ECMO in Poisoning

Introduction

Globally, acute poisoning with medications or other toxic substances is a common presentation to emergency department.¹ Conventional supportive therapy and specific antidotes administration are usually effective but may not be sufficient in cases of cardiovascular collapse due to life-threatening overdoses. Children are usually the victim of accidental overdoses and symptoms are usually apparent immediately while adult intoxication is usually deliberate and present late to emergency department.²

Poisoning-associated deaths both due to accidental ingestion and ingestion for self-harm have increased in the last few years. More than 5,000 poisoned patients are visiting emergency departments every day across the United States and unintentional poisoning is a significant cause of mortality, even exceeding road traffic accidents as a cause of death in the younger and middle age group. The poisoning victims are usually young though toxic substances varies across the world.³, ⁴

Extracorporeal membrane oxygenation (ECMO) has been used successfully in children with respiratory and cardiopulmonary failure. However, its use in adults remained limited until recently when the Cambridge Society for the Application of Research (CSAR) trials’ other reports showed a favorable outcome during H1N1 pandemic.⁵ The use of ECMO has increased more than fourfold in the last decade.⁶ ECMO supports the failing heart and/or lung functions unresponsive to conventional management until a specific endpoint has been achieved.⁷ It is often considered as a bridge therapy, buying time until definitive therapy has been instituted. For example, a deteriorating patient with a myocardial infarction and cardiogenic shock can be shifted for percutaneous coronary intervention (PCI) or a patient with a massive pulmonary embolus can undergo thrombectomy with ECMO support.

The main cause of death in patients with acute poisoning is failure of various vital organs. Intubation and mechanical ventilation has shown dramatic improvement in survival of sedative-induced respiratory failure, which was the leading cause of death in the Western world. Similarly, toxin-induced acute renal failure has successfully been managed with renal replacement therapy (RRT). Even liver transplant in drug-induced fulminant liver failure is reported in selected cases. However, the use of mechanical circulatory support in cardiac failure due to acute intoxication is still a matter of debate.⁸ ECMO helps in maintaining tissue perfusion and oxygenation in acutely intoxicated patient until the drug or toxin is eliminated by the body’s natural metabolism and excretory processes or possibly RRT may be instituted to enhance the elimination.

Once a toxin enters the systemic circulation and is distributed in the tissues, the cardiovascular collapse may require temporary support of circulatory function. This helps in hepatic detoxification over time,⁹ while providing reliable tissue perfusion and allowing sufficient antidote circulation.¹⁰ The various modalities such as continuous cardiopulmonary resuscitation (CPR; manual or with a mechanical device), intraaortic balloon (IAB) counterpulsation, and cardiopulmonary bypass (CPB) has been used.¹¹

The miniaturization of circuit, safe application of ECMO due to advancement of technology, and better outcome has allowed critical care specialists and emergency physicians to explore newer indications for use of ECMO in intensive care unit (ICU). However, ECMO has not been established as a rescue modality in acutely intoxicated patients with cardiovascular collapse or cardiac arrest. Even the Extracorporeal Life Support Organization (ELSO) guidelines and registry data do not address the use of ECMO in acute intoxication. This review focuses on the mortality associated with acute intoxication, difference in toxicology profile across the globe, available literature on use of extracorporeal life support (ECLS), and discusses the current practices.

Clinical Epidemiology

The poisoning substances can be broadly divided into three groups: chemicals used in agricultural and industries, medications and health care products, and biological poisons such as plant toxins and animal toxins. The toxicity of these poisoning substances ranges from mild symptoms to severe and life-threatening cardiovascular dysfunction. Poisoning may be intentional (suicidal, homicidal, misuse, or abuse) or unintentional (accidental, occupational, etc.).⁴ Usually, 85% of patients presenting with poisoning have minor toxic effect and usually do not require aggressive treatment. Intentional exposures have more severe effects and poor outcome for obvious reason.¹²

Worldwide, an estimated 3 million cases of pesticide poisoning occur every year, resulting in an excess of 250,000 deaths.¹³ Intentional and unintentional pesticide poisoning has been acknowledged as a serious problem in many agricultural communities of low- and middle-income countries, including China, India, Sri Lanka, and Vietnam.¹⁴

More than 400,000 victims die due to accident (both natural and unnatural) in India and acute poisoning contributes to 6.3% (~26,000) deaths every year. However, suicide due to acute intoxication leads to around 30,000 deaths every year.³ Pesticides are the most common substances used in the developing world for poisoning and is associated with high mortality.¹⁵, ¹⁶ However, the toxic profile is different in the Western world, and medications, especially cardiovascular medications, illegal drugs, and biologically active substances contribute mostly for cardiovascular collapse and death.³, ¹⁷ However, most of these poisoning victims irrespective of cause, method, type, or nation belong to relatively younger age group.³, ⁴, ¹⁸

Death due to Toxin-Induced Cardiovascular Shock

Severe poisoning may lead to hemodynamic instability or collapse, which is also associated with the deterioration of other organ functions such as respiratory arrest or depression, gas exchange abnormalities, convulsions, and electrolyte and acid-base disorders. These metabolic factors further deteriorate the cardiac function and may potentiate the toxicity. The immediate focus on managing the severely poisoned patient is to follow the resuscitation protocols— a prompt assessment and maintenance of compromised airway, supporting the breathing, and optimization of circulation. Poor respiratory efforts or inadequate ventilation may require short-term mechanical ventilatory support, till the toxin is reversed or metabolized.¹⁹ Optimization of blood pressure should be achieved initially with intravenous (IV) fluids boluses. Specific antidote administration may help to optimize blood pressure. Hypotension unresponsive to adequate fluid resuscitation may indicate the need of administration of vasopressor and inotropic agents depending on clinical presentation.²⁰ The inotropic agents are proarrhythmic and may further enhance the cardiovascular toxicity. Antiarrhythmic administration for the management of arrhythmias associated with poisoning should be avoided due to proarrhythmic potential and negative inotropic effect of these drugs. It is prudent to correct the acidosis, hypokalemia, hypomagnesaemia, and hypoxia, which reduces the chance of arrhythmia.²⁰ There is significant advancement in the management and improved outcome of toxin-induced cardiovascular shock in last three decades. This is contributed by improvement in bedside hemodynamic monitoring, better understanding of shock, and aggressive supportive therapy for hemodynamic optimization.²¹, ²² Still, the incidence of cardiovascular collapse in patients with acute intoxication is as high as 17%.²³ Sudden cardiac death in a younger and otherwise healthy population is most likely due to poisoning.²⁴ The onset of cardiovascular effects after poison ingestion is short and depends not only on ingested quantity but also on the severity of toxic profile and type of toxin as well.

Common Poisoning Substances with Cardiotoxic Potential

1. Drugs: The pathophysiology of drug-induced cardiotoxicity and hypotension include hypovolemia, depressed myocardial function, arrhythmias, and systemic vasodilatation. Mainly the acute toxic heart failure is due to systolic dysfunction secondary to reduced myocardial contractility.²⁵ Cardiotoxic potential is not restricted to cardiovascular drugs only, the mortality remains higher in compounds having membrane stabilizing activity.²⁶

   1. With membrane stabilizing activity:

      1. Antiarrhythmics (Vaughan Williams class I).

      2. Beta-blockers (propranolol, acebutolol, nadoxolol, pindolol, etc.).

      3. Dopamine and norepinephrine uptake inhibitors (bupropion).

      4. Antiepileptics (phenytoin and carbamazepine).

      5. Antimalarial agents (quinine and chloroquin).

      6. Polycyclic antidepressants (imipramine, desipramine, amitriptyline, and doxepin).

      7. Opioids (dextropropoxyphene).

      8. Recreational agent (cocaine).

      9. Amphetamine-like substances.

   2. Other drugs:

      1. Calcium channel blockers (nifedipine, nicardipine, verapamil, diltiazem, etc.).

      2. Meprobamate.

      3. Colchicine.

      4. Cardiac glycosides (digoxin).

      5. H1 antihistaminic.

      6. Beta-blockers (without membrane stabilizing activity).

2. Pesticides:

   1. Insecticides:²⁷

      1. Organophosphate, carbamates.

   2. Herbicides:

      1. Paraquet.

   3. Rodenticides:²⁸, ²⁹

      1. Aluminum phosphide.

      2. Yellow phosphorus.

      3. Zinc phosphide.

3. Plant toxins:³⁰, ³¹ The most severe form of plant toxins may produce complete heart block, bradyarrhythmia, tachyarrhythmia, or ventricular arrhythmia.

   1. Aconite.

   2. Taxus.

4. Others:

   1. Carbon monoxide.³²

   2. Cyanide.

Role of ECMO in Poisoning

The standard indication of using ECMO is acute severe heart or lung failure unresponsive to optimal conventional therapy with high mortality risk. ECMO should be considered if the mortality risk is 50% and ECMO should be started in most circumstances at 80% mortality risk,³³ which is similar for poisoned patients. Moreover, these patients are relatively young and otherwise healthy. One can expect a better outcome once the toxin is either metabolized or completely eliminated from the body. ECMO may be useful in providing adequate cardiac output and maintain tissue perfusion which helps in redistribution from central circulation and facilitate the metabolism and excretion of poison. ECMO supports both cardio respiratory function (venoarterial [VA] ECMO) and respiratory function alone (VV ECMO) for a longer duration depending on indication. It is primarily indicated in patients with such severe cardiovascular dysfunction or severe ventilation and/or oxygenation problems that they are unlikely to survive conventional therapies and mechanical ventilation.³⁴ Toxins such as organic hydrocarbon (paint remover, thinner) on aspiration damages the lungs and leads to acute respiratory distress syndrome (ARDS) without circulatory compromise. There are no guidelines for the appropriate time for ECMO initiation in severely poisoned patients. The decision about initiation primarily depends on the clinical judgment. The available scoring system for classifying the poisoning patients has its own limitations due to its subjective nature; however, it may help to identify the most severe form of patients (Grade 3 and 4).³⁵

Bridge to recovery: Toxic substances having potential for cardiotoxicity, where antidote is not available, may be fatal even with conventional support. VA ECMO can support the cardiac function in poisoned patients with severe cardiotoxicity who have severe left or right ventricular dysfunction, persistent life-threatening arrhythmias, or even cardiac arrest unresponsive to conventional management. Cardiovascular function starts recovering once the toxic substance is either metabolized or excreted from the body. The duration of ECMO support depends on several factors such as severity of toxicity and recovery of cardiac dysfunction, half-life of toxin, and organ dysfunction at the time of initiation of ECMO.³⁶, ³⁷ VA ECMO reduced cardiac oxygen consumption and provided both hemodynamic and respiratory support as a bridge to recovery.³⁸ Patients who have toxin-induced ARDS while stable hemodynamically and who are unresponsive to high ventilatory support can be managed with VV ECMO till the recovery of gas exchange function of the lungs.³⁹ Even in cases of multiple drug intoxication or unknown poisoning with cardiogenic shock, ECMO support can be beneficial.⁴⁰

Bridge to antidote: ECMO can be helpful in life-threatening arrhythmia or cardiovascular collapse with those toxins which can be managed successfully with antidote but which is not available readily due to short shelf-life and cost. Digoxin-specific antibodies fragments (Fab) rapidly improves the digitalis-induced arrhythmias and cardiac toxicity. However, digoxin poisoning is uncommon and Fab fragments are expensive with limited shelf-life. Patient can be supported with ECMO until Fab is administered.⁴¹, ⁴²

Review of Literature

There are no randomized trials on the use of ECMO in patients with severe intoxication having refractory shock or having ARDS. So, the available evidences are basically few animal studies, case reports, case series, and case cohort studies. A cautious interpretation of results is indicated due to potential for bias.

Drug toxins: Most of the available literature is from the Western countries and describe the use of ECMO in acute drug intoxication. The experimental evidences with three different trials using lidocain,⁴⁹ desipramine,⁵⁰ and amitryptaline⁵¹ in dogs and swine, respectively, have shown better outcome with ECLS in comparison to the conventional treatment using fluid, vasopressor, inotropes, antiarrhythmic agents, etc. The major drawback about all three studies was that the animals were put on ECLS immediately after collapse and the duration of ECLS was short. This may not hold true in actual human intoxication because they are not supported with ECLS immediately and the duration of ECLS is longer. However, these results are promising and encourage the use of ECMO in refractory shock due to poisoning. The experiences in human subject include an observational cohort which shows better outcome in six patients with severe intoxication with profound shock who received VA ECMO as compared with use of ECMO for other indications. The toxic substances were chloroquine, a tricyclic antidepressant, propafenone, a sclerotic agent, and diuretics.⁵² In another cohort of 17 patients where ECLS was initiated for refractory cardiac arrest, VA ECMO was instituted in all patients and a stable ECLS was achieved in 14 patients. The survival was better in patients with shock due to poisoning (25%) while none survived in the cardiogenic shock group.⁵³ A retrospective cohort analysis in two hospitals in France analyzed all poisoning patients presented to the hospital. There was statistically significant favorable outcome (86% vs. 48%) in severely intoxicated patients with refractory shock or cardiac arrest, who were managed with VA ECMO as compared with conventional management with fluid, vasopressors, and other supportive measures.⁵⁴ However, due to small number of patients treated with VA ECMO in this cohort, the interpretation of results should be done carefully.

Besides this, there are several case reports of successful management of drug intoxication with refractory shock using ECMO. The acute intoxication of drugs which has been supported successfully with ECMO include flecainide,⁵⁵, ⁵⁶ an antiarrhythmic agent, β-blocker,⁵⁷ calcium channel blockers,⁵⁸ digoxin,¹⁰ tricyclic antidepressant,⁴¹, ⁵⁹ buprioprion,⁶⁰ methamphetamine,⁶¹ and mepivacaine, a local anesthetic.⁶² These included both adult and pediatric patients, all of them were supported with VA ECMO but the time of initiation of ECMO and duration of ECMO was different in different cases. Common complications similar to any case of VA ECMO were reported such as bleeding, hypotension, thromboembolism, or minor neurological events. There is always a chance of reporting and publication bias in case reports but recovery and survival in such a critical population definitely encourages the use of ECMO in poisoned patients with profound shock. In another case series of 17 patients, who were severely intoxicated with different cardiotoxic drugs including membrane stabilizing agents, nearly 90% patients were successfully weaned off from emergency cardiopulmonary bypass (ECPB), and 76% were discharged without significant cardiac and neurological dysfunction. A few of them required CPR before commencing ECPB and four patients required RRT during ECPB to manage acute kidney injury. Although there were certain complications such as bleeding, limb ischemia, and thrombus formation, the authors concluded that ECPB is safe and effective in the management of severely poisoned patients (Fig. 1).⁴⁵

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Fig. 1

Proposed approach for extracorporeal membrane oxygenation (ECMO) initiation in severely poisoned patients refractory to conventional support.

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Other substances: The ECMO has not been used much in severe intoxication and refractory shock or severe ARDS with other toxic substances such pesticides, carbon monoxide, cyanide, and plant toxins. The available literature is restricted to case reports or case series with few patients only. These substances are commonly used as poison in the developing world with high mortality but ECMO is still not frequently available in this population. This may be a probable reason of underutilization of this modality. Carbon monoxide (CO) rapidly binds to hemoglobin to form carboxyhemoglobin, leading to tissue hypoxia, multiple organ failure, and cardiovascular collapse. Both VV and VA ECMO may be used to manage tissue hypoxia depending on the hemodynamic stability.⁶³ Aluminum phosphide, a deadly poison used as pesticide causing severe myocardial dysfunction, arrhythmia, and death, has been successfully managed with VA ECMO at different centres.²⁹, ⁶⁴, ⁶⁵, ⁶⁶ The plant toxin, Taxus-induced cardiogenic shock with ventricular arrhythmia has been successfully managed with VA ECMO.⁶⁷ ARDS induced with organophosphorus poisoning has also been supported with VV ECMO.³⁹ Even poison-induced lung fibrosis patient awaiting lung transplant is put on VV ECMO to improve gas exchange.⁴⁸

Conclusion

The use of ECMO in acutely poisoned patients with refractory cardiogenic shock or refractory hypoxemia to conventional therapies is getting popular among the emergency physicians and intensivists as salvage therapy. However, ECMO is still an underutilized modality both in the developed and developing countries. The available evidences are limited to case reports and case series, which may have reporting and publication bias but randomized trial may be ethically unacceptable. Poisoning is a unique subject, not only because of huge number of toxic substances available but also since each substance has different pharmacological, metabolism, and elimination profile. It is understandable that ECMO may be helpful in supporting the hemodynamics irrespective of poisoning substances if cardiovascular dysfunction is unresponsive to standard therapies. The complications associated with ECMO may be life threatening and is minimized with expertise. Our understanding regarding the use of ECMO in poisoning is still limited and several issues are yet to be answered. This include the right time of ECMO initiation in acute intoxication, when to combine RRT to facilitate metabolic correction, cost-effective management, clarifications regarding the prognostic factors in poisoning prior to ECMO initiation, and decision regarding the withdrawal of ECMO support after improvement. All these issues may be addressed in future research and publications. However, ELSO, the largest world organization for ECMO data registry, may provide an excellent platform by encouraging global data collection on the ECMO use in poisoning. The decision regarding ECMO support in poisoning must be made carefully since ethical issues may arise in a situation of bridge to nowhere if the patient has developed irreversible organ damage.