Drug-Induced Hyperthermia

Four syndromes share one picture: fever, a hypermetabolic muscle state and an altered mental status. Serotonin syndrome, neuroleptic malignant syndrome (NMS), malignant hyperthermia (MH) and sympathomimetic toxicity all start with a drug or an exposure. So the first question is what the patient took or was given. The answer decides your first actions.

• Serotonin syndrome: Too much serotonergic activity after one serotonergic drug, or a combination. Agitation, clonus, hyperreflexia and hyperthermia follow. Usually within hours of the dose change or the added drug.
• NMS: Dopamine blockade from antipsychotics, metoclopramide or promethazine, or an abrupt stop of a dopamine agonist. Rigidity, hyperthermia, creatine kinase (CK) elevation and autonomic lability build over days.
• Malignant hyperthermia: A hypermetabolic crisis in a susceptible patient exposed to a volatile anesthetic or succinylcholine. The root is the skeletal muscle ryanodine receptor (RyR1). Rising end-tidal CO₂ (EtCO₂), tachycardia, rigidity and acidosis follow. Often within minutes to hours.
• Sympathomimetic toxicity: Catecholamine excess from cocaine, amphetamines or MDMA. Expect agitation, hypertension, tachycardia, hyperthermia, seizures and rhabdomyolysis.

Serotonin toxicity (Hunter criteria)

No serotonergic drug, no Hunter criteria. Check the list first: SSRI, SNRI, MAOI, linezolid, tramadol, meperidine, methylene blue. The derivation study found that clonus, agitation, diaphoresis, tremor and hyperreflexia predict serotonin toxicity. Meet any one of these rule sets and you meet the criteria:

• Spontaneous clonus
• Inducible clonus plus agitation or diaphoresis
• Ocular clonus plus agitation or diaphoresis
• Tremor plus hyperreflexia
• Hypertonia plus temperature above 38 °C plus ocular or inducible clonus

Neuroleptic malignant syndrome (2011 consensus criteria)

Start with the drug. The international Delphi panel requires recent dopamine antagonist exposure or dopamine agonist withdrawal. Then the picture: hyperthermia, rigidity, altered mental status, CK elevation, sympathetic lability, and tachycardia with tachypnea. A negative work-up for other causes is also required. The numbers anchor it. Temperature above 38.0 °C on at least 2 occasions. CK at least 4 times the upper limit of normal. Systolic or diastolic blood pressure at least 25% above baseline, heart rate at least 25% above baseline and respiratory rate at least 50% above baseline.

Malignant hyperthermia

Think MH during or soon after anesthesia with a volatile agent or succinylcholine. The early signs: EtCO₂ climbing even with more minute ventilation, plus tachycardia, acidosis and hyperkalemia. Generalized rigidity and rhabdomyolysis come later. Temperature is a late sign. Don't wait for a fever.

Red Flags

• Temperature above 38 °C on repeated checks, with rigidity, altered mental status or clonus
• Rising EtCO₂ or rising ventilation needs in an anesthetized or ventilated patient
• Generalized or lead-pipe rigidity, or clonus that is spontaneous or inducible
• CK at least 4 times the upper limit of normal, or dark urine with myoglobin
• Hypotension, ventricular dysrhythmia or seizures, which signal organ compromise

The drug history and a glucose check come first. Don't wait for the full work-up before you treat a severe picture.

• Sepsis: Fever and tachycardia, but no clonus, no mydriasis and no dry skin. Those point away from serotonin or antimuscarinic toxicity. Check cultures and the source.
• Hypoglycemia and intracranial injury: Altered mental status with normal pupils. Check glucose, then image the head.
• Anticholinergic toxidrome: Dry, flushed skin, mydriasis and delirium. Antimuscarinic toxicity has dry skin, normal or reduced tone and no clonus. That last point is what separates it from serotonin toxicity. See Toxidromes.
• Salicylate or DNP toxicity: Tachypnea and a mixed acid-base disorder. Hyperthermia shows up late, and it is an ominous sign. Check a salicylate level and a blood gas.
• Thyroid storm or withdrawal states: Fever with tachycardia, tremor and agitation. Thyroid status, alcohol or sedative withdrawal history and the drug history separate these from the four syndromes.
• Heat stroke: An environmental cause with no drug trigger. Cooling is the treatment. Dantrolene has no established role.

The BLS plan is the same for all four syndromes. Protect the patient from injury, cool them, and get ALS early.

1. Scene and history: ask for recent drugs, including fluoxetine within about 5 weeks and long-acting injectable antipsychotics, plus antidepressants, linezolid, tramadol, other antipsychotics, anti-nausea drugs, stimulants and any recent anesthesia or surgery. Bring the pill bottles.
2. Airway and breathing: open the airway, give oxygen, and assist ventilation if breathing is poor.
3. Cool: remove heavy clothing and start rapid external cooling. The AHA 2023 focused update recommends rapid external cooling for life-threatening hyperthermia from sympathomimetic poisoning.
4. Protect from injury: pad the environment during seizures or clonus. Avoid prolonged physical restraint without sedation, which is potentially harmful.
5. Glucose: check it. Treat hypoglycemia per protocol.
6. Transport priority: early ALS request for any hot, rigid or agitated patient. Do not delay transport for the history.

Doses vary by protocol; follow local protocols and medical direction.

• Monitoring (Paramedic/RN/CCT): cardiac monitor, 12-lead ECG, EtCO₂ capnography, temperature, glucose, IV or IO access.
• Benzodiazepine first (Paramedic/RN/CCT): for agitation, seizures and hyperthermia in serotonin and sympathomimetic toxicity, titrate to calm. Lorazepam 2 mg IV or IM for severe agitation, repeated per protocol. See Lorazepam, Midazolam or Diazepam.
• Cooling (Paramedic/RN/CCT): rapid external cooling, reassessing temperature and mental status at each check. In MH, stop active cooling when the temperature falls below about 38 °C (MHAUS) to avoid overcooling.
• Malignant hyperthermia (Paramedic/RN/CCT): stop the trigger and give dantrolene 2.5 mg/kg actual body weight IV rapid push through a large-bore IV, repeated until EtCO₂, heart rate and rigidity improve. The 2.5 mg/kg initial dose is the MHAUS/EMHG regimen. The US Ryanodex label instead states a minimum of 1 mg/kg IV push, repeated up to 10 mg/kg cumulative, and restarted at 1 mg/kg if signs return. Local protocol governs. If there is no response by about 10 mg/kg total, reconsider the diagnosis and call MHAUS. Avoid calcium channel blockers (verapamil, diltiazem) with dantrolene because of hyperkalemia and myocardial depression. Dantrolene can cause sterile phlebitis if it leaks. See Dantrolene.
• Serotonin syndrome: stop all serotonergic drugs and give supportive care. Dantrolene is not recommended here.
• NMS (ALS): stop the dopamine antagonist and give supportive care. Do not give another dopamine blocker (haloperidol, metoclopramide, promethazine) for agitation, since these are the NMS triggers.
• Acidosis and hyperkalemia: treat per protocol, see Sodium Bicarbonate and Hyperkalemia. In MH, the usual options are calcium, insulin with glucose and bicarbonate, with hourly glucose after insulin; do not use calcium channel blockers.
• Antipyretics: do not rely on acetaminophen. Heat here comes from muscle activity and drug effect, not a fever set point.

• Serotonin syndrome (ED/ICU): cyproheptadine, an oral 5-HT antagonist. Start with 12 mg, then 2 mg every 2 hr if symptoms persist. Maintenance is 8 mg every 6 hr once stabilized. Check the 24-hour total against the label: usual range 4–20 mg/day, up to 32 mg/day occasionally needed, and not above 0.5 mg/kg/day. It sedates, it is anticholinergic, and it can cause hypotension. The label lists MAO inhibitor use as a contraindication. When an MAOI is the trigger, confirm with toxicology first. Use per toxicology advice. No E3 medication page yet.
• Refractory agitation or hyperthermia: deep sedation, then paralysis with a nondepolarizing agent and intubation per Rapid Sequence Intubation. In serotonin toxicity, a temperature above about 41.1 °C is the point to escalate this way. Antipyretics are not effective. In suspected MH, do not use succinylcholine. It is an MH trigger. Avoid it in rhabdomyolysis or hyperkalemia too. Stop active cooling near 38 °C to avoid overcooling. Adjust per medical direction.
• Malignant hyperthermia (ED/ICU): Keep dantrolene going at 1 mg/kg IV every 4–6 hr for at least 24 hr after the crisis. If it comes back, treat it as a new crisis with 2.5 mg/kg.
• MH monitoring: potassium, pH, lactate and CK every 8 hr; creatinine at least every 24 hr; glucose and compartment checks. See Potassium.
• NMS (ED/ICU): Stop the antipsychotic. Control temperature. Support circulation and kidneys. Dantrolene as an adjunct for severe rigidity and hyperthermia is off-label. Bromocriptine is a specialist decision, because it can worsen serotonin toxicity. Doses are per toxicology or specialist consult.
• Sympathomimetic toxicity (ED/ICU): Sedate for severe agitation. The AHA 2023 update recommends this to control hyperthermia and acidosis and to prevent rhabdomyolysis. In MDMA toxicity, check sodium and avoid hypotonic fluids. Excess water intake can cause hyponatremia. Beta-blockers are controversial in cocaine toxicity. See Labetalol and follow toxicology advice.

• Destination: Go to an ED with ICU and toxicology access for serotonin syndrome, NMS and sympathomimetic toxicity. For MH, call ahead to a hospital that stocks dantrolene. MHAUS minimum stock is 36 × 20 mg conventional vials or 3 × 250 mg Ryanodex vials.
• In transit: Watch EtCO₂, rhythm, SpO₂ and temperature the whole way. Keep a benzodiazepine drawn up. Keep cooling running. Reassess sedation and breathing after each dose.
• MH supplies: Mixing a conventional 20 mg vial takes time. It needs 60 mL sterile water. Ryanodex comes as 250 mg in 5 mL. Start mixing as soon as MH is suspected, or ask the receiving hospital to prepare it.
• Information: The MHAUS hotline for MH advice is 800-644-9737.
• Handoff: Hand over the drug and time of each trigger, every benzodiazepine dose, the temperature and EtCO₂ trend, dantrolene doses and CK or potassium results.

• Pediatrics: Kids get the same MH dantrolene start as adults: 2.5 mg/kg IV, on actual body weight. MHAUS guidance gives no separate pediatric dose. Benzodiazepine doses are weight-based. Lorazepam 0.1 mg/kg IV or IO (max 4 mg), or midazolam 0.2 mg/kg IM or IN (max 10 mg), per Weight-Based Dosing. Pediatric cyproheptadine dosing is not established on this page. Use toxicology advice. Vital-sign limits change with age (see Pediatric Vital Signs).
• Pregnancy: High fever and rigidity threaten the fetus as well as the patient. Involve obstetrics early. No specific adjustment for dantrolene or cyproheptadine in pregnancy is established in the sources used here. Treat the crisis, and check with medical direction.
• Older Adults and Polypharmacy: Count every serotonergic, dopamine-blocking and sedating drug in the history. Several together raise the risk of serotonin toxicity and NMS. The cyproheptadine label notes more sedation, dizziness and hypotension with antihistamines in older patients.
• Renal Impairment: Rhabdomyolysis from NMS, MH or stimulants can cause acute kidney injury. Watch urine output, creatinine and potassium.
• Hepatic Impairment: Oral dantrolene carries a boxed hepatotoxicity warning. IV dantrolene does not. After oral dosing, check liver tests.

• Error: Giving dantrolene for serotonin syndrome. It is not recommended. It did not help in animal models, and it does not treat the serotonin excess. Benzodiazepines, cooling and cyproheptadine are the tools.
• Error: Giving bromocriptine for suspected serotonin syndrome. It is a dopamine agonist, and it can push serotonin activity higher.
• Error: Giving another dopamine blocker for NMS agitation. Haloperidol, metoclopramide and promethazine are the dopamine-blocking triggers of NMS. Don't add one.
• Error: Trusting temperature in MH. EtCO₂ rises first. Give dantrolene on the trend, not on the fever.
• Error: A beta-blocker alone for sympathomimetic toxicity. The AHA 2023 update calls it controversial. The classic worry is unopposed alpha stimulation. Sedate first.
• Error: Holding an agitated patient down with no sedation. The AHA 2023 update flags this as potentially harmful.
• Error: Free water for MDMA-associated agitation or hyperthermia. Check sodium. Avoid hypotonic fluids.
• Error: Antipyretics alone for hyperthermia. The heat here comes from muscle activity, so antipyretics are not useful.