270 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 1, NO.6

Aluminium phosphide poisoningClinical toxicity and outcome in eleven intensively monitored patients

R. BAJAJ, H. S. WASIR, R. AGARWAL, A. MALHOTRA,P. CHOPRA, M. L. BHATIA

ABSTRACTEleven consecutive patients with severe toxicity toaluminium phosphide were prospectively studied betweenMarch and June 1987. Following admission into an inten-sive care unit they underwent continuous haemodynamicmonitoring which included Swan-Ganz and intra-arterialcatheterization. Two hourly haematocrit estimation,radio nuclide ventriculography and percutaneousendomyocardial biopsy were carried out in selectedpatients. Signs of early (first 24 hours) toxicity includedsevere acidosis, severe peripheral capillary leakage,electrocardiographic and enzyme evidence of globalmyocardial injury and a depressed left ventricular ejectionfraction. The most important manifestation of late (after24 hours) toxicity was the adult respiratory distress syn-drome. Nine of the 11 patients died: 3 with progressivehypotension, 4 following adult respiratory distress syn-drome, 1 after aspiration and 1 due to gastrointestinalbleeding.

INTRODUCTIONAluminium phosphide pellets ('Cellphos', 'Alphos','Quickphos' etc.) are easily available in northern Indiaand are used for the fumigation of stored foodgrains. Apellet weighing 3 g contains 70% aluminium phosphideand 30% aluminium carbonate. Less than one-sixth of apellet (0.5 g) is a fatal dose for a 70 kg adult. 1 Moisturereacts with aluminium phosphide (AlP) to release phos-phine (PH3), a highly reactive poisonous gas:

AlP + 3H20 ~ AI(OHh + PH3

Phosphine directly inhibits cytochrome oxidase III anaction similar to that of cyanide. 2

Over the last five years aluminium phosphide has gainednotoriety as an effective suicidal agent, resulting inthousands of deaths. As clinical features of phosphinetoxicity are poorly understood and there is no effectivetreatment, we intensively monitored 11 consecutivepatients over a period of four months.

All India Institute of Medical Sciences, New Delhi 110029, IndiaR. BAJAJ, H. S. WASIR, R. AGARWAL, A. MALHOTRA,

P. CHOPRA, M. L. BHATIACardiothoracic and Neurosciences Centre

Correspondence to H. S. WASIR

© The National Medical Journal of India, 1988

PATIENTS AND METHODSBetween March and June 1987, 13 males and 5 females(aged 15 to 55 years; mean 21.9 years) with reportedingestion of aluminium phosphide came to the emergencyservices of the All India Institute of Medical Sciences,New Delhi. They were all examined by one of the authorsand were given gastric lavage with normal saline or dilutepotassium permanganate solution. Patients with no evi-dence of toxicity were kept under observation for a fewhours. It was assumed that they had taken old, exposedpellets which rapidly lose toxicity. Patients who hadingested fresh tablets invariably had toxic manifestations.Such patients were resuscitated and quickly transferred tothe intensive care unit. Monitoring included continuouselectrocardiography and measurement of intra-arterialblood pressure, pulmonary artery wedge pressure (withSwan-Ganz catheters attached to strain gauge mano-meters), urine output (with indwelling urinary catheters),arterial blood gas and pH analysis and serum biochemistry.

In addition, serial cardiac isoenzyme estimation(Serum CPK-MB in 5 patients), radionuclide ventriculo-graphy using a gamma camera and 99mTechnetiumpertechnetate labelled RBCs (3 patients), serial two-hourly haematocrit (4 patients), endomyocardial biopsies(2 patients) and post-mortem biopsy (7 patients) wereperformed in a selected number. In case of deathimmediate autopsies were not possible because of thevarious legal procedures and the bodies were handed overto the medicolegal department.

TreatmentIntensive supportive therapy was administered andincluded mechanical ventilation, continuous nasogastricsuction, intragastric antacid instillation, intravenousranitidine and intravenous ampicillin. Hydrocortisone(100mg iv 8 hourly) was administered to 2 patients. Patientswere sedated with intravenous diazepam and morphine.

RESULTS

Patient ProfileSixteen of the patients had consumed these pellets inan attempt to commit suicide. Particularly vulnerablewere students reacting to a poor examination result (4),farmers (6), and psychiatrically ill patients (2). Fourpatients had swallowed old pellets that had been previously

BAJAJ, WASIR, AGARWAL, et al. : ALUMINIUM PHOSPHIDE POISONING

exposed to air and showed a minimal toxic reaction. Ofthe 14with severe toxicity, 2 could not be resuscitated anddied in the emergency room within minutes. One otherpatient who died (a lady who was seven months pregnant)had been admitted under another service and is excludedfrom this study. The remaining 11 patients form the basisof this report.

Fifteen of the 18patients consumed the pellets between6 p.m. and 12midnight. The time from ingestion to arrivalin hospital varied from one to four hours. One patient wasinitially treated in a district hospital, and transferred toour hospital 21 hours after ingestion.

Four patients each had consumed a single pellet,3 patients each had consumed two, 1 patient had taken3, another had taken 5, and 2 patients had swallowed theentire pack of 10pellets. Vomiting occurred in all patientsfrom 10 to 75 minutes after ingestion. In 8 patients it wasspontaneous and in 3 patients it was induced.

The appearance of the patients was remarkably similaron arrival in the emergency services. They were restless,with a thready or impalpable pulse, cold extremities andcomplaining of thirst and epigastric burning. Orientationand other higher cerebral functions were well preserved.Diarrhoea had occurred in the 2 patients who had con-sumed 10 pellets.

Cardiovascular ChangesThe heart rate on arrival was inappropriately slow for thedegree of circulatory shock (80-100 beats/min). In 6patients the rhythm was irregular with no evidence ofatrial activity on electrocardiography. In the other 5,supraventricular premature beats were frequent, andatrial fibrillation supervened in 4 of them. Reappearanceof normal P waves with appropriate sinus tachycardia(rates 140-200/min) occurred in 3 to 8 hours. Sinustachycardia persisted for up to one week in patients whosurvived.

Blood pressure: This was low initially (systolic <90 mmHg) in all but one patient who had been given initial treat-ment elsewhere, and correlated well with the number ofpellets ingested. In 3 patients who had ingested 5 to 10tablets, the blood pressure responded poorly to adequatehydration (wedge pressure> 18 mm Hg) and maximaladrenergic support. Death occurred in these threepatients within 12 hours.

In the 8 patients who had ingested 1 to 3 pellets, therewas an initial improvement of blood pressure (>80 mmHg systolic) with fluids and dopamine. Two patients hadhypotension again at 24 and 44 hours respectively. Thisoccurred when they developed adult respiratory distresssyndrome (ARDS) and needed mechanical ventilation.

Pulmonary artery wedge pressures: In 3 patients it wasdifficult to maintain the pressure lines because of theirsevere restlessness and we were unable to record anymeaningful data. Subsequently, we sedated all the otherpatients. In these, the initial wedge pressures were low ornormal and varied according to the volume of fluidsalready infused. During the first 12 to 18 hours, large(4600-9000 ml) infusions were required to maintainwedge pressures between 10 and 15 mm Hg. Slowing of

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the infusion rates produced a rapid fall in wedge pressures.After the first 18 to 24 hours, wedge pressures stabilized,and rapid infusions were no longer required. Three pa-tients developed facial puffiness and pitting oedema. The 2patients who survived had massive polyuria on the secondand third days, with slightly elevated wedge pressures andtachypnoea which responded to intravenous frusemide.

Serial haematocrits: Haemoconcentration was initiallypresent in 10 out of 11patients. Two-hourly haematocritsindicated that there was no haemodilution during rapidintravenous infusions that were administered during thefirst 18 to 24 hours, and there was no evidence ofhaemoconcentration during the massive polyuria thatoccurred on the second and third days.

Radionuclide ventriculography: The left ventricularejection fractions were 22%, 30% and 62% at 24, 72 and120 hours respectively in one of the three patients whounderwent serial ventriculography. The end diastoliccounts were high and there was global hypokinesia. Thispatient survived. In the other survivor the ejection fractionwas 62% at 36 hours. In the patient who died the ejectionfraction was 42% at36 hours. Studies were not possible inthe other patients because of their critical condition.

Creatine phosphokinase: Creatine phosphokinase car-diac isoenzyme (CPK-MB) was elevated (21-90 units) inall 5 patients tested. The levels were highest in the earliestsamples but became normal by the fourth day.

Electrocardiogram: The ECG showed characteristicchanges in addition to the rhythm disturbances describedpreviously. In 4 patients bizarre wide QRS-T complexesresembling ventricular tachycardia with right axis deviationwere seen (Fig. 1). There was partial normalization withcorrection of acidosis and hypokalaemia. However,bizarre complexes commonly persisted after 24 hours(even after the pH had returned to normal). CharacteristicST segment elevation in leads V2, V3 with ST segmentdepression in other leads was present in 5 patients (Fig.1). Two patients had ST depression with T wave inversionin multiple leads. One of these 2 patients survived, andthe ST depression disappeared by the tenth day.

Myocardial biopsies: Histological features varied withthe time interval between ingestion of the toxin and theperformance of the biopsy. In 3 patients who died within12 hours of consuming AlP, the myocardial histology wasnormal. Non-specific vacuolation and degeneration ofmyocardial fibres was present in 3 patients who diedbetween 12 and 72 hours. Toxic myocarditis with degene-ration of myocardial fibres and neutrophil and eosinophilinfiltration was present in 3 patients who had biopsiesafter 48 hours (Fig. 2).

Respiratory SystemThe adult respiratory distress syndrome (ARDS) occurredin 7 of the 11 patients (p02 < 50 mm Hg, pC02 < 40 mmHg and typical chest X-ray features) (Fig. 3). Two otherpatients had radiographs characteristic of ARDS but did

. not develop severe hypoxaemia. Pulmonary aspirationoccurred in 2 patients. In the rest ARDS was attributedsolely to poisoning. The earliest evidence of ARDS wasdetected within 6 hours and the condition was fully estab-

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FIG. I. Electrocardiogram of a patient 6 hours after ingestion of aluminium phosphide show-ing absent P waves and moderate QRS and ST-T abnormalities. Further worsening ofthese, especially when associated with tachycardia, simulates ventricular tachycardia.

FIG. 2. Chest X-ray showing patchyopacification of both lungsin a patient with ARDS.

lished by 24 hours. Inadvertent or ill-judged intravenousinfusions often produced pulmonary oedema without amajor rise in wedge pressures. In the 2 patients who didnot develop ARDS, death occurred within 12 hours.

Other ComplicationsCentral nervous system toxicity was minimal. Patientswere restless during hypotension and comatose duringsevere hypotension and metabolic derangement, especiallyif large doses of sedatives had been administered. Twopatients who died had complained of blindness, but theirpupillary reflexes were normal. Preventable complicationswere ischaemia of the hand following radial artery cannu-lation (1), gastrointestinal haemorrhage (1), pulmonaryaspiration (2) and near fatal hypoxaemia due to malfunc-tion of ventilator or endotracheal connections (2).

Metabolic acidosis (pH 6.9-7.2) was present in 7 out of

FIG. 3. Myocardial biopsy showing myofibre degeneration andleucocyte infiltration 7 days after ingestion of aluminiumphosphide.

9 patients tested during the initial 24 hours. We used largequantities of sodium bicarbonate to correct the acidosis,but this was not required after 24 hours. Serum potassiumlevels ranged between 2.5 and 3.4 mEq/L in 6 patients and1.7 and 2.4 mEq/L in 3 patients. Hypokalaemia was notedon the first day in 7 out of 9 patients and persisted for 4 to5 days in patients who survived. There were minor abnor-malities in blood counts, liver function tests, urea andcreatinine.

SurvivalEight of the 11 patients died 8 to 72 hours after ingestionof aluminium phosphide and 1 patient died on the sixthday with progressive ARDS. There was possibly a roughcorrelation between the quantity of poison ingested andthe length of survival as the 2 survivors had consumedonly one and two pellets respectively. The terminal events

BAJAJ, WASIR, AGARWAL, et at. : ALUMINIUM PHOSPHIDE POISONING

were: resistant hypotension (3), pulmonary aspiration(2), progressive hypoxaemia (2) and recurrence ofhypotension after initial stabilization (2).

DISCUSSIONThe Size of the ProblemAluminium phosphide is the most frequently ingestedpoison in northern India' and so has been our experiencein Delhi. Occasional case reports of aluminium phosphidepoisoning appeared in local journals'> around 1985 andtwo series have been reported in foreign journals.s-?Recently, 5 series which describe a total of over 230 caseswere submitted for presentation at the Forty-ThirdAnnual Conference of the Association of Physicians inIndia at Pune.

In India, rural hospitals see more cases than large referralcentres in the cities. Death is fairly quick and manypatients probably never reach a medical centre. Further-more, there is a great reluctance to bring medicolegalcases to hospitals so the size of the problem is probablymuch larger than has been reported.f

Epigastric burning, vomiting, thirst, cardiovascular col-lapse, acidosis and hypokalaemia are common featuresdescribed in all reports. We identified myocardial pumpfailure, peripheral capillary leakage and the adultrespiratory distress syndrome as the underlyingpathophysiological processes.

Myocardial DepressionHypotension and oliguria despite maintenance of normalpulmonary wedge pressures, and depressed left ventricu-lar ejection fractions are clear evidence of myocardialdepression. Elevated creatine phosphokinase-myocardialfraction (CPK-MB), grossly abnormal electrocardiogramssimilar to those seen with global myocardial ischaemia,"and myocardial histology showing vacuolation, myocyto-lysis and polymorphonuclear cell infiltration were otherevidences of myocardial injury. We did not measure cardiacoutput in our patients, but this has been found to be lowby others in preliminary unreported studies.

The myocardial toxicity. may be related to the greateroxygen requirements of myocardial cells as compared toother tissues in the body. Blood pressure and peripheralperfusion generally improved after 24 hours. Recurrenceof hypotension after initial stabilization occurred in2 patients, and was possibly caused by right ventriculardecompensation as ARDS developed.

Peripheral Capillary LeakageThe large volumes of infusion required during the first24 hours to. maintain normal wedge pressures, thedevelopment of pitting oedema after hydration, thehaemoconcentration at presentation, and the absence ofhaemodilution after the infusion, are all features ofperipheral capillary leakage. Autopsy evidence of wide-spread congestion and haemorrhage" are also features ofcapillary bed damage.

Adult Respiratory Distress SyndromeThis is invariably present in phosphine gas poisoning, and

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its occurrence after aluminium phosphide poisoning hasbeen reported previously. 10 The high incidence of ARDSfound by us is possibly related to the inclusion of very sickcases and the prevention of early death by controlled hy-dration. It is also possible that other workers have notdetected the occurrence of ARDS as serial blood gasanalysis, chest X-rays and pulmonary wedge cathetershave generally not been used by them. 10

Metabolic AcidosisThis is well documented, and is probably due to lacticacidosis, caused by blocking of oxidative phosphoryla-tion, similar to the effect of cyanide. II

TreatmentWe used intensive supportive care with modest success.The problems of acidosis and peripheral capillary leakagewere successfully overcome with intravenous bicarbonateand fluids. However, severe myocardial depression andARDS could not be corrected. More aggressive care suchas intra-aortic balloon counter pulsation to support thecirculation and more specialized respiratory care maysave the lives of more patients.

Where such facilities are not available managementshould include gastric lavage with a mild oxidizing agent(such as potassium permanganate) followed perhaps bycopious lavage with sodium bicarbonate solution (whichmay help to reduce systemic acidosis without causing fluidoverload); intravenous fluids guided by blood pressure,urine output and respiratory rate; and the use of oxygenwhen radiologically obvious ARDS supervenes. Vaso-pressors and frusemide may also be required. Digoxin,antibiotics and corticosteroids may have a limited role.

RecommendationsThe most effective way to prevent the ingestion ofaluminium phosphide is to ban its sale urgently. Some ofthe studies which may enable us to understand more fullyand treat aluminium phosphide poisoning more effectivelyare: In vitro experiments to determine effective agents toneutralize phosphine in the gut; experiments in animals todetermine the value of corticosteroids, magnesium" orany other potentially useful agents; and measurement ofpatients' blood phosphine and lactate levels; and cellularcytochrome oxidase levels.

ACKNOWLEDGEMENTSWe are grateful to the nursing staff of the coronary careunit for their help in the management of these patients.

REFERENCESGosselin RP, Smith RP, Hodge HC. Clinical toxicologyof commercialproducts. Williams and Wilkins, Baltimore, 1984;11-119.

2 Chefurka W, Kashi KP, Bond EJ. The effect of phosphine on electrontransport of mitochondria. Pesticide Biochem Physiol1976;6:65--84.

3 Siwach SB, Yadav DR, Arora B, Dalal S, Jagdish. Aluminiumphosphide poisoning in Haryana (India). An epidemiological andclinicopathological study. J Assoc Physicians India 1988;36:23.

4 Dashora UK, Swaroop D. The dreadful Cell Phos poisoning. JAssoc Physicians India 1985;34:227.

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5 Khosla SN, Chugh SN, Nand N, Saini RS. Systemic involvement inaluminium phosphide poisoning. J Assoc Physicians India1985;34:227-30.

6 Singh S, Dilawari JB, Vashist R, Malhotra HS, Sharma BK.Aluminium phosphide ingestion. Br Med J 1985;290:1110-11.

7 Chopra JS, Kalra OP, Malik VS, Sharma R, Chandna A.Aluminium phosphide poisoning: A prospective study of 16 cases inone year. Postgrad MedJ 1986;62:1113-15.

8 Bajaj R, Wasir HS. Epidemic aluminium phosphide poisoning innorthern India. Lancet 1988;1:820-1.

9 Quinn TJ, Ezri MD, Denes P. ECG changes in LV ischaemiasimulating wide complex tachycardia. Chest 1984;86:781-2.

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10 Chugh SN, Mehta LK, Arora BB, Malhotra KC. Adult respiratorydistress syndrome following aluminium phosphide ingestion. JAssoc Physicians India 1988;36:19.

11 Graham DL, Laman D, Theodore J, Robin ED. Acute cyanidepoisoning complicated by lactic acidosis and pulmonary edema.Arch Intern Med 1977;137:1051-5.

12 Ram A, Shrivastava SSL, Elhence GP, et al. A study of aluminiumphosphide (AlP) poisoning with special .reference to therapeuticefficacy of magnesium sulphate. J Assoc Physicians India1988;36:23-4.

A comparative study of one-, two- and multi-sampleantipyrine salivary testsR. RAVEENDRAN, C. ADITHAN, G. SIVAGNANAM,C. H. SHASHINDRAN, J. S. BAPNA

ABSTRACTSalivary antipyrine tests were evaluated in 20 healthy vol-unteers and 6 diabetics. After oral administration ofantipyrine (15 mg/kg), saliva was collected at 0, 4, 8, 24and 48 hours. In 9 healthy volunteers, plasma sampleswere also collected. Antipyrine concentration was mea-sured by high performance liquid chromatography. Themetabolic clearance rate (CL), elimination half-life (tl12)and apparent volume of distribution (Vd) obtained fromtwo-sample (T-APT) and single sample (S-APT) methodswere compared with the conventional multi-sample(C-APT) method. Except Vd, the S-APT values for theCL and t1/2agreed well with corresponding C-APTvalues.However, all the three measurements of T-APT weremore accurate than, and in closer agreement with, C-APTvariables. The salivary data of T-APT also closely corre-lated with that of conventional plasma antipyrine studies.The T-APT was also found to be applicable in diseasestates.

Jawaharlal Institute of Postgraduate Medical Education and Research,Pondicherry 605006, India

R. RAVEENDRAN,C. ADITHAN, G. SIVAGNANAM,C. H. SHASHINDRAN, J. S. BAPNA Department ofPharmacology

Correspondence to C. ADITHAN

© The National Medical Journal of India, 1988

INTRODUCTIONAntipyrine clearance is an indicator of quantitative liverfunction. I We had reported earlier that the two-sampleantipyrine test in plasma could replace the conventionalfour to seven sample test.? As the antipyrine level is iden-tical in the serum and saliva, samples of saliva are oftenused to determine the levels of antipyrine in the body. 3

Loft et al. described the use of single saliva sample forcalculating antipyrine clearance in children." As weare not aware of any report that compares the accuracy ofthe single sample antipyrine test with that of the two-sam-ple antipyrine test in saliva, we carried out this study todetermine whether the two-sample test could be appliedto saliva samples and whether it could be used in diseasestates.

PATIENTS AND METHODSThe study, approved by the hospital ethics committee,was carried out in two groups with the informed consentof all the subjects. The first group consisted of 20 normalhealthy volunteers (12 males and 8 females). Theirmean±S.D. values were: age 26.3±1O.9 (range 19 to 55years); body weight 52.9±9.4 (range 36.5 to 65 kg); andheight 167.0±8.9 (range 151 to 189 em). The secondgroup comprised 6 patients with diabetes (2 males and 4