High anion gap refractory metabolic acidosis as a critical presentation of endosulfan poisoning.

Organochloride insecticides are chlorinated cyclic hydrocarbons. One of such insecticides is endosulfan (6,7,8,9,10-10 hexachloro 1,5,5a,6,9,9a-hexahydro-6-methano-2,4,3-hexadithioxanthiep in 3-oxide) and it has been widely used in agriculture since 1960. The uncontrolled use of these compounds in developing countries has resulted in the deaths of animals and humans. Characteristic clinical signs following acute exposure are indicative of CNS disturbances or overstimulation. Mortality and morbidity rates are high and there is no specific antidote. We present an uncommon presentation of endosulfan poisoning in a 32-year-old male with high anion gap severe refractory metabolic acidosis. The patient was treated with continuous renal replacement therapy and was salvaged. Till date, there is no case report from India for endosulfan poisoning with severe metabolic acidosis and hypotension. Through this case report, we emphasize the role of continuous renal replacement therapy as a rescue therapy for endosulfan poisoning with severe refractory metabolic acidosis and hypotension, even though it is a non dialyzable poison.

Introduction

Organochloride insecticides are chlorinated cyclic hydrocarbons with molecular weights in the range of 300-550 Da.[1] They have a long half-life in the human body, and cause moderate toxicity.[23] One of such insecticides is endosulfan (6,7,8,9,10-10 hexachloro 1,5,5a,,6,9,9a-hexahydro-6-methano-2,4,3-hexadithioxanthiepin 3-oxide), which has been widely used in agriculture since 1960.[4] The uncontrolled use of these compounds in developing countries has resulted in the deaths of animals and humans.[3] There are isolated case reports of accidental and suicidal poisoning with endosulfan in the literature.[4] They are absorbed from gastrointestinal and respiratory tracts and skin. Acute poisoning is usually accompanied with nausea, vomiting, parenthesis, giddiness, convulsion, coma and respiratory failure. Hepatic, renal and myocardial toxicity, agranulocytosis, aplastic anemia and skin reaction have been reported. Mortality and morbidity rates are very high and there is no specific antidote.[5] Patients may present with severe metabolic acidosis. If severe metabolic acidosis is present, hemodialysis may be an important intervention and should be performed early.[6] Till date, there is no case report from India for the management of endosulfan poisoning with severe metabolic acidosis and hypotension. By reporting this case, we emphasize the role of continuous renal replacement therapy (CRRT) as a rescue therapy for endosulfan poisoning with severe metabolic acidosis and hemodynamic instability, even though it is a non dialyzable poison.

Case Report

A 32-year-old male was brought to casualty department on 13th of March 2009 with history of oral ingestion of a poison along with nausea, vomiting and three episodes of generalized tonic-clonic seizures with hypotension. On examination, his systolic blood pressure was 60 mm Hg and respiration was gasping. Pupils were semi dilated and reacting to light. Other systemic examinations were unremarkable. The patient was immediately intubated and shifted to critical care department. History could not reveal any information regarding the nature of poison. The patient had progressive worsening of blood pressure and blood gas analysis was suggestive of high anion gap severe metabolic acidosis [Table 1]. Supportive therapy like activated charcoal and gastric lavage was administered.

Table 1

Arterial blood gas and other investigations of patient

In view of high anion gap, metabolic acidosis with history of poisoning possibility of ethylene glycol poisoning was considered. He was treated with crystalloids, sodium bicarbonate and loaded with antiepileptic drug Phenytoin 20 mg/kg. Later Midzolam infusion was started with rate of 5 mg/kg/h for repeated seizures.Vasopressors were added as mean arterial pressure (MAP) was not responsive to fluid therapy. In view of repeated episodes of seizures, antiepileptic drugs were stepped up and the patient was started on infusion of thiopentone sodium with rate of 5 mg/kg/h. Thiopentone sodium was continued for four days and then tapered. In view of worsening of general condition and severe refractory metabolic acidosis, a decision to start continuous venovenous hemodiafilteraion (a form of CRRT) was taken. After starting of CRRT, there was a slow but steady improvement in metabolic acidosis. Within 3-4 h, blood pressure improved and HCO3- increased to16 meq/l [Table 1]. Initial serum creatinine was 1.8 mg/dl and the patient was having good urine output of around 2000 ml/day. His CPK-total, CPK-MB and liver enzymes were high on first day which gradually improved [Table 1]. The frequency of seizures decreased and the patient showed gradual improvement in his vitals. After two days, his serum pH and bicarbonate normalized [Table 1] with no fresh episode of seizures. CRRT was terminated. The patient weaned off gradually from ventilator. But even with good urine output, the patient continued to have hyperkalemia. Hence one session of potassium free conventional hemodialysis was given and the next day one more session of CRRT was given for 48 h. Hyperkalemia and sensorium improved and the patient was extubated on 26/3/2009. On reevaluation of history from the patient and recovery of container by relatives, it was found to be endosulfan poisoning. There was gradual withdrawal of the antiepileptic and the patient was discharged in stable condition.

Discussion

Endosulfan is a polychlorinated hydrocarbon pesticide used in agriculture. Acute toxicity may result in permanent neurological impairment.[7] The predominant toxicological effect is over stimulation of the CNS, by inhibiting Ca- and Mg-ATPase and antagonizing chloride ion transport in gamma-aminobutyric acid (GABA) receptors with little or no peripheral component. Characteristic clinical signs following acute exposure are indicative of include seizures, nausea, vomiting, abdominal discomfort, hyperesthesia of the mouth and face, tongue and extremities, headaches, agitation, hyperactivity, in coordination, confusion, dizziness, and myoclonus.[138] Endosulfan is also toxic to the liver, kidney and lung, and can cause rhabdomyolysis in higher doses.[8] Our patient had evidence of both liver and kidney toxicity.

In our case, the patient presented with nausea, vomiting and seizures and severe metabolic acidosis. His CPK enzyme was high and during later period of hospital course potassium was also high even with good urine output. These findings were in favor of rhabdomyolysis.

The toxic effects generally seem to be completely reversible; hence, it is necessary to identify the poison and to resuscitate the patient.[1] Gas chromatography can detect endosulfan in the serum, tissue, and urine.[3] A clinical diagnosis depends on a detailed history and suspicion and it may be necessary to measure concentrations of endosulfan for legal purposes. However, it has been reported that hemoperfusion is ineffective.[9]

Seizures should be controlled with a benzodiazepine, followed by phenobarbital if seizures persist. Phenytoin is probably less effective in these cases, given the effect of endosulfan on GABA receptors.[13] In our patient, seizures were refractory to benzodiazepine, but controlled with infusion of thiopentone sodium. Pulmonary toxicity associated with endosulfan poisoning has been reported as an important manifestation.[9] We did not encounter pulmonary edema in our case.

Yavuz et al.,[6] reported two cases of unintentional exposure to endosulfan, one of which presented with neurological manifestations, liver toxicity, and required mechanical ventilation and emergent hemodialysis; the other had only neurological manifestations and liver toxicity.

In literature, endosulfan poisoning with severe metabolic acidosis and hypotension has not been reported. In our case, the patient presented with severe high anion gap metabolic acidosis that responded well to CRRT.

In this case, predominant symptoms due to endosulfan poisoning were due to the involvement of the CNS and severe metabolic acidosis. Endosulfan poisoning should be suspected in unknown poisoning in the presence of primary CNS manifestations, with or without clinical or laboratory evidence of other organ dysfunctions such as liver failure and high anion gap metabolic acidosis in tropical countries like India.