- Email: [email protected]
Toxic clonidine ingestion in children
TOXIC CLONIDINE INGESTION IN CHILDREN HENRY A. SPILLER, MS, DABAT, WENDY KLEIN-SCHWARTZ, PHARMD, MPH, JONATHAN M. COLVIN, BSN, CSPI, DANNY VILLALOBOS, BS, CSPI, PAUL B. JOHNSON, BS PHARM, CSPI, AND DEBORAH L. ANDERSON, PHARMD
Objectives We performed a prospective case series to seek dosage or clinical parameters to better identify patients who need direct medical evaluation. Study design All clonidine ingestions in children younger than 12 years of age reported to 6 poison centers were followed for a minimum of 24 hours. Exclusion criterion was polydrug ingestion. Results The study included 113 patients, of whom 63 were male. Mean age was 3.8 years (±2.4 SD). Clinical effects were common, but severe adverse effects occurred in <10% of patients. The dose ingested was reported for 90 patients (80%); 61 (68%) children ingested <0.3 mg and none had coma, respiratory depression, or hypotension. The lowest dose ingested by history with coma and respiratory depression was 0.3 mg (0.015 mg/kg). Prior clonidine therapy did not affect outcome. Onset of full clinical effects in all cases was complete within 4 hours of ingestion. Conclusions We recommend direct medical evaluation for (1) all children 4 years of age and younger with unintentional clonidine ingestion of $0.1 mg, (2) ingestion of >0.2 mg in children 5 to 8 years of age, and (3) ingestion of $0.4 mg in children older than 8 years of age. Observation for 4 hours may be sufficient to detect patients who will develop severe effects. (J Pediatr 2005;146:263-6)
lonidine poisoning in children is a common event, with more than 1600 cases reported annually to poison centers in recent years.1 Of these, >50% were in children younger than 6 years of age. The majority of these ingestions (77%) resulted in minimal or no effects. Despite this, 84% were seen in a hospital emergency department and 50% were admitted overnight. The reason for this cautious approach is that clonidine has a very narrow therapeutic window.2 Reported clinical effects from overdose have included hypertension, hypotension, hypothermia, bradycardia, tachycardia, coma, respiratory depression, apnea, generalized hypotonia, hyporeflexia, and miosis.1-8 Death after overdose is rare, with only a single death reported in one study of more than 10,000 overdoses.1 The majority of publications on clonidine overdose are anecdotal reports.2-8 Most published studies are retrospective and provide no data on dosage response, toxicodynamic response in overdose, or other critical areas that might help guide the clinician.1,9 Review of the published case reports shows that prominent onset of adverse clinical effects in the severe cases was rapid, usually in <1 hour. However, the use of case reports as the sole source for decision-making can add significant bias. It is unclear if this rapid onset occurs in all cases and could be relied on as a diagnostic aid. The lack of a large study clarifying these issues leaves no clear guidance as to which, if any, From Kentucky Regional Poison Cencases can be managed outside of a hospital. Additionally, there is no clear guidance ter, Louisville, Kentucky; Maryland concerning those cases seen in the emergency department: which can be safely discharged Poison Center, Baltimore, MD; Uniafter a short observation period and which need to be admitted for treatment or a longer versity of Maryland, School of Pharmacy, Baltimore, MD; Cincinnati Drug observation period. We performed a prospective case series to evaluate if there were dosage and Poison Information Center, Cinor clinical data to better identify those patients who need direct medical evaluation from cinnati, Ohio; Southeast Texas Poison Center, Galveston, TX; Missouri Rethose who can be observed at home.
C
METHODS We conducted a prospective case series of all patients with clonidine ingestion reported to participating poison centers from September 1, 2002, to April 30, 2003. Entrance criteria included clonidine ingestion, age 12 years or younger, and follow-up to a known outcome (minimum, 24 hours). Exclusion criterion was polypharmacy ingestion. BP
Blood pressure
HR
Heart rate
gional Poison Center, St. Louis, MO; and Hennepin Regional Poison Center, Minneapolis, MN. Submitted for publication June 17, 2004; revision received Aug 13, 2004; accepted Sep 30, 2004. Reprint requests: Dr Henry A. Spiller, Kentucky Regional Poison Center, PO Box 35070, Louisville, KY 40232-5070. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.09.027
263
Table I. Definitions of signs and clinical features Sign or clinical feature Hypotension Bradycardia Coma Hypertension Hypothermia
Age 0 to 4 y
Age 5 to 12 y
Systolic ,80 mm Hg Heart rate ,75 beats per minute Unresponsive to verbal stimuli Systolic .110 or diastolic .75 mm Hg Temperature ,35.5C
Systolic ,80 mm Hg Heart rate ,60 beats per minute Unresponsive to verbal stimuli Systolic .120 or diastolic .80 mm Hg Temperature ,35.5C
Table II. Clinical effects of clonidine by age group Age 0 to 4 y (percent of age group)
Age 5 to 8 y (percent of age group)
Age 9 to 12 y (percent of age group)
Total
81 61 (75%) 10 (14%) 7 (9%) 7 (9%)
25 16 (64%) 2 (9%) 2 (8%) 1 (4%)
7 4 (57%) 1 (14%) 1 (14%) 0
113 81 (72%) 13 (12%) 10 (9%) 8 (7%)
6 (9%) 4 (5%) 0
1 (4%) 0 0
0 0 0
7 (6%) 4 (4%) 0
All patients in age group Drowsiness/lethargy Bradycardia Hypotension Respiratory depression with mechanical ventilation Coma Hypertension Hypothermia
Each case was identified at the time of the initial contact with the poison center. A separate data collection sheet recording demographics, dose, neurologic, and hemodynamic changes was initiated. Definition of clinical effects used in this study are provided in Table I. The study was approved by the human studies committee of the appropriate institution for each participating poison center. To evaluate clinical effects, dose, and treatments by age, study subjects were categorized into 3 groups: 0 to 4 years, 5 to 8 years, and 9 to 12 years of age. Statistics were descriptive and, for analysis of significance, x2 and Mann-Whitney tests were performed.
RESULTS The study population included 113 patients of whom 63 (56%) were male. The mean age of patients was 3.8 years (±2.4 SD), with a range of 6 months to 11 years. Ninety-seven patients (86%) were evaluated in an health care facility (HCF), and 63 of these children were admitted for medical care or observation. The clinical effects reported are listed in Tables II and III. Clinical effects were common, and serious clinical effects resulting invasive measures such as intubation or pressors were infrequent but were reported more frequently in the very young children. Onset of full symptoms was complete within 4 hours of ingestion in all cases, with a mean time to maximum level of central nervous system depression of 1.7 hours (range, 1 to 3 hours). The dose ingested was known for 90 patients (80%); 61 (68%) children ingested <0.3 mg, and none of these had coma, respiratory depression, or hypotension. The lowest dose 264
Spiller et al
ingested with coma and respiratory depression was 0.3 mg (0.015 mg/kg). This occurred in a 4-year-old, 20-kg boy with a history of cerebral palsy. He had a witnessed ingestion of 3 tablets of 0.1 mg of his own medication. Two hours before this, the child had been given his morning dose of 0.075 mg. The child’s medication schedule was 0.075 mg in the morning and 1 PM and 0.1 mg at hour of sleep, for a total of 0.25 mg/d. Within 20 minutes, the child was reported to be deeply somnolent and was transported to the hospital by emergency medical services. In the emergency department, the child was unarousable to voice and was intubated and placed on mechanical ventilation due to periods of apnea. His heart rate (HR) was 110 bpm and his blood pressure (BP) was 130/86 mm Hg. The HR decreased to 54 bpm within 3 hours of ingestion and BP decreased to 92/44 mm Hg. No specific therapy beyond mechanical ventilation and intravenous fluids was instituted. The child was extubated at 20 hours after ingestion and discharged after 48 hours. In the 5- to 8-year-old group, one 5-year-old girl received intubation, mechanical ventilation, atropine, and fluid challenge after ingesting an unknown amount of 0.1 mg tablets from an open bottle of her own medication. The single child in the 9- to 12-year-old group with symptoms requiring intervention was a 10-year-old boy who was reportedly given 30 of his own 0.1 mg tablets by a grandparent who misunderstood directions while babysitting. The boy received a fluid challenge for a BP of 84/30 mm Hg with an HR of 80 bpm and was discharged after 24 hours of observation without further problems. The remaining children in this age group ingested between 0.2 and 0.5 mg, with only drowsiness or lethargy reported. The Journal of Pediatrics February 2005
Table III. Major clinical effects by age group and dose Mean reported dose ingested with clinical effect Age 0 to 4 y Coma Respiratory depression Hypotension Age 5 to 8 y Coma Respiratory depression Hypotension Age 9 to 12 y Coma Respiratory depression Hypotension
Mean reported dose ingested without clinical effect
1.18 mg (±0.59 SD) 0.94 mg (±0.25 SD) 0.77 mg (±0.65 SD)
0.25 (±0.24 SD) 0.25 (±0.27 SD) 0.26 (±0.29 SD)
Dose not known Dose not known Dose not known
0.21 mg (±0.14 SD) 0.21 mg (±0.14 SD) 0.22 mg (±0.12 SD)
No patient with clinical effect No patient with clinical effect 3.0 mg
0.76 (±1.0 SD) 0.76 (±1.0 SD) 0.38 (±0.15 SD)
Table IV. Major symptoms by prior therapy versus no prior therapy Symptom
Patient’s own medication
No prior clonidine therapy
Coma Hypotension Respiratory depression
3 of 45 4 of 45 3 of 45
4 of 68 6 of 68 5 of 68
NS NS NS
NS, not significant.
In 43 patients (39%), the ingestions involved their own medicine. Unintentional misdosing involving inadvertent double doses occurred in 17 patients (15%). This occurred in 4 patients 4 years old or younger, 9 patients 5 to 8 years old, and 4 patients 9 to 12 years old. Lethargy was reported in all patients 4 years old or younger and 5 to 8 years old, but no other symptoms were reported. In the 9- to 12-year-old patients, 2 reported no symptoms and 2 reported drowsiness. Prior clonidine therapy did not affect outcome, incidence of coma, hypotension, or respiratory depression (P > .05) (Table IV). However, dose ingested had a significant impact on outcome and clinical effects reported (Table V).
DISCUSSION Clonidine is a recommended therapy for the treatment of attention deficit hyperactive disorder in children.10,11 As a result of this use in the pediatric population, there is widespread availability of clonidine to children, and frequent unintentional overdoses continue to occur.1,9 Despite this, there are limited data on outcomes of these sometimes lowdose exposures, with the majority of information derived from retrospective reviews of hospitalized patients. Our study design (prospective case series) allows for better capture of data regarding clinical effects, dose, and therapies. Severe symptoms resulting in invasive procedures were infrequent, with no fatalities (<10%, Table I). This finding is similar to previous reports. In 5 retrospective case series of children hospitalized for clonidine ingestion, intubation and mechanical ventilation Toxic Clonidine Ingestion In Children
were required in 8% to 12.7% of children.9,12-15 There were no fatalities in the total of 177 children in these cases series. In fact, only 2 fatalities, both in children, have been reported in the medical literature from isolated clonidine ingestion.1,16 A concern over the risk of severe symptoms, such as respiratory depression or hypotension, was most likely responsible for the large number of cases evaluated in the emergency department in this series. Our data suggest that ingestion of 0.1 mg or 0.2 mg does not warrant direct medical evaluation in the emergency department in all children. This is consistent with previous reports, in which specific doses were reported. Fiser et al14 suggested in a review of 11 patients that toddlers with ingestion of <0.01 mg/kg had only mild symptoms, which is less than 2 times the recommended dosage. With ingestion of 0.01 to 0.02 mg/kg (2 to 4 times maximum dosage), bradycardia and hypotension tended to occur, and with ingestion of >0.02 mg/kg, patients were at risk for respiratory depression.14 However, the number of patients in our series and previous series in which doses were specifically reported may have been too small to catch the rare case of significant symptoms in a low-dose ingestion. Wedin et al2 reported a case of a 3-year-old boy (weight not reported) with hypotension who received a dopamine infusion after ingestion of a single 0.2 mg tablet. Intubation was not necessary, and the symptoms resolved approximately 10 hours after ingestion. Unintentional misdosing involving inadvertent double doses occurred in 17 patients (15%) in our case series. Such cases present the clinician with a dilemma of whether the 265
Table V. Mean dose ingested of patients with and without major symptoms
Symptom
Mean (±SD) and median reported dose with clinical effect
Mean (±SD) and median reported dose without clinical effect
Two-sample test (Mann-Whitney)
Coma Respiratory depression Hypotension
1.2 mg (±0.59), 1.45 mg 0.94 mg (±0.54), 0.8 mg 0.66 mg (±0.64), 0.43
0.25 mg (±0.21), 0.2 mg 0.25 mg (±0.24), 0.2 mg 0.26 mg (±0.26), 0.2 mg
P , .05 P , .05 P = .14
patient requires direct medical evaluation in the emergency department or can be treated safely outside of the hospital setting. Although the number of patients in this group is small, the data suggest that an inadvertent double dose does not put the child at risk for significant symptoms beyond the expected drowsiness. At this time, it seems prudent to have all children 4 years old or younger to receive direct medical evaluation with unintentional clonidine ingestions of 2 times a therapeutic dose (0.005 mg/kg) or greater. Children 5 to 8 years old with ingestion of >0.2 mg may require direct medical evaluation. In children older than 8 years of age, $0.4 mg may require direct medical evaluation. All patients in the series recovered fully with observation and/or supportive therapy. This is an experience similar to previous reports.4-6,12-14 Romano et al4 reported a documented overdose of >2800 mg/kg in a 5-year-old boy treated with supportive care and naloxone. Similar favorable outcomes with supportive therapy have occurred in adults with inadvertent 1000-fold overdoses.17 Finally, in our case series, all clinical effects were evident rapidly after ingestion, with a mean of 1.7 hours. This is consistent with the findings of Wiley et al12 in a case series of 47 patients. Study limitations include the small number of patients, especially in the older age groups, and the possibility that in some cases dose information was inaccurate. Laboratory evaluation of plasma clonidine concentrations to confirm the history and dose are not available because therapeutic drug monitoring of clonidine concentrations is not routine. Since calls to poison centers are voluntary, sampling bias is possible. It is not possible to ascertain how cases not reported to poison centers differ from those reported to poison centers.
266
Spiller et al
REFERENCES 1. Klein-Schwartz W. Trends and toxic effects from pediatric clonidine exposures. Arch Pediatr Adolesc Med 2002;156:392-6. 2. Wedin GP, Richardson SL, Wallace GH. Clonidine poisoning in children. Am J Dis Child 1990;144:853-4. 3. Frye CB, Vance MA. Hypertensive crisis and myocardial infarction following massive clonidine overdose. Ann Pharmacother 2000;34:611-5. 4. Romano MJ, Dinh A. A 1000-fold overdose of clonidine caused by a compounding error in a 5-year-old child with attention-deficit/hyperactivity disorder. Pediatrics 2001;108:471-2. 5. Maggi JC, Iskra MK, Nussbaum E. Severe clonidine overdose in children requiring critical care. Clin Pediatr 1986;25:453-5. 6. Marruecos L, Roglan A, Frati ME, Artigas A. Clonidine overdose. Crit Care Med 1983;11:959-60. 7. Banner W, Lund ME, Clawson L. Failure of naloxone to reverse clonidine toxic effect. Am J Dis Child 2983;137:1170-1. 8. Yagupsky P, Gorodischer R. Massive clonidine ingestion with hypertension in a 9-month-old infant. Pediatrics 1983;72:500-2. 9. Kappagoda C, Schell DN, Hanson RM, Hutchins P. Clonidine overdose in childhood: implications of increased prescribing. J Pediatr Child Health 1998;34:508-12. 10. Hazell PL, Stuart JE. A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children. J Am Acad Child Adolesc Psychol 2003;42:886-94. 11. Plisszka SR. Non-stimulant treatment of attention-deficit/hyperactive disorder. CNS Spectrums 2003;8:253-8. 12. Wiley JF II, Wiley CC, Torrey SB, Henretig FM. Clonidine poisoning in young children. J Pediatr 1990;116:654-8. 13. Bamshad MJ, Wasserman GS. Pediatric clonidine intoxications. Vet Hum Toxicol 1990;32:220-3. 14. Fiser DH, Moss MM, Walker W. Critical care for clonidine poisoning in toddlers. Crit Care Med 1990;18:1124-8. 15. Nichols MH, King WD, James LP. Clonidine poisoning in Jefferson County, Alabama. Ann Emerg Med 1997;29:511-7. 16. Sanklecha M, Jog A, Raghavan K. Clonidine casualty [letter]. Indian J Pediatr 1993;60:611-2. 17. Rotellar JAO, Monsasterio ES, de la Cruz JS, Gene CG. Clonidine in thousand fold overdose. Lancet 1981;1:1312.
The Journal of Pediatrics February 2005
Objectives We performed a prospective case series to seek dosage or clinical parameters to better identify patients who need direct medical evaluation. Study design All clonidine ingestions in children younger than 12 years of age reported to 6 poison centers were followed for a minimum of 24 hours. Exclusion criterion was polydrug ingestion. Results The study included 113 patients, of whom 63 were male. Mean age was 3.8 years (±2.4 SD). Clinical effects were common, but severe adverse effects occurred in <10% of patients. The dose ingested was reported for 90 patients (80%); 61 (68%) children ingested <0.3 mg and none had coma, respiratory depression, or hypotension. The lowest dose ingested by history with coma and respiratory depression was 0.3 mg (0.015 mg/kg). Prior clonidine therapy did not affect outcome. Onset of full clinical effects in all cases was complete within 4 hours of ingestion. Conclusions We recommend direct medical evaluation for (1) all children 4 years of age and younger with unintentional clonidine ingestion of $0.1 mg, (2) ingestion of >0.2 mg in children 5 to 8 years of age, and (3) ingestion of $0.4 mg in children older than 8 years of age. Observation for 4 hours may be sufficient to detect patients who will develop severe effects. (J Pediatr 2005;146:263-6)
lonidine poisoning in children is a common event, with more than 1600 cases reported annually to poison centers in recent years.1 Of these, >50% were in children younger than 6 years of age. The majority of these ingestions (77%) resulted in minimal or no effects. Despite this, 84% were seen in a hospital emergency department and 50% were admitted overnight. The reason for this cautious approach is that clonidine has a very narrow therapeutic window.2 Reported clinical effects from overdose have included hypertension, hypotension, hypothermia, bradycardia, tachycardia, coma, respiratory depression, apnea, generalized hypotonia, hyporeflexia, and miosis.1-8 Death after overdose is rare, with only a single death reported in one study of more than 10,000 overdoses.1 The majority of publications on clonidine overdose are anecdotal reports.2-8 Most published studies are retrospective and provide no data on dosage response, toxicodynamic response in overdose, or other critical areas that might help guide the clinician.1,9 Review of the published case reports shows that prominent onset of adverse clinical effects in the severe cases was rapid, usually in <1 hour. However, the use of case reports as the sole source for decision-making can add significant bias. It is unclear if this rapid onset occurs in all cases and could be relied on as a diagnostic aid. The lack of a large study clarifying these issues leaves no clear guidance as to which, if any, From Kentucky Regional Poison Cencases can be managed outside of a hospital. Additionally, there is no clear guidance ter, Louisville, Kentucky; Maryland concerning those cases seen in the emergency department: which can be safely discharged Poison Center, Baltimore, MD; Uniafter a short observation period and which need to be admitted for treatment or a longer versity of Maryland, School of Pharmacy, Baltimore, MD; Cincinnati Drug observation period. We performed a prospective case series to evaluate if there were dosage and Poison Information Center, Cinor clinical data to better identify those patients who need direct medical evaluation from cinnati, Ohio; Southeast Texas Poison Center, Galveston, TX; Missouri Rethose who can be observed at home.
C
METHODS We conducted a prospective case series of all patients with clonidine ingestion reported to participating poison centers from September 1, 2002, to April 30, 2003. Entrance criteria included clonidine ingestion, age 12 years or younger, and follow-up to a known outcome (minimum, 24 hours). Exclusion criterion was polypharmacy ingestion. BP
Blood pressure
HR
Heart rate
gional Poison Center, St. Louis, MO; and Hennepin Regional Poison Center, Minneapolis, MN. Submitted for publication June 17, 2004; revision received Aug 13, 2004; accepted Sep 30, 2004. Reprint requests: Dr Henry A. Spiller, Kentucky Regional Poison Center, PO Box 35070, Louisville, KY 40232-5070. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.09.027
263
Table I. Definitions of signs and clinical features Sign or clinical feature Hypotension Bradycardia Coma Hypertension Hypothermia
Age 0 to 4 y
Age 5 to 12 y
Systolic ,80 mm Hg Heart rate ,75 beats per minute Unresponsive to verbal stimuli Systolic .110 or diastolic .75 mm Hg Temperature ,35.5C
Systolic ,80 mm Hg Heart rate ,60 beats per minute Unresponsive to verbal stimuli Systolic .120 or diastolic .80 mm Hg Temperature ,35.5C
Table II. Clinical effects of clonidine by age group Age 0 to 4 y (percent of age group)
Age 5 to 8 y (percent of age group)
Age 9 to 12 y (percent of age group)
Total
81 61 (75%) 10 (14%) 7 (9%) 7 (9%)
25 16 (64%) 2 (9%) 2 (8%) 1 (4%)
7 4 (57%) 1 (14%) 1 (14%) 0
113 81 (72%) 13 (12%) 10 (9%) 8 (7%)
6 (9%) 4 (5%) 0
1 (4%) 0 0
0 0 0
7 (6%) 4 (4%) 0
All patients in age group Drowsiness/lethargy Bradycardia Hypotension Respiratory depression with mechanical ventilation Coma Hypertension Hypothermia
Each case was identified at the time of the initial contact with the poison center. A separate data collection sheet recording demographics, dose, neurologic, and hemodynamic changes was initiated. Definition of clinical effects used in this study are provided in Table I. The study was approved by the human studies committee of the appropriate institution for each participating poison center. To evaluate clinical effects, dose, and treatments by age, study subjects were categorized into 3 groups: 0 to 4 years, 5 to 8 years, and 9 to 12 years of age. Statistics were descriptive and, for analysis of significance, x2 and Mann-Whitney tests were performed.
RESULTS The study population included 113 patients of whom 63 (56%) were male. The mean age of patients was 3.8 years (±2.4 SD), with a range of 6 months to 11 years. Ninety-seven patients (86%) were evaluated in an health care facility (HCF), and 63 of these children were admitted for medical care or observation. The clinical effects reported are listed in Tables II and III. Clinical effects were common, and serious clinical effects resulting invasive measures such as intubation or pressors were infrequent but were reported more frequently in the very young children. Onset of full symptoms was complete within 4 hours of ingestion in all cases, with a mean time to maximum level of central nervous system depression of 1.7 hours (range, 1 to 3 hours). The dose ingested was known for 90 patients (80%); 61 (68%) children ingested <0.3 mg, and none of these had coma, respiratory depression, or hypotension. The lowest dose 264
Spiller et al
ingested with coma and respiratory depression was 0.3 mg (0.015 mg/kg). This occurred in a 4-year-old, 20-kg boy with a history of cerebral palsy. He had a witnessed ingestion of 3 tablets of 0.1 mg of his own medication. Two hours before this, the child had been given his morning dose of 0.075 mg. The child’s medication schedule was 0.075 mg in the morning and 1 PM and 0.1 mg at hour of sleep, for a total of 0.25 mg/d. Within 20 minutes, the child was reported to be deeply somnolent and was transported to the hospital by emergency medical services. In the emergency department, the child was unarousable to voice and was intubated and placed on mechanical ventilation due to periods of apnea. His heart rate (HR) was 110 bpm and his blood pressure (BP) was 130/86 mm Hg. The HR decreased to 54 bpm within 3 hours of ingestion and BP decreased to 92/44 mm Hg. No specific therapy beyond mechanical ventilation and intravenous fluids was instituted. The child was extubated at 20 hours after ingestion and discharged after 48 hours. In the 5- to 8-year-old group, one 5-year-old girl received intubation, mechanical ventilation, atropine, and fluid challenge after ingesting an unknown amount of 0.1 mg tablets from an open bottle of her own medication. The single child in the 9- to 12-year-old group with symptoms requiring intervention was a 10-year-old boy who was reportedly given 30 of his own 0.1 mg tablets by a grandparent who misunderstood directions while babysitting. The boy received a fluid challenge for a BP of 84/30 mm Hg with an HR of 80 bpm and was discharged after 24 hours of observation without further problems. The remaining children in this age group ingested between 0.2 and 0.5 mg, with only drowsiness or lethargy reported. The Journal of Pediatrics February 2005
Table III. Major clinical effects by age group and dose Mean reported dose ingested with clinical effect Age 0 to 4 y Coma Respiratory depression Hypotension Age 5 to 8 y Coma Respiratory depression Hypotension Age 9 to 12 y Coma Respiratory depression Hypotension
Mean reported dose ingested without clinical effect
1.18 mg (±0.59 SD) 0.94 mg (±0.25 SD) 0.77 mg (±0.65 SD)
0.25 (±0.24 SD) 0.25 (±0.27 SD) 0.26 (±0.29 SD)
Dose not known Dose not known Dose not known
0.21 mg (±0.14 SD) 0.21 mg (±0.14 SD) 0.22 mg (±0.12 SD)
No patient with clinical effect No patient with clinical effect 3.0 mg
0.76 (±1.0 SD) 0.76 (±1.0 SD) 0.38 (±0.15 SD)
Table IV. Major symptoms by prior therapy versus no prior therapy Symptom
Patient’s own medication
No prior clonidine therapy
Coma Hypotension Respiratory depression
3 of 45 4 of 45 3 of 45
4 of 68 6 of 68 5 of 68
NS NS NS
NS, not significant.
In 43 patients (39%), the ingestions involved their own medicine. Unintentional misdosing involving inadvertent double doses occurred in 17 patients (15%). This occurred in 4 patients 4 years old or younger, 9 patients 5 to 8 years old, and 4 patients 9 to 12 years old. Lethargy was reported in all patients 4 years old or younger and 5 to 8 years old, but no other symptoms were reported. In the 9- to 12-year-old patients, 2 reported no symptoms and 2 reported drowsiness. Prior clonidine therapy did not affect outcome, incidence of coma, hypotension, or respiratory depression (P > .05) (Table IV). However, dose ingested had a significant impact on outcome and clinical effects reported (Table V).
DISCUSSION Clonidine is a recommended therapy for the treatment of attention deficit hyperactive disorder in children.10,11 As a result of this use in the pediatric population, there is widespread availability of clonidine to children, and frequent unintentional overdoses continue to occur.1,9 Despite this, there are limited data on outcomes of these sometimes lowdose exposures, with the majority of information derived from retrospective reviews of hospitalized patients. Our study design (prospective case series) allows for better capture of data regarding clinical effects, dose, and therapies. Severe symptoms resulting in invasive procedures were infrequent, with no fatalities (<10%, Table I). This finding is similar to previous reports. In 5 retrospective case series of children hospitalized for clonidine ingestion, intubation and mechanical ventilation Toxic Clonidine Ingestion In Children
were required in 8% to 12.7% of children.9,12-15 There were no fatalities in the total of 177 children in these cases series. In fact, only 2 fatalities, both in children, have been reported in the medical literature from isolated clonidine ingestion.1,16 A concern over the risk of severe symptoms, such as respiratory depression or hypotension, was most likely responsible for the large number of cases evaluated in the emergency department in this series. Our data suggest that ingestion of 0.1 mg or 0.2 mg does not warrant direct medical evaluation in the emergency department in all children. This is consistent with previous reports, in which specific doses were reported. Fiser et al14 suggested in a review of 11 patients that toddlers with ingestion of <0.01 mg/kg had only mild symptoms, which is less than 2 times the recommended dosage. With ingestion of 0.01 to 0.02 mg/kg (2 to 4 times maximum dosage), bradycardia and hypotension tended to occur, and with ingestion of >0.02 mg/kg, patients were at risk for respiratory depression.14 However, the number of patients in our series and previous series in which doses were specifically reported may have been too small to catch the rare case of significant symptoms in a low-dose ingestion. Wedin et al2 reported a case of a 3-year-old boy (weight not reported) with hypotension who received a dopamine infusion after ingestion of a single 0.2 mg tablet. Intubation was not necessary, and the symptoms resolved approximately 10 hours after ingestion. Unintentional misdosing involving inadvertent double doses occurred in 17 patients (15%) in our case series. Such cases present the clinician with a dilemma of whether the 265
Table V. Mean dose ingested of patients with and without major symptoms
Symptom
Mean (±SD) and median reported dose with clinical effect
Mean (±SD) and median reported dose without clinical effect
Two-sample test (Mann-Whitney)
Coma Respiratory depression Hypotension
1.2 mg (±0.59), 1.45 mg 0.94 mg (±0.54), 0.8 mg 0.66 mg (±0.64), 0.43
0.25 mg (±0.21), 0.2 mg 0.25 mg (±0.24), 0.2 mg 0.26 mg (±0.26), 0.2 mg
P , .05 P , .05 P = .14
patient requires direct medical evaluation in the emergency department or can be treated safely outside of the hospital setting. Although the number of patients in this group is small, the data suggest that an inadvertent double dose does not put the child at risk for significant symptoms beyond the expected drowsiness. At this time, it seems prudent to have all children 4 years old or younger to receive direct medical evaluation with unintentional clonidine ingestions of 2 times a therapeutic dose (0.005 mg/kg) or greater. Children 5 to 8 years old with ingestion of >0.2 mg may require direct medical evaluation. In children older than 8 years of age, $0.4 mg may require direct medical evaluation. All patients in the series recovered fully with observation and/or supportive therapy. This is an experience similar to previous reports.4-6,12-14 Romano et al4 reported a documented overdose of >2800 mg/kg in a 5-year-old boy treated with supportive care and naloxone. Similar favorable outcomes with supportive therapy have occurred in adults with inadvertent 1000-fold overdoses.17 Finally, in our case series, all clinical effects were evident rapidly after ingestion, with a mean of 1.7 hours. This is consistent with the findings of Wiley et al12 in a case series of 47 patients. Study limitations include the small number of patients, especially in the older age groups, and the possibility that in some cases dose information was inaccurate. Laboratory evaluation of plasma clonidine concentrations to confirm the history and dose are not available because therapeutic drug monitoring of clonidine concentrations is not routine. Since calls to poison centers are voluntary, sampling bias is possible. It is not possible to ascertain how cases not reported to poison centers differ from those reported to poison centers.
266
Spiller et al
REFERENCES 1. Klein-Schwartz W. Trends and toxic effects from pediatric clonidine exposures. Arch Pediatr Adolesc Med 2002;156:392-6. 2. Wedin GP, Richardson SL, Wallace GH. Clonidine poisoning in children. Am J Dis Child 1990;144:853-4. 3. Frye CB, Vance MA. Hypertensive crisis and myocardial infarction following massive clonidine overdose. Ann Pharmacother 2000;34:611-5. 4. Romano MJ, Dinh A. A 1000-fold overdose of clonidine caused by a compounding error in a 5-year-old child with attention-deficit/hyperactivity disorder. Pediatrics 2001;108:471-2. 5. Maggi JC, Iskra MK, Nussbaum E. Severe clonidine overdose in children requiring critical care. Clin Pediatr 1986;25:453-5. 6. Marruecos L, Roglan A, Frati ME, Artigas A. Clonidine overdose. Crit Care Med 1983;11:959-60. 7. Banner W, Lund ME, Clawson L. Failure of naloxone to reverse clonidine toxic effect. Am J Dis Child 2983;137:1170-1. 8. Yagupsky P, Gorodischer R. Massive clonidine ingestion with hypertension in a 9-month-old infant. Pediatrics 1983;72:500-2. 9. Kappagoda C, Schell DN, Hanson RM, Hutchins P. Clonidine overdose in childhood: implications of increased prescribing. J Pediatr Child Health 1998;34:508-12. 10. Hazell PL, Stuart JE. A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children. J Am Acad Child Adolesc Psychol 2003;42:886-94. 11. Plisszka SR. Non-stimulant treatment of attention-deficit/hyperactive disorder. CNS Spectrums 2003;8:253-8. 12. Wiley JF II, Wiley CC, Torrey SB, Henretig FM. Clonidine poisoning in young children. J Pediatr 1990;116:654-8. 13. Bamshad MJ, Wasserman GS. Pediatric clonidine intoxications. Vet Hum Toxicol 1990;32:220-3. 14. Fiser DH, Moss MM, Walker W. Critical care for clonidine poisoning in toddlers. Crit Care Med 1990;18:1124-8. 15. Nichols MH, King WD, James LP. Clonidine poisoning in Jefferson County, Alabama. Ann Emerg Med 1997;29:511-7. 16. Sanklecha M, Jog A, Raghavan K. Clonidine casualty [letter]. Indian J Pediatr 1993;60:611-2. 17. Rotellar JAO, Monsasterio ES, de la Cruz JS, Gene CG. Clonidine in thousand fold overdose. Lancet 1981;1:1312.
The Journal of Pediatrics February 2005