Malignant Hyperthermia Mimics in Critical Care

A Comprehensive Review for Postgraduate Critical Care Physicians

Dr Neeraj Manikath , claude.ai

Abstract

Malignant hyperthermia (MH) presents as a life-threatening hypermetabolic syndrome classically triggered by volatile anesthetics and succinylcholine. However, several critical conditions mimic MH presentation, creating diagnostic challenges that can prove fatal if mismanaged. This review examines three critical MH mimics: serotonin syndrome, neuroleptic malignant syndrome, and thyroid storm, focusing on distinguishing clinical features, diagnostic pearls, and management pitfalls that every critical care physician must recognize.

Keywords: Malignant hyperthermia, serotonin syndrome, neuroleptic malignant syndrome, thyroid storm, hyperthermia, critical care

Introduction

The constellation of hyperthermia, muscle rigidity, autonomic instability, and altered mental status strikes fear into the hearts of critical care physicians. While malignant hyperthermia (MH) remains the archetypal hypermetabolic crisis, several conditions present with remarkably similar clinical pictures, creating diagnostic dilemmas that demand immediate recognition and appropriate intervention.

The stakes could not be higher. Misdiagnosing serotonin syndrome as MH and administering dantrolene can worsen the condition. Conversely, missing true MH in favor of a mimic diagnosis can prove rapidly fatal. This review focuses on three critical MH mimics that every intensivist must master: serotonin syndrome, neuroleptic malignant syndrome (NMS), and thyroid storm.

Malignant Hyperthermia: The Gold Standard

Clinical Presentation

True MH presents with the classic tetrad:

Hyperthermia (often >39°C, rising 1-2°C every 15 minutes)
Generalized muscle rigidity (masseter spasm may be the first sign)
Autonomic instability (tachycardia, hypertension, arrhythmias)
Hypermetabolism (increased CO₂ production, metabolic acidosis)

Diagnostic Markers

Elevated creatine kinase (CK) levels >1000 U/L
Myoglobinuria
Hyperkalemia
Mixed respiratory and metabolic acidosis
Elevated lactate levels

Pearl: The pathognomonic early sign is an unexplained rise in end-tidal CO₂ during anesthesia, often before temperature elevation.

Serotonin Syndrome: The Great Imitator

Pathophysiology

Serotonin syndrome results from excessive serotonergic activity in the central nervous system, typically following therapeutic drug use, overdose, or drug interactions involving serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), or other serotonergic agents.

Clinical Presentation

The Clonus > Rigidity Distinction (Critical Teaching Pearl)

Unlike MH's generalized muscle rigidity, serotonin syndrome classically presents with:

Clonus (sustained, rhythmic contractions) - particularly ocular clonus and lower extremity clonus
Hyperreflexia more prominent in lower extremities
Tremor rather than true rigidity
Myoclonus - brief, shock-like muscle contractions

Clinical Pearl: Elicit ankle clonus by rapid dorsiflexion of the foot. Sustained clonus (>3 beats) is highly suggestive of serotonin syndrome.

Hunter Criteria for Serotonin Syndrome

In the presence of a serotonergic agent:

Spontaneous clonus, OR
Inducible clonus + agitation or diaphoresis, OR
Ocular clonus + agitation or diaphoresis, OR
Tremor + hyperreflexia, OR
Hypertonia + temperature >38°C + ocular or inducible clonus

Distinguishing Features from MH

Feature	Serotonin Syndrome	Malignant Hyperthermia
Onset	Hours to days	Minutes to hours
Muscle findings	Clonus, hyperreflexia	Generalized rigidity
Reflexes	Hyperactive	Often diminished
Pupils	Dilated	Variable
Trigger	Serotonergic drugs	Volatile anesthetics, succinylcholine
CK elevation	Moderate (usually <1000)	Severe (often >1000)

Management Hack: Discontinue all serotonergic agents immediately. Cyproheptadine (4-8 mg PO/NG q6h) is the antidote of choice, not dantrolene.

Oyster: Tramadol, fentanyl, and linezolid are often overlooked serotonergic agents that can precipitate syndrome.

Neuroleptic Malignant Syndrome: The CPK Pattern Matters

Pathophysiology

NMS results from dopamine receptor blockade in the basal ganglia and hypothalamus, most commonly following antipsychotic medication use. The syndrome can occur with any dopamine antagonist, including antiemetics like metoclopramide and prochlorperazine.

Clinical Presentation

The classic tetrad includes:

Hyperthermia (>38°C)
Generalized "lead-pipe" rigidity
Altered mental status
Autonomic dysfunction

The CPK Pattern Distinction (Critical Diagnostic Pearl)

CPK levels in NMS typically follow a specific pattern:

Peak levels often exceed 1000 U/L (can reach >100,000 U/L)
Gradual rise over 24-72 hours (unlike MH's rapid elevation)
Prolonged elevation lasting days to weeks
Slow normalization even after clinical improvement

Teaching Point: In NMS, CK levels may continue rising even after discontinuation of the offending agent and initiation of treatment, whereas in MH, CK levels plateau and decline more rapidly with appropriate therapy.

Distinguishing Features from MH

Feature	NMS	Malignant Hyperthermia
Onset	Days to weeks	Minutes to hours
Rigidity type	"Lead-pipe" (uniform)	Generalized, severe
Mental status	Catatonia, stupor	Varies
Trigger	Dopamine antagonists	Anesthetic agents
CK pattern	Gradual rise, prolonged	Rapid rise, faster decline
Response to dantrolene	Variable	Dramatic

Management Approach

Immediate discontinuation of all dopamine antagonists
Dantrolene 1-2.5 mg/kg IV every 6 hours (less effective than in MH)
Bromocriptine 2.5-10 mg PO/NG q8h (dopamine agonist)
Supportive care with aggressive cooling and fluid management

Clinical Hack: Consider empirical trial of dantrolene if unable to distinguish between NMS and MH - it may help both conditions, though response in NMS is less predictable.

Oyster: NMS can occur with dopamine withdrawal in Parkinson's patients ("parkinsonism-hyperpyrexia syndrome"). Always continue dopaminergic medications perioperatively in these patients.

Thyroid Storm: The Forgotten Beta-Blocker Contraindication

Pathophysiology

Thyroid storm represents severe thyrotoxicosis with life-threatening manifestations. It typically occurs in patients with underlying hyperthyroidism exposed to precipitating factors such as infection, surgery, or discontinuation of antithyroid medications.

Clinical Presentation

Hyperthermia (often >39°C)
Marked tachycardia (often >140 bpm)
Hypertension or hypotension
Altered mental status (agitation, delirium, coma)
Gastrointestinal symptoms (nausea, vomiting, diarrhea)

The Forgotten Beta-Blocker Contraindication (Critical Clinical Pearl)

Traditional teaching emphasizes beta-blockers as first-line therapy for thyroid storm. However, this recommendation comes with a critical caveat that is often forgotten:

Contraindication: Patients with congestive heart failure or cardiogenic shock secondary to thyrotoxicosis should NOT receive beta-blockers as initial therapy.

Pathophysiology: In thyrotoxic cardiomyopathy, the heart depends on high adrenergic tone to maintain cardiac output. Beta-blockade can precipitate cardiovascular collapse.

Clinical Hack: In patients with thyroid storm and heart failure:

Prioritize antithyroid therapy (methimazole 20-40 mg q6h)
Iodine solution (Lugol's iodine 5-10 drops q8h) - give 1-2 hours AFTER antithyroid drugs
Corticosteroids (hydrocortisone 200-400 mg q6h)
Consider calcium channel blockers for heart rate control instead of beta-blockers
Add beta-blockers only after stabilization of cardiac function

Burch-Wartofsky Point Scale for Thyroid Storm

A validated scoring system helping distinguish thyroid storm from severe thyrotoxicosis:

Temperature:

99-99.9°F (37.2-37.7°C): 5 points
100-100.9°F (37.8-38.3°C): 10 points
101-101.9°F (38.4-38.8°C): 15 points
102-102.9°F (38.9-39.4°C): 20 points
103-103.9°F (39.5-39.9°C): 25 points
≥104°F (≥40°C): 30 points

Central Nervous System Effects:

Absent: 0 points
Mild (agitation): 10 points
Moderate (delirium, psychosis): 20 points
Severe (seizures, coma): 30 points

Heart Rate:

90-109 bpm: 5 points
110-119 bpm: 10 points
120-129 bpm: 15 points
130-139 bpm: 20 points
≥140 bpm: 25 points

Score ≥45: Highly suggestive of thyroid storm

Distinguishing Features from MH

Feature	Thyroid Storm	Malignant Hyperthermia
Muscle rigidity	Absent	Prominent
GI symptoms	Common (diarrhea)	Rare
Thyroid function	Elevated T3/T4, suppressed TSH	Normal
CK elevation	Mild	Severe
Response to cooling	Good	Poor without specific therapy

Oyster: Apathetic thyrotoxicosis in elderly patients may present with bradycardia instead of tachycardia, mimicking other conditions.

Practical Clinical Approach: The 5-Minute Differential

When faced with a patient presenting with hyperthermia, rigidity, and autonomic instability, this rapid assessment framework can be life-saving:

Step 1: Exposure History (30 seconds)

Recent anesthesia → Consider MH
Serotonergic medications → Consider serotonin syndrome
Antipsychotics/antiemetics → Consider NMS
Known hyperthyroidism → Consider thyroid storm

Step 2: Physical Examination Focus (2 minutes)

Muscle examination:
- Generalized rigidity → MH or NMS
- Clonus/hyperreflexia → Serotonin syndrome
- Minimal rigidity → Thyroid storm
Pupil examination:
- Dilated → Serotonin syndrome or thyroid storm
- Normal/small → MH or NMS

Step 3: Rapid Laboratory Assessment (2 minutes)

Order stat:

Arterial blood gas (metabolic acidosis in MH)
Basic metabolic panel (hyperkalemia in MH)
CK level (highest in MH and NMS)
Lactate (elevated in all, highest in MH)
TSH, free T4, T3 if thyroid storm suspected

Step 4: Immediate Management Decision (30 seconds)

High clinical suspicion for MH → Dantrolene 2.5 mg/kg IV immediately
Serotonin syndrome likely → Discontinue serotonergic agents, consider cyproheptadine
NMS suspected → Discontinue dopamine antagonists, consider dantrolene
Thyroid storm → Antithyroid therapy, corticosteroids, careful beta-blockade

Evidence-Based Management Protocols

Malignant Hyperthermia Management

Immediate discontinuation of triggering agents
Dantrolene 2.5 mg/kg IV bolus, repeat every 2-3 minutes until symptoms resolve (average total dose: 8-10 mg/kg)
Hyperventilation with 100% O₂
Aggressive cooling (ice packs, cold saline, cooling blankets)
Correct acidosis with sodium bicarbonate
Manage hyperkalemia (calcium, insulin/glucose, albuterol)
Monitor for complications (ARF, compartment syndrome, coagulopathy)

Serotonin Syndrome Management

Discontinue all serotonergic agents
Supportive care (IV fluids, cooling measures)
Cyproheptadine 8 mg PO/NG initially, then 4 mg q2h until symptoms resolve
Benzodiazepines for agitation and muscle rigidity
Avoid dantrolene (may worsen hypotension)

NMS Management

Discontinue all dopamine antagonists
Dantrolene 1-2.5 mg/kg IV q6h
Bromocriptine 2.5-10 mg PO q8h
Supportive care with cooling and fluid management
Consider electroconvulsive therapy for severe, refractory cases

Thyroid Storm Management

Antithyroid therapy (methimazole 20-40 mg PO q6h OR propylthiouracil 200-400 mg PO q6h)
Iodine (Lugol's solution 5-10 drops PO q8h) - give 1-2 hours AFTER antithyroid drugs
Corticosteroids (hydrocortisone 200-400 mg IV q6h)
Beta-blockers (propranolol 1-2 mg IV q5min or 40-80 mg PO q6h) - CAUTION in heart failure
Supportive care (cooling, fluid management, treat precipitating factors)

Clinical Pearls and Teaching Points

Pearl 1: The "Dantrolene Decision"

Give empirically if unable to distinguish between MH and NMS
Avoid in serotonin syndrome - may worsen hypotension
Ineffective in thyroid storm

Pearl 2: The "Clonus Test"

Sustained ankle clonus (>3 beats) strongly suggests serotonin syndrome
Ocular clonus is pathognomonic for serotonin syndrome
Absence of clonus makes serotonin syndrome unlikely

Pearl 3: The "CK Curve"

Rapid rise and fall → MH
Gradual rise, prolonged elevation → NMS
Mild elevation → Serotonin syndrome or thyroid storm

Pearl 4: The "Timeline Tell"

Minutes to hours → MH
Hours to days → Serotonin syndrome
Days to weeks → NMS
Variable → Thyroid storm

Common Pitfalls and How to Avoid Them

Pitfall 1: Assuming All Rigidity is the Same

Solution: Learn to distinguish between generalized rigidity (MH/NMS), lead-pipe rigidity (NMS), and clonus/hyperreflexia (serotonin syndrome).

Pitfall 2: Reflexive Beta-Blocker Use in Thyroid Storm

Solution: Always assess cardiac function first. In heart failure, prioritize antithyroid therapy and consider alternative rate control.

Pitfall 3: Missing Drug Interactions

Solution: Always review the complete medication list, including recent additions, over-the-counter medications, and recreational drugs.

Pitfall 4: Inadequate Dantrolene Dosing in MH

Solution: Don't stop at one vial. Continue until symptoms resolve (average 8-10 mg/kg total dose).

Pitfall 5: Giving Iodine Before Antithyroid Drugs

Solution: The "block and drop" approach - block thyroid synthesis FIRST (antithyroid drugs), then drop thyroid release (iodine).

Future Directions and Research

Current research focuses on:

Genetic markers for MH susceptibility
Point-of-care diagnostics for rapid differentiation
Novel therapeutics for treatment-resistant cases
Artificial intelligence algorithms for early recognition

Conclusion

The differential diagnosis of malignant hyperthermia and its mimics represents one of the most challenging scenarios in critical care medicine. Success requires rapid recognition, systematic evaluation, and immediate appropriate intervention. The clinical pearls and management strategies outlined in this review provide a framework for navigating these life-threatening conditions.

Remember the key distinguishing features: clonus favors serotonin syndrome, CK patterns help differentiate NMS timing, and cardiac status determines beta-blocker safety in thyroid storm. When in doubt, err on the side of aggressive supportive care while pursuing definitive diagnosis and treatment.

The stakes are too high for diagnostic uncertainty - master these mimics to save lives in the critical care unit.

References

Litman RS, Rosenberg H. Malignant hyperthermia: update on susceptibility testing. JAMA. 2005;293(23):2918-2924.
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635-642.
Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870-876.
Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am. 1993;22(2):263-277.
Larach MG, Brandom BW, Allen GC, et al. Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from The North American Malignant Hyperthermia Registry. Anesth Analg. 2014;119(6):1359-1366.
Buckley NA, Dawson AH, Isbister GK. Serotonin syndrome. BMJ. 2014;348:g1626.
Picard LS, Lindsay S, Strawn JR, et al. Atypical neuroleptic malignant syndrome: diagnostic controversies and considerations. Pharmacotherapy. 2008;28(4):530-535.
Akamizu T, Satoh T, Isozaki O, et al. Diagnostic criteria, clinical features, and incidence of thyroid storm based on nationwide surveys. Thyroid. 2012;22(7):661-679.
Rosenberg H, Pollock N, Schiemann A, et al. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015;10:93.
Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010;81(9):1139-1142.
Caroff SN, Mann SC, Campbell EC. Atypical antipsychotics and neuroleptic malignant syndrome. Psychiatr Ann. 2000;30(5):314-321.
Klubo-Gwiezdzinska J, Wartofsky L. Thyroid emergencies. Med Clin North Am. 2012;96(2):385-403.
Hopkins PM. Malignant hyperthermia: pharmacology of triggering. Br J Anaesth. 2011;107(1):48-56.
Iqbal N, Irfan M, Zubairi ABS, et al. Neuroleptic malignant syndrome: three case reports. J Pak Med Assoc. 2009;59(8):559-561.

Friday, August 15, 2025