VA ECMO and Drug Intoxication

Abstract

ECMO support can help in maintaining tissue perfusion and oxygenation in acutely intoxicated patients until the drug or toxin is either eliminated by the body with natural metabolism and excretory processes or possibly renal replacement therapy may be instituted to enhance the elimination. Once cardiotoxic substances reach systemic circulation and are distributed in the various tissues, the patient is present with cardiovascular dysfunction, arrhythmia, or cardiovascular collapse. Cardiovascular collapse may require temporary support of the circulatory function. This helps in hepatic detoxification over time while providing reliable tissue perfusion and allowing sufficient antidote circulation. Extracorporeal membrane oxygenation (ECMO) use in cardiotoxic drug overdose is increasing. Calcium channel blockers (CCB) along with β-blockers constitute more than 65% of deaths from cardiovascular medications whereas in the 2021, American Association of Poison Control Centers’ National Poison Data System Annual report, Tricyclic Antidepressant (TCA) accounted for 4705 single exposures and 15 deaths. VA ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies and did not show any improvement along with refractory shock and acute renal failure like in CCB drug overdose and TCA-induced cardiac toxicity and cardiogenic shock, where the recovery depends mainly on maintaining perfusion. The procedure is considered as a lifesaving bridge either to recovery, to antidote, to toxin elimination with renal replacement therapy, or to transplant.

1. Introduction

Although there has been a significant advancement in management and improved outcomes of drug overdose-induced cardiovascular shock in the last 3 decades, this is contributed by improvement in bedside hemodynamic monitoring, a better understanding of shock, and aggressive supportive therapy for hemodynamic optimization [1, 2]. Still, the incidence of cardiovascular collapse in patients with acute intoxication is as high as 17% [3]. Sudden cardiac death in a younger and otherwise healthy population is most likely due to intoxication [4]. The onset of cardiovascular effects after drug ingestion is short and depends not only on the ingested quantity but on the severity of the toxic profile, and type of drug as well. One of the most aggressive supportive modalities available is extracorporeal membrane oxygenation (ECMO). ECMO is an external device that supports the cardiopulmonary system by providing oxygenation and cardiac function for a patient in cardiac and respiratory failure. ECMO has been successfully used in all ages for various medical and surgical conditions leading to cardiovascular collapse, respiratory failure, cardiogenic shock, or refractory hypotension [5, 6]. ECMO has also been used in toxicology cases when cardiac arrest or refractory cardiogenic shock develops. This has been studied in both animal models and human cases [7, 8]. In this chapter, we explore the use of VA ECMO for drug intoxication, especially those associated with cardiotoxic effects. Most of the available literature is from the Western countries, which describes the use of ECMO in acute drug intoxication. The experimental evidence with three different trials using lidocaine [9], desipramine [10], and amitriptyline [11] in dogs and swine, respectively, has shown better outcomes with extracorporeal life support (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 duration of ECLS is longer. However, these results are promising and encourage the use of ECMO in refractory shock due to poisoning.

2. Clinical epidemiology and mortality in drug intoxication

Drug intoxication ranges from mild symptoms to severe and life-threatening cardiovascular dysfunction. Intoxication may be intentional (suicidal, homicidal, misuse, or abuse) or unintentional (accidental) [12]. Usually, 85% of patients presenting with drug intoxication have minor toxic effects and usually do not require aggressive treatment. Intentional exposures have more severe effects and poor outcomes for obvious reasons [13]. An analysis between the years 2000 and 2014 of cases reported to United States poison control centers revealed that although there are numerous different substance exposures, the ones associated with the highest morbidity and mortality have consistently been related to TCA overdose [14]. In 1992, TCA overdose accounted for 1.12 exposures per 10,000 population of the USA [15]. Acute intoxication with cardiotoxic drugs is associated with high mortality, which is around 12% worldwide, however, mortality associated with psychotropic drugs and non-cardiotoxic analgesics is around 4%. CAs were the number one cause of fatality from drug ingestion until the last decade, when they were surpassed by analgesics. Only 2–3% of (CAs) overdose cases that reach a healthcare facility result in death [16].

3. Drugs with cardiotoxic potential

The primary reasons for drug-induced cardiotoxicity and hypotension include systemic vasodilation leading to circulatory failure, myocardial depression & dysfunction, life-threatening arrhythmias. The acute toxic cardiac dysfunction is primarily associated with systolic dysfunction secondary to reduced myocardial contractility [17]. Drug-induced cardiotoxicity, commonly in the form of cardiac muscle dysfunction that may progress to cardiogenic shock, represents a major adverse effect of some common traditional anti-neoplastic agents, e.g., anthracyclines, cyclophosphamide, 5 fluorouracil, as well as newer agents such as biological monoclonal antibodies, e.g., trastuzumab, bevacizumab, and nivolumab; tyrosine kinase inhibitors, e.g., sunitinib and nilotinib; antiretroviral drugs, e.g., zidovudine; antidiabetics, e.g., rosiglitazone; as well as some illicit drugs such as alcohol, cocaine, methamphetamine, ecstasy, and synthetic cannabinoids. Most of the affected patients had no prior manifestation of the disease [18].

The cardiotoxic potential is not restricted to cardiovascular drugs only, the mortality remains higher in other drugs having membrane stabilizing activity (Tables 1 and 2) [19].

Anti-arrhythmic agents (Vaughan Williams class I) Beta Blockers Dopamine and norepinephrine uptake inhibitors (bupropion) Anti-epileptics (Phenytoin/Carbamazepine) Antimalarial agents (Quinine/Chloroquine) Polycyclic antidepressants (Imipramine, Desipramine, etc.) Opioids (dextropropoxyphene) Recreational Agents such as Cocaine

Table 1.

Drugs with Membrane Stabilizing Activity (MSA).

Calcium channel blockers Meprobamate Colchicine Cardiac glycosides (digoxin) H1 Antihistaminic Beta Blockers (not associated with membrane stabilizing activity)

Table 2.

Other drugs with cardiotoxic potential [18, 19].

4. Mechanism of toxicity and clinical manifestations

The most common cardiotoxicity clinical Case Series were reported with Tricyclic Antidepressant (TCA) toxicity and other Cardiovascular medication overdoses like Calcium channel blockers (CCBs) and beta blockers. The exact mechanism of drug-induced cardiotoxicity remains unclear, though it is likely to be multifactorial.

4.1 Tricyclic antidepressant (TCA) toxicity

Tricyclic antidepressants (TCAs) were one of the first classes of commonly prescribed antidepressants to be approved by the Food and Drug Administration (FDA). However, due to severe and potentially fatal side effects, their use in the U.S. has now been replaced by newer and safer alternatives.

Tricyclic antidepressants (TCAs) are still being used for the treatment of various conditions, including depression, migraine, headache prophylaxis, neuropathic pain, obsessive-compulsive disorder, and nocturnal enuresis. Because of their neuropsychiatric indications, they are accessible for suicidal attempts and overdose in patients with major depression [20].

Unfurtunatlly TCAs medication pharmacokinetic properities represent an ideal properities enhancing overdose toxicity; Long elimination half-life (25 to 81 hours) [21]. Large volume of distribution (10–20 L/kg) [22]. Highly bound to plasma protein (up to 95%), high lipid solubility, narrow therapeutic index (200–300 ng/mL), non-dialyzable and hemodialysis is ineffective. Major toxicity and deaths are associated with concentrations above 1000 ng/ml (Table 3) [18, 24].

Possible mechanism	Its effect
Blockade of fast sodium channels in myocardial cells.	Prolongation of phase “0” of the myocardial action potential. QRS prolongation. Bradycardia.
Blockade of potassium channel.	QT prolongation. Torsade’s de pointes.
A quinidine-like toxic effect.	Myocardial depression. Hypotension.
Blockade of peripheral alpha-adrenergic receptors.	Hypotension.

Table 3.

Mechanisms of TCA-induced cardiac toxicity [23].

TCA poisoning-related cardiovascular toxicity is evident in the presence of arrhythmia and hypotension in patients. Commonly, it causes both tachyarrhythmias and bradyarrhythmia, along with a prolongation of the QT interval seen on ECGs thus, possibly leading to Torsade de pointes [23]. TCA-associated wide complex tachyarrhythmias that originate from a ventricular origin are commonly ventricular tachycardia and ventricular fibrillation [25]. The QRS prolongation has been a vital role in determining and predicting the severity of TCA poisoning. This is why ECGs are pivotal during acute TCA poisoning and have become preferable over routine laboratory testing [26]. Bradyarrhythmia also typically occurs due to an atrioventricular block. However, the most common arrhythmia to occur due to TCA toxicity is sinus tachycardia and this is due to the anticholinergic properties of TCAs and the inhibition of NE [27]. Hypotension occurs due to a reduction in myocardial contraction and reduced systemic vascular resistance due to the alpha-adrenergic blockade [28]. This is why patients with TCA poisoning may develop acidemia due to a metabolic component from under perfused end organs and eventually respiratory acidosis due to respiratory depression, thus causing a mixed acidotic picture [29, 30]. Overall decrease in myocardial function will inevitably lead to worsening tissue hypoperfusion and hyperlacticaemia (Figures 1–4).

Figure 1.

ECG with Wide complex tachycardia, concerning for polymorphic ventricular tachycardia.

Figure 2.

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

Figure 3.

CA toxicity, characteristics, and monitoring (created by Mohamed Nassef 09dec 2023).

Figure 4.

Approach for selecting severely poisoned patient for VA ECMO [31].

4.2 Cardiovascular medication overdose

Cardiovascular medication overdose constitutes about 3.5% of all drug overdoses, and it carries a mortality of about 16% [32]. Calcium channel blockers (CCBs) are among the most used cardiovascular drugs in the adult population. Like most other medications, when calcium channel blockers are taken beyond the appropriate recommended dosage, they can have untoward toxicities with a wide range of complications that can even be fatal. Calcium channel blockers (CCB) along with β-blockers and angiotensin receptor blockers constitute more than 65% of deaths from cardiovascular medications. Overdose can cause serious mortality and morbidity. Half-life of amlodipine and telmisartan are 34 to 50 hours and 24 hours, respectively [33]. The overdose of these drugs can cause profound refractory hypotension, bradyarrhythmia, and shock. The combination of these drugs may blunt the sympathetic and vasoconstrictive responses and worsen CCB toxicity [34]. Toxicity can be delayed up to 16 hours after the ingestion of sustained-release formulations. Initial symptoms may be as nonspecific as dizziness, fatigue, and lightheadedness, and in severe toxicities, it may rapidly decline to alter mental status, coma, hypotension, and bradycardia.

Hypotension and bradycardia, when progressive, can eventually lead to cardiogenic shock. Also, hyperglycemia is common with all subclasses of CCBs and can be a useful clinical marker for poisoning severity. Both effects lead directly to metabolic acidosis [35, 36, 37]. It is also common to develop mild hypokalemia and mild to severe hypocalcemia [38]. All CCBs are very well absorbed orally across the subtypes, undergo extensive hepatic first-pass metabolism, are lipophilic, bind readily to plasma proteins, and have a large volume of distribution (> 2 liters/kg). Elimination by hemodialysis or hemofiltration is ineffective because they are highly protein-bound with a large volume of distribution [39, 40]. The most common ECG abnormalities involving calcium channel blockers other than dihydropyridines are sinus bradycardia, variable degrees of atrioventricular blocks, bundle branch block, QT prolongation, and junctional rhythms. Dihydropyridines maintain normal sinus rhythm and can cause reflex sinus tachycardia. Echocardiography may show good left ventricular function, normal functioning valves, and an ejection fraction of 40–60%.

Because of their similarity of end-organ affinity, pharmacological action, and target patients, beta blockers are the most common confounders. Compared to CCBs, beta blockers are less likely to cause hyperglycemia in adult patients [41]. However, an initial presentation with bradycardia and hypotension should prompt consideration of a wide array of pharmacological agents, including:

• Beta blocker toxicity

• Tricyclic antidepressant toxicity

• Digoxin toxicity

• Clonidine overdose

• Sedative-hypnotic toxicity

• Opiate overdose

• Organophosphate poisoning

5. Evidence behind the role of VA ECMO in drug intoxication

The available literature is restricted to case reports or case series with few patients only. However, these results are promising and encouraging, the use of VA ECMO in refractory shock due to drug intoxication. 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 to use of ECMO for other indications [42]. VA ECMO is a lifesaving therapeutic option, considered a bridge for recovery in TCA and Venlafaxine-induced cardiac toxicity. Since 1993, Goodwin DA and colleagues reported a case of near-fatal TCA overdose that failed to respond to standard therapy but was resuscitated using extracorporeal circulation [43]. Weinberg et al. described the successful use of VA ECMO in two patients with refractory vasodilatory shock associated with amlodipine poisoning [44]. C. Vignesh and colleagues reported a clinical Case Series using veno-arterial extracorporeal membrane oxygenation (VA ECMO) circulatory support as a salvage therapy in patients resistant to maximal medical management for drug overdose [45]. The cornerstone of medical management for drug overdoses consists of limiting their absorption and hemodynamic support until they are metabolized and eliminated from the body. Gastric decontamination with activated charcoal to limit the absorption can be attempted when done early [46]. Volume resuscitation with fluids to overcome the relative hypovolemia associated with vasodilation and inotropic/vasopressor use are the mainstay. Treatment with sodium bicarbonate remains the standard of care for TCA poisoning [47]. In CCB overdose, calcium infusion can be initiated to overcome the calcium channel antagonism. The increased transcellular calcium gradient drives calcium intracellularly and antagonizes the effect of CCBs [48].

5.1 Role of VA ECMO in drug intoxication

The reversibility in cardiotoxicity, especially in the case of refractory shock not responding to conventional measures, may raise questions regarding the role of VA ECMO as a lifesaving procedure. VA ECMO may be useful in providing adequate cardiac output and maintaining tissue perfusion, which helps in redistribution of the toxic substances and their metabolites from central circulation and facilitates the metabolism and excretion of drugs by improving hepatic and renal blood flow [49].

5.1.1 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 are having 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 VA ECMO support depends on several factors such as severity of toxicity and recovery cardiac dysfunction, half-life of toxin, and organ dysfunction at the time of initiation of VA ECMO, etc. [50, 51] Veno-arterial (VA) ECMO reduced cardiac oxygen consumption and provided both hemodynamic and respiratory support as a bridge to recovery [52]. Even in cases of multiple drug intoxication or unknown poisoning with cardiogenic shock, ECMO support can be beneficial (Table 4) [55, 56].

Published case reports	Ingested agent	The duration of ECMO (hours)
Goodwin et al. 1993	Desipramine	60
Williams et al. 1994	Imipramine	7
Kobayashi et al. 2011	Nortriptyline	14
Kejiri et al. 2021	Amitriptyline	27

Table 4.

Duration of mechanical support as a bridge to recovery [43, 44, 45, 53, 54].

5.1.2 Bridge to antidote

VA ECMO can be helpful in life-threatening arrhythmia or cardiovascular collapse with those toxins that 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 improve the digitalis-induced arrhythmias and cardiac toxicity. However, Digoxin poisoning is uncommon and Fab fragments are expensive with limited shelf life. Patients can be supported with VA ECMO until Fab is administered [57, 58].

5.1.3 Bridge to toxin elimination with renal replacement therapy

VA ECMO may be considered to maintain hemodynamics. The RRT may be added to ECMO circuit or may be started separately to eliminate the toxin [59]. The various techniques used for toxin removal include dialysis, hemoperfusion, and hemofiltration. The basic principle of dialysis involves diffusion through a semipermeable membrane, whereas in hemoperfusion, the toxin is adsorbed on the adsorbent surface of the dialyzer. The mechanism of hemofiltration is convection across the membrane. These therapies may be used as a single or in combination. The decision about dialyzing the toxic substance depends on the molecular weight, protein binding, and volume of distribution of the toxin. Large molecular weight medications are poorly dialyzed. Toxic substances that are highly protein-bound are less available for removal through renal replacement therapy (RRT). If the toxic substance has a large volume of distribution, elimination of toxic substance will be prolonged because RRT will remove toxic substance from plasma space only [60].

5.1.4 Bridge to transplant

VA ECMO can be useful as a bridge to a permanent assist device and heart transplant in patients with persistent irreversible cardiac failure.

6. Approach for selecting severely poisoned patients for VA ECMO

7. Hemodynamic aspects of VA ECMO support

VA ECMO has the highest capability to reduce myocardial pressure-volume area (sum of myocardial potential energy and myocardial stroke work) in patients with cardiogenic shock CS reducing left ventricular end-diastolic volume (LVEDV) and left ventricular end-diastolic pressure (LVEDP) while providing complete hemodynamic and respiratory support. The myocardial pressure-volume area is further reduced by the weaning of inotropes and vasopressors. All these prevent the vicious cycle of maladaptive neurohormonal and vascular mechanisms. Also, native RV function is not critical to provide systemic perfusion due to its reduced reliance on transpulmonary flow. VA ECMO improves systemic perfusion by increasing the main arterial blood pressure MAP, reducing central venous pressure CVP, and increasing the systemic arteriovenous pressure gradient. This maintains the organ function and reduces the generation and accumulation of toxic metabolites. This may be particularly relevant to improving blood flow in organs with portal circulation, such as the liver and kidney. Fluid removal and reducing venous congestion can be further enhanced by splicing a continuous renal replacement therapy using veno-venous hemodialysis mode (CVVHD) into the VA ECMO circuit [61, 62, 63, 64, 65].

8. Conclusion

VA ECMO has been recognized as a pivotal advancement in the treatment of severe drug overdoses, particularly those leading to cardiovascular shock and complications. It transcends the capabilities of traditional therapies by offering critical, lifesaving support in instances of severe cardiotoxicity and refractory shock. Its primary functions include the stabilization of cardiovascular dysfunction, management of shock, and support during acute renal failure, often seen in overdoses involving cardiotoxic drugs like TCAs and CCBs. The importance of VA ECMO lies in its ability to ensure continuous tissue perfusion and oxygenation, thereby facilitating the detoxification process and aiding in the elimination of toxic substances from the body. This makes it an essential bridge to recovery or transplant, especially in cases where the patient’s condition does not improve with conventional treatment methods. Furthermore, VA ECMO plays a vital role in reducing cardiac stress and maintaining systemic circulation, which is crucial in managing the high mortality and morbidity associated with drug overdoses.

Overall, the increasing reliance on VA ECMO in the realm of critical care highlights its effectiveness in handling complex, life-threatening scenarios caused by drug intoxication. This underscores its indispensable role in modern medical practice, marking it as a cornerstone in the management of drug overdose-induced complications.

Acknowledgments

We extend our deep thanks to the Emirates Health Services (EHS) and its leadership for the unlimited support for the continuation of the ECMO program.

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

We would like to thank Dr. Javed khan, head of the ECMO program at Al Qassimi Hospital, and all the program members.

Thanks to Dr. Sumaya Abdulatif CMO of Al Qassimi Hospital.