Treatment of Aluminium Phosphide Poisoning with a Combination of Intravenous Glucagon , Digoxin and Antioxidant Agents

Aluminium phosphide (AlP) is used to protect stored grains from rodents. It produces phosphine gas (PH3), a mitochondrial poison thought to cause toxicity by blocking the cytochrome c oxidase enzyme and inhibiting oxidative phosphorylation, which results in cell death. AlP poisoning has a high mortality rate among humans due to the rapid onset of cardiogenic shock and metabolic acidosis, despite aggressive treatment. We report a 21-year-old male who was referred to the Afzalipour Hospital, Kerman, Iran, in 2015 after having intentionally ingested a 3 g AlP tablet. He was successfully treated with crystalloid fluids, vasopressors, sodium bicarbonate, digoxin, glucagon and antioxidant agents and was discharged from the hospital six days after admission in good clinical condition. For the treatment of AlP poisoning, the combination of glucagon and digoxin with antioxidant agents should be considered. However, evaluation of further cases is necessary to optimise treatment protocols.

A luminium phosphide (alp) is a very effective outdoor and indoor pesticide used for protecting stored grains from rodents and other pests. 1 In Iran, AlP tablets are widely used for protecting rice against pests and so are traditionally called "rice tablets". 2Phosphine gas (PH 3 ) is rapidly formed and released when AlP comes into contact with water or dilute acids, such as those found in the stomach, and is the fatal active form of the pesticide. 3he two main routes of acute toxicity due to AlP are the ingestion of AlP tablets and inhalation of released PH 3 .Although the exact mechanism of action of AlP is not clearly understood, PH 3 is thought to induce toxicity by blocking the cytochrome c oxidase enzyme and inhibiting oxidative phosphorylation which eventually leads to myocyte death. 1,2AlP poisoning has a very high mortality rate (30-100%) and survival is unlikely if more than 1,500 mg is ingested; the lethal dose for an individual weighing 70 kg is 150-500 mg. 1 Exposure to AlP is rarely accidental and the majority of cases of severe AlP poisoning are reportedly due to the deliberate ingestion of AlP tablets with suicidal intentions. 2,3Although there are reports of accidental inhalation of PH 3 gas, especially among workers, AlP is known as a suicide poison with no effective antidote that can be easily bought. 2 Presenting features of AlP intoxication include the rapid onset of shock, vomiting, nausea, retrosternal and epigastric pain, dyspnoea, anxiety, agitation and garlic-odour breath. 32][3][4] Other cardiovascular complications include cardiac arrhythmias and acute myocardial infarctions. 1 Profound circulatory collapse is commonly associated with AlP poisoning; this is believed to be due to the direct effect of PH 3 on the heart cells. 5Cardiogenic shock is one of the main causes of death. 5,6There is currently no known antidote for this poison and most treatment modalities are not successful; however, the effective treatment of AlP poisoning using an intra-aortic balloon pump (IABP) and digoxin has previously been reported. 5,6n addition, other researchers have reported that glucagon, digoxin or antioxidants administered individually to poisoned patients have had a beneficial effect. 3,5This report is the first to present the combined administration of glucagon, digoxin and antioxidants in the management of a patient with AlP poisoning.

Case Report
A 21-year-old man was referred to the Afzalipour Hospital, Kerman, Iran, in 2015 after the intentional ingestion of a 3 g rice tablet containing AlP.The patient had swallowed the tablet whole with one glass of water, without crushing the AlP tablet into a powder.He had vomited approximately 45 minutes after ingesting the tablet and was admitted to a local hospital four hours later.At this point, he was completely awake and complained of abdominal and retrosternal pain and severe thirst.He had previously had a ventricular septal defect which had been repaired five years earlier.At presentation to the local hospital, the patient's initial vital signs were as follows: blood pressure of 90/60 mmHg; pulse rate of 140 beats/minute; respiratory rate of 18 breaths/minute; axillary temperature of 36.4 °C; and oxygen saturation of 95% in ambient air.
Approximately 10 hours after ingestion of the tablet, the patient was referred to the Afzalipour Hospital, the main referral toxicology centre in Kerman province. 7He was confused and his vital signs were as follows: blood pressure of 85/40 mmHg; pulse rate of 130 beats/minute; respiratory rate of 16 breaths/minute; axillary temperature of 36.7 °C; and oxygen saturation of 93% in ambient air.Arterial blood gas analysis indicated that his pH, partial pressure of carbon dioxide, bicarbonate (HCO 3 ) and been suggested to be the inhibition of cytochrome C oxidase, secondary toxic myocarditis and AlP-induced oxidative stress that lead to pump failure and cardiac arrest. 1 There is currently no specific antidote for AlP poisoning and supportive therapy is the mainstay of treatment for poisoned patients. 3,5tioxidant therapy using vitamins E and C and NAC may theoretically have a therapeutic role in acute AlP poisoning, as one of the main mechanisms of AlPinduced toxicity is oxidative stress.Some researchers have suggested the use of these agents-especially NAC-to treat AlP poisoning. 9In the current case, the patient was treated successfully with vitamins E and C and NAC.The treatment of cardiogenic shock caused by AlP poisoning with digoxin and an IABP has been suggested for mechanical support of the heart in toxic myocarditis and refractory shock; this approach has also had positive responses. 5,6Tehrani et al. found that hospital stay duration and rates of intubation, ventilation and mortality were significantly lower among AlP-poisoned patients who received NAC in comparison to controls. 9In addition, there is some evidence suggesting that glucagon is useful for the treatment of cardiogenic shock. 10,11Glucagon is an antidote for β-blocker poisoning but is also used to treat cardiogenic shock due to verapamil and, sometimes, imipramine. 10It has been postulated that glucagon activates adenylate cyclase at a different site to β-adrenergic agents, resulting in an increase in cyclic adenosine monophosphate; this increases the calcium pool available for release during depolarisation and contractility. 11,12Glucagon can also increase heart rate but has no effect on arterial pressure; thus, it has been reportedly useful in increasing mean blood pressure and heart rate in amitriptyline toxicity, although it is still unclear whether glucagon increases blood pressure. 13Glucagon receptors in the ventricular myocardium cause its inotropic effects. 14Thus, glucagon is a probable antidote for AlP poisoning by potentially increasing blood pressure and heart rate.Moreover, treating cardiogenic shock with glucagon may result in enhanced tissue perfusion. 11A previous case report described the successful treatment of a woman with AlP poisoning in Kerman, Iran, and concluded that the early administration of glucagon to AlP-poisoned patients in refractory shock may be beneficial. 15n addition to routine supportive treatments, managing the two main hazards of toxicity-oxidative stress and cardiogenic shock leading to circulatory collapse and lactic acidosis-is essential for the successful treatment of AlP poisoning.For this reason, agents with antioxidant properties such as vitamins E and C and NAC were administered to the patient in the base excess were 7.18, 28.5 mmHg, 11.7 mmol/L and -17.6 mmol/L, respectively.Electrocardiography revealed that the patient had sinus tachycardia.Using bedside echocardiography, the left ventricular ejection fraction was 35%.Serial vital signs and laboratory findings over time are presented in Table 1.
The patient was prescribed 44 milliequivalents of sodium bicarbonate every 15 minutes until the metabolic acidosis was corrected.He was also given an intravenous infusion of normal saline and vasopressors; additionally, 1 mg of glucagon was administered intravenously every 5-10 minutes until his blood pressure normalised after a total of 4 mg of glucagon.This was followed by a 4 mg/hour slow intravenous infusion of glucagon.Subsequently, digoxin (0.5 mg initially followed by 0.25 mg every six hours for 24 hours and 0.25 mg daily thereafter), magnesium sulphate (1 g initially followed by 1 g every six hours), 10% calcium gluconate (1 g initially followed by 1 g every six hours), hydrocortisone (200 mg initially followed by 200 mg every six hours), vitamin C (1,000 mg every 12 hours via slow intravenous infusion), vitamin E (400 units intramuscularly) and N-acetylcysteine (NAC; 140 mg/kg orally as a loading dose followed by 70 mg/kg orally every 4 hours for up to 17 doses) were administered.With the improvement of the metabolic acidosis and stabilisation of the patient's vital signs, all medications were gradually tapered off.The patient was discharged from the hospital six days after admission in good clinical condition and completely symptom-free.He did not require tracheal intubation at any point during admission.Repeat echocardiography at discharge revealed that the left ventricle ejection fraction was 50%.

Discussion
AlP induces oxidative stress and boosts the extramitochondrial release of free oxygen radicals that lead to lipid peroxidation and protein denaturation of the cell membrane in various organs. 1 PH 3 inhibits mitochondrial cytochrome C oxidase and catalase, induces superoxide dismutase and reduces the concentration of glutathione in AlP-poisoned patients, which leads to the generation of superoxide radicals and cellular peroxides. 1,2Cellular injury subsequently occurs via lipid peroxidation and other oxidant mechanisms, such as protein denaturation of the cell membrane and hypoxic cell damage. 8The major lethal consequences of AlP ingestion (i.e.profound circulatory collapse) are reportedly secondary to the toxins generated which directly affect cardiac myocytes and cause fluid loss and adrenal gland damage. 1,3,4The main causes of cardiogenic shock in AlP poisoning have current case as well as glucagon and digoxin to allow for better tissue perfusion.Since the sites of entrance and accumulation of calcium ions within the cell are different, glucagon and digitalis have synergistic inotropic effects. 14Coadministration of glucagon and digoxin is more effective than utilising each alone. 16Due to the short duration of action, prolonged continuous infusion of glucagon is necessary. 12Although alternative therapies such as angiotensin-converting enzyme inhibitors, intravenous diuretics and other intravenous inotropes are usually safer and more effective in cases of acutely decompensated heart failure, these treatments are less effective for patients with AlP poisoning. 5Successful treatment in the current case with glucagon and digoxin suggests that the concurrent use of high doses of these two agents may be useful in the treatment of AlP poisoning; however, this finding needs to be confirmed by further studies.The patient in the present case suffered from late vomiting; Louriz et al. observed that vomiting is a common symptom of AlP poisoning and that a lack of vomiting is a poor prognostic factor. 17n the present case, levels of paraoxonase 1 as well as the total antioxidant and total oxidant statuses and oxidative stress index were not evaluated.These are important to determine the patient's oxidant and antioxidant status.Previous studies have demonstrated that IABPs are another excellent treatment modality in cases of AlP poisoning; 1,6 the addition of an IABP to the treatment protocol used in the present case is recommended, especially in severe cases of AlP poisoning.However, it is important to bear in mind that IABPs are not available at all poisoning centres.The authors of this report recommend that other strong antioxidants such as superoxide dismutase and intracellular antioxidants like tempol should be used when treating cases of AlP poisoning.

Conclusion
A combination of glucagon and digoxin with antioxidant agents was used to successfully treat a patient with AlP poisoning.However, the clinical significance of this approach requires further consideration and evaluation in order to optimise management protocols for AlP poisoning.