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					 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

   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



     California Poison Control System – San Francisco Division
                         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

    California Poison Control System – San Francisco Division
                           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:


    California Poison Control System – San Francisco Division
California Poison Control System – San Francisco Division
                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.


     California Poison Control System – San Francisco Division
California Poison Control System – San Francisco Division
                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.




     California Poison Control System – San Francisco Division
Complications of Drug-Induced Seizures

 • Hypoxemia
 • Shock                              Brain Damage
 • Hyperthermia
 • Rhabdomyolysis
 • Metabolic acidosis
 • Other drug-specific complications


      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




     California Poison Control System – San Francisco Division
            35%

            30%

            25%
Calls to the
SF Poison    20%                           1981
Center                                     1989
about drug- 15%                            2006
related
seizures     10%

             5%

             0%
                 As




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            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

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




California Poison Control System – San Francisco Division
Anticonvulsants for Drug-Induced Seizures


Benzodiazepine                             Specific antidote,
                                              if available


Phenytoin?


Phenobarbital


Pentobarbital, Propofol, or Midazolam

     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

       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




       California Poison Control System – San Francisco Division
                           Case

16 year old took 200 Benadryl™ tablets
Agitation, somnolence, seizure
Wide complex QRS




    California Poison Control System – San Francisco Division
                   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




      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


       California Poison Control System – San Francisco Division
      Pyridoxine for INH overdose

          ( -)    Pyridoxal-5-      (+)
INH                                        Pyridoxine (Vit B-6)
                  phosphate
                        +
                 Glutamic Acid
                 Decarboxylase



      Glutamate                               GABA



      California Poison Control System – San Francisco Division
                            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…



     California Poison Control System – San Francisco Division
California Poison Control System – San Francisco Division
                          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




      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



    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)




       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



    California Poison Control System – San Francisco Division
                      Case (cont.)

Leftover taquitos were found to contain
 the pesticide endrin
Organochlorine pesticides
   DDT
   Endrin

   Aldrin

   Lindane




      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




    California Poison Control System – San Francisco Division
                        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




       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

     California Poison Control System – San Francisco Division
                  Hot dude, cont.

Utox negative


LP: meningitis!!




     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

     California Poison Control System – San Francisco Division
        Hyperthermia (Temp > 40 C)

Heat Production                                Heat Dissipation

Basal metabolism                               Vasodilation

                             CORE
Muscle activity              TEMP              Conduction/Radiation


Ambient temperature                            Evaporation



        California Poison Control System – San Francisco Division
Drug-Induced Hyperthermia - Mechanisms

• Muscle hyperactivity:
   Cocaine, Amphetamines
   Seizures


• Reduced sweating:
     Anticholinergics
• Increased cellular metabolism:
   Salicylates
   Dintrophenol



       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

      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




      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



      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

       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




      California Poison Control System – San Francisco Division
     Management of Hyperthermia

Act quickly to prevent brain damage/death
         • Protect airway, assist ventilation
ABC’s    • Give supplemental oxygen
         • IV fluid bolus if hypotensive

Dextrose      if needed based on bedside BS


Anticonvulsants if seizures are present


      California Poison Control System – San Francisco Division
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



Neuromuscular paralysis • Most rapidly effective Rx
                                     • Use non-depolarizing agent




      California Poison Control System – San Francisco Division
Management of Hyperthermia (cont.)

persistent muscle rigidity
  despite NM paralysis



 Suspect muscle defect                  • Give Dantrolene
(malignant hyperthermia)                • Continue external cooling




       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.



                  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.




                         California Poison Control System – San Francisco Division

				
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