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PEDIATRICS Vol. 108 No. 2 August 2001, pp. 471-472
A 5-year-old child who weighed 17.5 kg received 50 mg of clonidine. The amount ingested was confirmed by analysis of the
suspension administered (clonidine HCl 9.78 mg/mL). To our knowledge,
this represents the largest ingestion in a child and the largest
ingestion on a milligram per kilogram basis in the medical literature.
The child's initial presentation included hyperventilation, an unusual feature of clonidine toxicity. The child was discharged without sequela
42 hours after admission. A serum concentration of clonidine 17 hours
postingestion was 64 ng/mL, the highest reported to date in a pediatric
patient. The intoxication was traced to a pharmacy compounding error in
which milligrams were substituted for micrograms. Increased prescribing
of clonidine in young children coupled with the requirement to compound
clonidine in a suspension and the narrow therapeutic index suggests
that the frequency of severe ingestions in children will increase in
the future.
ABSTRACT
Top
Abstract
Introduction
Discussion
References
agonists,
attention-deficit/hyperactivity disorder,
drug therapy,
overdose,
antihypertensive agents.
Clonidine HCl (clonidinum) is a centrally acting
A 5-year-old male presented to the emergency room after being
found limp and unresponsive at home. The patient had a
diagnosis of ADHD. His current medications included Adderall
(amphetamine/dextroamphetamine, Shire US Inc, Florence, KY), 5 mg every
morning and 2.5 mg every afternoon, and clonidine, 25 µg every
morning and afternoon and 50 µg every night. On the day of admission,
the parents refilled the clonidine prescription. The bottle was labeled
0.05 mg/5 mL, and the instructions for the evening dose were to take
one teaspoon. The patient received the first dose from this bottle on
the evening of admission. Twenty minutes later, the parents found the
child limp and unresponsive. The child was taken by private car to the emergency department.
The father noted that the new prescription looked and tasted different
from previous bottles. Twenty minutes after tasting the medication, the
father reported a brief period of dizziness.
In the emergency department, initial vital signs included a heart rate
of 52 beats/min, blood pressure of 133/103 mmHg, respirations of 40 breaths/min, and a temperature of 94°F with room air oxygen saturation of 94% by pulse oximetry. The child was described as listless, but responsive to pain with small pupils. An arterial blood
gas measurement showed the following: pH 7.586;
PaCO2 21.2 mmHg;
PaCO2 111.7 mmHg;
HCO On admission to the pediatric intensive care unit, the patient was
obtunded but became agitated and confused with painful stimulation.
Respirations were 5 to 8 breaths/min with 15- to 20-second apneic
periods; an electrocardiogram demonstrated sinus bradycardia of 47 beats/min, blood pressure 137/96 mmHg, and oxygen saturations of 100%
on a 5 L/min face mask. Weight was 17.5 kg. The pupils were 2 mm, equal
and reactive. The mouth and mucus membranes were dry; the skin was warm
and dry; lungs were clear; there were no cardiac murmurs, and the
peripheral pulses were strong; bowel sounds were present but decreased;
capillary refill was <2 seconds; and no rashes were noted.
The airway was managed with intermittent bag/valve/mask ventilation
while preparations were made to intubate the patient's trachea.
Atropine 0.2 mg intravenously was administered with a prompt increase
in the heart rate to 130 beats/min. Naloxone 2.0 mg intravenously was
administered with a rapid and dramatic improvement in the patient's
respiratory effort and rate to 16 breaths/min, regular without apnea.
Assisted ventilation and oxygen were discontinued. There was a modest
improvement in the patient's level of consciousness, and an intact gag
reflex was present after naloxone administration.
Two additional 2.0-mg doses of naloxone were administered over 25 minutes before institution of a naloxone infusion at 15 mg/hr. The
starting infusion dose was chosen to provide approximately twice the
dose required as intermittent bolus administration. The infusion was
continued for 25 hours at the following doses: 7 hours at 15 mg/hr; 6 hours at 10 mg/hr, 5 hours at 5 mg/hr, and 7 hours at 2 mg/hr, titrated
to the patient's respiratory effort and level of consciousness. The
dose of naloxone required in this case is unusually large4
and may reflect the extreme magnitude of the overdose. The patient
received 9 doses of atropine over 25 hours for bradycardia <60
beats/min. Maximum blood pressure was 141/97 mmHg 10 hours
postingestion. Hypotension did not occur. The patient was discharged
from the hospital 42 hours postingestion in his normal state of health.
A serum clonidine concentration obtained 17 hours postingestion was
64.0 ng/mL.
The clonidine HCl concentration of the suspension was 9.78 mg/mL,
approximately 1000-fold greater than the bottle label. The patient
weighed 17.5 kg and received 1 teaspoon of this suspension, yielding an
acute ingestion of approximately 50 mg, or 2857 µg/kg, of clonidine.
The incidence of clonidine poisoning has increased
dramatically,5,6 mirroring profound changes in prescribing practices for psychotropic medications in young children. Zito et
al2 surveyed prescription records for children 2 through 4 years of age from 2 Medicaid programs and 1 health
maintenance organization between 1991 and 1995. All categories of
psychotropic drugs studied showed significant increases. Clonidine
prescribing increased the most of any drug studied, with prevalence
rates increasing 6.8- to 28.2-fold over 5 years, depending on which program was studied. In recent series of poisonings, the source of the
clonidine is commonly the patient or a family member being treated for
ADHD.5,6 This is a distinct change from the epidemiology
of clonidine poisonings a decade ago.7
Clonidine has a narrow therapeutic window in children. Significant
toxicity in a child has been reported from the ingestion of a single
0.2-mg tablet,8,9 and many severe poisonings involve
ingestions of 10 to 40 µg/kg.5,8 A dose of 75 µg/d has
been suggested as a starting dose in children.10 A 10-fold
error in compounding the suspension or in drawing up this dose could
result in toxicity to the patient. Accidental ingestion of a few days'
worth of liquid could result in significant toxicity in a toddler.
Tachypnea has been reported in clonidine ingestions8,11
but is atypical. The respiratory effect may be time dependent; very
early in the ingestion, tachypnea may be present, with rapid
progression to respiratory depression and apnea.
Fortunately, mortality from clonidine ingestion is uncommon. A number
of cases of sudden death involving clonidine, usually in association
with other psychotropic medications, have been reported12;
these must be distinguished from acute poisoning fatalities. There are
4 reports in the literature of mortality from clonidine as an acute
single drug ingestion: a 3-year-old female accidentally consumed 20 to
30 tablets (total dose: 0.2-0.3 mg),13 2 adults who
ingested unknown amounts in suicide efforts,14,15 and a
23-month-old girl who ingested an unknown amount of clonidine and
developed cardiac arrest during intubation.16
The pharmacy that prepared the suspension was contacted. They reported
that the prescription specified a concentration of 0.05 mg/5 mL. A
verbal instruction given during the compounding process specified a
certain number of drug to be added to the bottle. This instruction did
not specify whether this number represented number of pills or a unit
of weight. This number was intended to represent micrograms of drug but
was interpreted as milligrams, leading to the 1000-fold error in
concentration.
Extemporaneous compounding is associated with a significant risk of
error. Temple and Nelson3 found that only 22.5% of
prescriptions for a salicylic acid solution were prepared within ±5%
of the prescribed concentration. Standard medication error reduction
strategies have been reported.17 We suggest the following
additional strategies if clonidine is prescribed as a suspension: 1)
avoid the use of concentrated formulations in which a 10-fold error in
dose volume is plausible; 2) instruct the family to seek medical
attention if the child becomes somnolent; and 3) urge the family to
question the pharmacist if a refilled prescription seems different from
previous bottles or if the instructions or dose volume is changed.
Parents frequently are unable to measure correctly a volume of
medication.18 When prescribing suspensions with a narrow
therapeutic index, it may be prudent for the physician or a staff
member to instruct the caregiver on drawing up the correct dose and
verify his or her ability to do so. This teaching may be reinforced by
including a syringe and orders to instruct the family in drawing the
dose on the prescription. Finally, practitioners should consider
carefully the criteria for the diagnosis of ADHD with respect to young
children and be aware of the issues surrounding psychotropic drug
therapy in this patient population.19
2 agonist indicated for the treatment of
hypertension.1 Clonidine is being prescribed with
increasing frequency for the treatment of
attention-deficit/hyperactivity disorder (ADHD), even in children as
young as 2 years.2 Clonidine is not available as a suspension; therefore, prescriptions for young children must be compounded. This process introduces an additional opportunity for a
medication error.3 We describe the results of such a
compounding error and report hyperventilation as an unusual feature of
severe clonidine toxicity.
CASE REPORT
3 act 19.7; and base excess
0.3 mmol/L. A urine toxicology screen was positive for amphetamine
(presumed to be Adderall) and negative for barbiturates,
benzodiazepines, cannabinoid, cocaine, and opiates. Alcohol,
acetaminophen, and salicylates were not detected in the patient's
serum.
DISCUSSION
Top
Abstract
Introduction
Discussion
References
Department of Pediatrics
Texas Tech University Health Sciences Center
Lubbock, TX 79430
From the Department of Pediatrics, Texas Tech University Health
Sciences Center, Lubbock, Texas.
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FOOTNOTES |
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Received for publication Sep 11, 2000; accepted Dec 4, 2000.
Reprint requests to (M.J.R.) Department of Pediatrics, Texas Tech University Health Sciences Center, 3601 4th St, Lubbock, TX 79430. E-mail: pedmjr{at}ttuhsc.edu
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ABBREVIATIONS |
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ADHD, attention-deficit/hyperactivity disorder.
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REFERENCES |
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Top
Abstract
Introduction
Discussion
References
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an emerging problem:
epidemiology, clinical features, management and preventative
strategies.
J Paediatr Child Health
1998;
34:280-282 [CrossRef][Medline]This article has been cited by other articles:
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  J. M. Burton, C. M. Bell, S. E. Walker, and P. W. O'Connor 4-AMINOPYRIDINE TOXICITY WITH UNINTENTIONAL OVERDOSE IN FOUR PATIENTS WITH MULTIPLE SCLEROSIS Neurology, November 25, 2008; 71(22): 1833 - 1834. [Full Text] [PDF]
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 V. S. Jorden, R. M Pousman, M. M Sanford, P. A. Thorborg, and M. P Hutchens Dexmedetomidine Overdose in the Perioperative Setting Ann. Pharmacother., May 1, 2004; 38(5): 803 - 807. [Abstract] [Full Text] [PDF]
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