Intermediate Syndrome after Organophosphate Intoxication in Patient with End-Stage Renal Disease

Abstract

A 42-year-old woman with a 24-year history of systemic lupus erythematous and lupus nephritis for 8 years who had been receiving regular hemodialysis for 4 years for nonoligoric end-stage renal disease (ESRD) ingested about 100 mL of 40.8% chlorpyrifos in a suicide attempt. On admission to our emergency department, she was drowsy. Gastric lavage, activated charcoal, pralidoxime (PAM), and atropine were administered 4 h later. Her consciousness level improved gradually with treatment, which included hemodialysis. However, on the second hospital day, intermittent fever to 38.4°C, sore throat, and trismus were noted. About 45 h after chlorpyrifos ingestion, the patient developed profound motor paralysis followed by respiratory arrest, consistent with the diagnosis of intermediate syndrome (IMS), even with adequate atropine and PAM. Chorealike involuntary movements of her upper limbs were noticed on the fifth day. Intermittent tonic-clonic seizures, each attack lasting for 3 to 5 min, appeared on the 13th day, which responded well to intravenous diazepam and phenytoin. She was discharged on the 18th day. This case suggests that patients with ESRD suffering chlorpyrifos intoxication are at risk of IMS. Prompt endotracheal intubation, intensive care, and hemodialysis are necessary for life support.

Keywords:

• end-stage renal disease (ESRD)
• hemodialysis
• intermediate syndrome (IMS)
• organophosphates

INTRODUCTION

Intermediate syndrome (IMS) has been described as delayed proximal and diaphragmatic muscle paralysis after improvement of the initial cholinergic signs and symptoms resulting from organophosphate (OP) poisoning.[1] The acute toxicity of anticholinesterase OP compounds is a consequence of inhibition of carboxylic esterase enzymes, of which acetylcholinesterase is clinically the most important. Most people agree that this syndrome is attributable to continuous cholinesterase inhibition, leading to both presynaptic and postsynaptic dysfunction of neuromuscular transmission.[2],[3] Extrapyramidal signs (EPS), including choreoathetosis, dystonia, cogwheel rigidity, and resting tremor, have been reported in patients poisoned with highly lipid-soluble OP compounds.[4],[5]

We describe the clinical features in a chlorpyrifos-poisoned female patient suffering end-stage renal disease (ESRD) resulting from lupus nephritis and receiving regular hemodialysis for 4 years.

CASE REPORT

A 42-year-old woman with a 24-year history of systemic lupus erythematosus (SLE) associated with lupus nephritis for 8 years had received regular hemodialysis for 4 years. Her urine output was around 1000 mL/day. She had been taking phenytoin for 6 years because of lupus encephalopathy with tonic-clonic seizure episodes, and it was effective. Delirium occurred at times.

She was sent to our emergency department approximately 4 h after taking about 100 mL of 40.8% chlorpyrifos to commit suicide; she did not receive any treatment outside the hospital. On admission, she was drowsy with nausea but no vomiting or diarrhea. The pupils were pinpoint. Examination of breathing sounds revealed bilateral basal crackles. The pulse was 86 bpm, blood pressure 167/102 mmHg, temperature 35.2°C, and ventilation 22 breaths/min. The initial Glasgow Coma Score was 5/15 (E2V1M2). No obvious salivation, lacrimation, or fasciculation was observed. Laboratory examination revealed a white blood cell count of 11,200/mL, sodium 141 mEq/L, potassium 4.0 mEq/L, bicarbonate 16.4 mEq/L, and creatinine 7.7 mg/dL. Arterial blood gas analysis showed pH 7.284, Paco₂ 35.4 mmHg, Pao₂ 67.6 mmHg, Hco₃ 16.4 mEq/L, and absolute base excess -10.3 mEq/L. An electrocardiogram showed normal sinus rhythm.

Gastric lavage and activated charcoal 50 g orally were administered immediately. Both pralidoxime (PAM) 1 g infused every 4 h for the first day and 2 g every 4 h the second day and atropine 1 mg intravenously given every hour, with the dosage adjusted to maintain clear breathing sounds, were also started immediately. Hemodialysis was performed. After 12 h, the serum cholinesterase level was 311 U/L. Consciousness had improved (E4V4M6), but both disorientation and irritability persisted, as did bilateral basal lung crackles. Intermittent fever to 38°C, sore throat, and difficult mouth opening were found on the second hospital day. Antibiotics were prescribed, and the fever declined. However, drowsiness worsened the morning of day 3, followed by apnea attack in the afternoon (about 45 h after chlorpyrifos exposure). She was intubated and transferred to the intensive care unit. Midazolam was infused because of her irritability. A sputum smear demonstrated rare neutrophils, and no bacteria were seen. Chest radiography revealed normal findings. Blood and sputum cultures were sterile. Involuntary movement of her upper limbs was also noticed on day 5. Urinalysis showed no pyuria but mild proteinuria (25 mg/dL) and glucosuria (0.1 g/dL). On the sixth hospital day, the complement levels were below the normal range, with C3 60 mg/dL (normal 73–124 mg/dL) and C4 15.8 mg/dL (normal 18–45 g/dL). The ANA titer was 1 : 40 in the nucleolar pattern and 1 : 320 in the homogeneous pattern, and the anti-double-stranded DNA level was 35 IU/mL.

Pralidoxime was discontinued on day 7. The cholinesterase level increased to 1068 U/L by day 9 and to 1639 U/L on day 11. She was extubated on day 12 and transferred to the general ward on day 13. The difficulty in opening her mouth improved gradually. Intermittent tonic-clonic seizures, each lasting 3 to 5 min, appeared on day 13 and responded well to diazepam-phenytoin infusion. Regular hemodialysis three times a week was maintained throughout the hospital course. She was discharged on the 18th hospital day, with complete recovery of proximal extremity strength without any neurologic sequelae.

DISCUSSION

IMS resulting from acute OP poisoning is a rare event in the patient with ESRD: We were not able to find any case report in a literature review. The first description of the clinical manifestations of IMS, a third type of OP-induced neurotoxicity, was published by Senanyake and Karalliede in 1987[1] and included sudden onset of respiratory failure; weakness in the areas of distribution of some motor cranial nerves, proximal extremities, and neck flexor muscles; and reduced deep tendon reflexes. The syndrome occurs between the end of cholinergic signs and the onset of delayed neuropathy.

We report on a female patient who tried to commit suicide by taking about 100 mL of chlorpyrifos, a highly lipid-soluble OP, a dose that is more than enough to suppress more than 50% of baseline acetylcholinesterase level.[2],[3] This poisoning led to severe symptoms, despite both atropine and PAM infusion. Around 45 h after the exposure to OP, intubation was mandated by the sudden onset of apnea. The time of onset of her IMS is compatible with other reports.[6–9] This patient survived due to successful urgent intubation and subsequent intensive care.

Organophosphates are metabolized by liver microsomal enzymes from thions to oxons.[10] The oxons irreversibly phosphorylate acetylcholinesterase, allowing accumulation of the neuromediator acetylcholine at neuroeffector junctions, synapses in autonomic ganglia, and the brain.[11],[12] The accumulation of acetylcholine in the neuromuscular junction, a postsynaptic effect, is the mechanism of IMS after exposure to highly lipid-soluble OP, and hence a patient with mild cholinergic signs and clear consciousness is not likely to develop IMS.[13–15] It is believed that IMS does not respond to atropine and PAM therapy.

Trismus in this patient was found on the second hospital day, and involuntary movement was noticed on the fifth day. Hsieh et al. said that EPS should be included in the differential diagnosis if any involuntary movement was noticed in patients with OP poisoning.[16] A case of chlorpyrifos-induced EPS with jerky and ceaseless involuntary movements that were responsive to atropine has been reported in a 23-year-old woman.[4]

EPS develop in patients with acute OP poisoning, especially highly lipid-soluble compounds. These effects include choreoathetosis, trismus, dystonia, resting tremor, cogwheel rigidity, chorea, drooling, hyperreflexia, dysarthria, and neck stiffness, and began 4 to 40 days after acute exposure, subsiding gradually over 1 to 4 weeks.[16],[17] Our patient was found to be suffering from trismus on the second hospital day, which is much earlier than in previously reported cases. It is suggested that EPS result from a reduced ratio of dopaminergic to cholinergic function within the basal ganglia and substantia nigra[5]; more severe poisoning might cause earlier clinical signs.

The drowsiness and seizures in our patient indicated the probable high level of acetylcholine accumulated in the brain.[3],[12],[18] Because this patient had SLE with lupus nephritis and encephalopathy, it is probable that both the encephalopathy and a high concentration of acetylcholine in the brain led to her drowsiness and seizures. Nevertheless, the serum complement level did not demonstrate high lupus activity.

Paraoxonase is an esterase that hydrolyzes OP compounds. The specific activity of serum PAM is decreased in uremic patients,[19],[20] which partially explains the severe toxic clinical manifestations in our patient.

Bardin et al. demonstrated renal insufficiency characterized as acute nonoliguric renal failure in about 13% of severe OP-poisoning cases.[21] The compounds can cause direct tubular damage,[22] and high lipid solubility makes some of these compounds more likely to persist than OPs with low lipid solubility. [23]

Chlorpyrifos metabolites 3,5,6-trichloro-2-pyridinol and alkylphosphates are excreted in the urine, and detection of urinary metabolites is a very sensitive indicator of exposure. The fast excretion phase takes only a few hours, whereas the half-time of the slow excretion phase is probably more than 5 days.[24–27] The fast and slow excretion phases could be much longer in nonoliguric uremic patients and defective in oliguric and anuric uremic patients; hence, urgent hemodialysis is necessary to remove this rapidly spreading, water-soluble, and highly persistent toxicant.

Hemoperfusion, hemodialysis, and exchange transfusion have not been shown to be effective in OP poisoning. However, there is a case report suggesting that hemofiltration is a successful method for the treatment of OP-induced acute renal failure.[28] Metabolic acidosis has occurred in severe poisonings,[29],[30] and presumably would be corrected by hemodialysis.

In conclusion, this is the first case report of acute OP poisoning leading to IMS in a patient with ESRD. Drowsiness, hypoxemia, metabolic acidosis, seizures, IMS, and EPS suggested severe poisoning. Urgent respiratory support, intensive care, and early administration of atropine and PAM are necessary. In addition, we suggest that immediate hemodialysis be considered to clear the accumulated acetylcholine, maintain the acid–base balance, minimize the severe OP poisoning, and decrease hospitalization.