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Fever and Hyperthermia

Human body generates 1oC/h from resting metabolism. 90% of this heat dissipated into environment via skin, 10% via exhaled gas. Radiation (emanation of electromagnetic infrared heat ray) accounts for approximately 60% of heat loss. Evaporation consists of 20% at rest but increases up to 70% during thermal stress. Conduction represents only 15% of resting heat loss and can be increased with application of ice-packs. Lastly, convection accounts for only 5% of heat loss at rest but increases during thermal stress as blood flow to the skin rises from a baseline of 250ml/min to 6-8L/min.
Temperature is sensed by neurons in the skin. Their afferent signals synapse in the preoptic nucleus of the anterior hypothalamus, where they are compared to a thermal set point. Temperatures above this set point is hyperthermia, in which the body tries to cool. In contrast, a raised thermal set point is fever, in which the body tries to generate heat. This is why, preceding a fever, most patients feel cold/chills and demonstrate shivering and pilo-erection.The cascade for cooling involves a complex interplay between the preoptic nucleus (thermostat), anterior hypothalamus (parasympathetics), posterior hypothalamus (sympathetics), and the spinal cord. The net effect is reduced sympathetic tone on the skin vasculature, which promotes blood flow, along with increased sympathetic tone on the eccrine sweat glands. The mechanism for this selective activation and deactivation of SNS is poorly understood. Almost all known neurotransmitters are involved, including dopamine which may explain the hyperthermic effects of dopamine antagonists in NMS.The cascade for warming involves 1) peripheral vasoconstriction, which ceases heat loss; 2) shivering, which produces heat though ATP dissociation and actin/myosin cross-bridging; and 3) metabolism, which produces heat through oxidative phosphorylation and mitochondrial uncoupling via uncoupling proteins (UCP).


The preoptic nucleus set point can be elevated by pyrogens: typically inflammatory cytokines IL-1, INFy, and IL-6. These are released by both innate and adaptive immunity following tissue injury or recognition of pathogen associated motifs. I emphasize the first point again because fever and infection are not synonymous: fever can be a normal response to injury. Post-op fever (within 48h) developed in 40% of gyn surgeries with infectious etiology in 10%; In a retrospective review of hip and knee arthroplasty, 200/200 patients developed fevers whereas none had infections. The degree of temperature elevation was not predictive of etiology. Tissue injury is also the mechanism by which trauma, clots, malignancy, and rhabdo cause fevers.Atelectasis, on the other hand, probably does not cause fever despite widespread misconception to the contrary. Atelectasis frequently develops after post-surgery as does fever (see above). And since every febrile post-surgical patient receives a CXR, atelectasis earned notoriety. Engoren monitored 100 patients following cardiac surgery with daily CXR. The incidence of fever declined as that of atelectasis increased. This negative correlation is also supported by studies of patients following abdominal surgery. Drug fever is typically due to hypersensitivity reactions through drug-antibody complexes or T-cell mediated response to drug fragments – all of which culminate in increased circulating pyrogens. Pyrogens change the thermoregulatory set point through prostaglandins and cyclooxygenase pathway. This is how acetominophen, aspirin, and NSAIDs reduce fever and also why they have no effect on hyperthermia. Acetaminophen is a poor COX inhibitor in peripheral tissue and does not display noteworthy anti-inflammatory activity; however, acetaminophen is oxidized in the brain by the p450 cytochrome system, and the oxidized form inhibits cyclooxygenase activity in the hypothalamus. There is no difference between oral aspirin and acetaminophen in reducing fever in humans but ASA at toxic levels can uncouple electron transport at the mitochondrial membrane. Hence, tylenol is probably safer. Prostaglandin has no role in normal thermoregulation; NSAIDs, APAP, and ASA do not cause hypothermia. Corticosteroids are also effective antipyretics: they reduce prostaglandin synthesis by inhibiting the activity of phospholipase A2 which is needed to release arachidonic acid from the membrane, and they block the transcription of the mRNA for the pyrogenic cytokines.

It is unclear if treating fever provides benefit when the temperature is only mildly elevated. After all, fever is an evolved process and targeting normothermia may be harmful in sepsis. Severely elevated temperatures, on the other hand, is an emergency. The critical thermal maximum is 41.6-42, at which severe protein denaturation and cell lysis occurs: the brain and liver are particularly sensitive to hyperpyrexia (T > 41.5). Some sources consider cell damage to start at T > 39.5.


In contrast with fevers, hyperthermia demonstrates a normal thermoregulatory set point but an inability for the thermoregulatory machinery to produce effect. It does not respond to NSAIDs, APAP, or ASA.

Toxin Mechanism
Anticholinergic muscular hyperactivity; anhidrosis;
Stimulants (PCP cocaine meth MDMA) muscular hyperactivity; peripheral vasoconstriction; adrenergic effects in CNS
Salicylates decouples electron transport at cytochrome C
Serotonin myclonus; possible adrenergic effects on CNS from new SNRIs
NMS interruption of hypothalamic signalling; rigidity; anhidrosis from anticholinergic effects
Malignant Hyperthermia sustained muscular contractions from intracellular calcium (RYR1 mutation)
Endocrine Mechanism
Thryoid Storm accelerated metabolism; muscular hyperactivity
Pheochromocytoma muscular hyperactivity; adrenergic effects in CNS; skin vasoconstriction
Neurologic Mechanism
Status epilepticus accelerated metabolism; muscular hyperactivity
Malignant catatonia
Parkinsonian-hyperprexia syndrome cessation of dopamine analogous to NMS (antagonism of dopamine)
Autonomic dysreflexia
Intrathecal baclofen withdrawal
Stiff Man Syndrome
Irukandji Syndrome