Cardiac injury in organophosphate poisoning after acute ingestion

Abstract

Introduction

Sparse data and conflicting evidence exist on the prevalence and prognosis of organophosphate (OP)-related cardiac toxicity. We aimed to characterize the cardiac abnormalities of OP after an acute cholinergic crisis in adults without previous cardiovascular conditions.

Patients and Methods

We did a prospective observational study in a tertiary-care hospital of north India (Postgraduate Institute of Medical Education and Research, Chandigarh) in 74 patients aged ≥ 13 years admitted with acute OP poisoning after self-ingestion. A systemic evaluation, including clinical characteristics, electrocardiography, and echocardiography, was performed to estimate the prevalence and prognosis of cardiac injury. A rate-corrected QT interval was calculated using Bazett’s method, and >440 milliseconds was used to define prolongation.

Results

Chlorpyrifos was the most commonly ingested OP (n = 29). The patients had a similar occurrence of hypotension (n = 10) and hypertension (n = 9) at admission, and electrocardiography demonstrated sinus tachycardia in 38 (51.3%) and sinus bradycardia in one case. During the hospital stay, 3 out of 74 patients had a prolonged rate-corrected QT interval (457, 468, and 461 milliseconds), and one patient developed supraventricular tachycardia. Eight (10.8%) patients developed the intermediate syndrome, and six (8.1%) died. None of the hemodynamic or electrocardiographic abnormalities was associated with in-hospital mortality or intermediate syndrome development on univariant analysis. Baseline echocardiography at hospital discharge was performed in 27 patients (admitted during 2018) and normal in all except mild tricuspid regurgitation in one. At a 6-month follow-up, 23 cases were available for cardiovascular screening (including echocardiography) and had a normal evaluation.

Conclusion

Cardiac toxicity is uncommon after acute OP self-ingestion and lacks prognostic significance.

Introduction

Pesticide ingestion continues to be important intentional self-harm in low-middle income countries that frequently presents as a medical emergency. Because of the ready availability in agricultural communities and rural areas, organophosphate (OP) compounds remain the most common pesticide used for self-poisoning [1–6]. The typical toxidrome of acute OP poisoning, i.e. cholinergic crisis, results from irreversible inhibition of acetylcholinesterase enzyme with acetylcholine accumulation at muscarinic and nicotinic synapses [7–12]. Muscarinic features consist of diarrhea, urination, miosis, bronchorrhea (or bronchospasm), bradycardia, emesis, lacrimation, low blood pressure, and salivation (an acronym DUMBBELLS is a helpful memory aid). Nicotinic stimulation at sympathetic ganglia and neuromuscular junction causes mydriasis, tachycardia, weakness, hypertension, fasciculations, shallow breathing (diminished respiratory effort), and sweating (can be remembered using the first letter of the days’ names from Monday to Sunday) [7–12]. Thus, a mnemonic ‘DUMBBELLS Monday to Sunday’ can be used to remember the overall cholinergic crisis. A combination of muscarinic and nicotinic features at presentation may be confusing and results in misdiagnosis [13, 14].

Cardiac or hemodynamic abnormalities like hypotension, bradycardia, or tachycardia are typical in acute OP poisoning and result from various mechanisms, such as autonomic disturbances (due to overstimulation of muscarinic and/or nicotinic acetylcholine receptors), consequences of hypovolemia or hypoxia, peripheral vasodilatation, and direct myocardial damage [15–24]. Muscarinic effects on the cardiovascular system include bradycardia, conduction block, and hypotension (parasympathetic overactivity), whereas nicotinic stimulation leads to hypertension and tachycardia (sympathetic overactivity). The cardiac electrophysiological abnormalities usually include ventricular tachyarrhythmias, torsades de pointes, and various electrocardiography (ECG) abnormalities such as QT interval prolongation, ST segment changes, tall T waves, premature contractions, and atrioventricular block [15–21, 25–35]. These abnormalities are strongly confounded by the hypoxia and hypovolemia associated with cholinergic crisis and more commonly reported before atropinization [12, 15].

Ludormisky et al. [36] described three phases of cardiac toxicity from OP—an initial phase of intense sympathetic stimulation is followed by the second phase of sustained parasympathetic activity, which is usually complicated with hypoxemia and manifested as ECG changes of ST-T or conduction abnormalities which can lead to ventricular fibrillation, and the final phase of prolonged QT that may be accompanied by torsades de pointes or ventricular fibrillation. Prolonged QT has also been linked with poor prognosis in a few studies [20, 31, 32]. Postmortem pathological findings in the cases with adverse cardiovascular events have described direct cardiotoxicity showing myocarditis with interstitial inflammation, lysis of myofibrils, Z-band abnormalities, and pericarditis [14, 17, 27–29]. These observations also raise an evident concern of delayed or long-term OP-induced cardiovascular effects, e.g. cardiomyopathy, heart failure, dysrhythmia, coronary artery disease, not unlike chronic neurotoxicity; however, studies addressing the issue are scarce [37].

Despite OP self-poisoning is one of the most common toxicological emergencies in India, investigations emphasizing its cardiac complications are limited. Thus, we performed this prospective observational study to estimate the prevalence and prognosis of the OP-induced cardiac effects after acute ingestion in adults.

Materials and Methods

Study design

This prospective cohort study was conducted between January 2018 and January 2020 at the emergency department (ED) of Postgraduate Institute of Medical Education and Research), Chandigarh (India). Ethical clearance was obtained from the Institutional Ethical Committee. Written informed consent was obtained from the patient or the legally authorized representative in case of the patients inability to give consent. All the authors vouch for the accuracy and completeness of study data. A.B. and A.K.P. developed the theoretical formalism. A.K.P. analyzed the data and wrote the first draft of the manuscript. All the authors were involved in managing the study patients. No one who is not an author contributed to the writing of the manuscript. A.B. supervised the project. There was no financial support or funding source for the research, authorship, or manuscript publication. A.B. (corresponding author) had full access to all the study data and had final responsibility for submitting it for publication.

Patients

We recruited consecutive adult patients (≥13 years of age) admitted because of acute consumption of OP for suicidal intention. The diagnosis was made with the history of OP self-ingestion and characteristic muscarinic and nicotinic manifestations of acute cholinergic crisis [7–10]. Patients with uncertain history, exposure with more than one or unknown compounds, preexisting cardiac conditions (e.g. coronary artery disease, cardiomyopathy, heart failure, dysrhythmia, adult congenital heart disease, rheumatic heart disease, or degenerative valve disease) were excluded.

The patients enrolled during the first year of the study (i.e. 2018) were followed at 6 months after discharge for screening for chronic cardiovascular effects with history, examination, and ECG. These patients also underwent echocardiography at the time of hospital discharge (baseline) and 6 months.

Management protocol

Emergency stabilization

Primary emergency medical care addressing the airway, breathing, and circulation was the main priority at ED admission. The patients were placed on a cardiac monitor (including ECG) and pulse oximetry. Oxygen supplementation was considered for low oxygen saturation, respiratory distress, or hypotension. Intravenous cannulation was established.

Specific therapy

Intravenous atropine was initiated by the doubling- or incremental-dose method, i.e. initially 2 mg bolus dose, to observe the patient every 5 min of each dose and to double the previous dose till atropinization [38]. Atropinization was defined based on the resolution of muscarinic cardiorespiratory features, i.e. adequate cardiovascular stability (blood pressure > 80 mm Hg and pulse rate > 80 beats per min) and dried pulmonary secretions (absent lung crackles on auscultation) [11, 12, 38]. Pupil size, sweating, muscle fasciculation, or other cholinergic features were not used to guide atropinization. For maintenance after atropinization, a per-hour atropine infusion of 10–20% of the total bolus dose required was initiated. The infusion was continued for at least 24 hours until resolution of all cholinergic features. After that, it was slowly tapered off with monitoring for recurrence of the symptoms. Oximes were not used as per standard institutional protocol given their unclear role [39, 40].

Decontamination

Gastric lavage was done within 1–2 hours of ingestion if not already performed in the previous hospital and only after the airway was secured in the patients with altered mental status. Removal of all clothing and body washing with soap and water or other antiseptics was done to prevent the cutaneous absorption of OP.

Intensive monitoring

The patients were admitted to a high-dependency emergency observation unit and were under regular cardiac monitoring. Poisoning risk stratification was done according to the Peradeniya OP severity scale based on five common manifestations of organophosphorus poisoning, i.e. pupil size, respiratory rate, heart rate, muscle fasciculation, level of consciousness (on a scale of 0 to 2 for each of five parameters, with aggregated scores of 8–11 indicating severe poisoning, 4–7 for moderate, and 0–3 for mild toxicity) [41]. The development of intermediate syndrome was clinically identified with motor weakness in the ocular, neck, bulbar, proximal limb, and respiratory muscles during resolution of the cholinergic crisis [42, 43].

Data collection

Investigators and ED staff gathered the data. During emergency stabilization, initial hemodynamic parameters, including pulse rate and blood pressure, were recorded. The patients were placed on a cardiac monitor with a five-lead ECG system (leads I, II, III, aVR, aVL, aVF, and V, applying five cardiac electrodes at both arms and legs and lower anterior chest) for immediate recognition of cardiac abnormalities. A 12-lead ECG was performed after initial resuscitation and atropinization (adequate cardiorespiratory stability). ECG was analyzed by one of the three authors (A.B., R.V., and S.G.) for heart rate, rhythm, wave(s) abnormalities, ST-T changes, and abnormal intervals. A particular emphasis was made to document the prolongation of the QT interval. Because the normal QT interval is rate-dependent (i.e. decreases as heart rate increases), a rate-corrected QT interval (QTc) was calculated using Bazett’s square root method (QTc = QT/√RR) [15, 16, 18, 20, 25, 31–33, 44]. An interval >440 milliseconds was used to define QTc prolongation. Some references provide the QTc upper normal limits as 410 milliseconds for men and 420 milliseconds for women, some give 420 milliseconds for men and 430 milliseconds for women, and others report 440 milliseconds for men and 450 milliseconds for women [25, 33, 44]. However, > 440 milliseconds cut-off is widely accepted and used in most studies describing OP’s cardiac toxicity [16, 18, 31, 32, 44]. Thus, we used it for an optimal comparison between the studies. A sinus rhythm with a heart rate of > 100 beats per min was defined as sinus tachycardia and < 60 beats per min as sinus bradycardia [44]. Hypotension was defined as a mean arterial pressure of < 70 mm Hg or systolic blood pressure of < 90 mm Hg, and hypertension as systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg.

Echocardiography was performed using the same equipment, EDGE-Sonosite Inc., USA, machine, by a trained cardiologist. Left ventricular ejection fraction (EF), cardiac chambers’ diameters, regional wall motion abnormality, and pericardial effusion were measured. Systolic dysfunction was defined with EF < 55%, and diastolic dysfunction was determined by measuring mitral inflow on Doppler analysis [e.g. the ratio of peak early filling (E) and late diastolic filling (A) velocities].

Demographic data, type and amount of OP, clinical features of toxidrome (with emphasis on cardiac symptoms, hemodynamic parameters, and cardiopulmonary auscultation), chest radiograph, and baseline laboratory tests (including complete blood count and biochemistry panel with serum electrolytes, renal and liver function tests) were systematically recorded.

Statistical analysis

The data were fed into Microsoft Excel (2016) and analyzed using SPSS version 25.0 (IBM) for mac. Descriptive statistics were obtained for all study parameters. Categorical variables were expressed in numbers and percentages. Continuous variables were analyzed as mean [± standard deviation (SD)] or median [interquartile range (IQR)] depending on whether data were normal in distribution. The Kolmogorov–Smirnov test and visual inspection of quantile–quantile plots checked the normalcy of data. Abnormal cardiac parameters were compared for the study outcomes (i.e. in-hospital mortality and development of intermediate syndrome) using the Chi-square test or Fisher exact test. The P value for statistical significance was set at < 0.05.

Results

We included 74 patients admitted with OP self-ingestion for suicidal intention. The median age was 24 years (IQR, 20–34; range, 13–92), and 42 (56.8%) were male. The study population mainly consisted of students (n = 27), farmers (n = 20), and housewives (n = 15). The OPs used for self-harm were chlorpyrifos (n = 29), phorate (n = 8), dichlorvos (n = 6), triazophos (n = 2), and unidentified compounds (n = 29). Before arrival at our medical emergency center, the median time elapsed was 8 hours (IQR, 5–18; range, 1–168). A total of 63.5% received first aid, including initial atropine treatment at the previous health care center.

All patients presented with cholinergic crisis features at ED admission. According to the Peradeniya score, the at-admission severity of the poisoning was mild, moderate, and severe in 33.8, 59.5, and 6.8% cases, respectively. Shortness of breath was the most common cardiorespiratory symptom, present in 75.7% of cases. Table 1 demonstrates baseline hemodynamic parameters, ECG abnormalities, and laboratory findings. About half of our study cohort had sinus tachycardia; in contrast, sinus bradycardia was present only in one patient. The heart rate of the patient with bradycardia did not improve after receiving initial atropine treatment in the previous hospital. The values of prolonged QTc were 457, 468, and 461 milliseconds, and the patients consumed phorate, chlorpyrifos, and an unidentified OP, respectively. The OP compound ingested by the patient with supraventricular tachycardia remained unknown. ST-T changes, premature contractions, conduction blocks, or other rhythm abnormalities were not detected in any patient during the entire hospital stay.

Table 1.

Baseline hemodynamic parameters, electrocardiography, laboratory testing in acute organophosphate self-poisoning (n = 74)

Variable(s)	Value(s)
Hemodynamic parameter  Pulse rate (beats per min), mean (± SD)  Systolic blood pressure (mm Hg), mean (± SD)  Diastolic blood pressure (mm Hg), mean (± SD)  Mean arterial pressure (mm Hg), mean (± SD)  Hypotension, n (%)  Hypertension, n (%)	86.1 (± 28.0) 109.9 (± 17.1) 69.9 (± 10.3) 83.1 (± 12.1) 10 (13.5%) 9 (12.2%)
Electrocardiographic abnormality  Sinus tachycardia, n (%)  Sinus bradycardia, n (%)  Supraventricular tachycardia, n (%)  Prolonged QTc (>440 milliseconds), n (%)  QTc value (milliseconds), mean (± SD)	38 (51.3%) 1 (1.4%) 1 (1.4%) 3 (4.1%) 397.4 (± 30.1)
Laboratory investigation, mean (± SD)  Hemoglobin (g/dL)  Total leucocyte count (per μL)  Platelet count (per μL)  Sodium (mEq/L)  Potassium (mEq/L)  Blood urea (mg/dL)  Creatinine (mg/dL)  Bilirubin (mg/dL)	12.6 (± 1.9) 14186.5 (± 5566.6) 207527.0 (± 88700.8) 139.9 (± 6.3) 3.8 (± 0.7) 29.9 (± 10.1) 0.7 (± 0.2) 0.8 (± 0.5)

The total dose of atropine required for resolving the cholinergic crisis was > 100, 11–100, and ≤ 10 mg in 45, 26, and 3 patients, respectively. Dosing of > 100 mg was required with chlorpyrifos (n = 13), phorate (n = 8), dichlorvos (n = 2), triazophos (n = 1), and unidentified compounds (n = 21). Invasive mechanical ventilation was needed in 35 (47.3%) patients during the hospital stay, most frequently in cases with chlorpyrifos (n = 11), phorate (n = 5), and unidentified compounds (n = 14). Eight (10.8%) cases developed the intermediate syndrome. The median duration of hospitalization was 5 days (IQR, 3–8; range, 1–21). Overall, six (8.1%) patients died. None of them had ECG abnormalities or dysrhythmia during the hospital stay as the patients underwent continuous cardiac monitoring. The mortality was attributed to hospital-acquired infections (n = 2), severe cholinergic crisis (n = 2), intermediate syndrome (n = 1), or pulmonary embolism (n = 1). The patients with prolonged QTc or supraventricular tachycardia did not develop the intermediate syndrome or require a hospital stay of >1 week (Table 2). The presence of hypotension, hypertension, or sinus tachycardia at admission did not predict in-hospital mortality or development of intermediate syndrome on a univariant analysis (Table 2).

Table 2.

Univariate analysis for cardiac abnormalities as predictive factors of in-hospital mortality and intermediate syndrome development in acute organophosphate poisoning (n = 74)

Parameter, n (%)	Died (n = 6)	Survived (n = 68)	P value	Patients with IMS (n = 8)	Patients without IMS (n = 66)	P value
Hypotension	2 (20.0%)	8 (80.0%)	0.184	1 (10.0%)	9 (90.0%)	0.929
Hypertension	1 (11.1%)	8 (88.9%)	0.725	0	9 (100%)
Sinus tachycardia	3 (7.9%)	35 (92.1%)	0.951	4 (10.5%)	34 (89.5%)	0.933
Prolonged QTc	0	3 (100%)		0	3 (100%)
Supraventricular tachycardia	0	1 (100%)		0	1 (100%)

IMS, intermediate syndrome.

All consecutive patients enrolled during 2018 (n = 27) underwent baseline echocardiography at the time of hospital discharge. The ingested OPs were chlorpyrifos (n = 19), dichlorvos (n = 3), triazophos (n = 1), phorate (n = 1), and unidentified compounds (n = 5). Baseline echocardiography (n = 27) was normal in all except one patient with mild tricuspid regurgitation. Post-discharge, 23 patients were available for cardiovascular screening at 6 months. Four patients lost to follow-up, including the patient with mild tricuspid regurgitation on baseline echocardiography. All were asymptomatic for chest pain, syncope, palpitation, and shortness of breath. Cardiac examination, including blood pressure, pulse rate, and heart sounds, was within normal limits in all. The ECGs were normal with a mean (± SD) heart rate of 72.9 (± 3.3) beats per min, and no abnormality was detected on echocardiography.

Discussion

Cardiotoxicity after OP self-ingestion is not usually a common concern in standard clinical practice. The present study provides a real-world scenario and demonstrates that acute and chronic cardiac injury is uncommon in adult patients admitted with a cholinergic crisis. These results contradict the previous finding of a high prevalence of various ECG abnormalities with OP poisoning and poor outcome with prolonged QT or hemodynamic abnormality. A normal cardiac evaluation (including clinical features, ECG, echocardiography) at a 6-month follow-up in about one-third of study patients also reduces the possibility of OP’s significant cardiac effects in the long term.

Consistent with most previous studies, our cohort also demonstrated sinus tachycardia more frequently than sinus bradycardia [15–20, 31]. Tachycardia has various mechanisms in OP poisoning, including direct sympathetic stimulation (accumulated acetylcholine stimulating nicotinic receptors), intravascular volume depletion (secondary to sialorrhea, diaphoresis, diarrhea, or urination), or antimuscarinic therapy [14–20]. Because nicotinic signs occur early in severe OP poisoning, the incidence of tachycardia increases with toxidrome severity [12–15]. Majority of our patients presented with moderate to severe poisoning despite ~60% received some atropine at the previous hospital, and about half required mechanical ventilation during the due course. Thus, tachycardia in our cohort, which had a severe end of the cholinergic crisis, does not exclusively reflect prior atropine administration. Moreover, none of the patients (~40%) who were brought directly to our center without primary hospital care had bradycardia at admission.

Prolonged QTc is considered a typical ECG abnormality in OP intoxication and can result in torsades de pointes, ventricular fibrillation, or sudden cardiac death [15–20, 25–32, 34]. The mechanism of prolonged QTc has been proposed as toxin-induced myocardial damage rather than autonomic effects [45]. This study observed QTc prolongation in only < 5%, which challenges the high prevalence reported in most previous reports. The most common OP ingested by our study patients was chlorpyrifos [World Health Organization (WHO) hazard class II OP]. In contrast, in previous studies showing a high prevalence of QT prolongation, the usual compounds were WHO class I a OP (e.g. methyl parathion) or WHO class I b (e.g. monocrotophos, dichlorvos, oxydemeton-methyl) [15–17, 20, 46]. Our results are also supported by unpublished data by Eddleston et al. [12], which found a very low prevalence of severe cardiac effects of WHO Class II OP in >1000 cases. Besides different OP compound ingestion, other factors such as ECG timing before or after atropine therapy, a lower cut-off value used for prolonged QTc, diverse study populations, and inherent selection bias in retrospective studies might have contributed to this discrepancy [15–20, 25–27, 33].

The possible predictive utility of the prolonged QT for intermediate syndrome and death, which has been inconsistently described previously, was not recollected in this study [20, 25, 31, 32, 34]. All three patients had a good prognosis. The only other significant ECG abnormality was supraventricular tachycardia, experienced in one case, and is rarely observed previously with OP poisoning [17]. However, in contrast to the previous reports, ST-T changes, PR prolongation, pre-excitation complexes, torsades de pointes, ventricular or atrial fibrillation, and atrioventricular block were not noted [15–20, 25–30].

Hypotension and hypertension were distributed almost equally at presentation, and their incidence correlated with previous data [15–20]. OP-induced circulatory failure may have various etiologies, including excess fluid loss, peripheral vasodilation, central sympatholytic action, or direct cardiotoxicity [15–24, 47]. Hypertension is mainly postulated to occur due to sympathetic overactivity [7, 15–19]. Hypotension or hypertension on admission did not predict a poor outcome in this study. All patients who followed up at 6 months remained normotensive.

As survival trends improve in patients with acute OP poisoning, late detrimental effects on neurological and cardiovascular functions become important considerations [37, 48]. Concerns about the potential chronic cardiac toxicity of OP have been raised by a retrospective population-based cohort study by Hung et al. [37], which had shown a higher prevalence of arrhythmia, coronary artery disease, and heart failure in patients previously admitted with acute OP poisoning than the normal population. However, our prospective study demonstrates no significant delayed cardiac complications after a systemic cardiac evaluation, including serial echocardiograms at discharge and a 6-month follow-up. Therefore, the report suggests that routine cardiovascular screening might not be required in previously healthy patients after toxidrome resolution. However, because these results represent that of a select cohort of cases, large-sized controlled studies with a longer follow-up are needed to establish the cardiac safety of OP compounds. If this low cardiac risk rate is confirmed, it will relieve additional anxiety to chronic neurotoxicity of OP.

Limitations

This study has many limitations. First, single-center experience lacks the generalizability of the results. Second, although this was the first study to our knowledge that followed OP poisoned patients with a systemic cardiac evaluation and serial echocardiography, only about one-third had an echocardiographic serial assessment because of logistic limitations. Third, circulating biomarkers of cardiac injury such as pro-B-type natriuretic peptides, troponins, creatine kinase-muscle/brain isoenzyme, and histopathological examination were not performed. Forth, in ~60% of patients referred from the primary health care centers, the precise clinical and management details (including administered atropine dosing) remained unknown; therefore, the patients were included in the study in different phases of poisoning. This also suggests that the risk stratification based on parameters before atropinization (Peradeniya scale) may not apply to a tertiary-care setup. Fifth, the OP compound remained unidentified in at least one-third of cases. We also did not document the details about the pesticide’s solvents that can contribute to systemic toxicity.

Conclusion

The current study challenges the previous findings and finds that acute and chronic cardiac injury is uncommon in adult patients admitted with a cholinergic crisis after OP self-ingestion in a real-world scenario. The presence of cardiac injury also lacks a negative predictive value for the in-hospital outcome. Systematic evaluation for chronic cardiac toxicity after toxidrome resolution might not be recommended as standard practice, as is required for chronic neurotoxicity. This study incites further investigations to evaluate cardiac abnormalities in other populations to confirm or refute these findings.

Funding

None.

Conflict of interest statement

None declared.