Hyperthermia is a condition where the body's temperature is abnormally elevated due to failed thermoregulation, where heat production exceeds heat dissipation. It is distinct from a fever, which involves a controlled rise in the body's temperature set-point by the brain's hypothalamus. Medication-induced hyperthermia is a serious and potentially life-threatening adverse drug reaction that can arise through various mechanisms, such as increased metabolic heat production or interference with heat-dissipating processes like sweating. Recognizing which medications can trigger this condition is crucial for both healthcare professionals and patients.
Drug-Induced Syndromes Causing Hyperthermia
Serotonin Syndrome
Serotonin syndrome is a potentially life-threatening condition resulting from an excess of serotonin in the central nervous system, often caused by combining two or more serotonergic agents or an overdose. Symptoms include altered mental status, neuromuscular excitation (e.g., clonus, hyperreflexia), and autonomic hyperactivity, which leads to hyperthermia.
Key medications involved in serotonin syndrome include:
- Antidepressants: Selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs).
- Opioid analgesics: Tramadol, meperidine.
- Stimulants and Illicit Drugs: MDMA (Ecstasy), amphetamines.
- Other: Lithium, metoclopramide, buspirone.
Neuroleptic Malignant Syndrome (NMS)
NMS is a rare but severe and idiosyncratic reaction to drugs that block central dopamine receptors, primarily antipsychotic medications. It is characterized by the classic triad of hyperthermia, severe muscle rigidity (often described as "lead pipe rigidity"), and altered mental status. It can also be triggered by the abrupt withdrawal of dopaminergic drugs used for Parkinson's disease.
Causative agents for NMS include:
- Typical Antipsychotics: Haloperidol, chlorpromazine.
- Atypical Antipsychotics: Risperidone, olanzapine, clozapine.
- Antiemetics: Metoclopramide, prochlorperazine.
- Withdrawal of Dopaminergics: Levodopa.
Malignant Hyperthermia (MH)
MH is a rare, inherited hypermetabolic disorder of skeletal muscle triggered by certain volatile anesthetics (e.g., sevoflurane, isoflurane) and the depolarizing muscle relaxant succinylcholine. The condition involves uncontrolled calcium release from muscle cells, leading to sustained muscle contraction, metabolic acidosis, and rapid, life-threatening body temperature increases.
Anticholinergic Syndrome
Hyperthermia in this syndrome is primarily caused by impaired heat dissipation rather than increased heat production. Anticholinergic drugs block the action of acetylcholine, leading to a disruption of the nervous signals that control sweating. This reduces the body's ability to cool itself, a risk exacerbated by hot weather or dehydration.
Examples of anticholinergic drugs include:
- Antidepressants: Tricyclic antidepressants (amitriptyline).
- Antihistamines: Diphenhydramine (Benadryl), promethazine.
- Antispasmodics: Oxybutynin.
- Antiparkinsonian agents: Benztropine.
Other Medications and Drug Overdoses
Stimulants (Sympathomimetics)
Psychostimulants, both prescribed and illicit, can increase metabolic heat production and cause hyperthermia, particularly at high doses.
Medications and substances that act as sympathomimetics include:
- Illicit Drugs: Cocaine, MDMA (Ecstasy), methamphetamine.
- ADHD Medications: Amphetamines, methylphenidate.
Salicylate Overdose
In toxic doses, salicylates like aspirin cause hyperthermia by uncoupling oxidative phosphorylation, a cellular process, leading to a massive increase in heat production. This is a sign of severe toxicity and is particularly dangerous in young children.
Diuretics and Antihypertensives
While these medications do not directly cause hyperthermia, they can significantly increase a person's risk of heat-related illness. Diuretics, or "water pills," increase urination, which can lead to dehydration and electrolyte imbalances, especially during hot weather. Beta-blockers and other antihypertensives can also interfere with the body's ability to dissipate heat by affecting blood vessel dilation and heart rate.
Comparison of Major Drug-Induced Hyperthermia Syndromes
| Feature | Serotonin Syndrome (SS) | Neuroleptic Malignant Syndrome (NMS) | Malignant Hyperthermia (MH) |
|---|---|---|---|
| Trigger Agents | SSRIs, MAOIs, TCAs, Tramadol, MDMA | Antipsychotics, Dopamine antagonist drugs | Volatile anesthetics, Succinylcholine |
| Underlying Cause | Excess serotonin in CNS | Central dopamine receptor blockade | Inherited defect in muscle calcium channel |
| Primary Mechanism | Increased CNS activity, neuromuscular excitation | Severe muscle rigidity, hypothalamus dysfunction | Uncontrolled calcium release in muscle cells |
| Onset | Usually rapid, within hours of exposure/dose change | Variable, often within days to weeks of therapy initiation | Acute, during or shortly after anesthesia |
| Key Symptoms | Clonus, hyperreflexia, agitation, tremor, diarrhea | Muscle rigidity, altered mental status, autonomic instability | Hypercarbia, tachycardia, muscle rigidity, acidosis |
| Diagnostic Labs | Often normal, may have elevated CPK | Elevated CPK, leukocytosis | Elevated CPK, metabolic/respiratory acidosis |
Conclusion
Drug-induced hyperthermia is a critical adverse event with diverse causes, from inherited susceptibility to medication interactions or overdose. The condition is often a feature of specific syndromes like serotonin syndrome, NMS, and MH, but can also arise from heat-related complications with drugs like diuretics. Due to the potential for severe organ damage and a high mortality rate if left untreated, prompt recognition is essential. Early identification of symptoms like extreme temperature elevation, altered mental status, and muscle rigidity, coupled with a thorough review of the patient's medication history, can facilitate life-saving intervention. Patients and clinicians should always be vigilant about the risk, especially during periods of high environmental heat or when initiating new medications that affect thermoregulation. For additional information on medication effects related to heat, the CDC provides detailed guidance.
