Seizures and Hyperthermia Associated with Poisoning or Drug Overdose

1. Seizures and Hyperthermia Associated with Poisoning or Drug Overdose Kent R. Olson, MD, FACEP, FACMT Medical Director, San Francisco Division California Poison Control System University of California, San Francisco

2. Causes of Status Epilepticus in the ED • 1980-1989 Urban SF Hospital – 154 pts • Anticonvulsant drug withdrawal: 39 • Alcohol-related: 39 • Drug Toxicity: 14 (9%) • CNS infection: 12 • Lowenstein DH & Alldredge BK et al: Neurol 1993; 43

3. Outline • Causes of drug-induced seizures (“drug” = drug or poison) • Consequences and complications of drug-induced seizures • Anticonvulsants for drug-induced seizures • Management of drug-induced hyperthermia

4. Case • A 27 yo man was admitted with an unknown drug overdose, unresponsive but breathing. Pupils 5 mm. Absent bowel sounds. • Frequent jerking movements. • BP 120/80, HR 100/min • ECG:

6. Case (continued) • Shortly after admission he developed recurrent generalized seizures. • With the onset of seizures, the QRS interval increased to 0.20 sec. • The BP fell to 70 mm systolic, and dopamine and norepinephrine were given.

8. Case (continued) • Three hours after admission, the rectal temperature was noted to be 107 F. • Despite intensive supportive care, he developed multi-organ failure and died.

9. Complications of Drug-Induced Seizures • Hypoxemia • Shock Brain Damage • Hyperthermia • Rhabdomyolysis • Metabolic acidosis • Other drug-specific complications

10. Common Causes of Drug-Induced Seizures • Cocaine, amphetamines, other stimulants • Tricyclic antidepressants • Other antidepressants & antipsychotics • Diphenhydramine • Isoniazid • Many others • Olson KR et al: Am J Emerg Med 1993; 11:565-568

11. Calls to the SF Poison Center about drug-related seizures

12. Treatment of Drug-Induced Seizures • ABCD’s: • Airway • Breathing • Circulation • Dextrose • Anticonvulsants • Specific antidote, if available • Cooling measures

13. Antiepileptic-Drug Therapy for Status Epilepticus. From: Lowenstein DH & Alldredge BK: NEJM 1998; 338:970

14. Anticonvulsants for Drug-Induced Seizures Specific antidote, if available Benzodiazepine Phenytoin? Phenobarbital Pentobarbital, Propofol, or Midazolam

15. Tricyclic and Related Antidepressants • Cardiotoxicity often worsened by seizures • Use bicarb to restore/maintain pH > 7.4 • Muscle twitching, absent sweating increase risk of hyperthermia • Consider neuromuscular paralysis • No specific antidote for seizures • Do not use physostigmine, phenytoin

16. Cocaine & Amphetamines • Seizures are usually brief, self-limited • Prolonged or multiple seizures suggests complications such as intracranial hemorrhage, head injury, hyperthermia, etc • Treatment: • Sedation • Anticonvulsants if needed • Cooling measures

17. Case • 16 year old took 200 Benadryl™ tablets • Agitation, somnolence, seizure • Wide complex QRS

18. Antihistamines • Diphenhydramine is most common • Seizures usually brief, self-limited • Accompanied by mild-moderate anticholinergic findings • Massive diphenhydramine OD may cause TCA-like cardiotoxicity • Treatment: • Anticonvulsants if needed • Bicarbonate for TCA-like QRS prolongation

19. Isoniazid (INH) • Common TB drug • Marked lactic acidosis • pH 6.8-6.9 common after even 1-2 brief seizures • Treatment of seizures: • Diazepam often effective • Pyridoxine is specific antidote - give 1 gm for each gm OD; 5 gm if dose unknown

20. Pyridoxine for INH overdose (-) (+) Pyridoxal-5- phosphate INH Pyridoxine (Vit B-6) + Glutamic Acid Decarboxylase GABA Glutamate

21. Case • 28 year old man had a seizure and was brought to the ER by a friend • Tox screen (+) for amphetamines • But, he denied amphetamine use • He had borrowed one of his friend’s pills, which had been obtained from…

23. Zyban™ • Bupropion • Antidepressant = Wellbutrin™ • Well-known cause of seizures • Can occur even at therapeutic antidepressant doses • Can give false-positive result for amphetamines on tox screening

24. Other antidepressants & etc • All the SSRI’s have been associated with seizures in OD • - Venlafaxine • - Fluoxetine • - Citalopram • Newer and older antipsychotics also

25. New Anticonvulsants Causing Seizures • Lamotrigine • Topiramate • Tiagabine • One case report of status epilepticus resistant to benzos, controlled with propofol • Haney ST et al: Internet J Toxicol 2004, 1(2)

26. Case of the hot taquitos • 5 people with new onset seizures • None had prior sz • Utox negative • All had eaten taquitos purchased from a convenience store

27. Case (cont.) • Leftover taquitos were found to contain the pesticide endrin • Organochlorine pesticides • DDT • Endrin • Aldrin • Lindane

28. Another case • 36 year old man ingested some Elston Gopher Getter™ Bait • Developed “seizures” (diffuse tonic spasms) but remained awake during and between events

29. Strychnine • Popular poison for thousands of years • Strychnos nux vomica • Not true “seizures” as CNS is minimally affected (until victim is hypoxic) • Spinal cord glycine receptor action • Inhibits inhibitory action of glycine on spinal cord reflex motor response • Similar to tetanus

30. Final “hot” case • 21 yo released from a drug rehab facility for a home visit • Became agitated, combative, shoving his brother, talking nonsense  GM seizure • HR 160/min, T 105.7 F • Skin red, dry • Incontinent

31. Hot dude, cont. • Utox negative • LP: meningitis!!

32. “Rule outs” • “A T O M I C” • A: alcohol withdrawal • T: trauma/tomography • O: overdose • M: metabolic • I: infection • C: carbon monoxide

33. Hyperthermia (Temp > 40 C) Heat Production Heat Dissipation Basal metabolism Vasodilation CORE TEMP Muscle activity Conduction/Radiation Ambient temperature Evaporation

34. Drug-Induced Hyperthermia - Mechanisms • Muscle hyperactivity: • Cocaine, Amphetamines • Seizures • Reduced sweating: • Anticholinergics • Increased cellular metabolism: • Salicylates • Dintrophenol

35. Complications of Hyperthermia • Hypotension due to vasodilation, sweating, MI • Brain injury from hypotension, hyperthermia, prolonged seizures, hypoxemia • Coagulopathy due to reduced production of clotting factors, and endothelial wall damage • Rhabdomyolysis caused by muscle hyperactivity, hyperthermia, and reduced muscle blood flow • Renal failure from myoglobinuria, hyperthermia

36. Malignant Hyperthermia • Specific disorder of muscle cell • Most commonly associated with general anesthetics (succinylcholine, halothane) • Rigidity, acidosis, hyperthermia • Specific treatment: • Dantrolene • NM paralysis is not effective

37. Neuroleptic Malignant Syndrome • Associated with chronic antipsychotic use (haloperidol, etc.) • Mechanism is central dopamine blockade • Lead-pipe rigidity, diaphoresis, altered mental status, hyperthermia • Specific treatment: • Bromocriptine? • NM paralysis

38. Serotonin Syndrome • SSRI OD or added to MAO inhibitors: • also: MAOI + Meperidine, Trazodone, Tryptophan, Dextromethorphan, others • Confusion, agitation, increased muscle tone (especially lower extr. clonus) • Specific Treatment: • Cyproheptadine? • NM paralysis

39. Anticholinergic Syndrome • Dilated pupils, tachycardia, decreased bowel sounds, urinary retention • Agitation, delirium, or coma • Muscular twitching common • Absent sweating • Treatment: • Physostigmine? (with caution) • Usual cooling measures

40. Management of Hyperthermia • Act quickly to prevent brain damage/death • Protect airway, assist ventilation • Give supplemental oxygen • IV fluid bolus if hypotensive ABC’s Dextrose if needed based on bedside BS Anticonvulsants if seizures are present

41. Management of Hyperthermia (cont.) Rapid external cooling • Strip clothing • Tepid sponging + fanning • Do not use ice packs T > 106 F or persistent sz or muscle rigidity • Most rapidly effective Rx • Use non-depolarizing agent Neuromuscular paralysis

42. Management of Hyperthermia (cont.) persistent muscle rigidity despite NM paralysis Suspect muscle defect (malignant hyperthermia) • Give Dantrolene • Continue external cooling

43. Evaporative Cooling Weiner JS, Khogali M: A physiological body-cooling unit for treatment of heat stroke. Lancet. 1980;1(8167):507-9.

44. Some References • Alvarez FG, Guntupalli KK. Isoniazid overdose: four case reports and review of the literature. Intensive Care Med. 1995 Aug;21(8):641-4. • Beaubien A et al. Antagonism of imipramine poisoning by anticonvulsants in the rat. Toxicol Appl Pharmacol 1976;38:1–6 • Blake KV et al: Relative efficacy of phenytoin and phenobarbital for the prevention of theophylline-induced seizures in mice. Ann Emerg Med. 1988 Oct;17(10):1024-8 • Centers for Disease Control (CDC). Endrin poisoning associated with taquito ingestion--California. MMWR Morb Mortal Wkly Rep. 1989 May 19;38(19):345-7. • Clark RF, Vance MV. Massive diphenhydramine poisoning resulting in a wide-complex tachycardia: successful treatment with sodium bicarbonate. • Haney ST et al: Tiagabine-induced status epilepticus responds to propofol. Internet J Toxicol 2004, 1(2) • Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43:483-488 • Lowenstein DH & Alldredge BK: Status epilepticus. NEJM 1998; 338:970 • Mayron R, Ruiz E. Phenytoin:does it reverse tricyclic antidepressant induced cardiac conduction abnormalities? Ann Emerg Med 1986;15:876–80 • Olson KR, Benowitz NL. Environmental and drug-induced hyperthermia. Pathophysiology, recognition, and management. Emerg Med Clin North Am. 1984 Aug;2(3):459-74. • Olson KR et al. Seizures associated with poisoning and drug overdose. Am J Emerg Med. 1994 May;12(3):392-5. • Stecker MM et al. Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 1998;39:18-26 • Yarbrough BE, Wood JP. Isoniazid overdose treated with high-dose pyridoxine. Ann Emerg Med. 1983 May;12(5):303-5. • Wood DM et al: Case report: Survival after deliberate strychnine self-poisoning, with toxicokinetic data. it Care. 2002; 6(5): 456–459 Ann Emerg Med. 1992 Mar;21(3):318-21.