Case #1
A 30 year old female with a history of Borderline Personality Disorder presents to the emergency department stating that she has taken a large number of pills about 90 minutes ago in a suicide attempt. She says she grabbed a large handful of a mixed variety of pills which included lorazepam, clonazepam, and amitriptyline which she washed down with vodka. She is uncertain how much of each drug she ingested. On examination she is slightly drowsy with slurred speech and has a HR of 100, a BP of 110/ 60, a RR of 18, and she is afebrile. How would you manage this patient?
Case #2
An 18 year old girl was found by her parents after she had ingested the contents of a bottle of 50 mg amitryptyline tablets. There was a suicide note at her side. When the ambulance arrived she was found to be drowsy and lethargic with a pulse of 130 and a blood pressure of 100/ 50. On arrival in the emergency department her pulse was 160, BP 70/40, and respirations 8 per minute. Her pupils were dilated to 8 mm bilaterally, her skin was warm and flushed, and bowel sounds were absent. The patient was immediately placed on a cardiac monitor which initially showed a narrow-complex tachycardia. Intravenous access was initiated. During the course of her physical examination she became progressively more unresponsive and neurological assessment demonstrated coma without any focal neurologic abnormalities. She then had a brief seizure, followed by the development of a wide-complex tachycardia at 150 beats/minute. How should this patient be managed?
Tricyclic antidepressants
In overdoses, Tricyclic Antidepressants exert toxicity by several mechanisms:
They have central and peripheral anticholinergic effects, which although probably not important in terms of morbidity and mortality, serve as useful markers of toxicity as the anticholinergic syndrome ( dilated pupils, dry mucus membranes, tachycardia, absent bowel sounds, urinary retention ) is relatively easy to pick up on physical exam.
They also block alpha receptors peripherally and thus can cause hypotension.
Furthermore, they block neurotransmitter reuptake (norepinephrine, serotonin) at central presynaptic terminals, and this may be the mechanism by which seizures are induced by TCA overdose.
Probably their most important pharmacologic effect in terms of mortality is myocardial sodium channel blockade. TCA’s slow sodium influx into myocardial cells during phase 0 of the action potential leading to intraventricular conduction delays, ventricular dysrhythmias, negative ionotropy, decreased cardiac output, and hypotension. This is similar to the effects of Type 1A antidysrhythmic agents such as quinidine.
The ECG is a helpful tool in terms of diagnosis of TCA overdose and is also helpful in determining who should be admitted for monitoring and who should be treated with sodium bicarbonate. Because of the anticholinergic effects of TCA’s, a sinus tachycardia is expected in mild to moderate overdoses in the absence of co-ingestants that would slow heart rate. By blockade of myocardial sodium channels a progressive QRS prolongation, QT prolongation, and PR prolongation result. Boehnert and Lovejoy have demonstrated that the maximal limb lead QRS duration is prognostic of seizures and cardiac dysrhythmias following acute TCA ingestions. Seizures occurred in 30 % with QRS durations greater than 100 mSec and cardiac dysrhythmias in 50 % with QRS > 160msec. No seizures or cardiac dysrhythmias occurred in patients with QRS durations less than these values. Thus it has been suggested that a QRS duration greater than 100 mSec should be the threshold for the initiation of sodium bicarbonate therapy in TCA overdoses. Patients with a QRS duration less than 100 msec should undergo assessment and stabilization of the ABC’s, cardiac monitoring, and gastric decontamination, but need not be alkalinized with NaHCO3. Furthermore, a rightward axis shift in the terminal 40 msec of the frontal plane QRS vector (terminal R in AvR, S in I, AvL ) along with sinus tachycardia and a prolonged QT , is highly specific and sensitive for the presence of TCA poisoning, but the absence of these findings is not exclusionary. It is not clinically useful or cost-effective to obtain a plasma TCA determination.
Treatment of a suspected TCA overdose begins with assessment and stabilization of airway, breathing, and circulation. If the patient has altered mental status, then naloxone, glucose, and thiamine should be considered. All patients should have cardiac monitoring and iv access instituted and undergo gastric decontaimination. Syrup of Ipecac is contraindicated because of the risk of sudden deterioration with seizures further complicated by the induced vomiting. Severe TCA overdoses should undergo gastric lavage and be given activated charcoal. Giving multiple doses of charcoal over time has been shown to enhance the rate of drug elimination.
Sodium bicarbonate induced alkalinization of the serum uncouples the drug from the myocardial sodium channels. Furthermore, the sodium load itself may help to overcome the toxicity due to sodium channel blockade. NaHCO3 has been demonstrated to be superior to antidysrhythmics for the treatment of TCA induced ventricular dysrhythmias. If the QRS duration is greater than 100 mSec, or ventricular dysrhythmias are present, a bolus of 1 - 2 mEq/Kg should be given followed by 3 amps ( 132 mEq ) in 1 L of D5W at 150 - 200 cc/hr. The aim is to maintain arterial pH 7.5 to 7.55.
Hypotension should be treated with crystalloid fluids, and alpha-agonists such as norepinephrine if necessary. Seizures must be treated promptly to avoid lactic acidosis which would increase cardiac toxicity. Seizures are due to complex interactions in central serotonergic, cholinergic, and adrenergic neurotransmitters, along with inhibition of the chloride ionophore of GABA receptor complex. They are best treated with benzodiazepines, barbituates, and alkalinization with NaHCO3. Flumazenil should be avoided in suspected TCA overdoses because of numerous case reports of seizure induction with this drug. Dilantin is no longer recommended due to limited efficacy, and a prodysrhythmic effect demonstrated in a dog model.
All patients with suspected TCA overdoses should be observed for at least 6 hours. If a life threatening event is going to occur, it should occur within the first 6 hours of hospitalization, and most often within the first two hours of admission to the emergency department. If the patient has no anticholinergic signs at 6 hours and no signs of TCA toxicity on the ECG he can be cleared medically and discharged to psychiatry. If the patient with a TCA overdose remains asymptomatic with a normal ECG for 6 hours of observation and has received only GI decontaimination and no serum alkalinization, the likelihood that he or she will develop late toxic effects is extremely small. All patients with altered mental status, seizures, or cardiac dysrhythmias, should be admitted to an intensive care unit and monitored for 24 hours after all supportive therapeutic interventions are discontinued
Several drugs should be avoided or used with great caution in suspected TCA overdoses. Syrup of Ipecac induced emesis can cause vagally mediated bradycardia and also can lead to aspiration if the patients mental status deteriorates after it is given and before vomiting begins. Type Ia and Ic antidysrhythmics worsen cardiac toxicity and hypotension. Flumazenil ( a benzodiazepine antagonist ) has been shown to induce seizures in TCA overdoses. Both flumazenil and TCA’s affect the GABA- chloride ionophore in the CNS. Phenytoin ( Dilantin ) has questionable efficacy in TCA induced seizures and increases ventricular tachycardia in animal models of TCA toxicity. Propranolol and verapamil have caused intractable hypotension when used to treat sinus tachycardia or supraventricular tachycardias. Finally, physostigmine, which had been recommended as an antidote in the past, increases cardiac toxicity and can induce asystole and should be avoided in suspected TCA overdoses.
Tricyclic antidepressants
- large Vd
- slow absorption
- extensive protein binding
- highly lipophylic
- liver metabolism, enterohepatic circulation
Mechanism of Toxicity
1) blockage of neurotransmitter reuptake at central presynaptic terminals (NE, serotonin)
2) anticholinergic/ antihistaminic - not impt for mortality - central and peripheral
3) Na channel blockade - type 1A, quinidine -like ( arrythmias ), membrane-depressant
slows Na influx into myocardial cells during phase 0 of the action potential
intraventricular conduction delays, ventricular dysrhytmias, negative ionotropy
decreased cardiac output, hypotension
4) peripheral alpha blockade
5) inhibition of central SNS reflexes
Symptoms and Signs
- Anticholinergic syndrome
- disorientation, lethargy, coma
- myoclonic or coreoathetoid movements
- Sz
- resp depression
- ECG
sinus tach
right axis of terminal 40msec frontal plane QRS vector
QRS prolongation
QT prolongation
PR prolongation
RBBB
ST and T abnormalities
complete heart block
- Boehnert and Lovejoy demonstrated that the maximal limb lead QRS duration was prognostic of seizures and cardiac dysrhythmias following acute TCVA ingestions.
Sz occurred in 30 % with QRS > 100 mSec / 0 % if <
Cardiac dysrhythmias in 50 % with QRS > 160msec / 0% if <
Rightward axis shift in terminal 40 msec ( R in AvR, S in I, AvL ) along with sinus tach and prolonged QT , is highly specific and sensitive for TCA poisoning but the absence of these findings is not exclusionary
-it is not clinically useful or cost-effective to obtain a plasma TCA determination. Life-threatening toxicity is found in patients with levels of less than 1000 ng/mL
Treatment
- ABC
- acid - base stabilization - acidosis will increase binding of drug to Na channels, slowing intraventricular conduction and predisposing the patient to dysrhythmias
- DONT for AMS
- cardiac monitoring
- iv access
- gastric decontaimination
MDAC shown to enhance rate of drug elimination
lavage - bad TCA’s excluded from Kuligs paper, delayed GI motility
syrup of Ipecac contraindicated - risk of deteriration with Sz
- sinus tach - no Rx
- SVT - hyperventilation, NaHCO3, CCB, BB
- VT - alkalinization, lidocaine, overdrive pacing, bretylium
- hypotension - Trendelenberg, fluids, SG, NE, phenylephrine, dobutamine,alkalinization, IABP, CPB ( avoid dopamine )
- Sz and coma - BZ, Barbs, alkalinization, GA, NMB
must be treated promptly to avoid lactic acidosis ( rhabdo, ARF )
DPH no longer recommended due to limited efficacy, prodysrhythmic in dogs
Sz due to complex interactions in central serotonergic, cholinergic, adrenergic neurotransmitters, inhibition of chloride ionophore of GABA receptor complex
avoid flumazennil
NaHCO3
1) alkalinization reduces the portion of the drug unbound to plasma proteins
uncouples the drug from the sodium channel
2) NaKATPase pump
3) direct effect of Na on Na channel
- superior to lidocaine, hyperventilation, hypertonic saline in animal models
- bolus of 1 - 2 mEq/Kg followed by 3 amps ( 132 mEq ) in 1 L of D5W at 150 - 200 cc/hr to maintain pH 7.5 to 7.55
- lidocaine may exacerbate hypotension
Disposition
- all TCA should be observed art least 6 hours
- no anticholinergic signs at 6 hours can be discharged
- isolated sinus tach < 120 ?
- all TCA with anticholinergic signs should be observed for at least 12 hours in ICU : small risk of sudden death
- half of patients who presented to the ED with trivial signs of poisoning had a catastrophic deterioration within one hour
- if a life threatening event is going to occur, it will occur within yhe first 6 hours of hospitalization, and most often within the first two hours of admission to the ED
Monitoring
- if the patient with a TCA overdose remains asymptomatic with a normal ECG for 6 hours of observation and has received only GI decontaimination and no serum alkalinization, the liklihood that he or she will develop late toxic effects is extremely small( 2 ).
Can be discharged to psychiatry
- patients with AMS, Sz, cardiac dysrhythmias, should be monitored for 24 hours after all supportive therapeutic interventions are discontinued
Drugs to be avoided
- syrup of Ipecac- emesis can cause vagally mediated bradycardia
- type IA and Ic antidysrhythmics - worsen cardiac toxicity and hypotension
- flumazenil - both affect GABA- chloride ionophore
- physostigmine- increases cardiac toxicity, asystole
- DPH - questionable efficacy, increases VT in animals
- propranolol, verapamil - intractable hypotension
References: Tricylic Antidepressants
1) Callaham M, Kassel D: Epidemiology of fatal tricyclic antidepressant ingestion: Implications for management. Ann Emerg Med 14: 1 - 9, 1985
2) Boehnert M, Lovejoy FH : Value of the QRS duration versus the serum drug levels in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 313: 474-479, 1985
3) Neimann JT, Bessen HA, et al: Electrocardiographic criteria for tricyclic antidepressant cardiotoxicity. Am J Cardiol 57: 1154-1159, 1986
4) Wolfe TR, Caravati EM, et al : Terminal 40-ms frontal plane QRS axis as a marker for tricyclic antidepressant overdose. Ann Emerg Med 18: 348-351,1989.
5) Sasyniuk BI, Jhamandas V, et al : Experimental amitriptyline intoxication: Treatment of cardiac toxicity with sodium bicarbonate. Ann Emerg Med 15: 1052-1059,1986
6) Pentel P, Peterson CD: Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med 9: 588-590, 1980