187-
Organophosphate Poisoning with Development Intermediate Syndrome Two Cases of
M.
Karademir, F. Ertürk & R. Koçak
Department Two
of
cases
of Internal
Medicine, Çukurova University Medical School, Adana, Turkey
of intermediate
syndrome
caused
by organophosphorus poisoning
are
reported.
Trichlorfon, propoxur (a carbamate pesticide) and fenthion were ingested in both attempts at suicide. After successful conventional therapy during the cholinergic phase, but before the time when the onset of delayed neuropathy might be expected, an intermediate syndrome developed. It affected the proximal limb muscles, neck flexors and respiratory muscles 2 d after pesticide ingestion. The two patients needed respiratory support. Recovery from the intermediate syndrome was complete in both patients, although one
subsequently developed delayed neuropathy. Introduction The initial symptoms of organophosphorus insecticide poisoning arise directly from the inactivation of acetylcholinesterase. Accumulated acetylcholine in the central nervous system, autonomic ganglia, parasympathetic nervous system and motor nerve end-plates induces the typical cholinergic phased This phase can usually be treated successfully, using atropine and oxime. However, a sensorimotor, distal and symmetrical polyneuropathy after 2-5 weeks of improvement may develop in some patients.2 This delayed peripheral polyneuropathy differs from the acute cholinergic phase clinically and pathophysio-
logically. After conventional therapy of the early cholinergic symptoms, some patients need urgent respiratory support because of acute respiratory failure. In a report in 1987, Senanayake and his colleagues called attention to this and defined it as the intermediate syndrome.3 This syndrome begins 24-96 h after the cholinergic crisis and predominantly affects the proximal limb muscles, neck flexors and certain cranial motor nerves. Paralysis of the respiratory muscles occurs and the syndrome is refractory to treatment with atropine and oxime. Therefore urgent respiratory support is necessary. In this report, two cases of the intermediate syndrome, occurring in the intensive care unit of
Correspondence:
Mustafa
the
Cukurova University Medical School’s hospital in 1988, are presented. We wish to emphasize the risk of death in this syndrome which is as dangerous as the cholinergic phase. Case reports Case 1 A 20-year-old female ingested about 50 ml of fenthion (in a 52.5% concentration) with cocacola in a suicide attempt. She was taken to a local hospital less than 30 min after inqestion and received gastric lavage, intravenous fluid and atropine therapy. She was sent to our emergency service 10 h after ingestion of the poison with definite symptoms of a cholinergic crisis, including hypersalivation, myosis, fasciculations of certain muscles and sweating, but she was still conscious upon hospitalization. The patient was treated with atropine (107 mg i.v. in the first 24 h - to a total dose of 300 mg), obidoxime (250 mg i.v. every 12 h for five doses), and i.v. fluid (dextrose 5% and isolyte solution to a total of 6 1 in 24 h). After the symptoms of the cholinergic crisis had been controlled, acute respiratory distress and cyanosis occured. This was 31 h after the suicide attempt. While conscious, she could not tolerate the endotracheal tube of the respirator,
Karademir, Department of Internal Medicine, Çukurova University Medical School,
Adana, Turkey.
Downloaded from het.sagepub.com at UCSF LIBRARY & CKM on March 15, 2015
188
therefore it was necessary to perform a tracheostomy 6 h after the appearance of the respiratory failure. The patient required the ventilatory support for 3 d. Muscle weakness was determined involving, primarily, the proximal limb muscles, neck flexors, and the muscles of respiration. However, the cranial nerves were intact and sensory impairment was absent. Deep tendon reflexes were hypoactive and plantar reflexes were flexor. From the second day onwards the weakness and poor function of the affected muscles had all begun to recover. She was disconnected from the respirator at the end of the third day and was discharged 14 d after admission. A delayed neuropathy shown by electromyographic (EMG) study developed a month after the suicide attempt. Case 2 A 19-year-old female was admitted to our hospital within 8 h of having a gastric lavage and atropine therapy in an other local hospital. The patient had ingested approximately 20 g of trichlorfon in an 80% concentration and 20 g of propoxur, a carbamate pesticide, in a 1 % concentration. All symptoms of cholinergic toxicity together with mental confusion were controlled with atropine (111 mg i.v. in the first 24 h - to a total dose of 205 mg), obidoxime (250 mg i.v. every 12 h for five doses) and i.v. fluid (dextrose 5% and isolyte solution totalling 6 1 in 24 h). About 40 h after the suicide attempt, respiratory distress developed, by which time there were no symptoms or clinical signs of cholinergic crisis. As in the first case tracheostomy was carried out for veritilatory support. No neuro-
logical signs
or
symptoms
were
detected, except
weakness of the respiratory and proximal limb muscles and depressed deep tendon reflexes. The
respiratory muscles were late to recover, therefore she required a respirator for 7 d. She remained in hospital for 19 d. Early and late EMG studies could not be performed. Haematologic, renal and liver function test values and electrocardiographic controls were normal for both patients. Assay of cholinesterase activity could not be carried out, because of the lack of laboratory facilities. Severe pneumonia developed in both patients and
was
patients remain
treated with suitable antibiotics. Both subject to long-term follow-up and
are
healthy.
Discussion our region insecticides are still used widely in agriculture and are present in homes. Thus
In
poisoning with these substances either accidentally or deliberately is often seen. Nearly 20 pesticide intoxication cases are admitted to our hospital every year.4 Being both the reference and university hospital for the region, only seriously-ill patients who can not get proper treatment in the environmental health centres are admitted. For this reason, the true number of such patients each year must be greater than the 20 that we encounter. In last 2 years, 418 adult poisoning cases were admitted to our emergency service, of whom only 11 (2.5%) died. Of these fatalities seven
(63.6%)
were
related
to
pesticides.
These results imply that insecticide poisoning is a definite problem. Typical cholinergic symptoms and clinical signs present no problem in the diagnosis of organophosphorus insecticide poisoning. Most of the cases are successfully treated with atropine and oxime. Some patients with severe poisoning die of central nervous system and respiratory complications. The distal symmetrical sensoriomotor neuropathy seen 2-5 weeks after organophosphorus poisoning does not carry the risk of death, although long-term motor incapacity is usual. Recent observations show that there is a third neurotoxic phase different from these two well known ones. Wadia et al., in their report on patients poisoned with diazinon, pointed out the two different paralytic neurological phases of organophosphorus intoxication. Type I signs (those present on admission), which included impaired consciousness and fasciculation, responded to atropine therapy, whereas type II signs (those appearing 24 h after poisoning) which included proximal limb weakness, areflexia and cranial nerve palsies, did not.~ Senanayake et al. suggest that the latter signs are indicative of an intermediate syndrome.3 Our patients appeared to have this intermediate syndrome. Paralysis due to poisoning with organophosphorus compounds has been described in animals)6,7 and pathological changes in the endplate region of striated muscles have been observed.8°9 The cause of the syndrome is not fully understood. Its pathophysiology probably can be related to neuropathy target esterase
(neurotoxic esterase) enzyme phosphorylation and inhibition and to the degradation of the phosphorylated enzyme complex.’o Inspired by EMG findings and experimental studies on animals, Senanayake et al. claimed that the defect in intermediate syndrome was at the neuromuscular end-plate and post-synaptic level, but stated that it was impossible for them to rule out the effect of neural and central components in producing the muscular weakness.3
Downloaded from het.sagepub.com at UCSF LIBRARY & CKM on March 15, 2015
189
Conclusion failure occuring 31-40 h after a suicide attempt, after complete recovery from cholinergic crisis symptoms, was seen in two of 18 (1.1%) organophosphorus intoxication cases admitted to our hospital in 1988. One case was related to fenthion use which has been shown to be related to the syndrome in four out of ten (40%) patients.3 The second case had ingested both trichlorfon and propoxur.
Respiratory
There was no discriminating sign in the presentation or in the response to conventional therapy of the patients who later developed this syndrome. Thus, more detailed laboratory and clinical tests are necessary to determine the exogenous and endogenous factors taking part in its development. It is particularly important that the early clinical signs and the types of insecticide responsible for its development are identified.
References 1
2
3
4
Dreisbach RH & Robertson WO. Handbook of Poisoning, pp. 110, 118. Library du liban: Appleton-Lange, 1987. Lotti M, Becker CE & Aminoff MJ. Organophosphate polyneuropathy: pathogenesis and prevention. Neurology 1984; 34: 658-62. Senanayake N & Karalliedde L. Neurotoxic effect of organophosphorus insecticides: an intermediate syndrome. New England Journal of Medicine 1987; 316: 761-3. Koçak R. Tanriverdi Z, Seyrek E & Alpaslan N. Acute poisoning: A two years retrospective study. Bulletin of Medical Faculty 1987; 12: 381-7. Wadia RS, Sadagopan C, Amin RB & Sardesai HV. Neurological manifestations of organophosphorus insecticide poisoning. Journal of Neurology Neurosurgery and Psychiatry 1974; 37: 841-7. Witter RF & Gaines TB. Relationship between depression
Çukurova 5
6
7
8
9
10
of brain or plasma cholinesterase and paralysis in chickens caused by certain organic phosphorus compounds. Biochemical Pharmacology 1963; 12: 1377-86. Gaines TB. Acute toxicity of pesticides. Toxicology and Applied Pharmacology 1969; 14: 515-34. Hayes WJ Jr. Pesticides Studied in Man pp.284-413. Baltimore: William & Wilkins, 1982. Asanuma S, Nakamura T, Suzuki A, Hirooka Y, Kurosawa K & Matsushima S. An experimental study on the organophosphorus pesticide residues in humans. Japanese Journal 16: 36-7. of Indian Health. 1974; Davies JE. Changing profile of pesticide poisoning. New England Journal of Medicine 1987; 316: 807-8.
(Received 20
October 1989;
Downloaded from het.sagepub.com at UCSF LIBRARY & CKM on March 15, 2015
accepted 27 November 1989)
Organophosphate Poisoning with Development Intermediate Syndrome Two Cases of
M.
Karademir, F. Ertürk & R. Koçak
Department Two
of
cases
of Internal
Medicine, Çukurova University Medical School, Adana, Turkey
of intermediate
syndrome
caused
by organophosphorus poisoning
are
reported.
Trichlorfon, propoxur (a carbamate pesticide) and fenthion were ingested in both attempts at suicide. After successful conventional therapy during the cholinergic phase, but before the time when the onset of delayed neuropathy might be expected, an intermediate syndrome developed. It affected the proximal limb muscles, neck flexors and respiratory muscles 2 d after pesticide ingestion. The two patients needed respiratory support. Recovery from the intermediate syndrome was complete in both patients, although one
subsequently developed delayed neuropathy. Introduction The initial symptoms of organophosphorus insecticide poisoning arise directly from the inactivation of acetylcholinesterase. Accumulated acetylcholine in the central nervous system, autonomic ganglia, parasympathetic nervous system and motor nerve end-plates induces the typical cholinergic phased This phase can usually be treated successfully, using atropine and oxime. However, a sensorimotor, distal and symmetrical polyneuropathy after 2-5 weeks of improvement may develop in some patients.2 This delayed peripheral polyneuropathy differs from the acute cholinergic phase clinically and pathophysio-
logically. After conventional therapy of the early cholinergic symptoms, some patients need urgent respiratory support because of acute respiratory failure. In a report in 1987, Senanayake and his colleagues called attention to this and defined it as the intermediate syndrome.3 This syndrome begins 24-96 h after the cholinergic crisis and predominantly affects the proximal limb muscles, neck flexors and certain cranial motor nerves. Paralysis of the respiratory muscles occurs and the syndrome is refractory to treatment with atropine and oxime. Therefore urgent respiratory support is necessary. In this report, two cases of the intermediate syndrome, occurring in the intensive care unit of
Correspondence:
Mustafa
the
Cukurova University Medical School’s hospital in 1988, are presented. We wish to emphasize the risk of death in this syndrome which is as dangerous as the cholinergic phase. Case reports Case 1 A 20-year-old female ingested about 50 ml of fenthion (in a 52.5% concentration) with cocacola in a suicide attempt. She was taken to a local hospital less than 30 min after inqestion and received gastric lavage, intravenous fluid and atropine therapy. She was sent to our emergency service 10 h after ingestion of the poison with definite symptoms of a cholinergic crisis, including hypersalivation, myosis, fasciculations of certain muscles and sweating, but she was still conscious upon hospitalization. The patient was treated with atropine (107 mg i.v. in the first 24 h - to a total dose of 300 mg), obidoxime (250 mg i.v. every 12 h for five doses), and i.v. fluid (dextrose 5% and isolyte solution to a total of 6 1 in 24 h). After the symptoms of the cholinergic crisis had been controlled, acute respiratory distress and cyanosis occured. This was 31 h after the suicide attempt. While conscious, she could not tolerate the endotracheal tube of the respirator,
Karademir, Department of Internal Medicine, Çukurova University Medical School,
Adana, Turkey.
Downloaded from het.sagepub.com at UCSF LIBRARY & CKM on March 15, 2015
188
therefore it was necessary to perform a tracheostomy 6 h after the appearance of the respiratory failure. The patient required the ventilatory support for 3 d. Muscle weakness was determined involving, primarily, the proximal limb muscles, neck flexors, and the muscles of respiration. However, the cranial nerves were intact and sensory impairment was absent. Deep tendon reflexes were hypoactive and plantar reflexes were flexor. From the second day onwards the weakness and poor function of the affected muscles had all begun to recover. She was disconnected from the respirator at the end of the third day and was discharged 14 d after admission. A delayed neuropathy shown by electromyographic (EMG) study developed a month after the suicide attempt. Case 2 A 19-year-old female was admitted to our hospital within 8 h of having a gastric lavage and atropine therapy in an other local hospital. The patient had ingested approximately 20 g of trichlorfon in an 80% concentration and 20 g of propoxur, a carbamate pesticide, in a 1 % concentration. All symptoms of cholinergic toxicity together with mental confusion were controlled with atropine (111 mg i.v. in the first 24 h - to a total dose of 205 mg), obidoxime (250 mg i.v. every 12 h for five doses) and i.v. fluid (dextrose 5% and isolyte solution totalling 6 1 in 24 h). About 40 h after the suicide attempt, respiratory distress developed, by which time there were no symptoms or clinical signs of cholinergic crisis. As in the first case tracheostomy was carried out for veritilatory support. No neuro-
logical signs
or
symptoms
were
detected, except
weakness of the respiratory and proximal limb muscles and depressed deep tendon reflexes. The
respiratory muscles were late to recover, therefore she required a respirator for 7 d. She remained in hospital for 19 d. Early and late EMG studies could not be performed. Haematologic, renal and liver function test values and electrocardiographic controls were normal for both patients. Assay of cholinesterase activity could not be carried out, because of the lack of laboratory facilities. Severe pneumonia developed in both patients and
was
patients remain
treated with suitable antibiotics. Both subject to long-term follow-up and
are
healthy.
Discussion our region insecticides are still used widely in agriculture and are present in homes. Thus
In
poisoning with these substances either accidentally or deliberately is often seen. Nearly 20 pesticide intoxication cases are admitted to our hospital every year.4 Being both the reference and university hospital for the region, only seriously-ill patients who can not get proper treatment in the environmental health centres are admitted. For this reason, the true number of such patients each year must be greater than the 20 that we encounter. In last 2 years, 418 adult poisoning cases were admitted to our emergency service, of whom only 11 (2.5%) died. Of these fatalities seven
(63.6%)
were
related
to
pesticides.
These results imply that insecticide poisoning is a definite problem. Typical cholinergic symptoms and clinical signs present no problem in the diagnosis of organophosphorus insecticide poisoning. Most of the cases are successfully treated with atropine and oxime. Some patients with severe poisoning die of central nervous system and respiratory complications. The distal symmetrical sensoriomotor neuropathy seen 2-5 weeks after organophosphorus poisoning does not carry the risk of death, although long-term motor incapacity is usual. Recent observations show that there is a third neurotoxic phase different from these two well known ones. Wadia et al., in their report on patients poisoned with diazinon, pointed out the two different paralytic neurological phases of organophosphorus intoxication. Type I signs (those present on admission), which included impaired consciousness and fasciculation, responded to atropine therapy, whereas type II signs (those appearing 24 h after poisoning) which included proximal limb weakness, areflexia and cranial nerve palsies, did not.~ Senanayake et al. suggest that the latter signs are indicative of an intermediate syndrome.3 Our patients appeared to have this intermediate syndrome. Paralysis due to poisoning with organophosphorus compounds has been described in animals)6,7 and pathological changes in the endplate region of striated muscles have been observed.8°9 The cause of the syndrome is not fully understood. Its pathophysiology probably can be related to neuropathy target esterase
(neurotoxic esterase) enzyme phosphorylation and inhibition and to the degradation of the phosphorylated enzyme complex.’o Inspired by EMG findings and experimental studies on animals, Senanayake et al. claimed that the defect in intermediate syndrome was at the neuromuscular end-plate and post-synaptic level, but stated that it was impossible for them to rule out the effect of neural and central components in producing the muscular weakness.3
Downloaded from het.sagepub.com at UCSF LIBRARY & CKM on March 15, 2015
189
Conclusion failure occuring 31-40 h after a suicide attempt, after complete recovery from cholinergic crisis symptoms, was seen in two of 18 (1.1%) organophosphorus intoxication cases admitted to our hospital in 1988. One case was related to fenthion use which has been shown to be related to the syndrome in four out of ten (40%) patients.3 The second case had ingested both trichlorfon and propoxur.
Respiratory
There was no discriminating sign in the presentation or in the response to conventional therapy of the patients who later developed this syndrome. Thus, more detailed laboratory and clinical tests are necessary to determine the exogenous and endogenous factors taking part in its development. It is particularly important that the early clinical signs and the types of insecticide responsible for its development are identified.
References 1
2
3
4
Dreisbach RH & Robertson WO. Handbook of Poisoning, pp. 110, 118. Library du liban: Appleton-Lange, 1987. Lotti M, Becker CE & Aminoff MJ. Organophosphate polyneuropathy: pathogenesis and prevention. Neurology 1984; 34: 658-62. Senanayake N & Karalliedde L. Neurotoxic effect of organophosphorus insecticides: an intermediate syndrome. New England Journal of Medicine 1987; 316: 761-3. Koçak R. Tanriverdi Z, Seyrek E & Alpaslan N. Acute poisoning: A two years retrospective study. Bulletin of Medical Faculty 1987; 12: 381-7. Wadia RS, Sadagopan C, Amin RB & Sardesai HV. Neurological manifestations of organophosphorus insecticide poisoning. Journal of Neurology Neurosurgery and Psychiatry 1974; 37: 841-7. Witter RF & Gaines TB. Relationship between depression
Çukurova 5
6
7
8
9
10
of brain or plasma cholinesterase and paralysis in chickens caused by certain organic phosphorus compounds. Biochemical Pharmacology 1963; 12: 1377-86. Gaines TB. Acute toxicity of pesticides. Toxicology and Applied Pharmacology 1969; 14: 515-34. Hayes WJ Jr. Pesticides Studied in Man pp.284-413. Baltimore: William & Wilkins, 1982. Asanuma S, Nakamura T, Suzuki A, Hirooka Y, Kurosawa K & Matsushima S. An experimental study on the organophosphorus pesticide residues in humans. Japanese Journal 16: 36-7. of Indian Health. 1974; Davies JE. Changing profile of pesticide poisoning. New England Journal of Medicine 1987; 316: 807-8.
(Received 20
October 1989;
Downloaded from het.sagepub.com at UCSF LIBRARY & CKM on March 15, 2015
accepted 27 November 1989)
