Organophosphate poisoning: Diagnosis of intermediate syndrome
Organophosphate compound (OPC) poisoning with suicidal intent is common in Indian ICUs. The effect of OPCs is to produce a persistent depolarization of the neuromuscular junction leading to muscle weakness. After initial recovery from cholinergic crisis, some patients have resurgence of respiratory muscle paralysis requiring continued ventilatory support. This is termed intermediate syndrome (IMS). This could be due to a change in the type of neuromuscular block to a non depolarisation block characterized by a fade on tetanic stimulation. However peripheral nerve stimulation using train-of-four ratio (TOF) and/tetanus have failed to consistently show such a change. We elected to study whether electro physiological monitoring using repetitive nerve stimulation might show a decremental response during IMS. Material & Methods: This was a prospective blinded study done from April 2002 to March 2003 in our ICU. 45 consecutive patients of OPC poisoning admitted during this period were included in this study. Repetitive nerve stimulation (RNS) using a train of ten at 3Hz 10Hz and 30Hz (slow , intermediate and fast speeds respectively) at the median nerve was done on all patients on day 1, 4, 7 and every 4th day thereafter until discharge. Patients were ventilated until ready to wean as per our usual protocol. The results of the RNS study were not revealed to the intensivist. Results: 9 out of 45 patients required ventilation for more than 6 days and showed overt signs of intermediate syndrome - proximal muscle weakness, twitching and respiratory weakness. Only 2 patients out of the 9 had a decremental response on RNS at 3Hz indicating a post-junctional dysfunction at the motor end-plate, Both patients had consumed a very large quantity of OPC and were deeply comatose for >4 days and required ventilation for >12 days. All other patients with IMS showed no changes on RNS. The exact type of poison consumed varied with each individual patient. Conclusion: RNS is a poorly sensitive marker in diagnosing intermediate syndrome after OPC poisoning. We need to develop more sensitive markers to diagnose IMS.
Pesticides comprise a wide range of compounds including insecticides, herbicides, fungicides and others. Thus far, more than 1,000 active substances have been incorporated in approximately 35,000 preparations of pesticides used in agriculture.
According to the WHO, one million serious accidental and two million suicidal poisonings due to insecticides occur worldwide every year, of which 200,000 patients die with most deaths occurring in developing countries. In India, organocompounds (OPCs)-organophosphates and organocarbamates, are the commonest pesticides used and due to their easy availability, there is widespread abuse of these compounds with suicidal intent,,,
OPCs are irreversible inhibitors of the enzyme aceylcholinesterase (AchE), binding to the esteratic site of the enzyme. They inhibit both cholinesterase and pseudo-cholinesterase activity. The inhibition of acetylcholinesterase causes accumulation of acetylcholine at synapses with resultant overstimulation of neurotransmission. The clinical features are due to excess acetylcholine at the muscarinic and nicotinic receptors which leads to initial stimulation and eventual exhaustion of cholinergic synapses. The mechanism of action of paralysis is persistent depolarization of the neuro end-plate eventually leading to desensitization.
There are three distinct phases:
Acute cholinergic crisis
Intermediate syndrome (IMS);
Delayed polyneuropathy (OPIDN).
Acute Cholinergic Crisis
The symptoms are due to stimulation of the muscarinic and nicotinic receptors: Nicotinic manifestations include increased or decreased muscle power and skeletal muscle fasciculations. Muscarinic manifestations include excessive salivation, miosis, diarrhea, bronchorrhoea, bronchospasm, bradycardia, urination. Other signs include vomiting, respiratory distress, abdominal pain, depressed level of consciousness, muscle fasciculations and muscle paralysis. Progression of paralysis may affect the muscles of respiration necessitating ventilatory support.
The cholinergic phase usually passes off within 48-72 hours but complete clinical recovery from all the effects may take up to a week. Treatment is supportive with oximes, atropine and mechanical ventilation, in addition to gastric lavage and decontamination.
Oximes (effective in the early phase) are clinically important reactivators of acetylcholinesterase, that can prevent degenerative effects of insecticide intoxication.
Intermediate Syndrome (Ims)
After the acute cholinergic phase, a second stage of weakness occurs 1 - 4 days later with or without a symptom - free interval, and, if left unrecognized, can lead to fatal respiratory depression.
Delayed Organophosphate Induced Polyneuropathy
Organophosphate induced delayed neuropathy (OPIDN) is an uncommon clinical condition. It occurs in association with the ingestion of large amounts of organophosphate and manifests as limb weakness persisting long after the acute cholinergic symptoms have subsided. The clinical picture is characterized by a distal paresis in lower limbs.
Clinical features of IMS
First termed by Wadia et al in 1974 as type II paralysis, IMS is a syndrome characterized by muscle paralysis following the acute cholinergic phase. The terminology was later changed by Senanayake and Karalliedde in 1987 to intermediate syndrome due to the fact that it arises between the period of early cholinergic syndrome and the late onset peripheral neuropathy.
IMS develops 12-96 hours after exposure and reflects a prolonged action of acetylcholine on the nicotinic receptors. The clinical features are muscular weakness in the ocular, neck, bulbar, proximal limb and respiratory muscles with occasional dystonic posturing, requiring mechanical ventilation in an intensive care unit for several days. Cranial-nerve palsies are common. The risk of mortality is due to the associated respiratory depression. The sensory functions characteristically remain normal and full recovery is evident in 4-18 days.
The incidence of IMS in different studies has been reported to be between 20-68%.
It has been commonly associated with OPCs like diazinon, dimethoate, methylparathion, methamidaphos, monocrotophos, fenthion and ethylparathion Despite its common occurrence, data on the risk factors of IMS, early diagnosis and prediction have remained elusive. Commonly used tests such as levels of plasma cholinesterase correlate poorly with the onset of IMS.
IMS could be due to a conformational change in the acetylcholine receptor altering the depolarisation neuromuscular block to a nondepolarisation block, characterized by a fade on tetanic stimulation, as reported by Senanayake and Karelliede. In their series of 3 patients with IMS, electromyographic studies showed fade on tetanic stimulation, absence of fade on low-frequency stimulation, and absence of post-tetanic facilitation, suggestive of a postsynaptic defect. However, these findings have not been duplicated, and repetitive nerve stimulation with a train-of-ten stimuli at varying frequencies have been used to detect subclinical fade. Wadia et al found no decrement in the amplitude of the compound muscle action potential at 3Hz and 10Hz, and a decremental response only at 30Hz in patients with IMS
However, in other series neuromuscular transmission studies show a decremental response with repetitive nerve stimulation at 3 Hz. Thus a whole spectrum of results: either decrements at low stimulation frequencies of 1 to 3 Hz, with normal series at 10, 20 or 50 Hz, or decrements at intermediate frequencies of 10 to 20 Hz, with normal findings at both low and higher frequencies have been recorded.,,,
In view of these conflicting studies, we elected to study the effects of repetitive nerve stimulation serially in patients with OPC poisoning in an attempt to uncover changes which might mark the onset and resolution of intermediate syndrome.
This study was done to evaluate whether repetitive nerve stimulation at 3, 10 or 30 Hz (train-of-ten) would show a definite change from baseline in patients with IMS.
45 consecutive patients with OPC poisoning were enrolled in this prospective blinded study done from April 2002 to March 2003 in a multidisciplinary ICU of a tertiary care hospital.
All patients were admitted to the ICU from the emergency room after decontamination as per our usual protocol.*
Repetitive nerve stimulation (RNS) at the ulnar nerve was done by observing the Compound Muscle Action Potential (CMAP) using a Nicolet NT® Viking IV System. Train-of-ten (TOT) stimulation. The frequencies used were 3 Hz and 10 Hz (slow and intermediate speeds respectively) in all patients, 30 Hz stimulation was added after patient no.5.** RNS was done on days 1, 4, 7 and every 4th day thereafter until discharge.
The results of the RNS study were not revealed to the intensivist caring for the patients.
Pharmacologic treatment included atropine in escalating doses from a baseline at 10mg/hr to control the bronchorrhea and maintain a heart rate above 100/min, pralidoxime 1gm q 6hours for 3 days. In severe poisoning a continuous infusion of 500mg/hour of pralidoxime was used. Patients on mechanical ventilation were weaned according to the following protocol:
If the cholinergic symptoms subsided, the atropine dose was less than1-2mg/hour, the vital signs were stable and the patients were alert and responding to commands with no evidence of atropine delirium, they were considered ready-to-wean and were put on a T-piece trial. (Unlike the usual practice of extubation after a 2-hour T-piece trial, OPC poisoned patients in our ICU are given a 6-8 hour trial on the T-piece because of the incidence of reintubations due to the emergence of IMS.) After extubation the patients were under observation in the ICU for 24 hours and in an intermediate care unit for a further 24 hours. The patients were termed to have IMS if after recovery from the cholinergic symptoms, new or worsening signs of proximal muscle weakness and respiratory paralysis (as evidenced by failure to wean, retention of carbon dioxide) or muscle fasciculations occurred any time after the first 12-24 hours.
The following factors were analysed for association with intermediate syndrome
Lead time to admission in the ICU
Students t test and chi square test
The study group included 34 males and 11 females aged between 16-65 years (mean age 30.53 years). All except one (which was an attempted homicide)were suicide attempts.
The poisons used covered a wide range of pesticides from insect repellants to agricultural pesticides like monochrotophos, parathion, chlorpyriphos, fenthion, dichlorvas, ethion, malathion and furadion. The type of poison consumed varied with each individual patient, and the amount was difficult to infer as often the only clue was the empty bottle. Several patients mixed pesticides with alcohol, sedatives or other pesticides.
23 (51%)patients underwent mechanical ventilation for acute respiratory failure.
5 patients were transferred from an outside hospital, already intubated
10 patients were intubated in the emergency room due to a low GCS
2 patients were intubated in the emergency room due to convulsions
6 patients were intubated in the ICU after a varying period of 4-24 hours:
3 patients had an acute respiratory arrest;
2 patients were intubated due to deterioration of arterial blood gases
1 patient was intubated for airway protection due to increasing somnolence.
9 out of 45 patients (20%) were considered to have IMS- after recovery from the cholinergic crisis and attempted weaning from mechanical ventilation, they showed overt signs of intermediate syndrome - proximal muscle weakness, twitching and respiratory paralysis, necessitating full ventilatory support for several more days.
2 of the 9 patients self-extubated on day 3 of ventilation, and needed to be re-intubated .
One patient was re-intubated within 4 hours due to respiratory distress, which did not respond to non-invasive ventilation
One patient was re-intubated after 12 hours due to rising PaCO2 on non-invasive ventilation.
7 patients were on a T-piece trial for periods of 2-6 hours after which they needed to go back on full ventilatory support.
4 patients had a tracheostomy on day 7 and were successfully decannulated by day 20
Repetitive nerve stimulation (RNS) at 3Hz and 10 Hz was done on all patients, and 30Hz was added from patient 5. (**The neurophysiological laboratory acquired the facility for 30Hz stimulation by June 2002).
There was no decrement at all frequencies in all patients without IMS on all days.
In all 9 patients with IMS, RNS at 30Hz was normal on all days.
2 patients showed a decremental response at 3Hz:
In 1 patient, (no. 21 ) there was a decremental response at 3Hz on day 4 with normalization by day 7. There was no correlation in this patient (who had consumed a very large quantity of monochrotophos) between the severity of IMS symptoms and decremental response to RNS.
He was deeply comatose with flaccid paralysis for 5 days and required mechanical ventilation for 15 days after which he had a complete recovery. He was presumed to have IMS as he recovered from the cholinergic symptoms but continued to have muscle paralysis and was unresponsive for 5 days, after which his sensorium improved but the muscle weakness persisted for 10 more days. The decrement seen on RNS on day 4 was completely resolved by day 7, and was no different from the baseline on day 1, in spite of persistence of clinical features of severe muscle weakness. Stimulation at 10 and 30 Hz showed no decrement.
In 1 patient (no. 40) there was a decremental response on day 4 with 3 Hz and an equivocal response to 10 Hz. There was no decrement at 30 Hz. On all other days the response was normal
Intermediate syndrome (IMS) occurs in 20-60% of patients with severe organophosphate poisoning., It is important to recognize the syndrome early to avoid fatal respiratory depression after discharge from the ICU, as it occurs at a variable time after the acute cholinergic crisis, at a time when the respiratory paralysis seems to have resolved.
Serum acetylcholinesterase levels have not been found to be indicative of IMS.
Electrophysiological studies done in the cholinergic phase revealed that single evoked compound muscle action potentials (CMAPS) were followed by repetitive discharges and decrement-increment phenomenon with 10, 20, 50 Hz supramaximal stimulation., On repetitive stimulation during OPC poisoning, Wadia et al found no decrement with three stimuli per second and only occasional decrement at 10 per second. At 30 Hz several cases showed a decrement even in the absence of paralysis.
Electrodiagnostic findings vary during the course of the exposure and delayed syndromes. During acute intoxication, findings may be similar to those observed with over-treatment of myasthenia gravis with pyridostigmine in the form of repetitive discharges following a single shock to a motor nerve. Atypical decremental responses to repetitive nerve stimulation can also be observed during the intermediate syndrome.
Especially during IMS, electrodiagnostic criteria based upon reported cases have shown conflicting results:
EMG abnormalities are not constant. Decrement studies may reveal
l decrement - increment or
l abnormal increment.
In a review of 19 cases of intermediate syndrome, de-Bleecker et al found variable responses: in the early stages the compound muscle action potential showed a decremental response at low or intermediate frequencies. These decremental responses were maximal at the second response, with a gradual but incomplete recovery by the ninth response. After the first day, either a decremental-incremental response at high frequencies or isolated increments at low frequencies were observed. Normal responses on electromyography were recorded in the days preceding clinical recovery from this syndrome. All these abnormal findings on electromyography suggested a combined pre- and postsynaptic defect.
In our study, the results of RNS were very different from others. We found a decrement only at 3 Hz in 2 patients during IMS.
A more useful test could be single fibre electromyography (SFEMG) which shows jitter in the absence of decrement on RNS, and is likely to be more sensitive. However, further prospective studies are required to see if the changes are constant and/or specific.
The conclusions derived from salient experimental and clinical studies are that intermediate syndrome relates to the severity of poisoning not the specific organophosphate and to prolonged inhibition of acetylcholinesterase activity of the erythrocytes, brain and muscle endplate with pre and post synaptic impairment of neuromuscular transmission
Some authors propose that poor regulation of acetylcholine receptors (AChRs) could explain the syndrome and neurophysiological findings Binding of the drug to the active site of the AChE, may also result in “ageing”; i.e. the chemical bond between the drug and AChE becomes progressively resistant to deactivators like pralidoxime. If ageing occurs the same AChE cannot be reactivated anymore and the physiologic activity at the site will be restored only by the synthesis of new enzyme. This process occurs in both tissues and plasma at varying rates and full restoration may take up to 6 weeks in untreated patients. The deactivation of RBC AChE persists throughout the lifespan of the RBC, unless reactivated (RBC turnover rate of 1% per day).
The ageing process is variable and related to the type of poison. Some drugs become bound to the AChE within minutes and others take longer.
IMS due to desensitization block; i.e. changing from depolarization to non-depolarisation block will cause decrement in slow and medium frequency RNS suggesting a post-synaptic defect.
A change in high frequency RNS could be due to a presynaptic defect, while ageing may not result in decrements in RNS.
It is possible that several other factors such as age of patients, the difference in the chemical structure of OPCs and the duration of initial intoxication could contribute to the differences in the results of neurophysiological monitoring. An atypical decremental response to repetitive nerve stimulation can be observed at any time during the course of the illness.
The lack of consistent decrements in our study on medium and high frequency RNS as reported by other authors could be due to differences in the dose and quantity of poison consumed as well as the type of poison. It is well known that OPCs encompass a wide range of products and although they are all inhibitors of AChE, the site and mode of inhibition could differ, leading to varied electrophysiological responses.
Animal experiments have shown that decrement of evoked CMAP following repetitive nerve stimulation was present only in the most severe acute poisoning. At the height of the intoxication no CMAP was evoked after the first few stimuli. The decrement-increment phenomenon occurred at milder stages of intoxication while in sub-acute organophosphate intoxication, there was a decremental response to repetitive stimulation.
The magnitude of organophosphate exposure appears to determine the occurrence and severity of intermediate syndrome, and in our study the patients who had a low GCS or convulsions on admission, with very low levels of acetylcholinesterase, indicating severe exposure, developed IMS. It is unclear whether patients who were severely comatose on admission and died within 24 hours would have developed IMS if they had survived longer. It is possible that IMS is not a discrete entity, but a continuum in severe poisoning; if patients survive the first 24 hours following severe poisoning, they could go on to develop IMS, and perhaps a centrally mediated phenomenon plays a role as well. The higher mortality in non IMS patients in our study occurred within the first 3 days in 8/9 patients, all of whom had very severe symptoms.
Is IMS a truly “intermediate” state in severely poisoned patients, between early death and the re-development of muscle paralysis after initial recovery?
A limitation of our study could be the days chosen for RNS testing: day4 could have been too late for detecting the onset of IMS (as it is commonly seen 12-96 hours after exposure). This was done for logistic reasons, as it was not always possible to shift the patients to the neurophysiology laboratory with greater frequency than once every 3 or 4 days.
In the field of organocompound poisoning, several unanswered questions remain:
1. Why do all OP poisoned patients with AChE inhibition not develop IMS?
2. What proportion of poisoned cases do develop IMS?
3. Is IMS present in a subclinical form in a higher proportion of patients than is clinically evident?
4. Would larger doses, and/or longer treatment with oximes rejuvenate the enzyme faster?
More studies are needed to find an answer to these and other questions, and until then, close monitoring of patients with OP poisoning is the only way to detect IMS.
IMS is an important complication of OPC poisoning and should be recognized and treated adequately. Since it is unclear which patients will develop this condition, a rapid means of identifying patients with IMS is desirable, to avoid reintubation. In previous studies, decrements in RNS revealed the existence of IMS. However, in our study only two patients who developed IMS showed a decrement in slow RNS on day 4 which recovered by day 7, even though the symptoms of IMS persisted. Thus in our study RNS was a poorly sensitive indicator of IMS.
** Protocol of treatment of OP poisoning;
l immediate gastric lavage
l gastric sample for analysis sent to the forensic laboratory
l blood sample for cholinesterase levels
l thorough washing of the skin with soap and water twice
l pralidoxime 500mg tds x 7days
l atropine 10mg/hour, escalating dose until bronchorrhoea decreased and heart rate >120/min.
l repeated sponging and change of clothing and sheets every 4 hours.
l activated charcoal through Ryle's tube q 4hours
l withholding NG feeding for at least 96 hours