1. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division OutlineOutline 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. California Poison Control System – San Francisco Division CaseCase 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:

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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.

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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. California Poison Control System – San Francisco Division Complications of Drug-Induced Seizures Hypoxemia ShockBrain Damage Hyperthermia Rhabdomyolysis Metabolic acidosis Other drug-specific complications

10. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division Calls to the SF Poison Center about drug- related seizures

12. California Poison Control System – San Francisco Division Treatment of Drug-Induced Seizures ABCD’s:  Airway  Breathing  Circulation  Dextrose Anticonvulsants  Specific antidote, if available Cooling measures

13. California Poison Control System – San Francisco Division Antiepileptic-Drug Therapy for Status Epilepticus. From: Lowenstein DH & Alldredge BK: NEJM 1998; 338:970

14. California Poison Control System – San Francisco Division Anticonvulsants for Drug-Induced Seizures Benzodiazepine Phenobarbital Phenytoin? Pentobarbital, Propofol, or Midazolam Specific antidote, if available

15. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division CaseCase 16 year old took 200 Benadryl™ tablets Agitation, somnolence, seizure Wide complex QRS

18. California Poison Control System – San Francisco Division AntihistaminesAntihistamines 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. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division Pyridoxine for INH overdose Glutamate GABA Pyridoxal-5- phosphate Glutamic Acid Decarboxylase + INH (-)(-) Pyridoxine (Vit B-6) (+)

21. California Poison Control System – San Francisco Division CaseCase 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…

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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. California Poison Control System – San Francisco Division Other antidepressants & etc All the SSRI’s have been associated with seizures in OD - Venlafaxine - Fluoxetine - Citalopram Newer and older antipsychotics also

25. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division Case (cont.) Leftover taquitos were found to contain the pesticide endrin Organochlorine pesticides  DDT  Endrin  Aldrin  Lindane

28. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division StrychnineStrychnine 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. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division Hot dude, cont. Utox negative LP: meningitis!!

32. California Poison Control System – San Francisco Division “Rule outs” “A T O M I C” A: alcohol withdrawal T: trauma/tomography O: overdose M: metabolic I: infection C: carbon monoxide

33. California Poison Control System – San Francisco Division Hyperthermia (Temp > 40 C) Heat Production Heat Dissipation Basal metabolism Muscle activity Ambient temperature CORE TEMP Vasodilation Conduction/Radiation Evaporation

34. California Poison Control System – San Francisco Division Drug-Induced Hyperthermia - Mechanisms Muscle hyperactivity:  Cocaine, Amphetamines  Seizures Reduced sweating:  Anticholinergics Increased cellular metabolism:  Salicylates  Dintrophenol

35. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division 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. California Poison Control System – San Francisco Division Management of Hyperthermia Act quickly to prevent brain damage/death ABC’s Dextrose Protect airway, assist ventilation Give supplemental oxygen IV fluid bolus if hypotensive if needed based on bedside BS Anticonvulsants if seizures are present

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

42. California Poison Control System – San Francisco Division Management of Hyperthermia (cont.) Suspect muscle defect (malignant hyperthermia) Suspect muscle defect (malignant hyperthermia) persistent muscle rigidity despite NM paralysis Give Dantrolene Continue external cooling

43. California Poison Control System – San Francisco Division Evaporative Cooling Weiner JS, Khogali M: A physiological body-cooling unit for treatment of heat stroke. Lancet. 1980;1(8167):507-9.

44. California Poison Control System – San Francisco Division Some References 1.Alvarez FG, Guntupalli KK. Isoniazid overdose: four case reports and review of the literature. Intensive Care Med. 1995 Aug;21(8):641-4. 2.Beaubien A et al. Antagonism of imipramine poisoning by anticonvulsants in the rat. Toxicol Appl Pharmacol 1976;38:1–6 3.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 4.Centers for Disease Control (CDC). Endrin poisoning associated with taquito ingestion--California. MMWR Morb Mortal Wkly Rep. 1989 May 19;38(19):345-7. 5.Clark RF, Vance MV. Massive diphenhydramine poisoning resulting in a wide-complex tachycardia: successful treatment with sodium bicarbonate. 6.Haney ST et al: Tiagabine-induced status epilepticus responds to propofol. Internet J Toxicol 2004, 1(2) 7.Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43:483-488 8.Lowenstein DH & Alldredge BK: Status epilepticus. NEJM 1998; 338:970 9.Mayron R, Ruiz E. Phenytoin:does it reverse tricyclic antidepressant induced cardiac conduction abnormalities? Ann Emerg Med 1986;15:876–80 10.Olson KR, Benowitz NL. Environmental and drug-induced hyperthermia. Pathophysiology, recognition, and management. Emerg Med Clin North Am. 1984 Aug;2(3):459-74. 11.Olson KR et al. Seizures associated with poisoning and drug overdose. Am J Emerg Med. 1994 May;12(3):392-5. 12.Stecker MM et al. Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 1998;39:18-26 13.Yarbrough BE, Wood JP. Isoniazid overdose treated with high-dose pyridoxine. Ann Emerg Med. 1983 May;12(5):303-5. 14.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.