Intravenous Lipid Emulsion Therapy and VA-ECMO rescue therapy for Massive Venlafaxine and Clonazepam Overdose

Adam Thomas1, Daniel Ovakim1, Hussein Kanji1, Leith Dewar1 and Gordon Finlayson2* 1Department of Emergency Medicine, University of British Columbia, Canada 2Department of Anesthesiology, Division of Critical Care Medicine, CCM Fellowship Program Director, Vancouver General Hospital, Vancouver, Canada *Corresponding author: Gordon Finlayson, Department of Anesthesiology, Division of Critical Care Medicine, CCM Fellowship Program Director, Vancouver General Hospital, Vancouver, Canada, Tel: 604-875-4304; Email: Gordon.Finlayson@vch.ca


Case Description
A 60 year old male presented to hospital following a witnessed, outof-hospital, cardiac arrest attributable to an intentional overdose of 20 grams extended release Venlafaxine and 60 milligrams Clonazepam. He was found by emergency medical services with an agonal breathing pattern and subsequently deteriorated to pulseless electrical activity (PEA) arrest upon arrival of paramedical staff. Return of spontaneous circulation was achieved after eight minutes of advanced cardiac life support (consisting of CPR, tracheal intubation, intra-osseous access, and epinephrine administration). Recurrent PEA arrest occurred during transport to hospital requiring an additional six minutes of CPR.
Upon arrival at our institution, initial treatment included administration of enteric charcoal and intravenous sodium bicarbonate. The provincial drug and poison information centre was notified and laboratory and diagnostic testing performed. Despite dramatic ECG changes (see figure), the patient remained stable on low dose vasopressors for approximately six hours when he developed malignant, wide complex arrhythmia. This transiently responded to conventional resuscitative efforts and lipid emulsion therapy (Intralipid®). Peripheral (femoral-femoral) VA ECMO was required to establish circulatory stability after recurrent cardiac arrest in the face of high dose inotrope and vasopressor support [1]. Given theoretical concerns surrounding oxygenator failure, lipid emulsion therapy was immediately discontinued upon ECMO initiation. Mechanical circulatory support was maintained for approximately 48 h with targeted temperature management of 36°C for the first 24 h. The presentation was further complicated by seizures and severe rhabdomyolysis, as has been previously reported in Venlafaxine overdose. Seizure activity was monitored clinically and treatment guided by continuous electroencephalogram. While controversial, whole bowel irrigation was attempted to mitigate further drug absorption, and cyproheptadine administered for symptoms compatible with serotonin syndrome. Continuous dialysis was initiated to treat concurrent rhabdomyolysis, acute renal failure and to facilitate potential clearance of Venlafaxine metabolites (though hemodialysis has not previously been established to be effective for this purpose). Interestingly, the patient demonstrated intermittent, spontaneous and self-resolving episodes of pulselessness while on ECMO (see video) without cardiac arrhythmia or perturbation of the ECMO circuit. We hypothesize this is attributable to venlafaxine associated cardiotoxicity. Despite an estimated total dose of 7.5 ml/kg of Intralipid TM the ECMO circuit performance was adequate, without any visible clot or component failure. After two days of ECMO support, the patient was decannulated, and ultimately discharged from hospital with complete neurologic recovery.

ECMO as a "Bridge to recovery"
ECMO is becoming more widely used and recommended in patients suffering cardiovascular instability and/or refractory cardiopulmonary arrest from reversible toxic ingestions [2][3][4].
Improved outcomes are observed with the incorporation of ECMO into standard ACLS resuscitation techniques (86% survivability versus 48%) [2,5]. Few reported intoxications involve cannulation following cardiac arrest (Maskel 2016). The present case highlights the utility of ECMO in the setting of cardiopulmonary arrest owing to massive Venlafaxine (20 g) and Clonazepam (60 mg) overdose. The literature to date has shown poor outcomes with ingestions over 8 g 6 likely related to the cardiac toxicity seen at this level [6,7].

Issues with intralipid rescue therapy
As experience increases with the use of intravenous lipid emulsion (ILE) as rescue therapy in severely poisoned patients, the complications and harms of this treatment are becoming apparent. Specifically, as highlighted by Hayes et al. [8,9], this therapy has the potential to cause, acute kidney injury, cardiac arrest, ventilation perfusion mismatch, acute lung injury, venous thromboembolism, hypersensitivity, fat embolism, fat overload syndrome, pancreatitis, extracorporeal circulation machine circuit obstruction, allergic reaction, and increased susceptibility to infection [9].
There is an increasing number of cases published (see http:// www.lipidrescue.org/, that demonstrate the concurrent use of ILE and ECMO [6,9,10] This is not without potentially serious complications. As highlighted by Albrecht et al. [11] the ECMO circuit may become impaired by "fat emulsion agglutination, malfunction of the membrane oxygenator, and increased risk of blood clot formation" [11]. Of note, these circuit complications have been observed in both in vitro studies, and clinical observation trials [12]. Consequently, some experts recommend that the total dose of ILE not exceed 10 ml/kg [11]. Given these concerns, we limited the total dose of Intralipid to 7.5 mg/kg.

Issues with drug absorption, elimination and serotonin syndrome
Traditionally, single dose charcoal is recommended for venlafaxine overdose to bind the parent drug and prevent further absorption [13]. We elected to combine single dose activated charcoal with whole bowel irrigation with the intent of preventing drug absorption and improving elimination. Although controversial, this technique has some evidence for use in stable patients with known Venlafaxine overdose [13].
Regrettably this attempt at whole bowel irrigation was unsuccessful owing to ileus paralytics.
Although the therapeutic benefits are disputed by toxicologists, this patient was treated with the serotonin antagonist Cyproheptadine. Of note, we observed an interesting phenomena following recovery of native cardiac output. After restoration of pulsatile circulation (while partially supported on VA ECMO) the patient's native output would disappear, with concordant decrease in left ventricular function as observed with bedside echocardiography. We hypothesize this was the result of direct cardiotoxicity from Venlafaxine. At high serum concentrations, Venlafaxine has been shown to block sodium channels within ventricular myocytes [14]. As well, there are previous reports of acute myocardial infarction and necrosis in patients receiving therapeutic doses of venlafaxine with normal coronary arteries on angiogram [15]. A proposed mechanism is autonomic instability from inhibition of norepinephrine (and dopamine) reuptake leading to catecholamine induced vasospasm that results in myocardial necrosis [6,16].

Conclusion
This case demonstrates one of the highest documented ingestions of Venlafaxine and Clonazepam. Successful resuscitation with a favorable neurologic outcome was attributable to the efficient deployment of VA ECMO.