Abnormal Electrocardiogram in Patients with Acute Aluminum Phosphide Poisoning

Aluminum phosphide (AlP) is used throughout the world as pesticides to protect stored grains from rodents and other pests (Cienki, 2001). The chemical is usually formulated in pellets, granules or as a dust. Upon contact with moisture in the environment, AlP undergoes a chemical reaction yielding phosphine gas (PH3), which is the active pesticidal component and a very toxic system poison, makes acute AlP poisoning (AAlPP) extremely dangerous (Sasser et al., 1998). AAlPP has been reported in literature since 1985. The majority of cases of AlP poisoning involving intentional suicide acts. It is a major health problem with a high mortality rate especially in developing countries where AlP is low cost and easily accessible (Mehpour et al., 2008; Louriz et al., 2009). Patients who intend to commit suicide take tablets. Once mixed with hydrochloric acid in the stomach, PH3 is immediately released and absorbed rapidly via the lungs causing systemic poisoning (Proudfoot, 2009). However, accidental exposure to AlP is a relatively common cause of poisoning from agriculture chemical exposure in many countries. The manufacture and application of AlP fumigants pose risks of inhalation exposure to PH3 (Sudakin, 2005). During the past 35 years, high mortality rates have been reported following significant exposures to aluminum phosphide. This mortality rates vary from 40% to 80% (Chugh et al., 1991).


Introduction
Aluminum phosphide (AlP) is used throughout the world as pesticides to protect stored grains from rodents and other pests (Cienki, 2001).The chemical is usually formulated in pellets, granules or as a dust.Upon contact with moisture in the environment, AlP undergoes a chemical reaction yielding phosphine gas (PH 3 ), which is the active pesticidal component and a very toxic system poison, makes acute AlP poisoning (AAlPP) extremely dangerous (Sasser et al., 1998).AAlPP has been reported in literature since 1985.The majority of cases of AlP poisoning involving intentional suicide acts.It is a major health problem with a high mortality rate especially in developing countries where AlP is low cost and easily accessible (Mehpour et al., 2008; Louriz et al., 2009).Patients who intend to commit suicide take tablets.Once mixed with hydrochloric acid in the stomach, PH 3 is immediately released and absorbed rapidly via the lungs causing systemic poisoning (Proudfoot, 2009).However, accidental exposure to AlP is a relatively common cause of poisoning from agriculture chemical exposure in many countries.The manufacture and application of AlP fumigants pose risks of inhalation exposure to PH 3 (Sudakin, 2005).During the past 35 years, high mortality rates have been reported following significant exposures to aluminum phosphide.This mortality rates vary from 40% to 80% (Chugh et al., 1991).

Toxicology of phosphine gas
The toxicity of AlP is attributed to the liberation of PH 3 gas which is cytotoxic and causes free radical mediated injury (Sudakin, 2005).PH 3 a nucleophile, acts as a strong reducing agent capable of inhibiting cellular enzymes involved in several metabolic processes.Early studies on PH 3 demonstrated specific inhibitory effects on mitochondrial cytochrome c oxidase.Experimental and observational studies have subsequently demonstrated that the inhibition of cytochrome c oxidase and other enzymes leads to the generation superoxide radicals and cellular peroxides.Cellular Fig. 1.Aluminum phosphide and liberation of phosphine gas.Al≡P : aluminum phosphide ; PH 3 : phosphine gas injury subsequently occurs through lipid peroxidation and other oxidant mechanisms (Chugh et al., 1996).Indeed, significant decreases in glutathione concentrations were shown in different tissues during AlP poisoning (Hsu et al., 2002).Glutathione is known to be an important factor protecting against oxidation by catalyzing the reduction of the oxygen peroxide in O 2 and H 2 O. Mutagenic effects resulting from oxidative damage to DNA have been reported in vitro.A cytogenetic study of phosphide fumigant applicators reported a significantly higher incidence of chromatid gaps and deletions in comparison to controls (Hsu et al., 1998).Very little information is available relating to the toxicokinetics of PH 3 in humans.In an investigation of a series of patients with acute AlP poisoning , indicators of oxidative stress (malonydialdehyde levels, superoxide dismutase and catalase activity) appeared to peak within 48 hours of exposure, with normalization of most indicators occurring by day 5 (Chugh et al., 1996a).Chugh et al. reported that, serum PH 3 levels correlate positively with the severity of poisoning and levels equal to or less than 1.067 ± 0.16 mg % appear to be the limit of PH 3 toxicity (Chugh et al., 1996b).A bedside test has been described for the diagnosis of AlP ingestion, using gastric aspirates and paper strips impregnated with silver nitrate.The test was found to be positive in 100% of cases of AlP ingestion (Chugh et al., 1994).The same test was also investigated to detect PH 3 gas in the exhaled air of patients with intoxication with AlP ingestion, and the results were positive in 50 % of cases.

Clinical features of AAlPP
AAlPP results in the rapid onset of gastrointestinal signs and symptoms, including epigastric pain and recurrent, profuse vomiting.Characteristic garlic smell of PH 3 in the patient's expired breath.Cardiovascular manifestations include hypotention and profound circulatory collapse.Neurological manifestations following acute poisoning include headache, anxiety and dizziness, frequently accompanied by a normal mental state (National Institute of occupational Safety and Health [NIOSH], 2003).Pulmonary injury and oedema have been described.Acute renal and liver injury can also develop.The prognosis from suicidal ingestion of AlP is poor.The major lethal consequence of AAlPP, myocardial suppression with profound circulatory collapse, is reportedly secondary to toxins generated, which lead to direct effects on cardiac myocytes, fluid loss induced by several episodes of vomiting and adrenal gland damage.The AAlPP is involving young patients without history of cardiac diseases.However, clinical, biological, electrical and histological observations suggest that myocardial involvement is responsible for the acute circulatory insufficiency (Lall et al., 1997).

Biological abnormalities in AAlPP
Increased CK with raised cardiac marker CK-MB fraction has been previously reported point to severe myocardial damage (Nakakita et al., 2009).Controversies exist about the magnesium level and prognosis of AAlPP.Some studies seem to suggest that there is hypomagnesaemia associated with AAlPP and that there is a direct relationship between abnormal electrocardiographic findings and low magnesium levels.They report reduced mortality rates with magnesium therapy in these patients (Chugh et al., 1991).However other studies have shown no such benefits and some have even demonstrated hypermagnesaemia in patients with AAlPP (Singh et al., 1991).The pathogenesis of magnesium level abnormalities was not clear.

Cardiotoxicity of AlP
The toxicity of AlP is systemic and can affect all organs, but particularly cardiac and vascular tissues.Myocardial injury following AlP poisoning has been documented on electrocardiograms in several studies.AlP induced cardiotoxicity was responsible for a high level of mortality.Cardiac toxicity due to AlP and PH 3 exposure is represented by a depression in myocardial cellular metabolism, as well as myocardial necrosis due to the release of reactive oxygen intermediates.Several studies noted electric abnormalities in 38% to 91% of cases (Chugh et al., 1991;Karla et al., 1991).There are conduction disorders such as right and left bundle branch block (25%), atrioventricular block (8%) and rarely, sinoatrial block (Karla et al., 1991).On the other hand, cardiac dysrhythmias were described as atrial fibrillation (4% to 61%), junctional rhythm (4% to 100%), ventricular and atrial extrasyxtoles (18%) and ventricular fibrillation (2%) (Gupta et al., 1995;Louriz et al, 2009).Finally, re-polarization disorders were also reported, such as ST segment depression (12% to 65%), ST segment elevation (4% to 65%) and T wave inversion (36%) induced by AAlPP (Lall et al., 1997).Indeed, in Shadnia's study, 39 patients admitted to the ICU with AAlPP were studied.Average time elapsed between poisoning and admission at the hospital was 3.4 ± 3.5 hours.Average ingested amount was 1.4 ± 0.9 tablets.ECG abnormalities were found in 17 (43.6%)cases at the time of admission with ST-T changes in 8 cases.Ischemic change in 3 cases and dysrhythmias in 6 cases.The nature of these dysrhythmias was not described.The mortality rate was high, about 67%.In this study, ECG abnormalities were a prognostic factor In Louriz's study, 49 patients were enrolled.The ingested dose was 1.2 ± 0.7 grams.The time between ingestion and admission to the medical ICU was 9.1 ± 10.7 hours.The ECG was abnormal in 28 cases (58.7%) at the time of admission with myocardial ischemia in 21 cases, atrial fibrillation in 6 cases, ventricular extrasystoles in 9 cases and ventricular fibrillation in one case.The mortality rate was 49%.In this study, ECG abnormalities were also a prognostic factor (Louriz et al., 2009).In Mathai's study, 27 patients with AAlPP were admitted into the ICU.One and half grams of poison was consumed.There was a mean delay of 2.1 ± 1.55 hours before presenting to the hospital.Thirteen (48.1%) patients had dysrhythmia at admission of which the majority (69%) of supraventricular origin.Ventricular arythmias was found in 4 cases.The mortality rate was 59.3%.In this study, the presence of ECG abnormalities did not predict mortality (Mathai et al., 2010).In these 3 studies cited above, there wasn't any association between the dose of poison consumed or the time delay in presentation to the hospital with the mortality.All the ECG abnormalities found in these studies were recorded at the admission to the hospital.However, other ECG changes could be found during the hospitalization.Indeed, Bogle et al described a case of a lethal AAlPP caused by deliberate ingestion of AlP.ECG showed a sinus tachycardia 2 hours after ingestion of a 10 g sachet of pesticide with 56% of AlP.ECG recorded 12 hours after ingestion showed extreme widening of the QRS complexe despite amiodarone therapy.The rate of ECG abnormalities resulting of AAlPP might be under estimated (Bogle et al., 2006).Some electrical abnormalities noted in our practice are reported in

Conclusion
The severity of the poisoning is judged by the cardiac failure and the unavailability of an antidote.Myocardial injury following AAlPP is responsible for significant mortality.Despite all intensive medical care efforts in supportive therapy, the prognosis of AAlPP is poor.Therefore the use and availability of the pesticide aluminium phosphide should be restricted as much as possible.
Reversible myocardial injury associated with aluminum phosphide poisoning.Clin Toxicol, No.45, pp.728-31 Arora B, Punia RS, Karla R, Chugh SN & Arora DR. (1995).Histopathological changes in aluminum phosphide poisoning.J Indian Med Assoc,No. 93, PH 3 also has corrosive effects on tissues.Louriz et al investigated microscopic changes in vital organs of the body, liver, heart and kidneys (Louriz et al., 2009).These changes were found to be suggestive of cellular hypoxia.Other recent studies with more patients were performed and showed congestion, edema and leukocytie or leukocyte infiltration in the liver, kidneys, heart, stomach, lungs, brain and adrenals (Arora et al., 1995; Sinha et al., 2005).Nakakita studied the histology of the heart.Histopathological finding of myocyte vacuolation and myocytolysis and degeneration are both suggestive of myocardial injury.The areas of increased waviness of myocardial fibers indicate an episode of myocardial infarction (Nakakita et al., 2009).

Fig. 3 .
Fig. 3. Echocardiographically parasternal long axis depicted improvement of ventricle function following aluminum phosphide poisoning .A) Echocardiogram obtained on the second day after admission depicts global hypokinesis with LVEF of 30% and dilatation of LV.B) Echocardiogram taken eight days after admission showed improvement of ventricle function.

Fig. 4 .
Fig. 4. Echocardiography parasternal long axis depicted improvement of ventricule function.Echocardiogram obtained at admission depicts global hypokinesis with left ventricle ejection fraction (LVEF) of 40% and important dilation of right ventricle and auricle.