1. Controversies in the management of TCA toxicity: bicarb and then what?? Rob Hall MD Case of the week November 28, 2003

2. Case of the week TCA case from this week TCA case from this week

3. ECG

4. Treatment Intubation, Gastric Lavage Intubation, Gastric Lavage NS 2 L bolus NS 2 L bolus Sodium Bicarbonate 2 amps iv bolus followed by bicarb drip: repeat boluses bicarb (total 6 amps) Sodium Bicarbonate 2 amps iv bolus followed by bicarb drip: repeat boluses bicarb (total 6 amps) What if there is no response to the above treatment despite pH being in target 7.50 – 7.55? What if there is no response to the above treatment despite pH being in target 7.50 – 7.55?

5. Objectives Is there any role for Hypertonic Saline or Phenytoin in the management of TCA overdoses? Is there any role for Hypertonic Saline or Phenytoin in the management of TCA overdoses?

6. Hypertonic Saline Theory Theory –Na+ load to overcome Na+ channel blockade by the TCA –Na+ load without the adverse effects of alkalosis as seen with sodium bicarbonate –Able to give a lot more Na+ than with normal saline »Normal Saline: 0.9% NaCl »Hypertonic Saline: 7.5% NaCl

7. Hypertonic Saline Goldfrank 2003 Goldfrank 2003 –Theoretical benefit but not adequately studied Ford 2001 Ford 2001 –Not mentioned

8. Hypertonic Saline Hoegholm. Clinical Toxicology. 1991 Hoegholm. Clinical Toxicology. 1991 –Case Report of TCA overdose –Hypotensive, wide QRS, recurrent VT and VF –Intubated, lavaged –Sodium bicarb, lidocaine, dopamine, and hyperventilation (how much of each???) –Sodium chloride 170 mEq given over 5 min »Immediate narrowing of the QRS, increased BP, no further VT or VF One case report, not much for details, amount of bicarb could have been more important One case report, not much for details, amount of bicarb could have been more important

9. Hypertonic Saline McCabe. Acad Emerg Med. 1994 McCabe. Acad Emerg Med. 1994 –Swine model of TCA toxicity –Nortiptyline until SBP 50% of baseline and QRS > 120 msec –Randomized groups »10 ml/kg of 7.5% hypertonic saline + 6% dextran »10 ml/kg of 0.9% normal saline –NO bicarbonate treatment arm

10. Hypertonic Saline: McCabe. Acad Emerg Med. 1994 BP 10 min after tx QRS 10 min after tx Survival at one hour HypertonicSaline 115 +/- 12 88 +/- 13 4/5 NormalSaline 45 +/- 8 180 +/- 8 0/5

11. Hypertonic Saline McKinney. Ann Emerg Med. 2003 McKinney. Ann Emerg Med. 2003 –Case Report –29 yo female ingested 8 gm of nortryptylline –Coma, BP 80/40, QRS 124 msec –Intubated, lavaged, hyperventilation, 3L normal saline, dopamine 20 ug/kg/min, norepinephrine 22 ug/min, 4 amps bolus sodium bicarb, pH 7.54 –QRS 135 msec –Given 200 ml of hypertonic saline (7.5%)

12. Hypertonic Saline McKinney. Ann Emerg Med. 2003 McKinney. Ann Emerg Med. 2003 –BP 03510 30 min 78/4285/50104/60112/68115/68 78/4285/50104/60112/68115/68 –QRS 136 msec120msec 136 msec120msec

13. Hypertonic Saline: other case reports Dolara. J Clin Tox Dolara. J Clin Tox –No bicarb given before H.S., physostigmine used Seitz. Dtsch Med Wochesnschr Seitz. Dtsch Med Wochesnschr –?german

14. Hypertonic Saline McCabe. Ann Emerg Med 1998 McCabe. Ann Emerg Med 1998 –Swine model (N=24) –Nortyptyline until SBP 120 msec –Group 1 = D5W 10 ml/kg –Group 2 = Hypertonic Saline 7.5% 10 ml/kg –Group 3 = Sodium Bicarb 8.4% 3mEq/kg –Group 4 = Hyperventilation to target pH 7.5-7.6 and D5W 10 ml/kg Hypertonic saline looked pretty good!!  Hypertonic saline looked pretty good!! 

15. Hypertonic Saline: McCabe. Ann Emerg Med 1998 QRSBeforetxQRS After tx SBPBeforetx SBP After txSurvival D5WN=614814456541/6 HTSN=615880571345/6 BicarbN=615610552852/6 HyperVN=614612550601/6

16. Hypertonic Saline: Conclusions There is animal evidence to support the use of hypertonic saline after other therapies have been maximized There is animal evidence to support the use of hypertonic saline after other therapies have been maximized Human evidence is limited to case reports Human evidence is limited to case reports Consider Hypertonic Saline for TCA toxicity if sodium bicarbonate ineffective and pH of 7.50-7.55 has been reached Consider Hypertonic Saline for TCA toxicity if sodium bicarbonate ineffective and pH of 7.50-7.55 has been reached

17. Hypertonic Saline: Conclusions Should Hypertonic Saline be used instead of sodium bicarbonate? Should Hypertonic Saline be used instead of sodium bicarbonate? NO NO –Lots of evidence for sodium bicarb and not much for hypertonic saline –Needs more study

18. What about phenytoin?

19. Phenytoin Theory: increases AV conduction thus enhances delivery of supraventricular impulses and suppresses ventricular rhythms; also decreases re-entry Theory: increases AV conduction thus enhances delivery of supraventricular impulses and suppresses ventricular rhythms; also decreases re-entry BUT isn’t phenytoin a Na+ channel blocker ---------------- could make things worse! BUT isn’t phenytoin a Na+ channel blocker ---------------- could make things worse!

20. Phenytoin Goldfranks 2003 Goldfranks 2003 –Not recommended Ford 2001 Ford 2001 –Not even discussed So what evidence is there? So what evidence is there?

21. Phenytoin Callaham. J Pharmacol Exp Ther. 1988 Callaham. J Pharmacol Exp Ther. 1988 –Dog model –Control group: amitriptyline infusion –Experimental group: phenytoin loading before amitriptyline infusion –Results »No differences in physiologic parameters »Ventricular tachycardia dramatically increased in phenytoin group

22. Phenytoin Kulig. Vet Hum Toxicol 1984 (abstract) Kulig. Vet Hum Toxicol 1984 (abstract) –Canine model –Amitiptyline until QRS 160 msec –Phenytoin pretreatment and rescue –No bicarb, no pressors –Phenytoin prevented ventricular arrythmias only when given as pretreatment –Details not provided

23. Phenytoin Mayron. Ann Emerg Med 1986. Mayron. Ann Emerg Med 1986. –Rabbit model –Amitripyline –Looked at “prophylaxis” and “rescue” treatment with phenytoin –Outcome measure was dose of amitriptyline necessary to cause wide QRS/arrythmia or death –NO BP data –Specifics of QRS width not presented

24. Phenytoin Mayron. Ann Emerg Med 1986. Mayron. Ann Emerg Med 1986. –Phenytoin had NO effect on the amitriptyline dose required to cause “toxicity” »No pretreatment: mean 11.4 mg/kg (2 – 39range) »Phenytoin pretx: mean 10.0 mg/kg (2.8-23.3 range) –Phenytoin had NO effect on the amitriptyline dose required for lethality –Phenytoin rescue dose after toxicity had an effect in 2/12 (narrowed the QRS) and no effect in 10/12 Concluded: no effect with pretreatment or rescue Concluded: no effect with pretreatment or rescue

25. Phenytoin Cantrill. J Emerg Med. 1983 Cantrill. J Emerg Med. 1983 –Case Report –33yo female with amitripyline overdose –BP 70, QRS 170 msec, comatose –Intubated, lavaged, charcoal, bicarb drip –Phenytoin given –QRS narrowed to 90 msec on an ECG 30 minutes later Concluded: Phenytoin is the drug of choice for TCA toxicity Concluded: Phenytoin is the drug of choice for TCA toxicity

26. Phenytoin Several other case reports exist in the literature Several other case reports exist in the literature

27. Phenytoin Hagerman. Ann Emerg Med. 1981 Hagerman. Ann Emerg Med. 1981 –10 patients with TCA poisoning –9/10 had wide QRS, 1/10 had normal QRS but wide PR interval –Phenytoin dose was 5 – 7 mg/kg –Don’t mention the use of bicarb, hyperventilation, normal or hypertonic saline –Note: there is NO control group

28. Phenytoin Hagerman. Ann Emerg Med. 1981 Hagerman. Ann Emerg Med. 1981 – Pre TreatmentPost Treatment –Mean QRS 130 +/-7106 +/-6 –Range QRS100 – 16080 – 140 –Mean PR204 +/- 12175 +/- 5 Concluded that phenytoin was useful Concluded that phenytoin was useful

29. Phenytoin: Conclusions Animal Data is conflicting Animal Data is conflicting Human data limited to case reports and case series Human data limited to case reports and case series No controlled human data exists No controlled human data exists Bicarbonate is the treatment of choice for QRS conduction abnormalities Bicarbonate is the treatment of choice for QRS conduction abnormalities Effect of phenytoin in cases refractory to bicarb essentially unknown Effect of phenytoin in cases refractory to bicarb essentially unknown –Hypertonic saline seems like a better choice

30. What other options are there? LidocaineMagnesiumPropranolol Topics for another day ………

31. Questions?Comments?