1. Cyclic Antidepressants: it’s all good. Toxicology Core Rounds Jan 15, 2004 Rob Hall PGY4 Randall Berlin ( toxicologist extrodinare!)

2. Objectives Walk through a case……………… Walk through a case……………… We need to know the presentation, diagnosis, disposition, and general management of TCA overdoses INSIDE and OUT! We need to know the presentation, diagnosis, disposition, and general management of TCA overdoses INSIDE and OUT! Specifically, we will focus on the complications of TCA overdoses Specifically, we will focus on the complications of TCA overdoses

3. Case of the day! EMS patches in ……… EMS patches in ……… ETA 10 min ETA 10 min 42yo female 42yo female Amitriptyline overdose Amitriptyline overdose Decreased LOC, hypotensive, tachycardic Decreased LOC, hypotensive, tachycardic

4. Case of the day! How would you prepare? How would you prepare? List four complications of TCA overdose that you should be prepared for? List four complications of TCA overdose that you should be prepared for? Resusc room, be ready to intubate, have ECG there, approach will be ABCs/monitor/iv/etc Four predictable complications –Hypotension –Wide complex tach –Seizures –Decreased LOC

5. Case of the day! EMS arrives EMS arrives Story = 42yo female, previous overdoses, found on floor in bathroom, amitriptyline bottle empty, estimated time since ingestion is 1.5 hours ago, no coingestants known Story = 42yo female, previous overdoses, found on floor in bathroom, amitriptyline bottle empty, estimated time since ingestion is 1.5 hours ago, no coingestants known T 38.1, HR 120, BP 85/60, C/S normal, sat 95% NRB, RR 15, GCS E1V2M4, dry red skin, no bowel sounds, motor X 4, pupils 5mm, hyporeflexic, no clonus, no rigidity, no signs of trauma T 38.1, HR 120, BP 85/60, C/S normal, sat 95% NRB, RR 15, GCS E1V2M4, dry red skin, no bowel sounds, motor X 4, pupils 5mm, hyporeflexic, no clonus, no rigidity, no signs of trauma What’s your management? What’s your management?

6. Case of the day! How would you intubate? How would you intubate? PEARLS of intubating the TCA overdose –Preoxygenate –Hyperventilate before you push drugs –AVOID resp acidosis –Give a bolus dose of bicarb with your pretreatment –Best intubator!

7. Case of the day: What is the role of gastric lavage? Evidence against lavage Evidence against lavage –Pond 1995: Gastric lavage can be omitted from the treatment protocol for acute overdoses –Merigan 1990: No benefit of gastric lavage –Kulig 1985: No benefit of gastric lavage unless performed < 1hr All three studies either excluded the critically ill or were underpowered to evaluate that subgroup All three studies either excluded the critically ill or were underpowered to evaluate that subgroup This patient SHOULD be lavaged, why? This patient SHOULD be lavaged, why? –Potentially lethal overdose, no good antidote, delayed gastric emptying b/c of anticholinergic effect

8. Case of the day: When do you expect toxicity? TCA overdoses will develop toxicity within 6 hours TCA overdoses will develop toxicity within 6 hours –Rapidly absorbed –Peak levels 6-8hrs –Highly lipophilic thus rapid delivery to heart, brain –Has relevance to when patient is “medically cleared”

9. TCA mechanisms of Toxicity Anti-cholinergic Anti-cholinergic Na+ channel blockade Na+ channel blockade K+ channel blockade K+ channel blockade Alpha 1 antagonism Alpha 1 antagonism Serotonin and NE reuptake inhibition Serotonin and NE reuptake inhibition GABA antagonism, etc GABA antagonism, etc Anticholinergic toxidrome Wide QRS Prolonged QT Hypotension Seritonin syndrome Seizures

10. Case of the day! After you intubate, patient has a generalized seizure After you intubate, patient has a generalized seizure Why? Why? –Anticholinergic effect –Gaba antagonism –Hypotension –Exact mechanism unknown! Why are seizures so bad? Why are seizures so bad? Management? Management?

11. TCA overdoses and seizures Seizure Acidosis Cardiac toxicity Shock DEATH

12. TCA toxicity and Seizures Management Management –First line: benzodiazepines –Second line: phenobarbital –Third line agents: propofol –Avoid dilantin (Na+ channel blockade) Should you give bicarb? Yes Should you give bicarb? Yes

13. Flumazenil Why is flumazenil contraindicated in a patient with BZD + TCA overdose? Why is flumazenil contraindicated in a patient with BZD + TCA overdose? Will precipitate seizures ----> acidosis, cardiac toxicity, death, call CMPA Will precipitate seizures ----> acidosis, cardiac toxicity, death, call CMPA Flumazenil is generally not indicated in the overdose setting for this reason Flumazenil is generally not indicated in the overdose setting for this reason –One exception may be a pediatric ingestion of BZD with absolutely no suspicion of coingestant –OK with therapeutic use

14. Any role for physostigmine in TCA overdoses?? Theory Theory –Block acetylcholinesterase, increases Ach at synapse, initially used to treat agitated delirium Results Results –Brady, asystolic arrests –Do not use

15. Case of the day! HR 120, BP 80/50 HR 120, BP 80/50 What is your management? What is your management? Why? Why?

16. TCAs and Hypotension Fluids, go early to pressors Fluids, go early to pressors Norepinephrine is the pressor of choice Norepinephrine is the pressor of choice If you are going to use dopamine, titrate up to alpha range (15 - 20 ug/kg/min) quickly If you are going to use dopamine, titrate up to alpha range (15 - 20 ug/kg/min) quickly Why is norepinephrine better theoretically than dopamine? Why is norepinephrine better theoretically than dopamine?

17. TCAs and Hypotension How does dopamine work? –Dopamine is a precursor to norepinephrine –Dopamine stimulates the release of stored norepinephrine –Dopamine stimulates adrenergic receptors

18. TCAs and Hypotension TCAs block alpha receptors

19. TCAs and Hypotension NO controlled human studies comparing pressors for hypotension NO controlled human studies comparing pressors for hypotension Animal studies are conflicting Animal studies are conflicting Teba. Am J Emerg Med 1988 Teba. Am J Emerg Med 1988 –Best human data –Retrospective review –26 hypotensive TCA overdoses –Better response rates to norepi than dopamine

20. TCAs and Hypotension Extreme options! Extreme options! –ECMO –Cardiac bypass –IABP

21. Case of the day! Interpretation? Will she have a bad outcome ?

22. TCA toxicity and the ECG Sinus tachycardia Sinus tachycardia Prolonged QT Prolonged QT Wide QRS Wide QRS Wide complex tachycardia Wide complex tachycardia –SVT with aberrancy –Vtach –Vfib Right BBB Right BBB Tall R wave in aVR Tall R wave in aVR R/S ratio in aVR > R/S ratio in aVR > Terminal 40 msec right axis Terminal 40 msec right axis

23. TCA toxicity and the ECG Tall R in aVR, R/S ratio in aVR > 0.7 Tall R in aVR, R/S ratio in aVR > 0.7

24. TCA toxicity and the ECG Terminal 40 msec right axis: what does that mean???? Terminal 40 msec right axis: what does that mean????

25. TCA toxicity and the ECG Terminal 40 msec right axis Terminal 40 msec right axis –What does a normal aVR look like? –Why a right axis?

26. TCA toxicity and the ECG Terminal 40 msec right axis: the poor man’s way –S in lead I –R in aVR

27. TCA toxicity and the ECG What ECG features are predictive of TCA toxicity? What ECG features are predictive of TCA toxicity? –QRS width –Tall R in aVR –R/S ratio in aVR –Terminal 40 msec right axis Which are the most sensitive/specific for TCA toxicity? Which are the most sensitive/specific for TCA toxicity?

28. QRS width Boehnert. NEJM 1985 Boehnert. NEJM 1985 –QRS > 100msec predictive of complications –33% had seizures –14% had ventricular dysrhythmias

29. QRS Width Liebelt. Ann Emerg Med 1995. Liebelt. Ann Emerg Med 1995. –Prospective cohort of 79 TCA overdoses –Used outcomes of seizures or arrythmias – SensitivitySpecificity –QRS > 100 msec82%58% –QRS > 120 msec59%87%

30. Tall R and R/S ratio in aVR Liebelt. Ann Emerg Med 1995. Liebelt. Ann Emerg Med 1995. –Tall R wave and R/S ratio > 0.7 in aVR was –Used outcomes of seizures or arrythmias – SensitivitySpecificity –QRS > 100 msec82%58% –QRS > 120 msec59%87% –R > 3mm in aVR81%72% –R/S > 0.7 in aVR75%77%

31. Terminal 40 msec right axis Wolfe. Ann Emerg Med 1995 Wolfe. Ann Emerg Med 1995 –Retrospective chart review –Only looked at symptomatic TCA overdoses –Outcome: seizure, arrythmia, vital sign changes, respiratory or level of consciousnous changes ------------------pretty vague!! –Terminal 40 msec right axis »Sensitivity 83% »Specificity 63%

32. ICU resident called to psych ward STAT (this isn’t going to be good!): What is the differential dx of wide QRS in toxicology?

33. ECG and Toxicology Wide QRS (Na+ channel blockade) Wide QRS (Na+ channel blockade) –TCAs –Antihistamines (gravol, benadryl) –Amphetamines –Cocaine –Carbemazepine –Chloroquine –Procainamide –Propoxyphene –Propranolol –Disopiramide –Quinine, quinidine Prolonged QTc –TCA –Haldol, Mellaril, etc –Ia: pdq –Ic: flec, ec –III: amio, sotalol –Celexa –Erythromycin, Terfenidine, astemizole –Lytes: Ca, Mg, K

34. Case of the day! What do you want to do now?

35. TCA and Sodium Bicarbonate Sodium Bicarbonate is the treatment of choice for cardiac toxicity Sodium Bicarbonate is the treatment of choice for cardiac toxicity Dose = 1-2 mEq/kg iv bolus q10 min prn Dose = 1-2 mEq/kg iv bolus q10 min prn End points = no indication, pH 7.50 - 7.55 End points = no indication, pH 7.50 - 7.55 Monitor response with repeat ECGs and ABGs Monitor response with repeat ECGs and ABGs

36. TCA and Sodium Bicarbonate: How does it work? Increases protein binding Increases protein binding –TCAs are albumin bound which is pH sensitive; minor role b/c large Vd and lipophilic thus most TCA is in tissue not serum Alkalosis Alkalosis –TCA binding to the voltage gated sodium channel is pH dependent thus elevating the pH decreases the binding of the TCA molecule to the Na+ channel Sodium loading Sodium loading –Na load with bicarb creates a larger gradient across the Na+ channel

37. TCA and Sodium Bicarbonate: How does it work?

38. TCA and Sodium Bicarbonate: What are the indications? Hypotension Hypotension Wide complex tachycardia Wide complex tachycardia Conduction blocks Conduction blocks –New/unexplained RBBB –R in aVR > 3mm, R/S ratio > 0.7, or terminal 40 msec right axis –QRS > 100 msec (or > 120 msec) »Recommendations vary with source »QRS width related to time from ingestion important ? Seizures ? Seizures –Makes sense to me but isn’t classically listed as an indication for bicarb

39. TCA and Sodium Bicarbonate: Bolus versus infusion ? Boluses are preferred for initial indications: Why? Boluses are preferred for initial indications: Why? –Studies showing effect of bicarb have used a bolus –NOTE: bolus = Na+ load, bicarb drip will increase your pH but is not a large Na+ load –Probably better b/c big Na load with bolus overcomes Na blockade; Na load likely more important than pH change NO controlled human studies to compare repeat boluses vs infusion NO controlled human studies to compare repeat boluses vs infusion Bicarb infusion resonable for patient requiring repeat boluses Bicarb infusion resonable for patient requiring repeat boluses

40. Controversies in the management of wide complex tachycardia with TCA toxicity: bicarb and then what??

41. You have given 3 amps bicarb and the ECG still looks like this. Management?

42. Controversy What if there is no response to the bicarb boluses despite pH being in target 7.50 – 7.55? What if there is no response to the bicarb boluses despite pH being in target 7.50 – 7.55?

43. Controversy Is there any role for Hypertonic Saline, Phenytoin, or Lidocaine, Magnesium, Amiodarone, or Propranolol in the management of wide complex tach in TCA overdoses? Is there any role for Hypertonic Saline, Phenytoin, or Lidocaine, Magnesium, Amiodarone, or Propranolol in the management of wide complex tach in TCA overdoses?

44. 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

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

46. 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

47. 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

48. 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

49. 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%)

50. 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

51. 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!! 

52. 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

53. 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

54. 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

55. What about phenytoin?

56. 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? BUT isn’t phenytoin a Na+ channel blocker? –Different Na+ binding site than TCA –Thought to increase conduction rather than block it although QRS prolongation can occur

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

58. 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

59. 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

60. 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

61. 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

62. 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

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

64. 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

65. 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

66. 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

67. Lidocaine Most commonly recommended antiarrythmic if refractory to bicarb Most commonly recommended antiarrythmic if refractory to bicarb Doesn’t make sense because it is a Na+ channel blocker thus has the potential to worsen the problem Doesn’t make sense because it is a Na+ channel blocker thus has the potential to worsen the problem Case reports are the “best” evidence Case reports are the “best” evidence NO controlled human trials NO controlled human trials Could try it if you are in a bind Could try it if you are in a bind

68. Magnesium Case Reports Case Reports –Citak. Eur J Emerg Med. 2002. Rat Model –Knudsen. CCM 1994. –Norepinephrine pretreatment –Amitriptyline infusion –Waited for Vtach to develop –Got Mg, Lidocaine, or Glucose –Mg: 9/10 converted to sinus tach –Lido: 1/10 converted to sinus tach –Glucose: 1/10 converted to sinus tach

69. What other options are there? Propranolol: few case reports of success, case series of crash and burn hypotension (Foulke. Am J Emerg Med 1986) Amiodarone: not studied

70. Could Fab fragments be the cure for the TCA overdose?? Watch for Fab fragments in the future.

71. PEARL! Anything unique about AMOXAPINE and MAPROTILINE? Anything unique about AMOXAPINE and MAPROTILINE? –Bad, refractory seizures –Less cardiotoxicity

72. Case of the day! ICU resident order serum TCA level and urine TCA screen ------> what do you say? ICU resident order serum TCA level and urine TCA screen ------> what do you say?

73. TCA and lab testing Urine TCA screen Urine TCA screen –Dip stick screen, immunoassay –HORRIBLE specificity thus the lab doesn’t even do it Serum TCA levels –Do NOT correlate with toxicity –False +ves »Benadryl »Gravol »Flexeril »Carbemazepine »Seroquel »Clozapine

74. TCA overdose and disposition Toxicity develops within 6 hrs Toxicity develops within 6 hrs Monitored for 6hrs: NO seizures, hypotension, arrythmias, no bicarb Rx Monitored for 6hrs: NO seizures, hypotension, arrythmias, no bicarb Rx –Can d/c home or to psych ICU for seizures, hypotension, arrythmias, decreased LOC ICU for seizures, hypotension, arrythmias, decreased LOC Telemetry for prolonged QTc Telemetry for prolonged QTc Duration of cardiac monitoring Duration of cardiac monitoring –24hrs after normalization of BP, off alkalinization/antidysrhythmics/pressors

75. ADORA Criteria AntiDepressant Overdose Risk Assessment AntiDepressant Overdose Risk Assessment Foulke. Am J Emerg Med. 1995 Foulke. Am J Emerg Med. 1995 High risk = any of QRS > 100 ms, arrythmia, conduction defect, altered LOC, seizures, resp depression, hypotension High risk = any of QRS > 100 ms, arrythmia, conduction defect, altered LOC, seizures, resp depression, hypotension Prospective study of 67 patients Prospective study of 67 patients Any high risk feature predicted the development of complications (surprise!) Any high risk feature predicted the development of complications (surprise!)

76. Key Points We need to know more about TCA overdoses than anybody (except toxicologist!!) We need to know more about TCA overdoses than anybody (except toxicologist!!) Aggressive decontamination Aggressive decontamination Expect complications Expect complications Be able to manage complications appropriately Be able to manage complications appropriately Know how, why, when, and how much bicarb to give Know how, why, when, and how much bicarb to give Be aware of ECG features of TCA overdose and their predictive value Be aware of ECG features of TCA overdose and their predictive value Have a good approach to monitoring and disposition Have a good approach to monitoring and disposition

77. The end. Questions?Comments?