Drug-Induced Hyperthermia Syndromes: Recognition and Acute Management

 

Drug-Induced Hyperthermia Syndromes: Recognition and Acute Management in Critical Care

A Comprehensive Review for Critical Care Practitioners

Dr Neeraj Manikath , claude.ai

Abstract

Background: Drug-induced hyperthermia syndromes represent potentially fatal medical emergencies that require rapid recognition and intervention. The three principal syndromes—neuroleptic malignant syndrome (NMS), serotonin syndrome (SS), and malignant hyperthermia (MH)—share overlapping clinical features but have distinct pathophysiological mechanisms and management approaches.

Objective: To provide critical care practitioners with a comprehensive understanding of these syndromes, emphasizing diagnostic differentiation, pathophysiology, and evidence-based acute management strategies.

Methods: This narrative review synthesizes current literature, clinical guidelines, and expert consensus on drug-induced hyperthermia syndromes, with particular emphasis on critical care management.

Conclusions: Early recognition through systematic clinical assessment, prompt discontinuation of offending agents, and aggressive supportive care form the cornerstone of management. Understanding the subtle differences between these syndromes is crucial for optimal patient outcomes.

Keywords: Neuroleptic malignant syndrome, serotonin syndrome, malignant hyperthermia, hyperthermia, critical care, drug toxicity

---

Introduction

Drug-induced hyperthermia syndromes constitute a group of potentially life-threatening conditions characterized by elevated core body temperature, altered mental status, and autonomic dysfunction. While sharing common clinical features, neuroleptic malignant syndrome (NMS), serotonin syndrome (SS), and malignant hyperthermia (MH) represent distinct pathophysiological entities requiring different therapeutic approaches¹². The critical care physician must rapidly differentiate between these syndromes to initiate appropriate treatment and prevent potentially fatal complications.

The incidence of these syndromes appears to be increasing, likely due to expanding use of psychoactive medications, improved recognition, and an aging population with multiple comorbidities³. Mortality rates, while declining with improved recognition and management, remain significant: NMS (10-20%), SS (2-12%), and MH (1-5%)⁴⁻⁶.

---

Pathophysiology

Neuroleptic Malignant Syndrome

NMS results from acute dopamine receptor blockade or withdrawal of dopaminergic agents, leading to disruption of central thermoregulation and muscle rigidity⁷. The primary mechanism involves blockade of D2 receptors in the hypothalamus, nigrostriatal pathway, and sympathetic nervous system. This creates a cascade of hyperthermia, rigidity, and autonomic instability⁸.

Clinical Pearl: The "lead pipe" rigidity of NMS is often asymmetric initially and may be subtle in the early stages, particularly in patients with underlying movement disorders.

Serotonin Syndrome

SS occurs due to excessive serotonergic activity in the central and peripheral nervous systems, primarily through 5-HT1A and 5-HT2A receptor overstimulation⁹. The syndrome can result from increased serotonin production, reduced metabolism, or enhanced receptor sensitivity¹⁰.

Clinical Hack: The presence of clonus (especially ocular and inducible) is pathognomonic for SS and helps differentiate it from NMS where clonus is typically absent.

Malignant Hyperthermia

MH is a pharmacogenetic disorder affecting genetically susceptible individuals exposed to volatile anesthetics or succinylcholine. Mutations in the ryanodine receptor (RYR1) or dihydropyridine receptor cause uncontrolled calcium release from the sarcoplasmic reticulum, resulting in sustained muscle contraction and hypermetabolism¹¹'¹².

Oyster Alert: Approximately 50% of MH-susceptible individuals have had previous uneventful anesthetics, making family history unreliable for risk stratification.

---

Clinical Presentation and Diagnosis

Neuroleptic Malignant Syndrome

Classic Tetrad:

• Hyperthermia (>38.5°C)
• Muscle rigidity ("lead pipe")
• Altered mental status
• Autonomic dysfunction

Timeline: Typically develops over 24-72 hours but can occur within hours or after weeks of drug exposure¹³.

Diagnostic Criteria (DSM-5-TR):

1. Recent dopamine antagonist use or dopamine agonist withdrawal
2. Severe muscle rigidity
3. Fever
4. Two or more of: diaphoresis, dysphagia, tremor, incontinence, altered consciousness, mutism, tachycardia, elevated BP, leukocytosis, elevated CK

Laboratory Findings:

• Markedly elevated CK (often >1000 IU/L)
• Leukocytosis with left shift
• Elevated liver enzymes
• Myoglobinuria
• Metabolic acidosis

Serotonin Syndrome

Clinical Triad:

• Altered mental status
• Autonomic hyperactivity
• Neuromuscular abnormalities

Hunter Serotonin Toxicity Criteria (most sensitive and specific): In the presence of a serotonergic agent, ONE of:

• Spontaneous clonus
• Inducible clonus + agitation or diaphoresis
• Ocular clonus + agitation or diaphoresis
• Tremor + hyperreflexia
• Hypertonia + temperature >38°C + ocular/inducible clonus¹⁴

Clinical Pearl: SS symptoms typically develop within hours of drug initiation or dose increase, unlike the more gradual onset of NMS.

Malignant Hyperthermia

Early Signs:

• Increased ETCO2 (earliest and most sensitive sign)
• Tachycardia
• Muscle rigidity (masseter spasm)
• Mixed acidosis

Late Signs:

• Hyperthermia (late finding, may be absent initially)
• Rhabdomyolysis
• Hyperkalemia
• Cardiac arrhythmias

Clinical Hack: An unexplained rise in ETCO2 >55 mmHg or a rapid increase of >5 mmHg should raise immediate suspicion for MH, even before temperature elevation.

---

Differential Diagnosis

Feature	NMS	Serotonin Syndrome	Malignant Hyperthermia
Onset	Hours to days	Minutes to hours	Minutes
Rigidity	Lead pipe, symmetric	Variable, lower > upper	Generalized
Reflexes	Normal to decreased	Hyperreflexic	Normal to increased
Clonus	Absent	Present (pathognomonic)	Absent
Mydriasis	Variable	Common	Variable
CK elevation	Marked (>1000)	Mild to moderate	Marked
Response to cooling	Poor	Good	Poor

Oyster: Anticholinergic toxicity can mimic these syndromes but typically presents with anhidrosis (dry skin) rather than diaphoresis, helping differentiate it from the hyperthermia syndromes.

---

Acute Management

General Principles

1. Immediate Assessment: ABC approach with rapid neurological assessment
2. Drug History: Comprehensive medication review including recent changes, over-the-counter medications, and supplements
3. Supportive Care: Aggressive cooling, fluid resuscitation, and organ support
4. Monitoring: Continuous cardiac monitoring, frequent vital signs, and serial laboratory assessments

Neuroleptic Malignant Syndrome

Immediate Management:

1. Discontinue all dopamine antagonists
2. Aggressive cooling (target core temperature <38.5°C)
   • Evaporative cooling preferred
   • Avoid shivering (counterproductive)
3. IV hydration and electrolyte correction
4. Monitor for complications: rhabdomyolysis, renal failure, respiratory failure

Pharmacological Treatment:

• Dantrolene: 1-3 mg/kg IV every 6 hours (continue until symptoms resolve)
• Bromocriptine: 2.5-10 mg PO/NG every 8 hours (dopamine agonist)
• Lorazepam: 1-2 mg IV every 2-4 hours PRN for agitation

Clinical Pearl: Early dantrolene administration (within 24 hours) significantly reduces morbidity and mortality in NMS¹⁵.

Serotonin Syndrome

Immediate Management:

1. Discontinue all serotonergic agents
2. Supportive care and cooling
3. Sedation for agitation and hyperthermia

Pharmacological Treatment:

• Cyproheptadine: 8 mg PO initially, then 4 mg every 2 hours until symptoms improve (5-HT2A antagonist)
• Lorazepam: 1-2 mg IV every 2-4 hours for sedation
• Avoid: Physostigmine, flumazenil, or other agents that may worsen serotonergic activity

Clinical Hack: Cyproheptadine can be crushed and given via nasogastric tube if the patient cannot swallow. Maximum dose is typically 32 mg in 24 hours.

Malignant Hyperthermia

Immediate Management (STAT Protocol):

1. Call for Help: Activate MH crisis team
2. Stop Triggers: Discontinue volatile anesthetics and succinylcholine
3. Hyperventilate: 100% oxygen, high fresh gas flows
4. Dantrolene: 2.5 mg/kg IV bolus, repeat every 1-2 minutes until signs abate (average total dose 8-10 mg/kg)

Ongoing Management:

• Continue dantrolene 1-3 mg/kg IV every 4-8 hours for 24-48 hours
• Aggressive cooling
• Treat hyperkalemia and acidosis
• Monitor for late complications (renal failure, compartment syndrome)

Critical Hack: Each vial of dantrolene requires 60 mL of sterile water for reconstitution. Prepare multiple team members for drug preparation as it's time-consuming during a crisis.

---

Complications and Monitoring

Common Complications

• Rhabdomyolysis: Monitor CK, myoglobin, and renal function
• Acute kidney injury: Maintain adequate perfusion and consider dialysis
• Cardiac arrhythmias: Continuous monitoring and electrolyte management
• Respiratory failure: Early intubation if indicated
• Disseminated intravascular coagulation: Monitor coagulation parameters

Long-term Considerations

• NMS: May recur with re-exposure; consider genetic counseling
• SS: Generally reversible with appropriate management
• MH: Refer for genetic testing and family counseling; maintain MH-safe anesthetic protocols

---

Prevention Strategies

Neuroleptic Malignant Syndrome

• Gradual dose adjustments of neuroleptics
• Adequate hydration in high-risk patients
• Recognition of risk factors: dehydration, agitation, recent drug changes

Serotonin Syndrome

• Careful drug interaction screening
• Gradual introduction of serotonergic agents
• Patient education on over-the-counter medications and supplements

Malignant Hyperthermia

• Comprehensive family history
• Use of trigger-free anesthesia in susceptible patients
• Maintain updated MH cart and protocols

---

Clinical Pearls and Practical Points

Pearl 1: The "4 C's" of hyperthermia syndrome differentiation:

• Clonus (SS only)
• CK elevation (marked in NMS and MH)
• Cooling response (good in SS, poor in NMS/MH)
• Course (rapid in SS/MH, gradual in NMS)

Pearl 2: In suspected SS, improvement within 24 hours of cyproheptadine administration supports the diagnosis.

Pearl 3: Consider atypical presentations: elderly patients may not develop high fever, and patients on muscle relaxants may not show rigidity.

Oyster 1: Moderate temperature elevation (38-39°C) with significant clinical symptoms should not be dismissed. These syndromes can be fatal even without extreme hyperthermia.

Oyster 2: Recent studies suggest that mild MH variants exist, presenting with isolated tachycardia or increased ETCO2 without temperature elevation¹⁶.

Clinical Hack: Create a "hyperthermia syndrome kit" in your ICU containing dantrolene, cyproheptadine, and bromocriptine for rapid access during emergencies.

---

Conclusion

Drug-induced hyperthermia syndromes represent critical care emergencies requiring rapid recognition and differentiation. While these conditions share overlapping features, understanding their distinct pathophysiological mechanisms and clinical presentations enables targeted therapy. The key to successful management lies in early recognition, immediate discontinuation of offending agents, aggressive supportive care, and appropriate pharmacological intervention.

Critical care practitioners must maintain high clinical suspicion, particularly in patients receiving psychoactive medications or undergoing anesthesia. The development of standardized protocols and regular staff education can significantly improve outcomes in these potentially fatal conditions.

Future research directions include better understanding of genetic predisposition, development of rapid diagnostic tests, and optimization of treatment protocols. Until then, clinical vigilance and rapid intervention remain our most powerful tools in managing these complex syndromes.

---

References

1. Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011;1(1):41-47.

2. 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.

3. Modi S, Dharaiya D, Schultz L, Varelas P. Neuroleptic malignant syndrome: complications, outcomes, and mortality. Neurocrit Care. 2016;24(1):97-103.

4. Picard LS, Lindsay S, Strawn JR, et al. Atypical neuroleptic malignant syndrome: diagnostic controversies and considerations. Pharmacotherapy. 2008;28(4):530-535.

5. Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010;81(9):1139-1142.

6. Litman RS, Rosenberg H. Malignant hyperthermia: update on susceptibility testing. JAMA. 2005;293(23):2918-2924.

7. Pelonero AL, Levenson JL, Pandurangi AK. Neuroleptic malignant syndrome: a review. Psychiatr Serv. 1998;49(9):1163-1172.

8. Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry. 1999;156(2):169-180.

9. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.

10. Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol. 1999;13(1):100-109.

11. Hopkins PM. Malignant hyperthermia: pharmacology of triggering. Br J Anaesth. 2011;107(1):48-56.

12. Rosenberg H, Davis M, James D, et al. Malignant hyperthermia. Orphanet J Rare Dis. 2007;2:21.

13. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed, text revision. Washington, DC: American Psychiatric Association; 2022.

14. Hunter Toxicology Service. The Hunter Serotonin Toxicity Criteria. https://www.huntertoxicology.com/hunters-serotonin-toxicity-criteria/

15. Reulbach U, Dütsch C, Biermann T, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care. 2007;11(1):R4.

16. Larach MG, Brandom BW, Allen GC, et al. Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012. Anesthesiology. 2014;120(6):1359-1369.