmic reticulum in skeletal muscle 3, 2
• In serotonin syndrome, severe cases (temperature >41.1°C) involve lactic acidosis that contributes to hyperpyrexia through increased metabolic demands 3
• Exertional rhabdomyolysis can lead to a cycle where muscle damage causes lactic acidosis, which increases metabolic rate and heat production, further worsening muscle damage 1

Diagnostic Considerations

• Laboratory findings in lactic acidosis with hyperpyrexia typically include arterial pH <7.3, elevated lactate levels (>5 mmol/L), and increased anion gap (>16) 1
• The respiratory exchange ratio (RER), measured as VCO₂/VO₂, will be greater than 1.0 due to CO₂ derived from lactic acid buffering 3
• Creatine kinase levels are often markedly elevated when lactic acidosis and hyperpyrexia are associated with rhabdomyolysis 3, 1

Management Implications

• Physical restraints should be avoided in patients with lactic acidosis and hyperpyrexia as they may exacerbate isometric muscle contractions, worsening hyperthermia and lactic acidosis 3
• Treatment should focus on addressing the underlying cause of lactic acidosis while providing supportive care including active cooling measures 3, 2
• Severe cases may require emergency sedation, neuromuscular paralysis, and intubation to reduce metabolic demands and heat production 3, 2
• Monitoring and correction of electrolyte abnormalities, particularly hyperkalemia, is crucial in managing lactic acidosis with hyperpyrexia 1

Clinical Pitfalls and Caveats

• Hyperpyrexia that begins before any evidence of increased carbon dioxide production is unlikely to be caused by lactic acidosis and other causes should be investigated 2
• The combination of lactic acidosis, hyperpyrexia, and rhabdomyolysis should be considered a medical emergency requiring immediate intervention 1
• Sodium bicarbonate administration may worsen lactic acidosis by increasing lactate production, potentially exacerbating hyperpyrexia 5
• Dichloroacetate stimulates pyruvate dehydrogenase and may improve laboratory values in lactic acidosis, but has not been shown to improve survival rates 5