2,4-D poisoning: a review with illustration of two cases

Introduction

Agriculture is a major source of income for much of the Asian population. In rural areas, the incidence of herbicide poisoning is high when intentional self-harm with these toxic compounds is used because of their ready accessibility.

2,4-dichlorphenoxyacetic acid (2,4-D) is a commonly used selective herbicide. Introduced in 1942, it has been permitted for use in many countries in the world. Significant oral ingestion, however, results in potentially fatal and non-organ-specific systemic toxicity that requires continuous monitoring and aggressive management.

The median lethal dose (LD₅₀) is estimated at c. 640 mg/kg. To illustrate, we describe two well-managed patients with 2,4-D poisoning.

Case 1

A 25-year old man presented with vomiting after ingestion of herbicide ‘Punch’ 58 (2,4-D Amine salt 58% soluble concentrate) with suicidal intent, 4 h before admission. He vomited intermittently. A gastric lavage was performed. A few hours later he became restless and developed weakness and stiffness of both hands. Myotonia of hand muscles (prolonged contraction followed by slow relaxation) was noted. Investigations revealed an elevated creatinine kinase (CK) level (27.37 μkat/L, reference range = 0.40–3.31) and slightly deranged renal function with blood urea 7.8 mmol/L and creatinine 132.63 µmol/L.

Urinary alkalinisation with sodium bicarbonate and forced diuresis with normal saline were commenced. Urine pH, serum electrolytes, kidney function and CK were closely monitored. Despite maintaining the urine pH > 8, and a slight reduction in CK and serum creatinine, his myotonia did not improve. On the third day, he became drowsy and disoriented, and hypotensive (90/60 mmHg). Haemodialysis was commenced. A dramatic improvement was observed: the myotonia disappeared; his sensorium returned to normal; and CK levels and renal function normalized.

Case 2

A 29-year woman was admitted with abdominal pain and drowsiness after ingestion of herbicide ‘Heera 44’ (2,4-D Ethyl Ester 38% emulsifiable concentrate) with suicidal intent. On arrival, she was comatose (Glasgow Coma Scale 8), normotensive (100/70 mmHg), tachycardic (130/min), tachypnoeic (26/min) and feverish (39.4℃). She was immediately intubated and was ventilated mechanically. A gastric lavage was performed. Investigation showed an elevated serum CK (20.13 μkat/L) and myoglobinuria (122.2 ng/mL, normal < 5). Kidney function was normal. Urinary alkalinisation was commenced with forced diuresis. After 48 h, her sensorium improved, the fever subsided and she was extubated. Myoglobinuria resolved and CK returned to normal.

Discussion

2,4-D belongs to the chlorphenoxy acid class of pesticides. These herbicides are a chemical analogue of auxin, a plant hormone for broad leaf weeds, which allows their uncontrolled and lethal growth. The relative safety and broad leaf selectivity makes it one of the most commonly used pesticides in the domestic sector.

Absorption is rapid and almost complete within 24 h after herbicide ingestion. Phenoxyacetates are weak acids; hence tissue distribution depends on plasma pH. Acidosis facilitates distribution by de-ionising the substance and allowing fatty tissue binding. At least 90% of an administered dose has renal elimination, almost 80% unchanged and the rest as conjugates. ¹ Renal clearance also depends on urine pH and urine flow. A higher urine pH and high urine flow rate facilitate decreased reabsorption from the distal tubule.

Pathophysiology. In severe poisoning, systemic absorption causes multi-organ dysfunction, suggesting that it is either non-specific in its action or that it interferes with a physiological process common to a number of organs. Proposed mechanisms include disruption of cellular membranes, uncoupling of oxidative phosphorylation and inhibition of acetyl coenzyme A metabolism. ² Skeletal muscle is a major target organ of 2,4-D. The mechanism of toxicity probably involves inhibition and dysfunction of the voltage gated chloride channel CLC-1 in skeletal muscles. ³

Clinical manifestations. Clinical features depend on the route, the degree and the duration of exposure. Gastrointestinal (GI) toxicity including nausea, vomiting, oropharyngeal or abdominal pain, and/or diarrhoea is the most common manifestation of acute poisoning. It may be mild and self-resolving. In severe poisoning, recurrent vomiting and severe diarrhoea may lead to dehydration. GI necrosis may occur with bleeding. ⁴ Circulatory shock is common and may develop promptly with large ingestion. Peripheral vasodilation, direct myocardial injury, cardiac arrhythmia and GI fluid losses may all contribute.^4–6 Coma is often prominent in severe cases, but a wide range of neurological manifestations may occur.^5,7 Peripheral neuromuscular manifestations are common and may have myopathy and/or neuropathy patterns.^6,9 These include muscle weakness, stiffness, spasm, fibrillation, myotonia, hypotonia, tremors and rhabdomyolysis. Apart from direct myotoxity, excess muscle toxicity and, in some cases, prolonged coma may contribute to rhabdomyolysis. Renal and metabolic impairment may occur secondary to circulatory compromise and/or rhabdomyolysis.^6–8 Respiratory failure may occur due to central respiratory depression or respiratory muscle weakness with generalised myopathy.^5,6

Diagnosis. 2,4-D poisoning is diagnosed on the basis of history of exposure and clinical features. Quantitative assays are not routinely available. Investigations should include serum electrolytes, muscle enzymes, RFT and blood gas analysis. Serum CK-NAC and urine myoglobin are tests for rhabdomyolysis.

Management. All patients with significant exposure particularly with ingestion warrant close monitoring (including cardiac monitoring), prompt resuscitation and aggressive management. In most reports of 2,4-D ingestion, gastric lavage and activated charcoal were administered, but supporting evidence is lacking. However, if the airway is secured, nasogastric aspiration and a single dose of activated charcoal should be used.

Case reports and animal studies suggest the role of urinary alkalinisation to increase the renal clearance of chlorphenoxy compound. It is achieved by intravenous sodium bicarbonate (1–2 mEq/kg rapid initial infusion with additional dosing) to increase urinary pH to 7–8. It has been suggested that urinary alkalinisation is more effective if accompanied by high urine flow rate with forced diuresis. Haemodialysis is considered the preferred elimination technique in severe poisoning. It produces similar herbicide clearance to alkaline diuresis without the need for urine pH manipulation or substantial amounts of intravenous fluid administration in an often already compromised patient. ⁵ Durakovich et al. reported four cases of 2,4-D poisoning treated with haemodialysis, two cases also received resin hemoperfusion and in one case 2,4-D clearance of 72.9 mL/min was achieved. ⁹

No specific antidote is available.

This index case series emphasises that it is important to initiate high-quality supportive care and urinary alkalinisation promptly in patients with significant ingestion of 2,4-D. In the absence of clinical improvement or further deterioration, renal replacement therapy should be started without delay even in the face of no or mild renal dysfunction.