Tricyclic antidepressant overdose treated with adjunctive lipid rescue and plasmapheresis

Abstract

Tricyclic antidepressant poisoning remains a major cause of morbidity and mortality, particularly in the setting of suicidal attempts. The current standard of care for treatment is the administration of sodium bicarbonate infusion. Adjunctive lipid emulsion therapy and plasmapheresis have received attention recently. We report an 18-year-old patient who was successfully managed with lipid emulsion and plasmapheresis as adjuncts to sodium bicarbonate treatment and review some of the recent literature.

Tricyclic antidepressant (TCA) poisoning presents a tremendous management challenge (1). While the selective serotonin receptor inhibitors are now increasingly prescribed for the treatment of depression, TCAs still play a role in the treatment of other conditions including enuresis, obsessive compulsive disorder, attention deficit hyperactivity, separation anxiety and neuralgic pain in children, and chronic pain and migraine in adults. Patients with suicidal ideation still seek TCAs as a way of attempting suicide (2). If abused, euphoria, hallucination, and a distorted sense of time may result (1). TCA overdose often represents a dire emergency with high mortality rates. The mainstay of management is the administration of intravenous sodium bicarbonate. Recently, adjunctive therapies, including intravenous lipid administration and emergent plasmapheresis (3–7), have been increasingly used. We present a case of amitriptyline overdose with suicidal intent in a young patient with major depression.

CASE PRESENTATION

An 18-year-old man was brought to the emergency department after being found unresponsive at home with empty bottles of amitriptyline and venlafaxine. He had a medical history of severe depression and attention deficit hyperactivity disorder, with three prior suicide attempts. His parents were not sure how many pills he had ingested. In the emergency department, he was minimally responsive to painful stimuli with sonorous respirations. His initial oxygen saturation was 70%. An initial electrocardiogram showed a widened QRS, prominent R waves in aVR, and frequent ventricular premature complexes (Figure 1). Within minutes of arrival, he went into cardiac arrest from ventricular fibrillation. He also had a witnessed generalized tonic clonic seizure during the episode of cardiopulmonary resuscitation. He was successfully resuscitated after receiving five rounds of intravenous epinephrine, shocks, and two rounds each of naloxone and 8.4% sodium bicarbonate. The patient was responsive immediately upon return of spontaneous circulation. He was then treated with activated charcoal to attempt gastric decontamination and 20% intravenous lipid emulsion before being transported to the intensive care unit and continued on a sodium bicarbonate infusion.

Figure 1.

The patient's 12-lead electrocardiogram in the emergency department showing widened QRS (duration ∼170 ms), prominent R waves in aVR, and frequent ventricular premature complexes.

Arterial blood gas analysis showed anion gap metabolic acidosis and respiratory acidosis. The patient was also treated with plasmapheresis on two occasions for the next two consecutive days. He remained hemodynamically unstable, requiring ventilator support and vasopressors. We also administered 2 g of intravenous magnesium sulphate to reduce the risk of recurrent ventricular arrhythmias. Serial 12-lead electrocardiograms were used to monitor his QT interval. His urine was positive for opiates and phencyclidine. Laboratory assay for acetaminophen and salicylate were unremarkable. An initial electrolyte panel revealed a serum potassium level of 5.8 mmol/L and serum creatinine of 2.39 mg/dL (reference range, 0.7–1.3), increased from his baseline of 0.93. The creatine kinase was 7350 U/L (reference range, 30–170) on presentation, peaking to 8162 on day 2.

In spite of aggressive treatment, the patient developed clinical and radiologic features of acute respiratory distress syndrome (ARDS). Serial chest x-rays showed extensive bilateral airspace opacities consistent with ARDS. He initially received intravenous vancomycin and piperacillin tazobactam for 7 days, but on account of inadequate clinical response was changed to aztreonam and clindamycin with better clinical response. Our patient improved gradually over the next 15 days. After his acute kidney injury, rhabdomyolysis, and ARDS resolved, he was discharged to the psychiatry unit for further management of his severe depression.

DISCUSSION

Our patient unsuccessfully attempted suicide with amitriptyline and possibly other medications. It has been estimated that 97% of the deaths from antidepressants are from TCAs (1–3). Our patient manifested classic clinical complications of TCA overdose, specifically the development of life-threatening arrhythmias (QRS prolongation, ventricular tachycardia/fibrillation), seizures, and hypotension. He also developed rhabdomyolysis, acute kidney injury, and ARDS, which although not as common have been reported following TCA overdose. Rhabdomyolysis has been reported as a rare complication following TCA overdose (8). The Table reviews other cases of TCA overdose, describing the patient's clinical features, as well as the interventions and their outcomes (3, 5, 9–16).

Table.

Published cases of tricyclic antidepressant overdose

Report and country	Patient demographics and presenting complaint	Patient key clinical features	Initial interventions	Definitive interventions and clinical outcome
Hendron, 2011, N. Ireland (9)	20-mo F, 45 mg/kg dosulepin	Drowsy, nystagmus, BP 80/40, HR 130, seizures	Diazepam, thiopentone, gastric lavage, sodium bicarbonate	ILE at 1 mL/kg then infusion of 150 mL/h for 1 h; discharged on day 3
Boegevig, 2011, Denmark (10)	36-y F, 5.25 g dosulepin	GCS 12, tachycardia, QRS 120 ms, seizures	Diazepam, propofol, sodium bicarbonate	ILE at 1.5 mL/kg (100 mL), then 400 mL over 20 min; QRS shortened, discharged on day 3
Nair, 2013, UK (11)	34-y F, 5.6 g amitriptyline and 2.4 g citalopram	GCS 3, BP 51/29, seizures, QRS 171 ms, VT	Diazepam, epinephrine, sodium bicarbonate	20% ILE at 1.5 mL/kg, then infusion for 60 min; complete recovery within 24 h
Karacı, 2013, Turkey (5)	15-y F, 22 mg/kg amitriptyline	GCS 5, depressed respirations and reflexes	Intubation, gastric lavage, sodium bicarbonate	Plasmapheresis for 4 h; GCS improved to 13
Blaber, 2012, UK (12)	36-y F, 2.25 g of dothiepin	GCS 4, BP 53/35, HR 130, pH 6.75, QTc 502	IV fluids, gastric lavage, sodium bicarbonate, amiodarone, transvenous pacing	1.5 mL/kg/min of 20% ILE then 400 mL infusion; sinus rhythm and complete recovery
Agarwala, 2014, USA (13)	44-y M, 2.25 g of amitriptyline	Unconscious, BP 65/42, QRS 160, seizures, PEA	Warming, vasopressors, sodium bicarbonate	20% ILE as 250 mL bolus followed by infusion; QRS duration decreased, BP stabilized
Scholten, 2012, Netherlands (14)	53-y F, amitriptyline, citalopram, and venlafaxine	GCS 3, RR 8, BP 75/35, idioventricular rhythm	Intubation, activated charcoal, sodium bicarbonate	20% lipid emulsion; narrowing of QRS complex and sinus rhythm, patient recovered
Harvey, 2012, New Zealand (3)	51-y M, 43 mg/kg amitriptyline, possibly quetiapine, citalopram, metoprolol, quinapril, aspirin	GCS 3, HR 150, BP 112/82, QRS 180 ms, wide complex tachycardia	Sodium bicarbonate, intubation, gastric lavage	100 mL 20% lipid emulsion, then 400 mL over 30 min; QRS narrowed, HR and BP stabilized
Levine, 2012, USA (15)	13-y F, unknown quantities of amitriptyline	RR 6, QRS 176 ms, QTc 477, seizure, cardiac arrest	Intubation, sodium bicarbonate, lorazepam, midazolam, epinephrine, phenobarbital	1.5 mg/kg of 20% ILE, continuous infusion of 0.25 mg/kg/min for 30 min; patient survived
Koschny, 2014, Germany (16)	21-y F, carvedilol, amlodipine, amitriptyline, torsemide, ketoprofen, nicotinic acid, gabapentin	Asystole, CPR with ROSC	ECMO, temporary pacing, plasmapheresis	Weaned from ECMO on day 4, extubated on day 8; no neurological sequelae

BP indicates blood pressure (mm Hg); CPR, cardiopulmonary resuscitation; ECMO, extracorporeal membrane oxygenation; F, female; GCS, Glasgow coma score; HR, heart rate (beats/min); ILE, intralipid emulsion; M, male; PEA, pulseless electrical activity; ROSC, return of spontaneous circulation; RR, respiratory rate (breaths/min); VT, ventricular tachycardia.

Ventricular fibrillation following TCA overdose has been reported in about 2% to 4% of cases and is more common in severe poisonings involving extreme QRS widening and QT prolongation (1). Our patient had very impressive QRS prolongation, up to 170 ms. QRS duration is thought to be a better predictor of morbidity than the plasma level of the TCA (1, 17). A duration >160 ms predicts a 50% chance of life-threatening ventricular arrhythmias (1, 17). A QRS duration >100 ms is an indication for bicarbonate therapy in the setting of TCA overdose (1). Electrocardiographic signs suggestive of toxicity include QRS duration >100 ms, abnormal QRS morphology, and abnormal size and ratio of the R and S waves in lead AVR, specifically R wave in AVR >3 mm and R to S ratio in AVR >0.7. Other cardiac manifestations of toxicity include the development of a bundle branch block, commonly a right bundle branch block (1, 17).

The TCAs exert their pharmacologic effects by the inhibition of presynaptic serotonin and norepinephrine uptake. TCAs are rapidly absorbed from the gut and reach high plasma levels within 2 to 8 hours. They have a high volume of distribution on account of their high lipid solubility. In plasma, TCAs circulate bound to alpha 1 acid glycoprotein. They undergo phase 1 metabolism in the liver with the action of the CYP2D6 enzyme and also glucuronidation (1). In the setting of an overdose, the clinical consequences are thought to be due to the ability of TCAs to block cardiac fast sodium channels and antagonize the central and peripheral muscarinic acetylcholine receptors, peripheral alpha adrenergic receptors, histamine H1 receptors, and central nervous system GABA A receptors. The clinical picture is also compounded by the presence of significant drug enterohepatic circulation and active metabolites of the drug following glucuronidation. It is difficult to predict drug kinetics when dosed therapeutically, as other effects such as acidemia, CYP2DC saturation, and decreased gut motility (from anticholinergic effects) help potentiate drug action (1).

Based on the clinical circumstances, our patient received treatment with activated charcoal for gastric decontamination, intravenous sodium bicarbonate, lipid rescue, and plasmapheresis. He was also intubated and mechanically ventilated initially for airway protection following cardiopulmonary resuscitation and then for management of ARDS. His refractory hypotension was treated with intravenous fluids and vasopressors, fluid administration being adjusted as appropriate because of the concomitant ARDS.

ARDS following TCA overdose has been reported infrequently in the literature over the last 20 to 30 years (18, 19). The exact mechanisms at play are not clearly defined but may relate to the effects of prolonged hypotension, aspiration of gastric contents, sepsis, and direct action of the drugs on the lung parenchyma. We treated our patient with antibiotics in the belief that he aspirated during the acute phase of TCA toxicity, as his mental status rapidly deteriorated with concomitant seizures and cardiopulmonary arrest and subsequent cardiopulmonary resuscitation.

Treatment with sodium bicarbonate remains the standard of care for TCA poisoning (1). This induces an alkalosis and provides a sodium load that helps improve cardiac conduction. The sodium loading also helps treat the ensuing hypotension seen in many patients. Alkalosis helps reduce the amount of free drug by increasing protein binding. However, the toxicity profile and the clinical instability of some patients in spite of sodium bicarbonate administration have necessitated the trial of other adjunctive therapies such as lipid emulsion treatment and plasmapheresis, as with our patient. In view of the lack of randomized trials that have demonstrated effectiveness, these treatments remain controversial and are not yet recommended by the standard treatment guidelines (1, 20). Another issue that presents a dilemma to clinicians is the fact that there is no certain method to determine that sodium bicarbonate has failed and that other treatments need be instituted. Clinicians tend to initiate other treatments depending on disease severity and response of electrocardiographic and hemodynamic parameters (1).

Lipid emulsion therapy is thought to work by counteracting the activity of lipophilic drugs, like the TCA drugs. Its use was first demonstrated in anesthetic agent overdose and gradually began to be used in TCA poisoning. It is thought to be able to sequester the ingested TCAs. There are multiple case reports of dramatic clinical response in cases of severe TCA poisoning managed with adjunctive intralipid administration in addition to sodium bicarbonate infusion (3, 7, 20).

Plasmapheresis involves the removal of the patient's plasma and replacement with another fluid (e.g., allogeneic donor plasma, colloid, crystalloid). This is useful in TCA poisoning because of the high lipid solubility and binding of TCAs. Reductions in plasma levels as much as 63% have been reported after plasmapheresis for TCA poisoning (5). The use of plasmapheresis in TCA poisoning has been controversial; while several case reports have suggested good outcomes following its use (1, 5, 6, 16), the Extracorporeal Treatments in Poisoning (EXTRIP) Working Group recommended against the use of plasmapheresis and extracorporeal treatment for TCA poisoning, citing the insufficient data regarding the benefits and effectiveness of plasmapheresis (8). Our report adds to the collection of clinical case reports where adjunctive plasmapheresis and lipid rescue have been associated with a good outcome in TCA overdose.