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Clinical Toxicology
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Cardiac abnormalities in acute organophosphate poisoning

S. Anand a; Surjit Singh a; Uma Nahar Saikia b; Ashish Bhalla a; Yash Paul Sharma c; Dalbir Singh d a Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India b Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India c Department of Cardiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India d Department of Forensic Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India First Published:March2009

To cite this Article Anand, S., Singh, Surjit, Nahar Saikia, Uma, Bhalla, Ashish, Paul Sharma, Yash and Singh, Dalbir(2009)'Cardiac

abnormalities in acute organophosphate poisoning',Clinical Toxicology,47:3,230 235

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Clinical Toxicology (2009) 47, 230235 Copyright Informa UK, Ltd. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.1080/15563650902724813

Cardiac abnormalities in acute organophosphate poisoning

LCLT

S. ANAND1, SURJIT SINGH1, UMA NAHAR SAIKIA2, ASHISH BHALLA1, YASH PAUL SHARMA3, and DALBIR SINGH4
Cardiac abnormalities in OP poisoning

Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India 3 Department of Cardiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India 4 Department of Forensic Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2

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Background. Potentially lethal cardiac complications can occur in patients with acute organophosphate poisoning (OPP) and may be overlooked. Patients and Methods. Thirty-six patients with acute OPP were studied. Clinical features and the nature of compound involved were recorded. The QT interval was plotted against heart rate to determine the risk for Torsades de Pointes using the Fossa nomogram. Echocardiography was undertaken in 29 patients. Twenty-four-hour Holter monitoring was performed on day 1 in five patients. Thirteen died. Necropsy was performed and hearts were studied both grossly and microscopically. Results. Gross examination of the heart in 13 cases revealed cardiac discoloration or blotchiness in 12, patchy pericarditis in six, auricular thrombus in six, right ventricular hypertrophy in four, and dilatation in three. On histopathology, all 13 cases had myocardial interstitial edema and vascular congestion, eight had patchy interstitial inflammation, two had patchy myocarditis, and six had a mural thrombus. Sinus tachycardia was the most common electrocardiographic abnormality. The others were corrected QT interval prolongation, STT changes, U waves, and ventricular premature contractions. Echocardiography in 29 patients showed minor abnormalities in 10. On Holter monitoring, episodic tachycardia and STT changes were observed in four, QT prolongation in three, and episodic bradycardia in two. Conclusions. Patchy myocardial involvement as a result of direct cardiac toxicity could be one of the factors responsible for serious cardiac complications. As myocardial involvement is patchy, it may not be manifest clinically or on echocardiography. Continuous cardiac monitoring should be undertaken to detect dynamic cardiac changes. Keywords Organophosphates; Electrocardiographic abnormalities; Echocardiographic abnormalities; Toxic myocarditis

Introduction
Organophosphate poisoning (OPP) with suicidal intent is a major cause for concern in developing countries1. These poisonings result in cholinergic and nicotinic signs and direct toxic effects on several organs2. Abnormalities on electrocardiography (ECG) may occur in patients with acute OPP and vary from nonspecific to fatal ventricular arrhythmias36. Patients who die following an apparent clinical recovery may have myocardial involvement, including myocardial necrosis and toxic myocarditis79. However, studies correlating ECG findings with changes in cardiac physiology and cardiac pathology are lacking2,10. The present study was carried out to identify changes in cardiac physiology in patients acutely poisoned with an organophosphate (OP).

Patients and methods

This was a prospective study of all patients older than 12 years of age who presented to the Emergency Department of Nehru Hospital in Chandigarh, India from January 2006 to June 2007 with a diagnosis of acute OPP. The diagnosis of OPP was based on history of exposure, clinical effects, and serum cholinesterase activity. Complete clinical profile of the patients was recorded using a standardized form. Patients with known carbamate poisoning, previous history of cardiac disease, or any suspicion of myocarditis because of other like viral myocarditis were excluded from the study. The involved pesticide was determined by history, the container label, or product information brought by the patient or, in some cases, from a report by the State Chemical Examiner. The pulse rate, blood pressure, respiratory rate, and temperature were monitored. Patients with acute OPP were treated with atropine and 2-PAM. Patients in whom the nature of exposure was not known were treated with atropine alone. Other supportive measures, such as mechanical ventilation, suction of secretions, intravenous fluids, and inotropes were instituted as needed. Five milligrams of atropine was given as bolus followed by 2 mg every 5 min until the patient was fully atropinized. Subsequently atropinization was maintained either with boluses of atropine or infusion depending on the dose required. 2-PAM was administered as

Received 12 May 2008; accepted 6 January 2009. Address correspondence to Surjit Singh, Department of Internal medicine, 4th floor, Block F, Room 16, Nehru Hospital, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. E-mail: surjit51@hotmail.com; surjit51200@yahoo.co.in

Clinical Toxicology vol. 47 no. 3 2009

Cardiac abnormalities in OP poisoning a 7.5 mg/kg/h infusion until the patient recovered or died. Cardiac monitoring was undertaken throughout the stay. An ECG was recorded on admission and was repeated twice daily and whenever an arrhythmia or any other abnormality was observed on cardiac monitor. The ECG was analyzed for rate, rhythm, axis, voltage, ST and T wave abnormalities, conduction defects, PR interval, QT interval, and corrected QT interval (QTc). The ECGs were analyzed both by machine and manually without blinding. PR interval was considered to be short if duration was <0.12 s and long if >0.20 s. QRS duration of >0.12 s was taken as wide. The median QT interval of six leads, including chest leads, was determined and plotted against heart rate (HR) using the Fossa nomogram11,12. Patients who had QT intervals above the Fossa nomogram curve were considered at risk for development of Torsades de Pointes (TdP). An isoelectric ST segment was considered to be normal. A chest radiograph was taken on admission and repeated as required. Serum electrolytes were measured daily. Serum CK-MB was determined at admission and later as necessary (normal 25 units/L). Two-dimensional echocardiography, done as soon as possible after admission and repeated before discharge, was performed using a GE Vivid 5 machine with 2.5 MHz transducer. Measurements were taken according to the criteria by the American Society of Echocardiography13. Twenty-four-hour Holter monitoring was done in five patients for 24 h on the day of admission. Maximum and minimum HRs, QTc interval at different times of the day, STT changes, and any specific arrhythmias were noted. In case of death, complete necropsy was performed. All organs were retrieved and were examined grossly with heart being specifically examined in detail. The chambers were examined for any mural thrombus, myocardial discoloration or blotchiness was recorded, and standard sections from all the chambers of the heart and other representative areas were taken for histopathology. Histochemistry testing for pigment, elastic tissue, or collagen was done as required. Descriptive statistics were used as appropriate. Data were expressed as mean SD and range. Statistical significance was calculated for categorical variables using chi-square test and for parametric variables using Student t-test. p-Value 0.05 was considered significant. The study was approved by the Ethics Committee of the Institute.
Table 1. Compounds involved in survivors and dead Compound Dimethoate Monocrotophos Methylparathion Chlorpyrifos Phorate Malathion Mixture Unknown Total Survivors 1 3 2 4 1 2 3 7 23 Died 1 0 0 0 1 0 1 10 13

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exposures were intentional; the rest occurred during agricultural spraying with a water solvent. Intentional cases had swallowed them as such except in one who took alcohol along with OP. The median time between exposure and arrival to hospital was 6 h. The clinical features at admission are shown in Table 2. Twenty-one patients had a Glasgow Coma Scale (GCS) score of 38, nine had a GCS score of 912, and six had a GCS score of 131514. The mean serum cholinesterase using acetyl thiocholine as substrate was 0.453 0.280 IU/mL (range 0.010.99 IU/mL; reference 12 IU/mL). The ECG abnormalities on admission are shown in Table 3. Of 26 patients who had sinus tachycardia, 12 had received atropine before reaching us (dose unknown). The mean systolic blood pressure (SBP) was 115 22.1 mmHg (range

Table 2. Clinical features at presentation in 36 patients Symptoms/signs Cholinergic Miosis Vomiting Salivation Sweating Cough/frothy sputum Lachrymation Loose stools Urinary incontinence Bradycardia Hypotension Nicotinic Fasciculations Tachycardia Hypertension Weakness Others Convulsions GCS score 38 912 1315 N = 36 36 33 32 24 19 16 10 12 4 9 20 26 6 1 7 21 9 6

Results
Thirty-six patients (24 men) admitted during the study period with acute OPP fulfilled the inclusion criteria and were included in the study. The mean age was 26.5 9.1 years (range 1562 years). The involved substances are shown in Table 1. Fifteen patients were exposed to a single OP, four to a mixture of OPs, and 17 to unidentified OPs. Twenty-nine

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232
Table 3. Electrocardiographic abnormalities at admission Abnormality Sinus tachycardia (100160 beats/min) Sinus bradycardia (4468 beats/min) VPCs PR prolongationa QTc prolongation QTc narrowing STT changes U waves Right axis deviation Left axis deviation Right bundle branch. Block
a

S. Anand et al.
Table 4. Echocardigraphic abnormalities Abnormality Mild mitral regurgitation Mild tricuspid regurgitation Mild pulmonary regurgitation Sclerodegenerative aortic valve Left ventricular dilatation Left ventricular hypertrophy Mild LV diastolic dysfunction Number (N = 29) 2 2 1 1 2 3 5

Number (N = 36) 26 4 4 2 7 4 7 7 5 1 2

First-degree AV block.

70160 mmHg) and diastolic blood pressure (DBP) was 70 9.1 mmHg (range 5090 mmHg). Significant hypotension (SBP 90 mmHg) was present in nine patients on admission and they received inotropic support for varying durations (mean 20.3 h; range 1456 h). The dose of atropine varied from patient to patient. The mean total dose was 296.23 200.6 mg (range 30840 mg) and duration was 4.26 3.1 days (range 112 days). Significant hypoxemia (SaO2 90%) on admission was present in 15 patients and 13 of them received assisted mechanical ventilation for durations ranging from 48 to 122 h. Four patients with sinus bradycardia and 21 patients with sinus tachycardia were at risk of developing TdP. STT changes in four patients consisted of ST depression (>2 mm) in leads II, III, AVF, and V4V6; two patients had T wave inversion in V2V6; one had ST elevation (>2 mm) in leads V2V4; and one had tall T waves. After treatment, sinus tachycardia developed in all. Firstdegree heart block in two patients and STT changes and U waves in three patients reversed with treatment. In three patients, prolonged QTc normalized and ventricular premature contractions (VPCs) disappeared in two. However, new VPCs appeared in three patients. Soon after admission, one patient who had prolonged QTc developed significant ST depression (>5 mm) in all leads and right bundle branch block; within the next few hours he developed ventricular asytole and died. None of our patients developed TdP, ventricular tachycardia (VT), or ventricular fibrillation (VF). Eight patients who had sinus tachycardia had hypoxia. Other changes were U waves in four patients and STT changes in three. Two patients who had VPCs, prolonged QTc, and U waves on admission also had hypokalemia. These cardiac abnormalities resolved with correction of the hypokalemia. There was no significant correlation between any particular ECG abnormality and involved substance. Similarly, there was no significant correlation between ECG changes and C-MB levels or with patients mean serum cholinesterase activity.

Two-dimensional echocardiography was done in 29 patients and minor abnormalities were observed in 10 patients (Table 4). More than one abnormality was observed in six patients. Left ventricular (LV) systolic function was normal in all the patients. On repeat echocardiography before discharge, LV diastolic dysfunction had resolved in four patients. There was no significant correlation between echo abnormalities and the involved substance. There was no significant difference in ejection fraction (EF) expressed as percentage between survivors and those who died (67.0 3.9 vs. 65.8 5.4; t = 2.98; p > 0.05) on admission. Similarly no statistically significant difference in EF was observed between that on admission and that before discharge (67.0 3.9 vs. 65.28 2.4; t = 2.99; p > 0.05) in survivors. Six of the 13 patients who died had echocardiography and the results were normal (except one elderly patient who had a sclero-degenerative aortic valve, LV dilation and hypertrophy, and LV diastolic dysfunction). Twenty-four-hour Holter monitoring was done in five patients at admission for 1 day only. Episodic tachycardia and STT changes were observed in four patients, QTc prolongation in three, episodic bradycardia in two, and supraventricular ectopic beats in one. Thirteen patients died and underwent necropsy. In 10 patients, the type of OP and solvent were unknown. The results of gross examination of heart are shown in Table 5. In three cases superficial hemorrhages were seen on posterior aspect of LV and left atrium. The microscopic findings are shown in Table 6. No significant correlation was observed between any

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Table 5. Gross cardiac pathology Gross findings Right auricular thrombus Left auricular thrombus Right atrial enlargement Right atrial thrombus Left ventricular dilatation Right ventricular dilatation Myocardial blotchiness/discoloration Vascular thrombus Dilated coronary sinus Epicardial and subendocardial hemorrhages Patchy pericarditis Number (N = 13) 4 2 3 1 1 3 12 4 2 3 6

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Cardiac abnormalities in OP poisoning

Table 6. Cardiac histopathological features Abnormalities Myocarditisa Interstitial edema Interstitial inflammation Vascular congestion Pericarditis Thrombus Hemorrhages Terminal ischemia Abnormal pigments
a

233 attributed to electrolyte abnormalities3. In addition, increased levels of free fatty acids (FFAs) were found in 10 patients. The arrhythmogenic potential of elevated FFAs has been suggested in patients with myocardial infarction19. None of our patients had ventricular arrhythmias but VPCs were observed in five patients on admission. Changes consistent with transient myocardial ischemia have been reported3,14. STT changes were observed in eight of our patients on admission; the changes normalized in three patients but persisted in the others. In another five patients, changes appeared during therapy; in four of these patients, the changes persisted until discharge. This persistence suggests that these changes are unlikely to be because of ion shifts and may be because of a direct myocardial toxic effect7. Parasympathetic and sympathetic overactivity has been shown to cause myocardial damage. Parasympathetic overactivity may play a role in coronary artery spasm20,21. Intracoronary injection of ACh induces coronary artery spasm in adult humans and it has been used to predict the outcome in patients with acute myocardial infarction22,23. This may explain STT changes in the acute stage. Derangements in myocardial perfusion as a result of hypoxia may be an important factor in the development of cardiomyopathy24. The STT changes in our patients suggest an acute ischemic event. However, some of these changes persisted after acute phase disappeared, which suggests long-lasting myocardial damage7. TdP occurs in patients with OP poisoning in the setting of prolonged QTc intervals3,4,16. The exact mechanism that generates TdP in these patients is unknown. However, it has been suggested that focal areas of necrosis interspersed with normal myocardium may produce potential areas of re-entry and non-homogeneity of repolarization resulting in TdP25. In animal experiments, prolongation of the QT interval is a direct myocardial pesticide effect and is independent of cholinergic effects26. The Fossa nomogram gives an assessment of risk at slower HRs12. However, the Fossa nomogram was able to assess the risk of TdP in our patients with faster HRs (100 160 beats/min). The exact time interval from exposure to cardiac complications is unpredictable and it is not possible to predict which patients will develop cardiac abnormalities. However, the general impression is that in severe poisonings cardiac abnormalities are common and a cause of delayed mortality7,17. To detect these dynamic cardiac changes, some form of continuous cardiac monitoring seems advisable. Echocardiographic abnormalities were present in 10 of 29 patients. In survivors, though LV EF was statistically lower at discharge, this reduction was clinically irrelevant. The absence of myocardial depression on echocardiography could be because of insufficient time for structural changes to develop. Seventy-six autopsies were conducted in patients with acute organophosphorous poisoning8. Three cases had soft, flabby hearts with epicardial hemorrhages and dilated pericardial and epicardial vessels. Microscopy was done in nine

Number (N = 13) 2 13 8 13 4 6 4 11 1

Myocarditis documented according to Dallas criteria15.

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particular histopathological change and involved substance. Although varied ECG abnormalities were observed in all 13 patients, there was no correlation between ECG abnormalities and histopathological changes.

Discussion
OPs can produce a variety of clinical features because of cholinergic and nicotonic stimulation and direct toxic effect on different organs2. The majority of deaths occur as a result of respiratory failure. However, it has been observed that a small number of patients who initially improve, develop rebound acute pulmonary edema which proves fatal in many such instances5,6,16. The cause of this phenomenon is unknown but it has been postulated that this could be because of direct toxic effect on myocardium79,16. The cardiovascular effects of OPs reflect the net result of excitatory and inhibitory actions of accumulated acetylcholine (ACh) at ganglionic, medullary, vasomotor, and cardiac centers6. These effects are further compounded by hypoxia, local release of catecholamines, and disturbances of ion transport7. Ludormisky et al.17 described three phases of cardiotoxicity: an initial intense sympathetic phase, a second prolonged parasympathetic phase usually accompanied by hypoxemia and often manifesting as STT changes and AV conduction disturbances which can degenerate to VF, and a third phase of QT prolongation followed by TdP and VF. Various ECG changes have been described36. Many of these normalize following correction of electrolyte disturbances, acidosis, and hypoxemia. Sinus tachycardia is the commonest abnormality and was observed in 26 of our patients on admission. Sinus tachycardia occurs as a result of intense sympathetic stimulation, nicotinic stimulation of ganglionic sites by excess ACh, atropine administration, and dehydration. Twelve of our patients had received atropine before reaching us and this could have contributed to sinus tachycardia observed on admission. Ventricular arrhythmias are frequent3,5,7,18. In the study of 168 patients, 56 had ventricular arrhythmias with 9%

Clinical Toxicology vol. 47 no. 3 2009

234 cases and three cases had cloudy swelling, hyperemia, and mild necrosis of myocytes. In another study, autopsies of three cases with malathion poisoning found prominent vessels on epicardial surface and pericardium and petechial hemorrhages on posterior aspect of the heart; microscopy showed evidence of myocarditis in all these three patients7. Dalvi et al.9 found evidence of micronecrosis and myocarditis in five patients with severe OPP. Necropsy of 13 of our cases showed myocardial blotchiness, patchy pericarditis, subepicardial, and hemorrhages on the posterior aspect of left atrium and LV in three cases. Auricular thrombus (both right and left) was found in six cases but its significance is not clear. Myocardial blotchiness or discoloration could be because of early direct myocardial toxicity though some changes could be attributed to the terminal cardiopulmonary resuscitation efforts. However, epicardial and subendocardial hemorrhages, especially on the posterior surface of the heart and left border, seem to be independent of cardiopulmonary resuscitation7,8. The petechial hemorrhages and ecchymoses may represent direct toxic injury to the heart rather than hypoxia8. Hemorrhages because of hypoxia are characteristically petechial and larger hemorrhages support direct toxic injury. In our study, microscopy of the heart found interstitial edema and vascular congestion of varying degrees in all cases7,8. The endocardium was normal and hemorrhages were confined to subendocardium and pericardium. Another prominent finding was evidence of terminal myocardial ischemia (wavy fibers, altered staining characteristics). In one patient, increased myocyte lipofuschin was found in the degenerated myocardium. In the study by Limaye8, patients who initially improved and then suddenly deteriorated despite higher doses of atropine had acute pulmonary edema at necropsy. This deterioration could have been because of development of acute toxic myocarditis leading to LV failure and pulmonary edema. However, as these patients died early, myocarditis was not found as there was insufficient time for the development of pathological findings. Though frank myocarditis was absent in our patients, early toxic injury could have led to ECG changes. The patchy involvement of myocardium may explain the absence of significant cardiac alterations in echocardiography. The mechanisms by which OPs lead to histomorphological changes are not known. The STT changes can be attributed to coronary artery spasm. In addition, OPs could lead to apoptosis of myocardial and endothelial cells as has been observed in drug-induced toxic myocarditis27. Corticosteroids have been used in patients with drug-induced myocarditis28; whether they will improve cardiac outcome in OPP will be determined in future studies.

S. Anand et al. measured. Of 13 who died, in 10 nature of OP was unknown and in one it was mixed. Twelve patients had received atropine before reaching us and in none of them the exact dose of administered atropine could be known. Holter monitoring is better at detecting dynamic cardiac changes and should have been undertaken in all patients throughout the stay. We could undertake it in only five patients and for the first 24 hours only.

Conclusions
Patchy myocardial involvement as a result of direct cardiac toxicity could be one of the factors responsible for cardiac complications and sudden death in some patients with acute anticholinesterase poisoning. Continuous cardiac monitoring appears to be indicated and a systematic study of the benefits of such monitoring is warranted. Close watch should be kept for prolonged QTc, ventricular arrhythmias, and myocardial ischemia to avoid sudden death. In addition, correction of electrolyte imbalance and hypoxia is important as a number of electrocardiographic abnormalities can be corrected through symptomatic and supportive care.

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Limitations
In 17 of 36 patients, the nature of compound was not known and in none of the patients compound involved could be

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