 |
|
Trends and Toxic Effects From Pediatric Clonidine Exposures
Wendy Klein-Schwartz, PharmD, MPH
Arch Pediatr Adolesc Med. 2002;156:392-396.
ABSTRACT
| |
Objective To analyze the trends, demographics, and toxic effects associated with
pediatric clonidine hydrochloride exposures reported to poison centers.
Design Retrospective.
Setting and Patients Clonidine-only exposures followed up to known outcome in children younger
than 19 years reported to the American Association of Poison Control Center's
database from January 1, 1993, through December 31, 1999.
Main Outcome Measures Frequency of exposures over time, acuity, reason, symptoms, management
site, treatment, and outcome.
Results There were 10 060 reported exposures with 57% reported for children
younger than 6 years, 34% for children between 6 and 12 years old, and 9%
for adolescents between 13 and 18 years old. In 1999 there were 2.5 times
as many exposures as in 1993. In 6- through 12-year-olds, clonidine was the
child's medication in 35% of the exposures, compared with 10% in children
younger than 6 years and 26% in adolescents. The proportion of cases involving
the child's medication increased over 7 years. While unintentional overdose
was most common in children younger than 6 years, therapeutic errors and suicide
attempts predominated in 6- through 12-year-olds and adolescents, respectively.
In 6042 symptomatic children (60%), the most common symptoms were lethargy
(80%), bradycardia (17%), hypotension (15%), and respiratory depression (5%).
Most exposures resulted in no effect (40%) or minor effects (39%). Moderate
effects occurred in 1907 children (19%), major effects in 230 children (2%);
there was 1 fatality in a 23-month-old.
Conclusions While most of the clonidine exposures resulted in minimal toxic effects,
serious toxic effects and death can occur. The trend toward increasing the
number of exposures in children, especially with evidence of toxic effects
in children receiving clonidine therapeutically, is cause for concern.
INTRODUCTION
CLONIDINE hydrochloride, an imidazoline-derived agent, has stimulatory
effects on central  2-adrenergic receptors resulting in a
decrease in peripheral resistance, renal vascular resistance, heart rate,
and blood pressure. The only approved indication for clonidine is management
of hypertension. Clonidine is also used for several unlabeled indications
including ethanol and opioid withdrawal, smoking cessation, and mania and
psychosis. Off-label uses in children include the management of attention-deficit/hyperactivity
disorder (ADHD) and Tourette syndrome. The prevalence of pediatric clonidine
use has been increasing. Zito et al1 reported
an up to 28-fold increase in clonidine use in preschoolers from January 1,
1995, through December 31, 1995, compared with January 1, 1991, through December
31, 1991. As clonidine's therapeutic use increases in the pediatric population,
the potential exists for an associated increase in adverse effects and poisonings.
This study assessed the trends and evaluated the demographics and toxic effects
associated with pediatric clonidine exposures reported to poison centers nationally.
METHODS
The American Association of Poison Control Center Toxic Exposure Surveillance
System (AAPCC TESS) was analyzed for pediatric clonidine exposures followed
up to known outcome in children younger than 19 years reported from January
1, 1993, through December 31, 1999. The number of poison centers submitting
cases to TESS remained stable over the study period (64-67 centers); however,
the proportion of the population of the United States served by these centers
increased from 70% in 1993 to 96% in 1999. Data were analyzed for age group,
acuity, reasons for the exposure, clinical effects, management site, therapy
and medical outcome. The term "unintentional general" was used for accidental
exposures. Ages were categorized as younger than 6 years, from 6- through
12 years, and from 13 through 18 years. In "acute-on-chronic" (acute exposure
in a child receiving long-term clonidine therapy) and "chronic" exposures,
the clonidine was assumed to be the child's medication. Clinical effects coded
as related to the clonidine exposure were included; clinical effects coded
as unrelated or unknown if related were excluded. Known medical outcomes as
defined by AAPCC TESS were no effect (no signs or symptoms as a result of
the exposure), minor effect (signs or symptoms that were minimally bothersome
and resolved rapidly), moderate effect (signs or symptoms that were more pronounced,
more prolonged, or more systemic in nature than minor, usually requiring treatment
but not life-threatening), major effect (signs or symptoms that were life-threatening
or resulted in significant residual disability), or death (death resulted
from the exposure or a direct complication of the exposure). The total number
of pediatric poisonings reported to poison centers in 1993 and 1999 was obtained
from published AAPCC TESS annual reports as was case detail on fatalities.2-3
Data were analyzed using Access (Microsoft Corp, Seattle, Wash) and
Excel (Microsoft Corp). Summary statistics were generated and  2 tests performed to compare findings in the 3 age groups. The study
was reviewed by the institutional review board of the University of Maryland,
Baltimore, and determined to be exempt from the institutional review board
approval process.
RESULTS
The study population consisted of 10 060 children younger than
19 years who were followed up until their outcome was known. Most exposures
(56.6%) occurred in children younger than 6 years, accounting for 5696 cases.
There were 3470 exposures (34.5%) in 6- through 12-year-old children, and
894 exposures (8.9%) in adolescents (aged 13-18 years). Exposures occurred
more often in boys, accounting for 6579 cases (65.4%). The number of exposures
increased each year, with the greatest increase occurring between 1993 and
1995 (Figure 1). While the total
number of cases involving children younger than 19 years reported to AAPCC
TESS increased by 21% between 1993 and 1999, total clonidine exposures increased
more than 2.5-fold in 1999 compared with 1993.2-3
After adjusting for the higher proportion of the US population served by reporting
poison centers in 1999 compared with 1993, total clonidine exposures increased
1.9-fold.
|
|
|
|
Figure 1. Trends in clonidine hydrochloride
exposures by age group.
|
|
|
Clonidine was the child's own medication in 2011 exposures (20.0%).
In the 6- through 12-year-old age group, clonidine was the child's medication
in 1198 cases (34.5%). For children younger than 6 years and for the 13 through
18-year-old age group, 581 (10.2%) and 232 (26.0%) of the exposures, respectively,
were to the child's medication. The proportion of cases in which clonidine
was the child's medication increased in all 3 age groups during the study
period. Comparing data for 1993 and 1999, exposures involving the child's
medication increased from 2.6% to 13.1% of the cases in children younger than
6 years, 22.1% to 40.4% in 6- through 12-year-olds, and 16.7% to 25.5% in
adolescents (13 through 18-year-olds).
The reason for exposure varied depending on age. In children younger
than 13 years, the exposures were usually unintentional. Unintentional general
was the primary reason for exposure in children younger than 6 years accounting
for 4925 cases (86.5%) followed by therapeutic errors in 686 (12.0%). In children
from 6- through 12 years old, therapeutic error in 1975 cases (56.9%) was
the most frequent reason for the exposure followed by unintentional general
in 996 (28.7%), suicide attempt in 163 (4.7%), and intentional misuse or abuse
in 132 (3.8%). In adolescents older than 12 years, 395 (44.2%) of the exposures
were suspected suicide attempts, 204 (22.8%) were therapeutic errors, 146
(16.3%) were unintentional general, and 97 (10.9%) were intentional misuse
or abuse. In all age groups, the remaining reasons included a small percentage
coded as adverse drug reaction or other/unknown reason.
In 4018 children and adolescents (40%), no symptoms were reported. Table 1 lists the clinical effects in the
6042 symptomatic cases (60%). Twenty-three children experienced respiratory
arrest.
|
|
|
|
Table 1. Clinical Manifestations in 6042 Symptomatic Pediatric Clonidine*
Exposures
|
|
|
The exposure was managed on-site (home or another nonhealth care facility)
for 2605 children (25.9%) and at a health care facility for 7111 children
(70.7%) (Figure 2). For children
younger than 6 years, 16.5% (940) were managed on site compared with 42.7%
(1481) of the 6- through 12-year-olds, and 20.6% (184) of the adolescents
(24 = 841, P<.001).
For children younger than 6 years, 49.0% (2256) of those seen in the health
care facility were admitted for medical care compared with 32.8% (610) of
the 6- through 12-year-olds and 48.5% (317) of the adolescents (22 = 147, P<.001). In addition,
28 children from 6- through 12 years old and 60 adolescents were admitted
for psychiatric care.
|
|
|
|
Figure 2. Management site. HCF indicates
health care facility; ICU, intensive care unit.
|
|
|
Gastrointestinal (GI) tract decontamination included activated charcoal
in 4272 children (42.5%), cathartic in 2372 children (23.6%), lavage in 1274
children (12.7%), and syrup of ipecac in 289 children (2.9%). For children
treated in a health care facility, moderate or major outcomes were more frequent
in those receiving GI tract decontamination than in those who did not receive
GI tract decontamination (23 = 108, P<.001). Other therapies included naloxone hydrochloride (n = 917),
atropine sulfate (n = 160), intubation (n = 174), mechanical ventilatory assistance
(n = 105), and vasopressors (n = 61). No specific therapy was administered
to 3836 children (38.1%).
Most exposures (78.7%) resulted in no effect or minor effects (Table 2). Less serious outcomes occurred
in children younger than 13 years than in those aged 13 through 18 years (26 = 141, P<.001). For major
effects, 164 (71.3%) were in children younger than 6 years, 43 (18.7%) were
in 6- through 12-year-olds, and 23 (10.0%) were in 13 through 18-year-olds.
Of the moderate and major outcomes, 19.8% (377) and 11.7% (27), respectively,
involved the child's own medication. Children with chronic exposures developed
symptoms related to the exposure more often than children with acute-on-chronic
exposures or acute exposures (Figure 3).
Only 28 (20.4%) of the 137 subjects with chronic exposures were asymptomatic
compared with 674 (36.0%) of the 1874 subjects with acute-on-chronic exposures
and 3311 (41.2%) of the 8020 subjects with single acute exposures. The distribution
of medical outcomes varied depending on whether the exposure was acute, acute-on-chronic,
or chronic (26 = 65, P<.001).
|
|
|
|
Table 2. Medical Outcome of Pediatric Clonidine Exposures*
|
|
|
|
|
|
|
Figure 3. Distribution of outcome based
on acuity.
|
|
|
There was 1 fatality—a 23-month-old girl with an acute unintentional
overdose of an unknown number of 0.3-mg clonidine hydrochloride tablets. In
the emergency department the child's stupor and bradycardia responded to a
combined treatment of naloxone and atropine. Bradycardia recurred during intubation,
progressing to pulseless electrical activity; resuscitative efforts were unsuccessful.
Autopsy showed lung edema and a postmortem plasma clonidine concentration
of 47 ng/mL.3
COMMENT
Clonidine poisoning in children has been described in numerous case
reports and small case series dating back to the 1970s. These poisonings all
involve young children who were symptomatic and whose condition was managed
in a hospital. The 10 published case series with 6 or more cases describe
a total of 352 children.4-13
To our knowledge, the 10 060 pediatric clonidine exposures described
herein represent the largest series to date as well as the only series that
includes children whose exposures were managed in both a nonhealth care facility
and a health care facility. The 7-year time frame allows for an assessment
of trends in pediatric clonidine exposures.
The most common off-label indication for clonidine in children is the
management of ADHD, which occurs in 3% to 6% of the school-aged children.14 Although stimulant drugs are the first-line therapy
for ADHD, other drugs are used in children who are either unresponsive to
or intolerant of stimulants. Clonidine may be beneficial in children who have
hyperarousal, hyperactivity, impulsiveness, and defiance.15
Clonidine can be used in conjunction with stimulants or may be useful for
sleep disturbances associated with ADHD or its treatment.16-17
Meta-analysis of 11 reports of clonidine for ADHD concluded that clonidine
is less effective than stimulants but may be an effective second-line treatment.18
As the prevalence of pediatric clonidine use for childhood behavioral
disorders increases,1 children may be at greater
risk of toxic exposures. A review of 14 hospital admissions in 13 children
between 1985 and 1995 found that 8 admissions occurred in 1994 and 1995.5 Similarly, a medical record review of emergency department
visits between 1990 and 1997 reported that all but 1 of 16 pediatric overdoses
occurred between 1994 and 1997.4 These medical
record reviews concluded that the incidence of pediatric clonidine poisoning
has increased. These findings are supported by poison center data that show
that total pediatric clonidine exposures increased from 693 in 1993 to 1762
in 1999. After adjusting for differences in population served by these poison
centers in 1999 compared with 1993, there was close to a 2-fold increase in
exposures. Possible explanations for this increase include an increase in
pediatric use for ADHD and Tourette syndrome as well as an increase in off-label
uses in adults. These trends in therapeutic use increase the likelihood of
therapeutic errors in children as well as overdoses caused by greater availability
in homes.
Recent studies suggest a changing pattern in the source of clonidine
in clonidine poisonings. Several studies of unintentional pediatric clonidine
poisonings implicate grandparents as the primary source of the drug.6-7,10 Two recent studies
found that 14 of 16 poisonings and 8 of 14 poisonings resulted from exposures
to clonidine belonging either to the child, a sibling, or another child.4-5 Although only 20% of poison center
cases in the current study involved the child's medication, over the 7-year
study period the proportion of cases in which clonidine was the child's medication
increased in all pediatric age groups. The increase in proportion was 50%
for adolescents compared with a 2-fold increase in the 6- through 12-year-olds
and a 5-fold increase in children younger than 6 years. Presumably some of
the other clonidine exposures were to medication belonging to another child
or sibling. Given the increasing therapeutic use of clonidine in children,
it is likely that in the future even higher proportions of clonidine exposure
cases reported to poison centers will involve a child's medication. In cases
involving the child's medication, the child was more likely to experience
symptoms than in cases of single acute ingestions. This finding may reflect
the fact that for single acute ingestions, the poison center was called as
soon as the ingestion was discovered prior to symptom development whereas
for children with either acute-on-chronic or chronic exposures the impetus
for the call was the development of adverse effects.
Most cases were managed in a health care facility. For children younger
than 6 years and adolescents, 80.8% and 73.0%, respectively, were treated
in a health care facility while only 53.5% of the 6- through 12-year-olds
received this level of care. Since as little as 0.1 to 0.3 mg (1 tablet) of
clonidine hydrochloride can cause significant central nervous system depression
in young children,13, 19 some poison
centers refer young children with a history of ingesting any amount to the
emergency department. Similarly, intentional adolescent overdoses are referred
to a health care facility rather than attempting home management. On the other
hand, many of the exposures in 6- through 12-year-olds resulted from therapeutic
errors where presumably the exact dose was known (eg, an extra dose administered),
or the dose ingested was lower and hence the chance of a serious toxic effect
was lower. Therefore, a higher proportion of these children could be managed
outside a health care facility.
No specific treatment was provided in 38.1% of the children. For those
children receiving treatment, the primary treatment modality was GI tract
decontamination and children who received GI tract decontamination were more
likely to experience a moderate or major outcome. This is most likely explained
by the fact that children with a higher dose by history and/or symptomatic
patients are more likely to receive GI tract decontamination. Although 62%
of children received some type of treatment, only 19% experienced a moderate
toxic effect and 2% developed a severe toxic effect. This disparity between
a clinical toxic effect and treatment suggests that either treatment minimizes
toxic effects or that concern regarding clonidine's potential for toxic effect
results in more children being treated than actually require treatment.
Study limitations should be considered in interpreting and generalizing
the results of this study. The retrospective design of the study has its inherent
limits. Factors such as the voluntary nature of reporting to poison centers
and the change in the proportion of the US population served by poison centers
during the study period may have introduced some reporting bias. Since some
data entry systems default to acute in the acuity field and the specialist
in poison information may not always change the default, use of acute-on-chronic
and chronic as surrogates for child's medication may have resulted in an undercount
of cases in which the clonidine was the child's medication. During the years
of this study there was no dose or laboratory information available in AAPCC
TESS data. However, laboratory confirmation of clonidine is usually impossible
because plasma clonidine concentrations are not routinely available.
In 1990 Bamshad and Wasserman8 warned
that clonidine intoxications would become more common as the market for antihypertensive
drugs expands. That warning is even more applicable today as clonidine use
in children leads to greater availability and an ever-increasing number of
clonidine exposures. Strategies for prevention will vary depending on the
age group. For children younger than 6 years, child-resistant packaging and
improved storage are potential methods of decreasing poisonings. For all children
receiving clonidine therapeutically, especially those from 6- through 12 years
old, prevention should focus on education directed at children and their parents
regarding correct dosing and storage. Recognition and management of depression
and substance abuse in adolescents and limiting access to large quantities
of drugs would be potential avenues for preventing or minimizing the potential
for toxic effects in this age group.
CONCLUSIONS
Most pediatric patients in this study exhibited minimal toxic effects
following exposure to clonidine alone. However, in overdose clonidine can
cause a serious toxic effect. With the expanding therapeutic role of clonidine
in the pediatric population and associated greater in-home accessibility,
the number of pediatric clonidine exposures reported to the AAPCC has dramatically
increased over the years. This trend toward increasing number of exposures
in children, toxic effects in children receiving clonidine therapeutically,
and the serious nature of some of these cases are causes for concern.
| What This Study Adds
The clinical manifestations of pediatric clonidine poisoning have been
well described in numerous case reports and small case series. These poisonings
all involve a small number of young children who are symptomatic and whose
conditions are managed in a hospital setting. The 10 060 pediatric clonidine
exposures described herein represent the largest series to date as well as
the only series that includes children whose exposures were managed in both
nonhealth care facility and health care facility. The 7-year time frame demonstrates
a trend toward increasing numbers of clonidine exposures annually as well
as a growing proportion of cases involving the child's medication. Although
most children (79%) exhibited no toxic effects or mild effects, moderate and
major toxic effects occurred in 19% and 2% of the children, respectively.
|
|
AUTHOR INFORMATION
Accepted for publication January 3, 2002.
This study was presented in part at the XXI International Congress of
the European Association of Poisons Centres and Clinical Toxicologists, Barcelona,
Spain, May 18. 2001.
I thank Annette Salliey for assistance with importing AAPCC TESS data
from D-base files into Access and preparing data for analysis.
Corresponding author: Wendy Klein-Schwartz, PharmD, MPH, Maryland
Poison Center, Department of Pharmacy Practice and Science, University of
Maryland School of Pharmacy, 20 N Pine St, Baltimore, MD 21201 (e-mail: wkleinsc{at}rx.umaryland.edu).
From the Maryland Poison Center, Department of Pharmacy Practice and
Science, University of Maryland School of Pharmacy, Baltimore.
REFERENCES
| |
1. Zito JM, Safer DJ, dosReis S, Gardner JF, Boles M, Lynch F. Trends in the prescribing of psychotropic medications to preschoolers. JAMA. 2000;283:1025-1030.
FREE FULL TEXT
2. Litovitz TL, Clark LR, Soloway RA. 1993 Annual report of the American Association of Poison Control Centers
Toxic Exposure Surveillance System. Am J Emerg Med. 1994;12:546-584.
FULL TEXT
|
ISI
| PUBMED
3. Litovitz TL, Klein-Schwartz W, White S, Cobaugh DJ, Youness J, Drab A, Benson BE. 1999 Annual report of the American Association of Poison Control Centers
Toxic Exposure Surveillance System. Am J Emerg Med. 2000;18:517-574.
FULL TEXT
|
ISI
| PUBMED
4. Kappagoda C, Schell DN, Hanson RM, Hutchins P. Clonidine overdose in childhood: implications of increased prescribed. J Paediatr Child Health. 1998;34:508-512.
FULL TEXT
|
ISI
| PUBMED
5. Erickson SJ, Duncan A. Clonidine poisoning—an emerging problem: epidemiology, clinical
features, management and preventative strategies. J Paediatr Child Health. 1998;34:280-282.
FULL TEXT
|
ISI
| PUBMED
6. Nichols MH, King WD, James LP. Clonidine poisoning in Jefferson County, Alabama. Ann Emerg Med. 1997;29:511-517.
FULL TEXT
|
ISI
| PUBMED
7. Fiser DH, Moss MM, Walker W. Critical care for clondine poisoning in toddlers. Crit Care Med. 1990;18:1124-1128.
ISI
| PUBMED
8. Bamshad MJ, Wasserman GS. Pediatric clonidine intoxiciations. Vet Hum Toxicol. 1990;32:220-223.
ISI
| PUBMED
9. Heidemann SM, Sarnaik AP. Clonidine poisoning in children. Crit Care Med. 1990;18:618-620.
ISI
| PUBMED
10. Wiley JF, Wiley CC, Torrey SB, Henretig FM. Clonidine poisoning in young children. J Pediatr. 1990;116:654-658.
FULL TEXT
|
ISI
| PUBMED
11. Olsson JM, Pruitt AW. Management of clonidine ingestion in children. J Pediatr. 1983;103:646-650.
PUBMED
12. Anderson RJ, Hart GR, Crumpler CP, Lerman MJ. Clonidine overdose: report of six cases and review of the literature. Ann Emerg Med. 1981;10:107-112.
PUBMED
13. Stein B, Volans G. Dixarit overdose: the problem of attractive tablets. BMJ. 1978;2:667-668.
14. Goldman LS, Genel M, Bezman RJ, Slanetz PJ. Diagnosis and treatment of attention-deficit/hyperactivity disorder
in children and adolescents. JAMA. 1998;279:1100-1107.
FREE FULL TEXT
15. Dulcan M Work Group on Quality Issues of the American Academy of Child and Adolescent
Psychiatry. Practice parameters for the assessment and treatment of children, adolescents,
and adults with attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1997;36(suppl 10):85S-121S.
16. Wilens TE, Spencer TJ, Swanson JM, Connor DF, Cantwell D. Combining methylphenidate and clonidine: a clinically sound medication option. J Am Acad Child Adolesc Psychiatry. 1999;38:614-619.
FULL TEXT
|
ISI
| PUBMED
17. Prince JB, Wilens TE, Biederman J, Spencer TJ, Wozniak JR. Clonidine for sleep disturbances associated with attention-deficit
hyperactivity disorder: a systematic chart review of 62 cases. J Am Acad Child Adolesc Psychiatry. 1996;35:599-605.
FULL TEXT
|
ISI
| PUBMED
18. Connor DF, Fletcher KE, Swanson JM. A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity
disorder. J Am Acad Child Adolesc Psychiatry. 1999;38:1551-1559.
FULL TEXT
|
ISI
| PUBMED
19. Neuvonon PJ, Vilska J, Keranen A. Severe poisoning in a child caused by a small dose of clonidine. Clin Toxicol. 1979;14:369-374.
ISI
| PUBMED
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Dexmedetomidine Overdose in the Perioperative Setting
Jorden et al.
The Annals of Pharmacotherapy 2004;38:803-807.
ABSTRACT
| FULL TEXT
Prescribing of Psychotropic Medications for Children by Australian Pediatricians and Child Psychiatrists
Efron et al.
Pediatrics 2003;111:372-375.
ABSTRACT
| FULL TEXT
Trends in Pediatric Clonidine Exposures
JWatch Emergency Med. 2002;2002:9-9.
FULL TEXT
|
