Acute Renal Failure Following para‐Phenylenediamine (PPD) Poisoning: A Case Report and Review

Abstract

We report a case of systemic poisoning with para‐phenylenediamine (PPD) presenting with characteristic features of severe angioneurotic edema, rhabdomyolysis and intravascular hemolysis with hemoglobinuria culminating in acute renal failure. Though rare in western countries, such poisoning is not uncommon in East Africa, Indian subcontinent and Middle East countries. We discuss here the clinical features and key management issues of systemic PPD poisoning.

• para‐phenylenediamine (PPD) poisoning
• Rhabdomyolysis
• Angioneurotic edema
• Intravascular hemolysis
• Hemoglobinuria

Introduction

para‐Phenylenediamine (PPD), a derivative of para‐nitroaniline is widely used in hair dye formulations, in dyeing furs and in photochemical industries. Lately it has been commonly used to intensify the color of henna (Lawsonia alba), the dried leaves of which are applied to stain the soles and palms, and as a red hair dye. This is a popular custom in some of the East African countries, Middle East and in the Indian subcontinent. PPD reduces the amount of henna required and accelerates the dyeing process. Local application of PPD in susceptible individuals may result in dermatitis, asthma, arthritis, lacrimation, exophthalmos or even permanent blindness when applied to the eyes.[1], [2] Oral ingestion of PPD results in rapid development of severe edema of face, tongue, neck and laryngeal edema with respiratory distress often requiring emergency tracheostomy. This is usually followed by rhabdomyolysis, myoglobinuria and acute renal shut down.[3], [4] We present a patient of systemic PPD poisoning with a suicidal intent who developed both rhabdomyolysis and intravascular hemolysis and subsequent development of oliguric acute renal failure.

Case Report

A previously healthy 22‐year‐old male was brought to the emergency department two hours after ingestion of an unidentified substance. He presented with recurrent vomiting, swelling of the tongue, face, neck and severe respiratory distress. On examination, he was conscious, oriented and with pulse 104/min, blood pressure 130/86 mmHg, and a respiratory rate of 30/min. There was cyanosis, marked swelling of the tongue and neck with an inspiratory stridor for which he underwent an emergency tracheostomy along with intravenous steroids and subcutaneous adrenaline (0.5 ml of 1:1000 solution). His respiratory distress improved significantly after the tracheostomy. Four hours after admission, he developed stiffness and pain in all four limbs. On examination, all the limb muscles were exquisitely tender on palpation. His cardiovascular, respiratory and rest of the nervous system examination were normal. Over the next few hours, he developed oliguria with passage of dark chocolate brown colored urine (urine output—50 ml over 16 hours).

Investigations revealed hemoglobin of 9 g/dL, white cell count of 20,000/mm³ with polymorphs (92%) and lymphocytes (8%) and platelet count of 1.5 lacs/mm³. Peripheral smear showed anisopoikilocytosis, fragmented RBCs suggestive of hemolysis with reticulocyte count of 3%. The other biochemical investigations were: blood sugar 108 mg/dL, urea 120 mg/dL, serum creatinine 3.8 mg/dL, serum sodium 134 meq/L, potassium 7.1 meq/L, bicarbonate 18.3 meq/L. Serum bilirubin was 1.1 mg/dL, AST 84 IU (normal < 40 IU), ALT 104 IU, alkaline phosphatase 8 KA units/dL. Prothrombin time (PT) and partial thromboplastin time were normal.

The serum creatine phosphokinase (CPK) was 296,000 IU/L (normal up to 150 IU/L) and lactate dehydrogenase was 16,000 IU/L. Urine analysis tested positive for both myoglobin and hemoglobin. Arterial blood gas analysis showed partially compensated metabolic acidosis and ECG revealed sinus tachycardia with tall‐tented T waves suggestive of hyperkalemia. Coomb's test (direct and indirect) was negative and chest x‐ray was unremarkable. Further enquiries from the patient's father revealed that the patient had consumed approximately 20 grams of a crystalline substance (later identified as PPD) with a suicidal intent.

The patient was managed with intravenous fluids, bicarbonate and mannitol and underwent hemodialysis for renal failure and hyperkalemia. However, despite appropriate supportive management, patient had a cardiac arrest and died on second day of admission.

Discussion

para‐Phenylenediamine is an aromatic diamine and is structurally related to para‐aminobenzene, a coal tar product. For dyeing purposes, PPD is added with hydrogen peroxide resulting in the formation of Bandrowski's base, which is highly allergic and toxic. In 1924, Nott described the first case of systemic toxicity with PPD in a hairdresser who suffered from intermittent illness due to handling of the dye.[5] A number of cases of systemic poisoning have been reported since then. Though reactions due to local application are restricted to the area exposed to PPD, systemic toxicity may also occur from percutaneous absorption.[6]

In 1982, Chugh et al. reported for the first time two patients who developed acute oliguric renal failure following PPD intoxication.[7] This was also accompanied by angioneurotic edema, intravascular hemolysis and methemoglobinemia. Renal biopsy showed acute tubular necrosis in both of them. Renal failure was attributed to hemolysis and methemoglobinemia. Later, other authors also reported cases of PPD intoxication where initial phase of angioneurotic edema and respiratory distress was followed by rhabdomyolysis and acute renal failure.[4], [8]

There is a remarkable consistency in the presenting features of systemic PPD poisoning. Ingestion of PPD produces two types of toxic effects. The first appearing shortly after ingestion characteristically consists of vomiting and severe edema of face, neck, pharynx, larynx and upper airways culminating in acute respiratory distress, often requiring emergency tracheostomy.[2], [4], [9] The edema production is said to be due to increased permeability of the blood vessels. In 1991 Yagi et al. reported the first series of 18 cases with acute hair dye (PPD) poisoning over a period of two years.[2] Poisoning was with a suicidal intent in 70% of the cases and accidental in rest. Sixteen cases were classified as serious requiring tracheostomy. Four out of 18 patients died with a mortality rate of 22%. Complete recovery occurred in the rest except one patient who suffered from permanent blindness. In another series Hashim et al. from Sudan reported 31 children with PPD poisoning from year 1984 to 1989.[6] Again, all children presented with acute and severe angioneurotic edema with 15 of them requiring tracheostomy.

The second phase which appears later in a significant number of victims who have consumed more than 3 grams of PPD, includes stiffness and pain in the limbs, rhabdomyolysis and passage of chocolate brown‐colored urine culminating in acute oliguric renal failure. In the case series of Hashim et al., renal failure occurred in five out of 31 children requiring peritoneal dialysis. Thirteen children died which was mainly attributed to respiratory failure or circulatory collapse unlike in adults with PPD poisoning in whom renal failure was the main culprit.[6]

Rhabdomyolysis has been a consistent feature in several other reports as was in our case and has been implicated as a cause of acute renal failure.[4], [8], [10] Toxicity of PPD is dose related with higher doses causing severe rhabdomyolysis and renal failure. Ingestion of more than 7–10 grams of PPD has been observed to be lethal.[2], [6] In the patients described by Chugh et al.[7] who developed acute renal failure, muscle pain and evidence of rhabdomyolysis were absent. Since PPD is chemically related to benzene and aniline, and intravascular hemolysis, hemoglobinuria and renal failure have also been observed after exposure to these chemicals, they attributed renal failure in patients with PPD poisoning to hemolysis and methemoglobinemia and/or direct toxic effects of PPD on renal parenchyma.

Our patient developed the complete spectrum of systemic PPD poisoning starting with severe angioneurotic edema and respiratory distress requiring emergency tracheostomy. This was followed by stiffness and pain in the limbs, rhabdomyolysis and acute renal failure. Our patient also developed intravascular hemolysis as evidenced by positive urinary hemoglobin, peripheral smear and high reticulocyte count. Since coomb's test was negative, hemolysis may be attributed to direct toxic effect of the chemical or its products on red cell wall membrane rather than immune‐mediated red cell destruction. To the best of our knowledge, this is the first time that both intravascular hemolysis and rhabdomyolysis have occurred in the same patient resulting in acute renal failure.

Other less commonly reported features of PPD poisoning are liver failure,[11] drowsiness,[12] altered sensorium and convulsions, gastrointestinal symptoms,[13] pure motor neuropathy,[14] exophthalmos[2] and chronic renal failure.[15]

In fact, the clinical features of systemic toxicity of PPD are so characteristic that passage of chocolate brown‐colored urine along with angioedema could be taken as a confirmatory evidence of hair dye (PPD) poisoning even in the absence of laboratory studies or history of consuming PPD.[2]

Treatment of systemic PPD poisoning is mainly supportive as there is no specific antidote. Asphyxia during the initial phase of the poisoning and renal failure during the subsequent phase is the major threat to life. Since endotracheal intubation would be difficult if not impossible in a patient with laryngeal edema, all patients with severe angioneurotic edema and respiratory distress should undergo tracheostomy. This has been shown to be life saving in 67% of patients in a case series.[2] Milder cases may be managed with intravenous antihistamines and steroids alone without tracheostomy. In a patient with evidence of rhabdomyolysis, renal injury may be minimized by administration of large volume of fluids (up to 8–10 liters/day), intravenous mannitol and bicarbonate to alkalinize the urine, as theoretically it would enhance the excretion of putative toxin. Extreme care should be taken to avoid dehydration and anoxia as it has been shown that renal injury and fall in GFR due to hemoglobinuria or myoglobinuria is aggravated in presence of anoxia or dehydration. Findings of very high plasma urate (> 750 µmol/L) and phosphate (> 2.5 mmoles/L) along with low plasma calcium (< 1.5 mmoles/L) in any patient with acute renal failure should lead to serious consideration of myoglobinuria as the cause of renal failure. Renal failure and hyperkalemia should be managed by hemodialysis or peritoneal dialysis.

To conclude, presence of angioneurotic edema, intravascular hemolysis and rhabdomyolysis in a patient with subsequent development of acute renal failure should strongly suggest systemic toxicity with para‐phenylenediamine (PPD). Early clinical diagnosis and therapeutic interventions in the form of tracheostomy, intravenous fluids and hemodialysis may lead to full recovery.