Pradeepa Jayawardane

The spectrum of intermediate syndrome following acute organophosphate poisoning: a prospective cohort study from Sri Lanka

Background Intermediate syndrome (IMS) is a major cause of death from respiratory failure following acute organophosphate poisoning. The objective of this study was to determine repetitive nerve stimulation (RNS) predictors of IMS that would assist in patient management and clinical research. Methods and Findings Seventy-eight consenting symptomatic patients with organophosphate poisoning were assessed prospectively with daily physical examination and RNS. RNS was done on the right and left median and ulnar nerves at 1, 3, 10, 15, 20, and 30 Hz. The study was conducted as a prospective observational cohort study in the Central Province, Sri Lanka. IMS was diagnosed in ten out of 78 patients using a priori clinical diagnostic criteria, and five of them developed respiratory failure. All ten patients showed progressive RNS changes correlating with the severity of IMS. A decrement-increment was observed at intermediate and high frequencies preceding the onset of clinical signs of IMS. As the patient developed clinical signs of IMS, decrement-increment was progressively noted at low and intermediate frequencies and a combination of decrement-increment and repetitive fade or severe decrement was noted at high frequencies. Severe decrement preceded respiratory failure in four patients. Thirty patients developed forme fruste IMS with less severe weakness not progressing to respiratory failure whose RNS was characterized by decrement-increment or a combination of decrement-increment and repetitive fade but never severe decrements. Conclusions Characteristic changes in RNS, preceding the development of IMS, help to identify a subgroup of patients at high risk of developing respiratory failure. The forme fruste IMS with the characteristic early changes on RNS indicates that IMS is a spectrum disorder. RNS changes are objective and precede the diagnosis and complications of IMS. Thus they may be useful in clinical management and research.

Electrophysiological correlates of intermediate syndrome following acute organophosphate poisoning.

Introduction. Organophosphate (OP) poisoning is a major global health problem. The late onset of respiratory failure associated with intermediate syndrome (IMS) is a major contributor to the high morbidity, mortality, and cost of OP poisoning. This is particularly important as most poisoning occurs in the under-resourced developing world. Repetitive nerve stimulation studies. An understanding of the abnormalities observed in repetitive nerve stimulation studies during the progression and development of IMS spectrum disorder may help clinicians to utilize electrodiagnostic testing in the better management of their patients with acute OP poisoning. In addition, it will allow researchers to interpret future research that utilizes repetitive nerve stimulation as an outcome measure. A review of the clinical and experimental electrophysiological studies in the IMS shows that subclinical electrophysiological abnormalities are common, progressive, and precede the onset of the clinical IMS. Serial repetitive nerve stimulation studies have been most commonly used and are the most accessible for clinicians. Clinical and experimental studies demonstrate a progression through early initial decrement–increment patterns at high rates of stimulations, which correlate with moderate muscle weakness, to decrement–increment patterns at intermediate- and low-frequency stimulations. Progression to a combination of decrement–increment and repetitive fade patterns correlates with clinical deterioration; severe decrement pattern is usually observed immediately before the onset of respiratory failure. Although electrophysiological features closely parallel clinical severity during progression of IMS, the same is not true during recovery. Electrophysiological changes sometimes improve long before the patient recovers normal strength and respiratory function. Intermediate syndrome. Thus, IMS can be regarded as a spectrum disorder affecting the neuromuscular junction (NMJ) with two main forms: a forme fruste variety associated with mild weakness and the classical IMS with weakness of 3/5 or less than 3/5 on the Medical Research Council (MRC) grading; patients in the latter category are at risk of developing late onset respiratory failure. While IMS remains a clinically important entity, the early occurrence of abnormalities on repetitive nerve stimulation studies suggest that this is part of the continuum of nicotinic receptor stimulation. Conclusions. Reviewing the anatomical and the functional structure of the NMJ and neuromuscular transmission helps to provide an understanding of the pathophysiological nature of the neuromuscular transmission failure observed in IMS. This includes potential mechanisms of presynaptic feedback which may reduce acetylcholine release and postsynaptic receptor desensitization and provides some explanation for the time course of IMS. It also suggests other potential strategies to reduce OP-induced NMJ toxicity in which repetitive nerve stimulation is likely to be an important tool in judging efficacy.

Electrophysiological correlates of respiratory failure in acute organophosphate poisoning: Evidence for differential roles of muscarinic and nicotinic stimulation

Background. Respiratory failure in acute organophosphate (OP) poisoning can occur early and also relatively late in the clinical course, and the pathophysiology of respiratory failure at these different phases may have important clinical implications. Objective. To compare the electrophysiological findings in patients with early and late respiratory failure following acute OP poisoning. Methods. A prospective observational case series of consenting symptomatic patients with acute OP poisoning were assessed with daily physical examinations and repetitive nerve stimulation (RNS) studies. RNS was done on right and left median and ulnar nerves at 1, 3, 10, 15, 20, and 30 Hz. Outcomes such as need for ventilation and development of intermediate syndrome (IMS) were noted. Early respiratory failure was defined as occurring within 24 hours of ingestion. Results. Seventy-eight patients were recruited for the clinical and electrophysiological study and of those 59 (75.6%) patients had ingested chlorpyrifos. Seven patients developed respiratory failure within 24 hours of ingestion with overt muscarinic signs. They had no electrophysiological abnormalities at median and ulnar nerves before intubation. Three of them later developed “forme fruste” IMS. Five other patients developed late respiratory failure after 24 hours of ingestion, and all of them showed progressive RNS changes indicating severe IMS prior to intubation. Conclusion. The normal RNS in all patients developing early respiratory failure suggests that it is due to a central nervous system (CNS) and muscarinic effect. This emphasizes the need for early rapid atropinisation as a priority, combating the nicotinic effects being less urgent. This is in contrast with the late respiratory failure, which has been shown to be associated with neuromuscular dysfunction. Further studies are needed to quantify CNS and muscarinic dysfunction to assist in the development of better treatments for the severe and early OP poisoning.

Comment on late-onset intermediate syndrome due to organophosphate poisoning

Due to deterioration in the condition of the patient and progressing neurological symptoms the patient was transferred to the Department of Nephrology, Transplantology, and Internal Medicine at Pomeranian Medical University in Szczecin, with the initial diagnosis of thallium intoxication. On admission to our department, the patient complained of pain in his legs that interfered with normal walking. He reported nausea, dysgeusia, and severe epigastric pain. Oliguria was noted and the patient experienced growing weakness, insomnia, nocturnal anxiety, and audiovisual hallucinations. Physical examination done on the third day after ingestion revealed general paleness, psoriatic lesions on the left calf and head, elevated temperature, and sweating. There were no abnormalities in the subcutaneous tissues. Lymph nodes were not enlarged, sense organs were normal, and the respiratory system was normal. His heart rate was 50 beats/minute and his blood pressure was 200/100 mmHg. The examination of the abdomen was normal. There were limitations in active and passive mobility of the ankles, as well as superficial and deep paresthesias of the feet and calves. Laboratory tests revealed a white blood cell count of 10.4 × 10/L with normal erythrocyte and platelet values. Urine pH and specific gravity were 5.5 and 1.015, respectively. Urinalysis showed glucose, protein, and erythrocytes. A 24-hour urine collection had a volume of 3100 mL and protein of 1.12 g. Capillary blood gases analysis disclosed pH 7.456, pCO2 33.6 mmHg, pO2 88.0 mmHg, HCO3 at 23.1 mmol/L, and Base Excess 0.0 mmol/L. Serum electrolytes were normal, creatinine was 1.57 mg/dL, and urea was 35 mg/dL. Other laboratory results were aspartate aminotranferase 51 U/L (reference 0 to 35 U/L), alanine aminotransferase 40 U/L (reference 0 to 35 U/L), creatine kinase 526 U/L (reference 0 to 130 U/L), lactate dehydrogenase 616 U/L (reference 50 to 150 U/L); serum and urine amylase, γ-glutamyl transferase, and alkaline phosphatase were normal. No abnormalities in abdominal ultrasound and chest radiograph were noted. An electrocardiogram (ECG) revealed a normal sinus rhythm and a rate of 54 beats/minute. No ophthalmologic abnormalities were disclosed. Electromyography (EMG) disclosed distal axonal-demyelinization polyneuropathy with loss of innervation of foot muscles, absence of response to stimulation of peroneal nerves, and significant neurographic abnormalities of tibial nerves. Gastroduodenoscopy revealed acute gastritis and mucosal biopsy provided evidence for Helicobacter pylori infection. The patient was given one dose of carbamazepine (200 mg). Diuresis was stimulated, and Vitamin B complex and atropine were administered. At this point, the thallium concentration in the urine sample collected at the county hospital was reported to be 11,600 μg/L (reference blood and urine value ≤1μg/L or 5 nmol/L), measured using flame atomic absorption spectrometry. The diagnosis of thallium intoxication was made, the patient was given Prussian blue 4 grams every six hours during two weeks and placed on daily hemodialysis during one week (4). The patient gradually improved, mobility of lower extremities normalized and pain subsided. The thallium concentration in urine after 7 days of treatment was 1929 μg/L. Tachycardia and hypertension were managed with propranolol 10 mg increased after a few days to 20 mg, three times per day. During the second week of hospitalization the patient reported pain in the thorax, dyspnea, hyperventilation with apnea lasting a few seconds, and blackouts. ECG disclosed abnormalities of repolarisation in the form of high-voltage T waves in precordial leads and transient elevation of ST segments in V2. Enzyme concentrations ruled out local myocardial lesions. These findings spontaneously resolved during a 24-hour stay in the Intensive Care Unit. The patient reported gradual alleviation of pain and paresthesias in the legs and was able to walk unassisted. Intense hair loss and trophic lesions of the nails were noted during the second week of hospitalization. The patient was seen by a psychiatrist because of the suicidal attempt but no personality disorders were diagnosed. The patient was discharged after 14 days of hospital stay, following general improvement, and normalization of blood pressure, ophthalmologic and neurological examinations. Recommendations included regular blood pressure measurements, follow-up visits to the neurologist and ophthalmologist, and EMG. On-going therapy consisted of propranolol 20 mg three times per day, amlodipine 10 mg daily, Vitamin B complex three tablets daily, Vitamin B12 0.005 mg daily, Carbamazepine 200 mg daily, acetylsalicylic acid 100 mg daily, and omeprazole 20 mg daily. The patient continued to report mild limitations in mobility and superficial paresthesias, principally affecting the toes.

A comment on 'Predicting outcome in acute organophosphorus poisoning with a poison severity score or the Glasgow coma scale'.

Sir, We read with interest the article ‘Predicting outcome in acute organophosphorus poisoning with a poison severity score or the Glasgow coma scale’.1 Organophosphate (OP) poisoning is a major global health problem and a high mortality is seen in resource poor settings.2 A clinically based scoring system to predict outcome is of utmost importance …