|Year : 2017 | Volume
| Issue : 3 | Page : 115-121
Evaluation of the potential cardiotoxic effects in acute organophosphate toxicity as a prognostic factor
Ayman El-Sheikh1, Ahmad Hashem2, Mona Elgohary2, Arwa Abo Elfadl2, Heba Lashin2
1 Department of Cardiovascular Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Submission||25-Jan-2017|
|Date of Acceptance||08-Jun-2017|
|Date of Web Publication||29-Nov-2017|
Department of Cardiovascular Medicine, Tanta University, Elnady Street, 31422, Tanta
Background/aim Organophosphorus compounds are the most commonly used pesticides as a result of their easy availability. They are highly toxic compounds for human beings. The study aimed to evaluate the potential cardiotoxic effects in acute organophosphate toxicity as a prognostic factor.
Patients and methods This study was carried out on 48 organophosphate acutely intoxicated adult patients. All participants were subjected to the following: sociodemographic study, patient’s history, clinical examination, laboratory investigations, ECG (ECG changes were graded as minor, moderate, and severe), and echocardiography.
Results Regarding acute organophosphorus poisoning (OPP) severity, patients with mild, moderate, and severe intoxication represented 18.6, 35.4, and 45.8 of the studied patients, respectively. Of acute OPP patients, 81.25% had abnormal ECG with ischemic changes in 66.7% of patients and arrhythmia in 43.6%. Inverted T-wave and elevated ST segment were the most frequent among ischemic findings while atrial fibrillation was the most frequent arrhythmic finding. The ECG changes induced by acute OPP were graded as moderate in 68.75% of patients and severe in 12.5%. Only one case of acute OPP was diagnosed as acute myocardial infarction. No cases with minor ECG grading were recorded. There was a statistically significant difference between acute OPP severity and ECG grading. Patients with acute OPP have shown a mean QTc interval of 0.46±0.062 s. In all, 47.9% of patients reported prolonged QTc interval. QTc interval was significantly more prolonged in severely intoxicated patients.
Conclusion ECG grading and corrected QT interval are a predictor for both primary and major outcome in patients with acute OPP.
Keywords: cardiac disease, organophosphorus toxicity, prognosis
|How to cite this article:|
El-Sheikh A, Hashem A, Elgohary M, Elfadl AA, Lashin H. Evaluation of the potential cardiotoxic effects in acute organophosphate toxicity as a prognostic factor. Tanta Med J 2017;45:115-21
|How to cite this URL:|
El-Sheikh A, Hashem A, Elgohary M, Elfadl AA, Lashin H. Evaluation of the potential cardiotoxic effects in acute organophosphate toxicity as a prognostic factor. Tanta Med J [serial online] 2017 [cited 2018 Nov 19];45:115-21. Available from: http://www.tdj.eg.net/text.asp?2017/45/3/115/219443
| Introduction|| |
Organophosphate pesticides comprise more than 50% of all pesticides used worldwide. Moreover, they have low toxicity and short persistence in the mammalian system. Therefore, many of the human population are exposed to them ,. The easy availability of these compounds resulted in a gradual increase in accidental and suicidal poisoning mainly in developing countries. Furthermore, it has been a major reason of morbidity and mortality that causes public health problems . Hence, medical and health professionals should be aware and learn more about toxicity and proper management of organophosphorus poisoning (OPP).
WHO has estimated three million cases of organophosphorus compound (OPC) poisoning and 2.5 million deaths worldwide annually . In Egypt, OPP is a common cause of morbidity and mortality and represents more than 50% of patients with insecticide poisoning .
The main toxic mechanism of OPCs is inhibition of acetylcholinesterase enzyme at muscarinic and nicotinic synapses. This results in the accumulation of acetylcholine and overstimulation of cholinergic synapses in the central nervous system, somatic nerves, parasympathetic nerve endings, and sweat glands .
Cardiac complications associated with OPP are not fully appreciated by many medical practitioners. The mechanism by which OPCs induces cardiotoxicity is still uncertain . Moreover, studies on cardiac effects of OPP have been inconclusive, and sometimes conflicting results have been reported .
Hence, this work has been established to study some cardiac parameters that can be influenced due to acute OPP and their role as a prognostic factor.
| Patients and methods|| |
This prospective observational cohort study was carried out on 48 organophosphate acutely intoxicated adult patients admitted to the Poison Control Center (Emergency Hospital, Tanta University) from September 2013 to August 2014. This study was approved by the ethics committee of our institution; informed consent was obtained from all patients after full explanation of the procedure. It was approved by the Research Ethical Committee, Faculty of Medicine, Tanta University.
Patients’ selection criteria
Adult patients who were diagnosed with acute OPP. Diagnosis in all cases was based on the criteria as guided by Liu et al. .
Patients with a history of cardiac diseases, coingestion with other agents, patients who had any medical treatment for acute OPP in any medical center before admission without documented medical report, other clinical conditions in which serum cardiac troponin I (Tn-I) level may be elevated, and patients with any pre-existing chronic diseases .
The severity of acute OPP was clinically evaluated and classified according to Minton and Murray  and Kumar et al.  into: mild, moderate, and severe OPP.
All participants under study were subjected to the following:
- Sociodemographic study: age, sex, residence, occupation, and education.
- Patient’s history: toxicological and medical history.
- Clinical examination: consciousness level, vital signs, and general clinical examination.
- Laboratory investigations: arterial blood gas analysis, determination of serum sodium and potassium levels, complete blood cell count, liver enzyme tests, kidney function tests, random blood sugar level, butyryl cholinesterase level, and serum cardiac Tn-I level.
- ECG: ECG was performed on admission. It was repeated every 6 h and whenever an arrhythmia or any other abnormality was observed on cardiac monitor until the ECG returned to normal. The ECG changes induced by acute OPP were graded according to the poisoning severity score done by Persson et al.  and Akdur et al.  into: minor: isolated extrasystoles. Moderate: sinus tachycardia [heart rate (HR): 140–180 in adults], frequent extrasystoles, atrial fibrillation/flutter, atrioventricular block I–II, prolonged QRS (more than 0.12 second) and QTc-interval (more than 0.44 second), repolarization abnormalities, or myocardial ischemia. Severe: severe sinus bradycardia (HR <40 in adults), severe tachycardia (HR >180 in adults), life-threatening ventricular dysrhythmias, atrioventricular block III, asystole, or myocardial infarction.
- Echocardiography: it was done within 24 h after admission.
- Others: endotracheal intubation and assisted ventilation when needed:
- The total amount of atropine and oximes administered was recorded.
- The duration of hospitalization and the type of discharge were recorded.
- The primary outcome was either the patient improvement, death, or unknown outcome.
- The secondary outcome included: need for endotracheal intubation, need for mechanical ventilation, and/or death (major adverse outcome).
Data were collected and entered in a computer using the SPSS program for statistical analysis (version 20) (SPSS Inc., Chicago, Illinois, USA). Data were entered as numerical or categorical, as appropriate. Kolmogorov–Smirnov (D) test was used to test normality of the distribution of variables, but nonparametric statistics (minimum and maximum, median and interquartile range) were adopted even when the Kolmogorov–Smirnov test was not significant, and comparison using Kruskal–Wallis test was used to test several independent samples, and Mann–Whitney U-test was used to test two independent samples. χ2-Test (Monte Carlo corrected) for n×m table or Yate’s correction (for 2×2) tables were used to test association of categorical variables.
In this study the α level was set to 5% with a significance level of 95%, and a beta error accepted up to 20% with a power of study of 80% .
Receiver operating characteristic curve analysis
Receiver operating characteristic (ROC) curves were constructed using 10% stepwise increments in predicting the major outcome . The best cutoff points, sensitivities, and specificities in predicting the major outcome was determined and the area under the ROC curve was computed.
| Results|| |
Regarding acute OPP severity, patients with mild, moderate, and severe intoxication represented 18.6, 35.4, and 45.8% of the studied patients, respectively. The mean age of the studied patients was 36.06±12.93 years (range: 18–65 years). Age was significantly less in severely intoxicated patients.
The majority of the studied patients were male (83.3%) farmers (47.9%) from rural areas (72.9%). Moreover, illiterate patients represented the highest percentage of all the studied patients. No significant difference could be detected among the studied patients regarding sex, residence, and educational level but statistically significant difference was detected regarding their occupation and age.
Of the patients, 81.25% with acute OPP had abnormal ECG. Ischemic findings were reported in 66.7%, while arrhythmic findings were reported in 43.6%. Inverted T-wave and depressed ST segment were the highest among ischemic findings (61.5%), while atrial fibrillation was the most frequent arrhythmic finding (29.4%).
Only one case of acute OPP was diagnosed as acute ST segment elevation myocardial infarction. No cases with minor ECG grading were recorded. There was a statistically significant difference between acute OPP severity and the ECG grading.
Totally, 54.2% of patients with acute OPP had normal echocardiography versus 35.4% with abnormal findings. The most frequent echocardiographic finding was impaired diastolic function (58.8%). Moreover, no significant difference could be detected in left ventricle ejection fraction among patients with different OPP severity subgroups.
There was a statistically significant difference between acute OPP severity and ECG grading. The majority of patients with moderate intoxication showed moderate ECG grading (76.5%), while severe intoxication registered moderate and severe ECG grading (72.7 and 27.3%, respectively). The majority of patients with acute OPP with normal and moderate ECG grading were men (87.9%), while women represented 66.7% of patients with severe ECG grading.
All patients with severe ECG grading attempted suicide with ingestion; whereas, the majority of patients with moderate ECG grading were exposed during organophosphorus pesticides spraying with combined inhalational and dermal route (51.5%). Moreover, there was no significant difference regarding the prehospitalization period and suspected OPCs involved in toxicity.
Systolic, diastolic, and mean arterial blood pressure showed no significant difference among ECG grading subgroups, while oxygen saturation was significantly decreased in patients with severe ECG grading.
Totally, 52.1% of the patients studied had shown normal QTc interval. Meanwhile, 47.9% of patients were having prolonged QTc interval (QTc interval >0.44 s). QTc interval was significantly prolonged in severely intoxicated patients. Furthermore, the mean of serum cardiac Tn-I level was higher in patients with prolonged QTc interval than patients with normal QTc interval.
Outcome assessment: even though neither primary nor major outcomes of the studied patients had shown significant relation with serum cardiac Tn-I level, it was noticed that both patients who died and had major outcome had shown higher mean serum cardiac Tn-I level than patients who improved or had no major adverse outcome.
For an assessment of the accuracy of QTc interval and serum cardiac Tn-I level (peak value) in predicting the major adverse outcome in patients with acute OPP, ROC curves were constructed ([Table 1],[Table 2],[Table 3],[Table 4],[Table 5],[Table 6]). It was found that QTc interval could be considered as a good predictor for morbidity and mortality in patients with acute OPP. A QTc interval of more than or equal to 0.46 s is considered an alarming sign of major adverse outcome.
|Table 1 Incidence of cardiovascular manifestations in patients with acute organophosphorous poisoning recorded at admission and their distribution among mild, moderate, and severe intoxication|
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|Table 2 Comparison of ECG grading among mild, moderate, and severe organophosphorous intoxication|
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|Table 3 Comparison of QTc interval among patients with mild, moderate, and severe organophosphorous intoxication|
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|Table 4 Comparison of primary outcome in patients acute organophosphorous poisoning|
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|Table 5 Comparison of major adverse outcome in patients with acute organophosphorous poisoning|
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|Table 6 The best cutoff value, sensitivity, specificity, and area under the curve of QTc interval and serum cardiac troponin I level for predicting major adverse outcome in patients with acute organophosphorous poisoning(95% confidence interval)|
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| Discussion|| |
Cardiac complications such as various arrhythmias, conduction disturbances, blood pressure changes, and myocardial damage have been reported with OPP; nevertheless, they are not considered among established diagnostic clinical signs of OPP. Such complications might be serious and are often fatal. However, they are potentially preventable if they are recognized early and treated adequately ,,,.
In this study, bradycardia was recorded in 45.8% of patients, while tachycardia was found in 25% of cases. These results were in accordance with the study of Akdur et al. , who reported that bradycardia was more frequent than tachycardia (11.1 and 5.6%, respectively). In contrast, Karki et al.  reported sinus tachycardia as being a more frequent finding (40.5%) than bradycardia (18.9%).
Reference wise, there were wide variations in results regarding the dominance of tachycardia or bradycardia among different studies assessing patients exposed to acute OPP. This could be explained by differences in the prehospitalization period. Following OP exposure, initial tachycardia is observed due to sympathetic activation, followed by bradycardia due to parasympathetic activation. Thus, bradycardia was observed more frequently in patients who present later to the hospital and this finding was strongly associated with mortality .
In this study, more than half of the studied patients (54.2%) were normotensive, while 29.2% were hypotensive, and only 16.7% were hypertensive. In a comparable study, by Ghonem et al.  hypotension was reported in 30%, while hypertension was reported in 16.67% of cases. On the contrary, Gouda et al.  reported that hypertension was more common than hypotension in acute OPP.
Hypotension associated with acute OPP could be attributed to intravascular volume depletion because of vomiting, diarrhea, or excessive secretion, in addition to, the negative inotropic and chronotropic effects of OPCs and accumulated acetylcholine . In this study, hypertension in such cases could be explained by the predominance of the nicotinic effect of OPCs .
Regarding ECG changes in the current study, ischemic findings were recorded to be more frequent than arrhythmic findings in patients with acute OPP. Inverted T-wave and depressed ST segment were the highest among ischemic findings (42.3 and 19.2%, respectively) while atrial fibrillation was the most frequent arrhythmic finding (29.4%). Although, several researches had described similar ECG changes in acute OPP, yet the mechanism of such ECG changes is not well known. However, it might include sympathetic and parasympathetic overactivity, hypoxemia, acidosis, electrolyte derangements, and direct cardiotoxic effect of OPCs ,,,,,.
Nevertheless, Ludomirsky et al.  described three phases of cardiac toxicity in acute OPP. The first phase was a brief period of increased sympathetic tone. The second one was a prolonged period of parasympathetic activity and the third phase in which QT prolongation is followed by ventricular tachycardia, polymorphous ventricular tachycardia (torsade de pointes), and then ventricular fibrillation. ST elevation was suggestive of transmural myocardial ischemia and T-wave inversion was of subendocardial myocardial ischemia .
In this study, there was a statistically significant difference between severity of organophosphorous toxicity and ECG grading. This was compatible with the studies of Karki et al. , Yurumez et al. , and Gouda et al. , who assured that cardiac changes were directly related to the severity of acute OPP.
However, other studies have shown different results; Abuelfadl et al.  and El-Ebiary et al.  found that the ECG changes in patients with OPP were not alone reliable in determining the OPP severity or short-term prognosis with no relationship with poisoning severity score. Such difference might be related to the variability in sample size.
Regarding QTc interval, the current study showed prolonged QTc interval in 47.9% of patients. Comparable studies by Grmec et al. , Karki et al. , Shadnia et al. , Lakhair et al. , Abuelfadl et al. , and El-Ebiary et al.  signified prolonged QTc interval in 37.8, 65, 59.5, 67, 39.5, and 23.1% of acute OPP cases, respectively. Overall, the frequency of QTc prolongation in several series of severe acute OPP was shown to be 20–80% depending on the poisoning severity and toxic agent type .
The exact cellular mechanism of OP-induced QT prolongation has not been fully understood. It may involve inhibition of potassium outward channels. The ensuing intracellular surplus of positive ions delays ventricular repolarization (thus prolonging the QT interval) and may trigger early after depolarizations. These early after depolarizations may reach threshold amplitude and trigger ventricular arrhythmias ,.
Malfunction of ion channels lead to intracellular excess of positively charged ions by inadequate potassium outflow or excess sodium inflow. This intracellular excess of positively charged ions extends ventricular repolarization and results in QT interval prolongation .
In this study, no significant relation could be detected between primary outcome and QTc interval. On the other hand, patients with prolonged QTc interval had shown statistically significant difference regarding major outcome when compared with patients with normal QTc interval.
Similarly, previous literatures have identified a low Glasgow coma score and respiratory failure in patients with prolonged QTc interval rather than in those with normal QTc interval in acute OPP . Patients with prolonged QTc interval had poor prognosis as they might have higher rates of ventricular premature contractions, and mortality compared with patients without QTc prolongation ,.
The previous finding had been confirmed by Chuang et al.  and Shadnia et al.  who reported that OP-exposed patients with QTc interval prolongation had a significantly high-mortality ratio, compared with those without QTc interval prolongation.
Wahab et al.  have stated that as reported in a previous experimental study, the prolonged QTc interval induced by acute OPP was found to be due to direct myocardial effect of the pesticide independent of its cholinergic action. Since the QT interval represents the duration of activation and recovery of the ventricular myocardium, prolonged QTc interval should be considered as a major prognostic factor for acute OPP outcome. Prolonged recovery of ventricular myocardium from electrical excitation increased the likelihood of dispersing refractoriness, when some parts of the myocardium might be refractory to subsequent depolarization.
The aim of this study was to observe if major outcomes can be assessed depending on the clinical parameters at presentation. The corrected QT interval could be considered as a good predictor for morbidity and mortality in patients with acute OP poisoning. QTc interval greater than or equal to 0.46 s was an alarming sign of major outcome in acute OPP patients.
The principal limitation of the study was its small sample size precipitated by the wide range of inclusion and exclusion criteria.
| Conclusion|| |
Acute OPP can be associated with severe cardiac complications within few hours of exposure including myocardial infarction. ECG grading is a predictor for both primary and major adverse outcome of patients with acute OPP. The corrected QT interval could be considered as an excellent parameter to predict morbidity and mortality in patients with acute OPP and it was an alarming sign of major outcome in patients with acute OPP. Serum cardiac Tn-I level could be considered an effective predictor of direct myocardial toxic effect induced by OPCs. Moreover, the ability of severe OPP to cause direct myocardial injury apart from rhythm disturbances was assured.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]