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Drug ingestions associated with miosis in comatose children
PEDIATRIC PHARMACOLOGY AND THERAPEUTICS Paul S. Lietman, Editor
Drug ingestions associated with miosis in comatose children The occurrence of pupillary constriction in children comatose as a result of the acute ingestion o f common drugs has been studied in a large pediatric hospital by reviewing records of patients admitted between 1965 and 1974. Among 94 patients with an acute drug ingestion, the fkequency of miosis in relation to the cause of coma was 88% for narcotics, 72% for phenothiazines, 35% for ethanol, and 31% for barbiturates. In contrast, miosis was noted in only 3% of 105 patients with coma from head injuries or infection of' the central nervous system. Miosis was associated with all four drug ingestions among patients in deep coma and with narcotic and phenoth(azine ingestions among patients in light coma. The frequency of miosis was found to increase with increasing depth of coma in patients with all four drug overdoses, particularly among patients with phenothiazine and barbiturate ingestions.
Allen A. Mitchell, M.D., Frederick H. Lovejoy, Jr., M.D.,* and Peter Goldman, M.D., Boston, Mass.
PROPER DECISIONS in the initial management of the patient with drug-induced coma are best made when the ingested agent has been identified. Although the identity of the agent can usually be determined from a reliable history or by analysis of appropriate body fluids, critical clinical decisions are frequently required before this information becomes available. Thus, physical examination of the patient may provide the only information upon which initial therapeutic decisions can be~made. Constricted pupils are thought to be of value in elucidating the etiology of coma, since miosis is traditionaliy associated with narcotic ingestions. Should other drug ingestions be associated with miosis, however, the utility of this clinical sign would require re-evaluation. It is the purpose of this report to determine the extent to From the Clinical Pharmacology Unit and Department of Medicine, The Children's Hospital Medical Center, and Departments o f Pediatrics and Pharmacology, Harvard Medical School, and Boston Poison Information Center. Supported in part by a grant from the Burroughs Welleome Fund. *Reprint address: Children's"Hospital Medical Center, 300 Longwood Ave., Boston, Mass. 02115.
which various common drugs are associated with miosis in children comatose as the result of acute drug ingestion.
MATERIALS AND M E T H O D S Charts of patients discharged between 1965 and 1974 from the Children's Hospital Medical Center with a diagnosis of acute drug poisoning were reviewed. Patients were excluded if more than one drug was ingested unless the agents taken were of the same class (e.g., phenothiazincs). The diagnosis of a specific drug ingestion was accepted only if laboratory analysis of blood or urine confirmed the presence of the drug, or if the clinical history was judged to be reliable. Laboratory confirmation was present in all instances of poisoning with aspirin (13) and iron (15), and in 92% (33/36) of barbiturate, 88% (15/17) of ethanol, 44% (11/25) of phenothiazine, and 31% (5/16) of narcotic ingestions. The level of consciousness recorded on admission for each patient was graded on a scale of 0 to IV (adapted from Matthew and associatesl),i Grade 0, fully awake; Grade I, drowsy with response t0~verbal command; Grade II, comatose and responsive tO mild painful stimuli; Grade III, comatose and responsive only to deep painful stimuli; Grade IV, comatose and unresponsive to painful The Journal o f P E D I A T R I C S Vol. 89, No. 2, pp. 303-305
303
304
The Journal of Pediatrics August 1976
Mitchell, Lovejoy, and Goldman
lOO t/)
o
9 80 9
/ / I I
0
...'"
Table I. The frequency of miosis in patients with various levels of coma induced by different drugs*
.'"
Coma Grade
.,,'~
I
-
.." ....
/ ~ ....
I
// -/
/
20
,."
oj
/
4O
0
f
f
~
ell
u. 0
J
.-"
-r
60
,"
~
~X! .. ~176176176
I COMA
II
Ill
I-V
GRADE
Fig. 1. Miosis by grade of coma for selected drugs. Key: Narcotics . . . . . . . . ; phenothiazines . . . . ; barbiturates ......... ; ethanol . . . . . ; no drug stimuli, areflexic, with or without cardiorespiratory depression. Pupillary size was abstracted from the patient record only after coma had been classified by grade. Miosis was considered to have been present if any of the following descriptions of the pupils was noted on the admission physical examination: "miotic," "constricted," "pinpoint," or "_<2mm." In addition, charts were reviewed of patients discharged with a diagnosis of head trauma or acute central nervous system infection (meningitis or encephalitis) to determine whether coma of other etiologies could b e the cause of miosis. Adequate n u m b e r s of patient records with these diagnoses were obtained by reviewing admissions from 1971 to 1974. Patients were excluded from this part of the study if they had received any drugs (excluding antibiotics or antipyretics) within two days prior to admission. In these patients coma a n d pupillary size were evaluated in the m a n n e r described for the ingestion cases. RESULTS
AND DISCUSSION
The frequency of miosis and the grade of coma in patients who had ingested the various drugs are summarized in Table I. The overall frequency of miosis was 88% for narcotic, 72% for phenothiazine, 35% for ethanol, and 31% for barbiturate poisonings. Pupillary constriction was not described in the records of any patients who had ingested aspirin or iron; all but one of these patients had coma of Grades 0 to 1. Patients with these ingestions were therefore excluded from further analysis. Miosis was noted in 6% (2/32) of patients with infection of the central nervous system and in 1% (1/75) of patients with head trauma. Because the n u m b e r of patients was
Drug
0
Diphenoxylate Propoxyphene Methadone All narcotics (% Miotic)
2/3 . 2/3 4/6 (67)
Chlorproma-
0/1
zinc Trifluoperazine 0/3 Thioridazine 0/1 Promazine Other All phenothia- 0/5 zincs (% Miotic) (0)
I .
I II
lie
2/2 . 1/1 3/3 (100)
1/1
2/2
-1/1 (100)
7/9
3/3
1 IV
-2/2 (100)
-2/2 2/2 4/4 (100)
7/8 2/2 5/6 14/16 (88)
1/1
-
11/14
-1/1 2/2
---
0/3 1/ 2 1/1 5/5 18/25
.
. . . 1/ 1 . . 1/1 1/1 3/3 10/12 6/6
Total
. .
.
(83)
(100)
(100)
-
(72)
Phenobarbital Seco/pentabarbital Other All barbiturates (% Miotic)
0/3 0/2
0/10 1/4
2/3 -
2/2 2/2
2/2 -
6/20 3/8
0/5
2/7 3/21
~2/3
0/1 4/5
2/2
2/8 11/36
(0)
(14)
(67)
(80)
(100)
(31)
Ethanol (% Miotic) CNS infection Head trauma All controls (% Miotic)
0/8 0/14 0/22 (0)
2/9 (22) 1/15 1/45 2/60 (3)
1/2 (50) 0/2 0/7 0/9 (0)
3/6 (50) 1/6 0/5 1/ i I (9)
0/1 0/4 0/5 (0)
6/17 (35) 2/32 1/75 3/107 (3)
*The fraction represents the number of patients with miosis among the total number of patients classified by ingested drug and grade of coma.
small, those patients not having a drug ingestion were considered as a single group and those with various grades of coma from each ingestion were combined so that Grades 0 to 1 were designated "light coma" and Grades II to IV were designated "deep coma." Patients in light coma from phenothiazine or n~rcotic ingestion were more likely to have miosis than patients not having an ingestion (p < 0.001)2; patients in deep coma from an ingestion of any of the four drugs were more likely to have miosis than patients in c0ma from the other causes (p < 0.05). Fig. 1 confirms the well-known finding of miosis among noncomatose patients who have ingested narcotics. It should be stressed, however, that patients who ingested other classes of drugs show an increased frequency of miosis as depth of coma increases: the correlation between depth of coma and frequency of miosis is significant for the barbiturate and phenothiazine groups (p < 0.01). 3
Volume 89 Number 2
The data o f this study were derived from records at a large pediatric hospital serving a diverse population with changing patterns of drug exposure. Further, the study was restricted to records o f patients for w h o m a single drug ingestion had been established. These results, therefore, cannot necessarily be used as a basis for implicating a specific agent when the cause of coma is unknown. They simply provide documentation that drugs in addition to narcotics, barbiturates, ~ and those active on the peripheral autonomic system frequently can be associated with miosis, particularly if taken in amounts sufficient to cause deep coma. Although drugs other than narcotics can be associated with miosis, a proven safe and effective antidote is available only for acute narcotic ingestion.* Thus, when miosis is present in a comatose pediatric patient and there is a suspicion of narcotic ingestion, an adequate therapeutic trial with the narcotic antagonist naloxone appears justified2 (The use of naloxone has been discussed in a previous communication?) Such a trial entails little risk; if *Two recent case reports suggest that naloxone may be effectivealso in reversing symptoms of poisoning with certain non-narcotic agents?.~ These reports require confirmation before a broader role for naloxone can be advocated.
Drug ingestions associated with miosis
305
pupillary dilatation and the expected clinical response s do not occur, other drugs such as barbiturates, phenothiazines, and ethanol should be considered as possible offending agents. We are indebted to Dr. Stuart Hartz for biostatistical assistance. REFERENCES
1. Matthew H, Mackintosh TF, Tompsett SL, and Cameron JC: Gastric aspiration and lavage in acute poisoning, Br Med J 1:1333, 1966. 2. Dunnett CW: New tables for multiple comparisons with a control, Biometrics 20:482, 1964. 3. Bartholemew D J: A test of homogeneity for ordered alternatives, I, Biometrika 46:36, 1959. 4. Arena J: Poisoning, ed 3, Springfield, Ill., 1974, Charles C Thomas, Publisher. 5. Bell EF: The use of nalo• in the treatment of diazepam poisoning, J PEDtATR87:803, 1975. 6. Moss LM: Naloxone reversal of non-narcotic induced apnea, J Am Coll Emer Phys 1:46, 1973. 7. Evans LEJ, Swainson CP, Roscoe P, and Prescott LF: Treatment of drug overdoseage with naloxone, a specific narcotic antagonist, Lancet 1:452, 1973. 8. Lovejoy FH Jr, Mitchell AA, and Goldman P: The management of propo• poisoning, J P~DIATR85:98, 1974.
Drug ingestions associated with miosis in comatose children The occurrence of pupillary constriction in children comatose as a result of the acute ingestion o f common drugs has been studied in a large pediatric hospital by reviewing records of patients admitted between 1965 and 1974. Among 94 patients with an acute drug ingestion, the fkequency of miosis in relation to the cause of coma was 88% for narcotics, 72% for phenothiazines, 35% for ethanol, and 31% for barbiturates. In contrast, miosis was noted in only 3% of 105 patients with coma from head injuries or infection of' the central nervous system. Miosis was associated with all four drug ingestions among patients in deep coma and with narcotic and phenoth(azine ingestions among patients in light coma. The frequency of miosis was found to increase with increasing depth of coma in patients with all four drug overdoses, particularly among patients with phenothiazine and barbiturate ingestions.
Allen A. Mitchell, M.D., Frederick H. Lovejoy, Jr., M.D.,* and Peter Goldman, M.D., Boston, Mass.
PROPER DECISIONS in the initial management of the patient with drug-induced coma are best made when the ingested agent has been identified. Although the identity of the agent can usually be determined from a reliable history or by analysis of appropriate body fluids, critical clinical decisions are frequently required before this information becomes available. Thus, physical examination of the patient may provide the only information upon which initial therapeutic decisions can be~made. Constricted pupils are thought to be of value in elucidating the etiology of coma, since miosis is traditionaliy associated with narcotic ingestions. Should other drug ingestions be associated with miosis, however, the utility of this clinical sign would require re-evaluation. It is the purpose of this report to determine the extent to From the Clinical Pharmacology Unit and Department of Medicine, The Children's Hospital Medical Center, and Departments o f Pediatrics and Pharmacology, Harvard Medical School, and Boston Poison Information Center. Supported in part by a grant from the Burroughs Welleome Fund. *Reprint address: Children's"Hospital Medical Center, 300 Longwood Ave., Boston, Mass. 02115.
which various common drugs are associated with miosis in children comatose as the result of acute drug ingestion.
MATERIALS AND M E T H O D S Charts of patients discharged between 1965 and 1974 from the Children's Hospital Medical Center with a diagnosis of acute drug poisoning were reviewed. Patients were excluded if more than one drug was ingested unless the agents taken were of the same class (e.g., phenothiazincs). The diagnosis of a specific drug ingestion was accepted only if laboratory analysis of blood or urine confirmed the presence of the drug, or if the clinical history was judged to be reliable. Laboratory confirmation was present in all instances of poisoning with aspirin (13) and iron (15), and in 92% (33/36) of barbiturate, 88% (15/17) of ethanol, 44% (11/25) of phenothiazine, and 31% (5/16) of narcotic ingestions. The level of consciousness recorded on admission for each patient was graded on a scale of 0 to IV (adapted from Matthew and associatesl),i Grade 0, fully awake; Grade I, drowsy with response t0~verbal command; Grade II, comatose and responsive tO mild painful stimuli; Grade III, comatose and responsive only to deep painful stimuli; Grade IV, comatose and unresponsive to painful The Journal o f P E D I A T R I C S Vol. 89, No. 2, pp. 303-305
303
304
The Journal of Pediatrics August 1976
Mitchell, Lovejoy, and Goldman
lOO t/)
o
9 80 9
/ / I I
0
...'"
Table I. The frequency of miosis in patients with various levels of coma induced by different drugs*
.'"
Coma Grade
.,,'~
I
-
.." ....
/ ~ ....
I
// -/
/
20
,."
oj
/
4O
0
f
f
~
ell
u. 0
J
.-"
-r
60
,"
~
~X! .. ~176176176
I COMA
II
Ill
I-V
GRADE
Fig. 1. Miosis by grade of coma for selected drugs. Key: Narcotics . . . . . . . . ; phenothiazines . . . . ; barbiturates ......... ; ethanol . . . . . ; no drug stimuli, areflexic, with or without cardiorespiratory depression. Pupillary size was abstracted from the patient record only after coma had been classified by grade. Miosis was considered to have been present if any of the following descriptions of the pupils was noted on the admission physical examination: "miotic," "constricted," "pinpoint," or "_<2mm." In addition, charts were reviewed of patients discharged with a diagnosis of head trauma or acute central nervous system infection (meningitis or encephalitis) to determine whether coma of other etiologies could b e the cause of miosis. Adequate n u m b e r s of patient records with these diagnoses were obtained by reviewing admissions from 1971 to 1974. Patients were excluded from this part of the study if they had received any drugs (excluding antibiotics or antipyretics) within two days prior to admission. In these patients coma a n d pupillary size were evaluated in the m a n n e r described for the ingestion cases. RESULTS
AND DISCUSSION
The frequency of miosis and the grade of coma in patients who had ingested the various drugs are summarized in Table I. The overall frequency of miosis was 88% for narcotic, 72% for phenothiazine, 35% for ethanol, and 31% for barbiturate poisonings. Pupillary constriction was not described in the records of any patients who had ingested aspirin or iron; all but one of these patients had coma of Grades 0 to 1. Patients with these ingestions were therefore excluded from further analysis. Miosis was noted in 6% (2/32) of patients with infection of the central nervous system and in 1% (1/75) of patients with head trauma. Because the n u m b e r of patients was
Drug
0
Diphenoxylate Propoxyphene Methadone All narcotics (% Miotic)
2/3 . 2/3 4/6 (67)
Chlorproma-
0/1
zinc Trifluoperazine 0/3 Thioridazine 0/1 Promazine Other All phenothia- 0/5 zincs (% Miotic) (0)
I .
I II
lie
2/2 . 1/1 3/3 (100)
1/1
2/2
-1/1 (100)
7/9
3/3
1 IV
-2/2 (100)
-2/2 2/2 4/4 (100)
7/8 2/2 5/6 14/16 (88)
1/1
-
11/14
-1/1 2/2
---
0/3 1/ 2 1/1 5/5 18/25
.
. . . 1/ 1 . . 1/1 1/1 3/3 10/12 6/6
Total
. .
.
(83)
(100)
(100)
-
(72)
Phenobarbital Seco/pentabarbital Other All barbiturates (% Miotic)
0/3 0/2
0/10 1/4
2/3 -
2/2 2/2
2/2 -
6/20 3/8
0/5
2/7 3/21
~2/3
0/1 4/5
2/2
2/8 11/36
(0)
(14)
(67)
(80)
(100)
(31)
Ethanol (% Miotic) CNS infection Head trauma All controls (% Miotic)
0/8 0/14 0/22 (0)
2/9 (22) 1/15 1/45 2/60 (3)
1/2 (50) 0/2 0/7 0/9 (0)
3/6 (50) 1/6 0/5 1/ i I (9)
0/1 0/4 0/5 (0)
6/17 (35) 2/32 1/75 3/107 (3)
*The fraction represents the number of patients with miosis among the total number of patients classified by ingested drug and grade of coma.
small, those patients not having a drug ingestion were considered as a single group and those with various grades of coma from each ingestion were combined so that Grades 0 to 1 were designated "light coma" and Grades II to IV were designated "deep coma." Patients in light coma from phenothiazine or n~rcotic ingestion were more likely to have miosis than patients not having an ingestion (p < 0.001)2; patients in deep coma from an ingestion of any of the four drugs were more likely to have miosis than patients in c0ma from the other causes (p < 0.05). Fig. 1 confirms the well-known finding of miosis among noncomatose patients who have ingested narcotics. It should be stressed, however, that patients who ingested other classes of drugs show an increased frequency of miosis as depth of coma increases: the correlation between depth of coma and frequency of miosis is significant for the barbiturate and phenothiazine groups (p < 0.01). 3
Volume 89 Number 2
The data o f this study were derived from records at a large pediatric hospital serving a diverse population with changing patterns of drug exposure. Further, the study was restricted to records o f patients for w h o m a single drug ingestion had been established. These results, therefore, cannot necessarily be used as a basis for implicating a specific agent when the cause of coma is unknown. They simply provide documentation that drugs in addition to narcotics, barbiturates, ~ and those active on the peripheral autonomic system frequently can be associated with miosis, particularly if taken in amounts sufficient to cause deep coma. Although drugs other than narcotics can be associated with miosis, a proven safe and effective antidote is available only for acute narcotic ingestion.* Thus, when miosis is present in a comatose pediatric patient and there is a suspicion of narcotic ingestion, an adequate therapeutic trial with the narcotic antagonist naloxone appears justified2 (The use of naloxone has been discussed in a previous communication?) Such a trial entails little risk; if *Two recent case reports suggest that naloxone may be effectivealso in reversing symptoms of poisoning with certain non-narcotic agents?.~ These reports require confirmation before a broader role for naloxone can be advocated.
Drug ingestions associated with miosis
305
pupillary dilatation and the expected clinical response s do not occur, other drugs such as barbiturates, phenothiazines, and ethanol should be considered as possible offending agents. We are indebted to Dr. Stuart Hartz for biostatistical assistance. REFERENCES
1. Matthew H, Mackintosh TF, Tompsett SL, and Cameron JC: Gastric aspiration and lavage in acute poisoning, Br Med J 1:1333, 1966. 2. Dunnett CW: New tables for multiple comparisons with a control, Biometrics 20:482, 1964. 3. Bartholemew D J: A test of homogeneity for ordered alternatives, I, Biometrika 46:36, 1959. 4. Arena J: Poisoning, ed 3, Springfield, Ill., 1974, Charles C Thomas, Publisher. 5. Bell EF: The use of nalo• in the treatment of diazepam poisoning, J PEDtATR87:803, 1975. 6. Moss LM: Naloxone reversal of non-narcotic induced apnea, J Am Coll Emer Phys 1:46, 1973. 7. Evans LEJ, Swainson CP, Roscoe P, and Prescott LF: Treatment of drug overdoseage with naloxone, a specific narcotic antagonist, Lancet 1:452, 1973. 8. Lovejoy FH Jr, Mitchell AA, and Goldman P: The management of propo• poisoning, J P~DIATR85:98, 1974.