Extracorporeal membrane oxygenation in carbamate (methomyl) intoxication: systematic review of the literature and case presentation

1. Introduction

The original cardiopulmonary bypass was developed for adequate blood oxygenation during cardiac surgery, and extracorporeal life support was first employed for the management of acute respiratory distress syndrome in neonates. Over the past several decades, this groundbreaking device has considerably progressed, and the innovative instrument is currently accepted as an invaluable tool for treating critical patients, especially those suffering from serious respiratory and/or cardiac failure refractory to conventional management. Although there have been several reports that extracorporeal membrane oxygenation (ECMO) support is life- saving in patients with severe acute poisoning, it is extremely difficult to determine what patient should be managed with ECMO support, when ECMO support should be applied, and when ECMO support should be stopped. Because ECMO can only afford supportive therapy rather than disease-modifying treatment, patient selection is essential for the best ECMO outcome. Furthermore, ECMO support requires specialized expertise resources as well as considerable financial support; and physicians and centers frequently encounter ethical issues as well as dilemmas on proper patient selection for ECMO support. Despite remarkable advances in ECMO and critical care management, application of ECMO support for the treatment of acute poisoning is beyond the scope of our investigation. Like our presentation, the majority of reports are on a single case, and only a few excellent review articles are available on this abstruse issue. In patients with acute intoxication, definite determination of the natural history, and efficacy or alteration in invasive ECMO procedures is still lacking [1, 2, 3, 4, 5]. We investigated the organophosphate and carbamate intoxication cases treated with extracorporeal life support and/or ECMO. We reported our case of a patient with methomyl intoxication who was successfully treated using venoarterial (VA) ECMO along with detailed systematic literature review.

2. Materials and methods

3. Results

Twenty-nine published studies were carefully evaluated. Of the 29 studies, 21 were excluded and the remaining 8 were subjected to our analysis, with only 1 met the study criteria. Thus, 2 studies that include 1 previously published case and ours were systematically reviewed (Fig. 1). One case of a child treated with ECMO for carbamate intoxication was identified in the literature. After methomyl intoxication, the patient had severe clinical signs, including neurological deficits, renal insufficiency, and severe respiratory failure. This child was treated with continuous hemofiltration and ECMO, but expired after 38 days of the treatment. Our patient also presented severe cholinergic excess, which provoked cardiorespiratory his symptoms were similar to those of failure, and showed cholinergic symptoms similar to methomyl intoxication, including muscarinic and nicotinic manifestations. He also showed neurological deficits, renal insufficiency, and severe respiratory failure. He was treated with antidote along with administration of atropine and pralidoxime, hypothermia, mechanical ventilation, continuous renal replacement therapy, and ECMO. He recovered from the intoxication after 7 days of VA-ECMO. In spite of active treatment with VA-ECMO, his conscious level on discharge day was identified as a drowsy to stupor state, and a failure to full recovery to normal consciousness was related not only to acute poisoning, but also to cerebral ischemia after cardiac arrest, concerned with insufficient atropine administration.

Fig. 1.Flow diagram of the study selection process.

4. Discussion

The insecticide methomyl has the following features: Chemical Abstracts Service (CAS) Registry Number, 16752-77-5: chemical name, S-methyl N-(methylcarbamoyloxy) thioacetimidate; chemical formula, C5H10N2O2S; molecular weight, 162.20; appearance, white crystalline solid; odor, slight sulfur-like; and melting point, 78 ${}^{O}C$ to 79 ${}^{O}C$. It was first introduced by E.I. du Pont de Nemours in 1968 and was classified as a restricted-use pesticide by the US Environmental Protection Agency (EPA) in 1978 (Table 2). Methomyl is one of the carbamate insecticides that acts as a cholinesterase inhibitor and controls a broad spectrum of agricultural and household insects. It is a representative broad-spectrum carbamate insecticide which is mainly used to prevent and control pests. It is also known as lannate, mesomile, methomex, or nudrin. Methomyl is one of the most commonly used carbamate insecticides worldwide. Methomyl has a nature of white solid with sulfur smell and is soluble in water, acetone, ethanol, methanol, and other organic solvents. Methomyl pesticide is generally stable in water, so that a mixture of water and methomyl pesticide is grossly indistinguishable from water alone, which has frequently led to water-borne outbreaks [8]. It might gain access to the body not only through the respiratory tract, but also via the skin or digestive tract [9, 10, 11]. Methomyl has highly significant toxicities, and its 50% lethal dose (LC${}_{50}$ value) is reported to be 17-45 mg/kg in rats. In general, the clinical outcome of acute methomyl pesticide intoxication is poor, and human exposure to methomyl causes 3 different degrees of toxic reactions according to the exposure route: oral exposure, highly toxic; inhalation, moderately toxic; and dermal exposure, slightly toxic. It is also highly toxic to mammals, fish, and aquatic invertebrates [12].

Similar to intoxications with other carbamate insecticides, methomyl intoxication usually inhibits the activity of AChE in synaptic junctions between neurons. When acetylcholinesterase is inhibited, the hydrolytic deactivation of acetylcholine is completely blocked, which continuously stimulates postsynaptic receptors to cause nerve and tissue failures. Most of the human vital functions are controlled by the peripheral nervous system, and inhibition of these functions can be fatal in mammals. Methomyl poisoning in humans has not been fully understood, and most studies have reported sporadic cases or series of methomyl poisoning occurring accidentally as well as for suicide. The toxic effect in methomyl intoxication is considered to be perioxidative damage to hepatic, renal, and splenic cell membranes as well as DNA damage to these organs [13]. Nicotinic effects in methomyl intoxication are summarized as follows: fasciculation, muscle weakness, paralysis, depolarization due to the action of succinylcholine, central nervous and respiratory dysfunction, seizures, and unconsciousness. Generally, carbamate is less toxic than organophosphate compounds because of relatively short-term cholinesterase inhibition and rapid cholinesterase inhibitor enzyme reactivation. Actually, acute symptoms of carbamate intoxication, such as methomyl intoxication, are very similar those of cholinergic excess observed in the case of organophosphate compound intoxication. However, there is no significant difference in mortality and morbidity between carbamate and organophosphate compound intoxications [14, 15]. Therefore, for a better understanding of methomyl intoxication, it is essential to consider both carbamate and organophosphate compound intoxications. Most of these toxic materials were banned in the United States in 2001. Unfortunately, organophosphate could not be completely withdrawn from the market or banned from use due to its wide use. Especially in developing countries, it is more widely used for effective crop and vegetable protection with its advantages (1) in eliminating a broad spectrum of insects, (2) no effect on seed activity, (3) considerable cost-effectiveness, and (4) small amounts of residue on food grains [16, 17]. Several organophosphorus agents, such as tabun, sarin, and soman, were initially developed in Germany during the 1940s, the Second World War, for military purposes. The main mechanism of organophosphate toxicity is associated with neutered AChE which it renders a non-functional form. Acetylcholinesterase is the main enzyme responsible for hydrolyzing acetylcholine into choline and acetic acid, and organophosphorus compounds friendly bind with RBC AChE. Inactivated acetylcholinesterase leads to acetylcholine accumulation at neuronal synapses and neuromuscular junctions, bringing about reluctance to AChE reactivation over exposure time. Conformational change of acetylcholinesterase-organophosphorus compound is reported as aging, which render AChE irreversibly resistant to reactivation by the antidote oxime. In addition, neuropathy target esterase (NTE) are inhibited by organophosphate. However, the clinical significance of their inhibitions and interactions have not yet been fully evaluated [18].

Carbamate compounds are mainly derived from carbamic acids. Similar to organophosphorus agents, carbamate is rapidly absorbed via various exposure routes including the skin, lungs, and gastrointestinal tract. Unlike organophosphate, carbamate is a transient cholinesterase inhibitor and spontaneously hydrolyzes at the cholinesterase enzymatic site within 48 hours. However, a clear differentiation between organophosphate and carbamate intoxications is essential in clinical practice because both of them show relatively similar features. Carbamate toxicities may have shorter duration than toxicities caused by equivalent doses of organophosphate, despite similar mortality rates between subjects exposed to organophosphates and carbamate [16]. Medical applications of the carbamate compounds echothiophate, pyridostigmine, tacrine, and donepezil include reversal of neuromuscular blockade, by neostigmine or pyridostigmine/edrophonium, and treatment of glaucoma, myasthenia gravis, and Alzheimer disease. The major respiratory effects of carbamate intoxication are neuromuscular depression, bronchospasm, excessive secretion, and respiratory failure. Cardiovascular collapse or cardiorespiratory failure could be fatal, although its exact mechanism is not completely understood. Primary cardiac effects are heart block, ischemia, QT prolongation, prolonged arrhythmia, and cardiac arrest. It is not clear whether these cardiac arrhythmias are caused by direct toxicity or secondary hypoxemia [19]. Renal damage, such as acute kidney injury or acute tubulointerstitial nephritis, is relatively common and may occasionally require intermittent hemodialysis or continuous renal replacement therapy. Gastrointestinal damage, such as pancreatitis, is also uncommon.

Clinical features of carbamate intoxication generally manifest within minutes or hours after exposure, and most of the acute toxicities are related with cholinergic excess. Cholinergic excess symptoms of the intoxications can be summarized as the so-called SLUDGE-BBB: salivation, lacrimation, urination, defecation, gastric emptying, bradycardia, bronchospasms, and bronchorrhea. Other cholinergic excess symptoms are summarized as the so-called DUMBBELS: diarrhea, urination, miosis/muscle weakness, bronchorrhea, bradycardia, emesis, lacrimation, and salivation/sweating. During the period of acute toxicity, respiratory insufficiency and failure may result from respiratory muscle weaknesses, decreased respiration drives from the central nervous system, increased secretions, and bronchospasm. The symptoms of carbamate intoxication occur just 24 to 96 hours after exposure. Bulbar, respiratory, and proximal muscle weaknesses generally resolve within 1 to 3 weeks after exposure. Within several weeks after organophosphate exposure, delayed peripheral neuropathy (OPIDN) usually occurs, primarily involves motor function, resolves spontaneously, but may result in permanent neurological deficits.

A diagnosis of carbamate intoxication is based on clinical features. The clinical features of cholinergic excess should initially be considered as the possibility of carbamate poisoning, even in the absence of ingestion or exposure history. Some of the carbamate agents have characteristic petroleum- or garlic-like odor, which might be helpful in establishing the diagnosis. In clinical practice, carbamate intoxication is suspected in patients who present with the absence of anticholinergic signs, such as tachycardia, mydriasis, decreased bowel sounds, and dry skin. In patients suspected of carbamate ingestion, 1.0 mg of atropine in adults (or 0.01 to 0.02 mg/kg in children) should be administered. Atropine challenge might be helpful and life-saving, especially if a definite diagnosis is difficult to make. Diminution in signs and symptoms by anticholinergic effects following atropine administration strongly suggests acetylcholinesterase inhibitor poisoning. RBC AChE activity should be measured to make a confirmative diagnosis of carbamate intoxication. The level of RBC AChE activity is useful for evaluating the degree of toxicity. Serial measurement of RBC AChE activity ca be performed to assess the effectiveness of oxime therapy in reactivating acetylcholinesterase enzyme during chronic or occupational carbamate exposure. However, most hospital laboratories are unable to perform this measurement that requires a specialized high level of laboratory, so they measure plasma- or pseudo-cholinesterase activity instead. However, in the majority of cases, plasma cholinesterase or pseudo-cholinesterase activity does not completely reflect the severity of carbamate intoxication and should not be used in a standard rescue therapy.

Initial treatment strategies for acute toxicity are respiratory support, with 100% oxygen delivery, early intubation, and avoidance of similar pharmacological drugs such as succinylcholine. In the case of oral ingestion, decontamination with activated charcoal (50 in adult or 1.0 g/kg in children) within 1 hour would be helpful, and dermal and ocular irrigation might also be helpful. The management of carbamate intoxication focuses on treating cholinergic toxicity. Cholinergic toxicity can be treated with 2 rescue medications: one is atropine and the other is pralidoxime. Atropine has strong effects on muscarinic receptors, and tachycardia or mydriasis is not an absolute contraindication into atropine treatment. It is usually injected as a regimen of bolus doubling dose and should be escalated as a double dose every 3 to 5 minutes until bronchial secretions and wheezing resolve: loading dose, initially 2.0 mg intravenous injection, after 5 minutes 4.0 mg, after another 5 minutes 8.0 mg (total loading dose, 14 mg until atropine saturation; maintenance dose, 1.4 mg/hour). Atropine has profound effects on secretion clearance and bronchospasm relief. In several intoxication cases, hundreds of milligrams of atropine are needed for several days. Pralidoxime exerts effects on main nicotinic and minor muscarinic receptors. Pralidoxime is usually intravenously given as a dose of 2.0 (25 mg/kg in children) for 30 minutes as a loading dose and at a dose of 8.0 mg/kg/hour (10 mg/kg/hour in children) as a maintenance dose. It has significant effects on dissociation of organophosphate and AChE band as well as reactivation of acetylcholinesterase, which terminates the action of the neurotransmitter acetylcholine. The main mechanisms underlying pralidoxime rescue are AChE reactivation, acetylcholine degradation, and consequently decreased acetylcholine concentration. However, atropine has a little different rescue medication effect: competition with an intoxication regimen on acetylcholine receptors. Taken together, both atropine and palidoxime are essential for the treatment of the intoxication. Furthermore, benzodiazepine therapy using intravenous (IV) diazepam 10 mg in adults (0.1 to 0.2 mg/kg in children) should be repeated as if seizures occur [16, 17, 18, 19].

The clinical features and characteristics observed in our case are not different from those of a previous case report, except for application of extracorporeal membrane oxygenation to treat respiratory and cardiac failures in methomyl intoxication. ECMO is commonly defined as a device that supports the cardiopulmonary system by adequate oxygenation, carbon dioxide removal, and adequate perfusion in a patient with cardiac and/or respiratory failure. The ECMO unit pumps hypoxic and hypercapnic blood out of a patient’s body, runs it through an artificial lung membrane where carbon dioxide is adequately removed and oxygen is supplied, and then returns oxygenated and eucapnic warm blood into the patient’s body. In intoxication, ECMO bypass of the heart and lungs permits the heart, lungs, and involved organs to recover from toxic insult and to maintain the delivery of oxygenated, eucapnic, nutritious blood to all tissues while allowing for continual elimination of toxins. To the best of our knowledge, this is the first case report of successful application of extra-corporeal membrane oxygenation for the treatment of respiratory failure and cardiac failure which resulted from methomyl intoxication. Direct evidence originates from case reports, case series, and observational cohort studies. Symptomatic and supportive care still remains the mainstay of intoxication treatment. Extracorporeal membrane oxygenation, a supportive treatment option, would be the most aggressive supportive modality. As previously described, extracorporeal membrane oxygenation is commonly defined as a device that supports the cardiopulmonary system by adequate oxygenation, carbon dioxide removal, and adequate perfusion in a patient with cardiac and/or respiratory failure. This is an external instrument that supports the cardiopulmonary system through sufficient oxygenation and hemodynamic support in a patient with cardiac and/or respiratory failure, caused by various medical and surgical conditions, leading to cardiovascular collapse, respiratory failure, cardiogenic shock, or refractory hypotension. ECMO could be an effective modality of treatment for patients with toxin exposure, because hemodynamics and oxygenation would be supported while the toxin is metabolized and eliminated. ECMO might be helpful in the setting of toxin exposure that results in cardiorespiratory failure or metabolic dysfunction, and for itself does not remove or neutralize any toxins, but provides hemodynamic support and oxygenation until elimination of the toxin or eventual end-organ recovery. ECMO might play a role in managing severe intoxication patients, along with other rescue therapies and supportive interventions.

Numerous human case reports/series have shown considerably favorable outcomes after ECMO application in intoxication patients involving a variety of pharmaceuticals including tricyclic antidepressants, cardiovascular medications, and anti-dysrhythmics such as lidocaine, amitriptyline, verapamil, acebutolol, flecainide, digoxin, disopyramide, diltiazem, and betaxolol. Most of the pharmaceutical exposures in individual cases were similar to those in cases already reported in the literature, leading to cardiotoxicity or hemodynamic collapse. Non-pharmaceutical exposure to non-pharmaceutical agents, such as carbon monoxide, zinc, arsenic, hydrocarbon, and taxus, which requires ECMO as a treatment modality, has been sparingly reported. Despite successful treatment of intoxicated patients with ECMO, it is not clear whether ECMO would improve survival in intoxicated patients and exactly when ECMO should be initiated. ECMO application prior to cardiovascular collapse can improve overall survival. As mentioned above, our case displayed signs of severe toxicity, including metabolic acidosis, seizures, coma, cardiac dysrhythmias, and hypotension, prior to receiving ECMO. An attempt to initiate ECMO during cardiac arrest is extremely difficult because it requires a relatively long time of pauses in cardiopulmonary resuscitation during cannulation. In addition, apart from clinical course of intoxication, ECMO itself is at high risk of potential complications, including limb ischemia, compartment syndrome, stroke, acute kidney injury, bleeding, emboli, and infection. Furthermore, physicians must consider several risk factors in individual patients, such as advanced age, co-morbidities, risk for complications, survivability, exposure to specific drugs or chemicals, and duration of hypoperfusion or cardiac arrest. Large amounts of resources are required to perform and manage ECMO, and only a few facilities have the ability to activate ECMO in a timely fashion.

DeLange et al. [4] reported 16 patients with toxin-induced refractory shock and acute respiratory distress syndrome requiring ECMO as well as calcium channel antagonists, beta blockers, and hydrocarbons, in their retrospective chart review using the California Poison Control System (CPCS) database from the American Association of Poison Control Centers (AAPCC). They analyzed patients who were treated with ECMO for a wide array of clinical manifestations, such as hypotension (69%), asystole (44%), and respiratory arrest (31%) as well as side effects of cardiovascular drugs such as beta-blockers, diltiazem, amlodipine, flecainide, digoxin, and hydrocarbons. Of the 16 patients who received ECMO, 12 were managed with VA-ECMO and 4 were treated with venovenous ECMO; 13 (81%) recovered and 3 (19%) died. Wang et al. [20] performed a retrospective review of the American College of Medical Toxicology (ACMT) Toxicology Investigators Consortium (ToxIC) for the evaluation of ECMO application in toxin exposure. They evaluated 26,271 patients (male : female, 4 : 6) reported to the ToxIC Registry from January 1, 2010 to December 31, 2013, and found only 10 (0.0038 %) patients receiving ECMO treatment, who were exposed to carbon monoxide/smoke inhalation, bitter almonds, methanol, or several medications, including antihistamines, antipsychotic/antidepressant, cardiovascular drugs, analgesics, sedative/hypnotics, and antidiabetics. They showed the overall survival rate of as high as 80% after treatment with ECMO and concluded that ECMO should be initiated prior to cardiovascular failure. Weiner et al. [21] performed clinical analysis of 104 poisoning patients with severe or refractory drug-induced cardiovascular shock who were managed with VA-ECMO, by systematic search of the Extracorporeal Life Support Organization (ELSO) ECMO case registry. The first case of poisoning treated with VAMO occurred in 2009 and the remaining cases had developed until 2017. In the 104 intoxicated patients under ECMO, the most common poison was cardiovascular agents (n = 49, 47.1%), followed by opioids (n = 9, 8.7%), cocaine (n = 4, 3.8%), antidepressants (n = 4, 3.8%), anticoagulants (n = 3, 2.8%), solvents (n = 3, 2.8%), antiepileptics, antineoplastics, hypoglycemic phosphorus (n = 2, 1.9%, respectively), antibiotics, hallucinogen, metals, smoke, propionic acids, carbon monoxide, aminophenol, psychostimulants, and tranquilizers (n = 1, 0.9%, respectively).

In the cases presented, it is not easy to assess why and how the extremely toxic symptoms, such as respiratory failure and cardiac failure, developed just 1-2 minutes after ingestion of a suspected drink. This catastrophic presentation is due partly to quick delivery of the poison absorbed from the stomach to vital organs and partly to the synergism between methomyl and other toxic chemicals.

5. Conclusions

ECMO has rarely been applied in intoxicated patients. ECMO shows a variety of clinical courses. In most cases, including ours, ECMO might be a useful supportive treatment option when administered prior to cardiac arrest, improving survival. Decisions should be made in conjunction with a multidisciplinary team of toxicologists, intensivists, and surgeons. Intoxications by anticholinesterase compounds are not uncommon, and this public health threat should be prevented and completely eradicated by the health authorities. Severe and serious intoxications can be complicated by life-threatening multiorgan failure during and after the initial phase of intoxication, and can progress into prolonged disability or even death. In such intoxications, ECMO support can be an alternative to overcome cholinergic excess symptoms such as respiratory, cardiovascular, and cardiorespiratory failures.

Abbreviations

AAPCC, American Association of Poison Control Centers; AChE, acetylcholinesterase; ACMT, American College of Medical Toxicology; ADM, admission day; ALB, albumin; AML, amylase; AMN, ammonia; aPTT, activated partial thromboplastin time; ARDS, acute respiratory distress syndrome; AT-III, anti-thrombin-III; BE, base excess; BNP, Brain natriuretic peptide; Bu-AChE, butyl-cholinesterase; BUN, blood urea nitrogen; Ca, calcium; CAS, Chemical Abstracts Service; CK-MB, Creatine Kinase MB isoenzyme; Cl, chloride; CPCR; cardio-pulmonary cerebral resuscitation; CPCS, California Poison Control System; CPK, creatine phosphokinase; CPR, cardiopulmonary resuscitation; Cr, creatinine; CRP, C-reactive protein; CRRT, continuous renal replacement therapy; DB, direct bilirubin; ECMO, extracorporeal membrane oxygenation; EDC, emergency department center; ELSO, Extracorporeal Life Support Organization; EPA, Environmental Protection Agency; FDP, fibrin degradation product; GCS, Glasgow coma scale; Glu, glucose; r-GTP, gamma-glutamyltransferase; Hb, hemoglobin; Hct, hematocrit; HD, hospitalization day; ICU, intensive care unit; IRB, Institutional Ethics Committee/Review Board; INR, international normalized ratio; IV, intravenous; K, potassium; LC50, the acute 50% lethal concentration lethal dose; LDH, lactate dehydrogenase; Na, sodium; na, not available; OPIDN, organophosphorus agent-induced delayed peripheral neuropathy; OSM, osmolarity; P, phosphate; PDT, percutaneous tracheostomy; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PT, prothrombin time; RA, re-arrest; RBC, red blood cell; ROSC, return of spontaneous circulation; SGOT, serum glutamate oxaloacetic transaminase; SGPT, glutamate pyruvate transaminase; TB, total bilirubin; Ti, Troponin I; T-PRO, total protein; ToxIC, Toxicology Investigators Consortium; VA, veno-arterial; WBC, white blood cell.

Ethics approval and consent to participate

The present study was approved by the Institutional Ethics Committee/Review Board of Konkuk University Chungju Hospital, which waived the requirement for informed patient consent due to its retrospective case reporting nature (IRB approval no., KUCH 2020-02-005). All subjects enrolled in this research have given their informed consent, which has been approved by my institutional committee on human and/or animal research, and this protocol has been found acceptable by them.

Authors contribution

HY Kim, JS Kim, WS Lee, SA Lee, JY Kim, YH Kim, CK Chee and Michael JI conceived of and designed the study, collected and interpreted the data, and drafted the manuscript. WS Lee and JS Kim collected and interpreted the data. SA Lee, WS Lee and Michael Ji analyzed and interpreted the data, and performed statistical analyses. WS Lee and JJ Hwang participated in the study design, and revised the manuscript. WS Lee and Michael Ji critically reviewed the manuscript. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work.

Acknowledgments

Thanks to all the peer reviewers for their opinions and suggestions.

Conflict of interest

The authors declared no conflict of interest with respect to the authorship and/or publication of this article.

Availability of data and material

The datasets generated and/or analyzed during the present study are available from the corresponding author on reasonable request.

Footnotes

1. Reporting Checklist: The authors have completed the PRISMA reporting checklist.

2. Conflicts of Interest: The authors declared no conflict of interest with respect to the authorship and/or publication of this article. All authors have completed the ICMJE uniform disclosure form.

3. Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

4. Consent for publication: Written informed consent for publication of clinical data and clinical images was obtained from the patient.