Pesticides and cardiotoxicity. Where do we stand?

Cardiovascular diseases are among the most significant causes of mortality in humans. Pesticides toxicity and risk for human health are controlled at a European level through a well-developed regulatory network, but cardiotoxicity is not described as a separate hazard class. Specific classification criteria should be developed within the frame of Regulation (EC) No 1272/2008 in order to classify chemicals as cardiotoxic, if applicable to avoid long-term cardiovascular complications. The aim of this study was to review the cardiac pathology and function impairment due to exposure to pesticides (i.e. organophosphates, organothiophisphates, organochlorines, carbamates, pyrethroids, dipyridyl herbicides, triazoles, triazines) based on both animal and human data. The majority of human data on cardiotoxicity of pesticides come from poisoning cases and epidemiological data. Several cardiovascular complications have been reported in animal models including electrocardiogram abnormalities, myocardial infarction, impaired systolic and diastolic performance, functional remodeling and histopathological findings, such as haemorrhage, vacuolisation, signs of apoptosis and degeneration.

The safety of high-dose insulin euglycaemia therapy in toxin-induced cardiac toxicity.

CONTEXT: High-dose insulin euglycaemia (HIE) is recommended in the management of toxin-induced cardiac toxicity, with increasing insulin doses now being used. We aimed to investigate the safety of HIE in toxin-induced cardiac toxicity. METHODS: This was a retrospective review of cases from two clinical toxicology units. Demographics, toxin(s) ingested, clinical effects, investigations (serum glucose, electrolytes), treatments (insulin, glucose, electrolyte replacement), length of stay (LOS) and outcomes were extracted from the patients' medical records. Associations between insulin and glucose/electrolyte homeostasis were explored by comparing insulin administration and glucose or electrolyte concentrations and replacement. RESULTS: There were 22 patients (12 females), median age 57 years (15-88 years) treated with HIE. There were 12 beta-blocker, six calcium channel blocker and three combined beta-blocker and calcium channel blocker ingestions. A total of 19 patients had a systolic blood pressure <80mmHg and 18 patients required inotropes in addition to HIE. There were three deaths. Despite glucose and electrolyte replacement, 16 patients (73%) developed hypoglycaemia (Reference range [RR] < 3.5 mmol/L or <63 mg/dl). In 7 patients, hypoglycaemia was mild (2.5-3.4 mmol/L or 45-62 mg/dl) and in nine was severe (<2.5 mmol/L or <45 mg/dl). There were no neurological effects from hypoglycaemia. A total of 18 patients (82%) developed hypokalaemia (<3.5 mEq/L). In 16 patients, this was mild (2.5-3.4 mEq/L). There were no cardiac arrhythmias associated with this hypokalaemia. There was no apparent association between insulin dosing and severity of hypoglycaemia or hypokalaemia, or in glucose or potassium replacement. Median insulin loading dose was 80U (range 50-125 U) and the median maximum insulin infusion rate was 150 U/h (range 38-1500 U/h). Median glucose infusions rates were 37.5g/h (range 4-75g/h). There was no apparent association between insulin and glucose administration. Glucose was administered for a median of 18h after ceasing insulin. The duration of glucose administration after ceasing insulin increased with the rate and total insulin administered during HIE. DISCUSSION: Despite the benefits of HIE in toxin-induced cardiac toxicity, it caused significant disruption to glucose and electrolyte homeostasis, although there were no apparent complications from this. There was no association by comparing the amount of insulin administered on adverse effects or glucose administered, suggesting higher doses of insulin are associated with no more adverse effects.

Death of a South American fur seal (Arctocephalus australis) after the ingestion of toads--evaluation of toad poisoning by toxicological analysis.

Animals in zoological gardens are at risk of severe and even lethal poisoning when they accidentally ingest toads. Here we report the case of an eleven month old male South American fur seal (Arctocephalus australis) which was found dead in its outdoor enclosure in the zoo of Dortmund, Germany. Autopsy revealed the presence of two adult, partly digested common toads (Bufo bufo) in the stomach. Toxicological analysis of the stomach content using high performance liquid chromatography coupled to time-of-flight mass spectrometry (LC-TOF MS) proved the presence of bufadienolides, the major cardiotoxic components of toad poisons. Using electrochemical luminescens immunoassay (ECLIA) compounds equivalent to digitoxin were detected in the blood sample confirming the absorption of toad poison components from the intestines into the circulation potentially leading to cardiac failure. In zoological gardens special precautions are necessary to protect non-native animals from encountering toads and the risk of poisoning, particularly in early spring, the spawning period of the toads.

Venoarterial extracorporeal membrane oxygenation for patients in shock or cardiac arrest secondary to cardiotoxicant poisoning: a cost-effectiveness analysis.

PURPOSE: Venoarterial extracorporeal membrane oxygenation represents an emerging and recommended option to treat life-threatening cardiotoxicant poisoning. The objective of this cost-effectiveness analysis was to estimate the incremental cost-effectiveness ratio of using venoarterial extracorporeal membrane oxygenation for adults in cardiotoxicant-induced shock or cardiac arrest compared with standard care. MATERIALS AND METHODS: Adults in shock or in cardiac arrest secondary to cardiotoxicant poisoning were studied with a lifetime horizon and a societal perspective. Venoarterial extracorporeal membrane oxygenation cost effectiveness was calculated using a decision analysis tree, with the effect of the intervention and the probabilities used in the model taken from an observational study representing the highest level of evidence available. The costs (2013 Canadian dollars, where $1.00 Canadian = $0.9562 US dollars) were documented with interviews, reviews of official provincial documents, or published articles. A series of one-way sensitivity analyses and a probabilistic sensitivity analysis using Monte Carlo simulation were used to evaluate uncertainty in the decision model. RESULTS: The cost per life year (LY) gained in the extracorporeal membrane oxygenation group was $145 931/18 LY compared with $88 450/10 LY in the non-extracorporeal membrane oxygenation group. The incremental cost-effectiveness ratio ($7185/LY but $34 311/LY using a more pessimistic approach) was mainly influenced by the probability of survival. The probabilistic sensitivity analysis identified variability in both cost and effectiveness. CONCLUSION: Venoarterial extracorporeal membrane oxygenation may be cost effective in treating cardiotoxicant poisonings.

Intravenous lipid emulsion for the treatment of drug toxicity.

Intravenous lipid emulsion (ILE) has emerged as a powerful antidote for the treatment of drug toxicity in the past decade. Initial efficacy of ILE was shown in the setting of local anesthetic systemic toxicity (LAST), but recent case reports suggest its consideration in a variety of other drug toxicities. In this review, we will summarize the experimental evidence as well as the clinical experience in using ILE as an antidote. Specifically, we will look at the evidence for using ILE in LAST as well as toxicity due to beta-blockers, calcium-channel blockers, and tricyclic antidepressants. We will also review the current dosing recommendations as well as potential side effects of ILE as an antidote.

Delayed bupropion cardiotoxicity associated with elevated serum concentrations of bupropion but not hydroxybupropion.

CONTEXT: Bupropion overdose commonly causes generalized seizures and central nervous system depression. Less commonly, cardiotoxicity has been reported. The toxicity of the parent drug compared to its active metabolite hydroxybupropion is uncertain. CASE DETAILS: A 31-year-old man presented to the emergency department with altered mental status after an intentional overdose of bupropion. Three hours after admission he developed status epilepticus requiring intubation, and 13 h after admission he developed marked widening of the QRS complex and prolongation of the QTc interval. Serial serum bupropion levels peaked with the onset of cardiotoxicity (334 ng/mL) and fell into the therapeutic range within 24 h, which coincided with normalization of his ECG intervals. Levels of the metabolite hydroxybupropion peaked later (4302 ng/mL) and remained elevated even after neurological and cardiotoxic symptoms resolved. DISCUSSION: Cardiotoxicity appears to be caused primarily by bupropion rather than its active metabolite hydroxybupropion.

A review of emergency cardiopulmonary bypass for severe poisoning by cardiotoxic drugs.

Cardiovascular collapse remains a leading cause of death in severe acute drug intoxication. Commonly prescribed medications such as antidysrhythmics, calcium channel antagonists, and beta adrenergic receptor antagonists can cause refractory cardiovascular collapse in massive overdose. Emergency cardiopulmonary bypass (ECPB), a modality originating in cardiac surgery, is a rescue technique that has been successfully implemented in the treatment of refractory cardiogenic shock and cardiac arrest unresponsive to traditional medical interventions. More recently a growing number of animal studies, case reports, and case series have documented its use in refractory hemodynamic collapse in poisoned patients. This article will review current ECPB techniques and explore its growing role in the treatment of severely hemodynamically compromised poisoned patients.

[Intravenous fat emulsions in toxicology]. / Dozylne emulsje tluszczowe w toksykologii.

Lipid emulsion intravenous infusion is recommended in reversing cardiac toxicity of local anaesthetics. Recent reports indicate, that it may be useful in the treatment of cardiotoxic drug overdose. While the mechanism of action is not fully understood, creation of a "lipid sink" is the predominant effect. The aim of the paper is to present the efficacy and indications for the use of lipid emulsion in acute poisoning, basing on the medical literature.

Prognostic value of plasma B-type natriuretic peptide in patients with severe cardiotoxic drug poisoning.

BACKGROUND/OBJECTIVES: Cardiotoxic drug poisoning can lead to severe cardiac shock (CS) and death. B-type natriuretic peptide (BNP) is a well-established diagnostic and prognostic marker in heart failure but has never been assessed in patients with cardiotoxic drug poisoning. The aim of the study was to determine whether BNP could be useful for early stratification of patients admitted to intensive care unit. METHODS: 30 consecutive patients experiencing shock and cardiotoxic drug exposure were enrolled in a prospective monocentric study and underwent at least two BNP measurements within the first 24 h after admission. RESULTS: While BNP values on admission were poorly informative, subsequent BNP measurements (11 ± 6 h after admission) were significantly increased in patients with CS compared to those with non-CS (756; [364-1130] versus 24; [15-65] pg/ml respectively; P = 0.008). This second BNP level was also significantly increased in non-survivor patients compared to survivor patients (784; [654-1028] versus 29; [15-104] pg/ml respectively; P = 0.05): BNP levels above 360 pg/ml predicted in-hospital mortality (sensitivity = 100%, specificity = 92%). In a multivariate analysis, BNP, SAPS II score and lactate blood level were associated with death. CONCLUSIONS: Serial BNP measurements after admission for cardiotoxic drug poisoning are useful to identify patients at the highest risk of CS as well as in-hospital death.

Cardiotoxic overdose treated with intravenous fat emulsion and high-dose insulin in the setting of hypertrophic cardiomyopathy.

High-dose insulin (HDI) and intravenous fat emulsion (IFE) are used in overdoses, although rarely combined. To our knowledge, IFE therapy has not been reported in overdoses of diltiazem, metoprolol and amiodarone. We report a severe overdose of these drugs treated with HDI and IFE in a patient with hypertrophic cardiomyopathy (HCM). We also discuss the potential clinical implications of the inotropic effects of HDI in the setting of HCM and the use and efficacy of IFE in this overdose.

Intravenous lipid emulsion in clinical toxicology.

Intravenous lipid emulsion is an established, effective treatment for local anesthetic-induced cardiovascular collapse. The predominant theory for its mechanism of action is that by creating an expanded, intravascular lipid phase, equilibria are established that drive the offending drug from target tissues into the newly formed 'lipid sink'. Based on this hypothesis, lipid emulsion has been considered a candidate for generic reversal of toxicity caused by overdose of any lipophilic drug. Recent case reports of successful resuscitation suggest the efficacy of lipid emulsion infusion for treating non-local anesthetic overdoses across a wide spectrum of drugs: beta blockers, calcium channel blockers, parasiticides, herbicides and several varieties of psychotropic agents. Lipid emulsion therapy is gaining acceptance in emergency rooms and other critical care settings as a possible treatment for lipophilic drug toxicity. While protocols exist for administration of lipid emulsion in the setting of local anesthetic toxicity, no optimal regimen has been established for treatment of acute non-local anesthetic poisonings. Future studies will shape the evolving recommendations for lipid emulsion in the setting of non-local anesthetic drug overdose.

Double lethal coconut crab (Birgus latro L.) poisoning.

We report a double lethal coconut crab Birgus latro L. poisoning in New Caledonia. Both patients died after showing gastro-intestinal symptoms, major bradycardia with marked low blood pressure, and finally asystolia. Both had significative hyperkaliemia, suggesting a digitaline-like substance intoxication. Traditional knowledge in the Loyalty Islands relates coconut crab toxicity to the consumption of the Cerbera manghas fruit by the crustacean. Elsewhere previous descriptions of human poisoning with the kernel of fruits of trees belonging to the genus Cerbera, known to contain cardiotoxic cardenolides, appear to be very similar to our cases. Cardenolides assays were performed on patient's serum samples, fruit kernel and on the crustacean guts, which lead us to suppose these two fatal cases were the result of a neriifolin intoxication, this toxin having been transmitted through the coconut crab.

Intravenous lipid emulsion as antidote beyond local anesthetic toxicity: a systematic review.

OBJECTIVES: The objective was to asses the efficacy of lipid emulsion as antidotal therapy outside the accepted setting of local anesthetic toxicity. METHODS: Literature was accessed through PubMed, OVID (1966-February 2009), and EMBASE (1947-February 2009) using the search terms "intravenous" AND ["fat emulsion" OR "lipid emulsion" OR "Intralipid"] AND ["toxicity" OR "resuscitation" OR "rescue" OR "arrest" OR "antidote"]. Additional author and conference publication searches were undertaken. Publications describing the use of lipid emulsion as antidotal treatment in animals or humans were included. RESULTS: Fourteen animal studies, one human study, and four case reports were identified. In animal models, intravenous lipid emulsion (ILE) has resulted in amelioration of toxicity associated with cyclic antidepressants, verapamil, propranolol, and thiopentone. Administration in human cases has resulted in successful resuscitation from combined bupropion/lamotrigine-induced cardiac arrest, reversal of sertraline/quetiapine-induced coma, and amelioration of verapamil- and beta blocker-induced shock. CONCLUSIONS: Management of overdose with highly lipophilic cardiotoxic medications should proceed in accord with established antidotal guidelines and early poisons center consultation. Data from animal experiments and human cases are limited, but suggestive that ILE may be helpful in potentially lethal cardiotoxicity or developed cardiac arrest attributable to such agents. Use of lipid emulsion as antidote remains a nascent field warranting further preclinical study and systematic reporting of human cases of use.