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Cyclic Antidepressants: it’s all good.

Cyclic Antidepressants: it’s all good. Toxicology Core Rounds Jan 15, 2004 Rob Hall PGY4 Randall Berlin ( toxicologist extrodinare !). Objectives. Walk through a case……………… We need to know the presentation, diagnosis, disposition, and general management of TCA overdoses INSIDE and OUT!

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Cyclic Antidepressants: it’s all good.

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  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……………… • 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

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

  4. How would you prepare? 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 Case of the day!

  5. Case of the day! • 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 • 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?

  6. 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! Case of the day!

  7. Case of the day:What is the role of gastric 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 • 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 • Rapidly absorbed • Peak levels 6-8hrs • Highly lipophilic thus rapid delivery to heart, brain • Has relevance to when patient is “medically cleared”

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

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

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

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

  13. Flumazenil • Why is flumazenil contraindicated in a patient with BZD + TCA overdose? • Will precipitate seizures ----> acidosis, cardiac toxicity, death, call CMPA • 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 • Block acetylcholinesterase, increases Ach at synapse, initially used to treat agitated delirium • Results • Brady, asystolic arrests • Do not use

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

  16. TCAs and Hypotension • Fluids, go early to pressors • Norepinephrine is the pressor of choice • 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?

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

  18. TCAs and Hypotension TCAs block alpha receptors

  19. TCAs and Hypotension • NO controlled human studies comparing pressors for hypotension • Animal studies are conflicting • 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! • ECMO • Cardiac bypass • IABP

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

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

  23. TCA toxicity and the ECG • 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????

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

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

  27. TCA toxicity and the ECG • 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?

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

  29. QRS Width • Liebelt. Ann Emerg Med 1995. • Prospective cohort of 79 TCA overdoses • Used outcomes of seizures or arrythmias • Sensitivity Specificity • QRS > 100 msec 82% 58% • QRS > 120 msec 59% 87%

  30. Tall R and R/S ratio in aVR • Liebelt. Ann Emerg Med 1995. • Tall R wave and R/S ratio > 0.7 in aVR was • Used outcomes of seizures or arrythmias • Sensitivity Specificity • QRS > 100 msec 82% 58% • QRS > 120 msec 59% 87% • R > 3mm in aVR 81% 72% • R/S > 0.7 in aVR 75% 77%

  31. Terminal 40 msec right axis • 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. 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 ECG and Toxicology

  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 • Dose = 1-2 mEq/kg iv bolus q10 min prn • End points = no indication, pH 7.50 - 7.55 • Monitor response with repeat ECGs and ABGs

  36. TCA and Sodium Bicarbonate: How does it work? • 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 • 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 • 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 • Wide complex tachycardia • 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 • 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? • 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 • 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?

  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?

  44. Hypertonic Saline • 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 • Theoretical benefit but not adequately studied • Ford 2001 • Not mentioned

  46. Hypertonic Saline • 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

  47. Hypertonic Saline • 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

  49. Hypertonic Saline • 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 • BP 0 3 5 10 30 min • 78/42 85/50 104/60 112/68 115/68 • QRS • 136 msec 120msec

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