CHAPTER 54 Temperature Dysregulation Susan M. Wilson and Ian A. Ross Normal human body temperature ranges from drug, idiosyncratic reactions, and hypersensitivity 36.7°C to 37°C measured orally. Axillary tempera- reactions.1 tures and those measured rectally are 1°C lower and A drug may alter thermoregulation by disrupt- 1°C higher, respectively. Intraindividual body tem- ing central dopamine or serotonin homeostasis, perature varies throughout the day and over time, or via peripheral alteration of normal hypotha- and slight variations may also be noted between lamic temperature balance, creating an imbalance individuals. The anterior hypothalamus maintains of increased heat production and reduced heat dis- body temperature within a relatively narrow range sipation.2 Two such drug- induced dysregulation by sensing core body temperature and adjusting diseases— neuroleptic malignant syndrome (NMS) (homeostatic) mechanisms in the autonomic ner- and serotonin syndrome— will be discussed in sub- vous system. Central dopaminergic and seroto- sequent sections. A rare, but serious, late effect of nergic pathways are also involved in temperature salicylate toxicity is fever resultant of excess heat regulation via the autonomic nervous system. production due to an uncoupling of mitochondrial A relative decrease in serum dopamine concentra- oxidative phosphorylation.3 Additionally, drugs may tions or alterations in serotonin balance may lead to affect thermoregulation via modulation of periph- autonomic impairment and dysregulation in body eral factors that help maintain normal body tem- temperature. Drugs may act as antigens to induce perature, including cutaneous and regional blood an immune- mediated response, causing the release flow, hormonal responses, shivering, and sweating.4-6 of endogenous pyrogens such as interleukin-1 and Drugs such as anticholinergics, sympathomimetics, tumor necrosis factor from leukocytes, resulting in prostaglandins, general anesthetics, and thyroid sup- a febrile response. plements that affect these peripheral factors directly Drug- induced hyperthermia may be divided or indirectly will not be discussed in detail in this into five general categories: altered thermoregula- chapter. tory mechanisms, drug administration–related fever, Drug administration–related fever is caused by fevers relating to the pharmacologic action of the pyrogens or endotoxins and is often encountered 1185 1186 DRUG-INDUCED DISEASES: Prevention, Detection, and Management in association with agents derived from micro- is another condition in which hyperthermia is often bial products. These pyrogens induce an immune- observed. A comparison of the signs and symptoms mediated response causing the release of cytokines of the various drug-in duced hyperthermic condi- such as interleukin-1 and tumor necrosis factor tions is presented in Table 54-1. from leukocytes, leading to fever. Examples include Although antipyretics are effective in the treat- fever during amphotericin B and bleomycin infu- ment of hyperthermia due to drug fever and serum sion. Further, an administration- related response sickness- like reaction, careful temperature monitor- associated with fever may occur in association with ing during their use is very important. The mechanism drugs given intravenously (phlebitis) or intramus- of fever in these cases is a hypothalamus-m ediated cularly (sterile abscess). Pentazocine and paralde- increase in the body’s core temperature. Antipyretics hyde are known to induce such a response when are not effective for the treatment of hyperthermia administered intramuscularly. secondary to NMS, serotonin syndrome, or malig- Fevers relating to the pharmacologic action of nant hyperthermia because the hyperthermia rep- drugs are most commonly observed in the treat- resents an alteration in thermoregulatory balance ment of infections or cancer as pyrogen is released and hypermetabolism and not a fever. from damaged or dying cells. The classic example is Drug- induced hypothermia is much less com- the Jarisch–Herxheimer reaction that occurs during mon than hyperthermia and is associated more com- the treatment of syphilis. Patients taking clozapine monly with illicit drugs rather than with prescription may experience fever potentially due to the immu- or nonprescription medications. Agents with agonist nomodulating effects of increased concentrations of activity at the gamma-a minobutyric acid (GABA) 7,8 interleukin-6 and tumor necrosis factor. receptor, such as gamma- hydroxybutyrate (GHB), Malignant hyperthermia is a specific idiosyn- are often associated with hypothermic effects. GABA cratic reaction that results in the development of is a primary inhibitory central neurotransmitter. severe fever and muscle damage in susceptible indi- GABA, dopamine, serotonin, and opioid peptides viduals receiving causative drugs. Approximately are mediators in temperature regulation; the pri- 5–8% of patients treated with the antiretroviral drug mary effect of GABA is to decrease temperature. abacavir experience a hypersensitivity reaction char- acterized by fever, rash, malaise, gastrointestinal, and respiratory symptoms that has been linked to HYPERTHERMIA DUE TO the major histocompatibility complex allele HLA- DRUG FEVER B*5701. Reactions can be severe enough that screen- ing prior to therapy initiation is required for safe use.9,10 A diagnosis of “drug fever” is generally established when there is a febrile response to a medication, no Finally, the most common cause of drug- induced other cause of the fever may be elucidated, and the hyperthermia is a hypersensitivity reaction. The fever resolves upon discontinuation of the suspect reaction is mediated through immunologic mecha- agent.1,11 Drug fever tends to be a diagnosis of exclu- nisms and caused by drugs or their metabolites, most sion following a review of a patient’s drug therapy, commonly antibiotics.1 clinical presentation characteristics, and labora- Conditions to consider in the differential diag- tory values. An early presumptive diagnosis of drug nosis of the drug- induced hyperthermia include pri- fever and initiation of treatment may reduce unnec- mary central nervous system disorders (infection, essary further evaluation and patient discomfort. tumors, ischemic or hemorrhagic stroke, trauma, seizures), systemic diseases (infections, cancer, met- abolic conditions, endocrinopathies, autoimmune CAUSATIVE AGENTS disorders), and toxins (carbon monoxide, phenols, Although any drug has the potential to cause strychnine, tetanus). Drug reaction with eosino- drug fever, certain medications should be con- philia and systemic symptoms (DRESS), discussed in sidered with a higher level of suspicion. Drugs Chapter 6: Drug Allergy and Cutaneous Diseases, .