Publikasjoner som omhandler klonidinoverdoser på barn opptil 18 år før 2009 og nyere.

FØR 2009

Deadly Ingestions

Keith Henry, MDa, Carson R. Harris, MDb,T

aEmergency Medicine Department, Saint John’s Hospital, Maplewood, MN 55109-1169, USA

bEmergency Medicine Department, Regions Hospital, 640 Jackson Street, St. Paul, MN 55101, USA

Clonidine

Clonidine is a commonly prescribed, centrally acting antihypertensive, which

recently has enjoyed an expanded therapeutic role in the treatment of pediatric

attention deficit hyperactivity disorder and Tourette’s syndrome. Clonidine is

a central a-adrenoreceptor agonist that allows inhibition of sympathetic outflow.

Because of its widespread use in all age populations, clonidine remains a

common substance of pediatric ingestion. In 2002, the TESS reported over

1600 (31%) ingestions in children under the age of 6 years [46]; and in 2003,

5402 clonidine exposures occurred, with 1736 (32%) exposures in children under

the age of 6 years [1]. Lethality is attributed largely to toxic effects on the CNS

and cardiovascular systems and may be seen with doses as small as 10 mg/kg. The

typical exposure scenario is the child who ingests the drug while visiting grandparents, where tablets

have been left out on the nightstand or in a loosely

capped pill container, which allow easy access for the child.

Clinical presentation

Because of a functional overlap in the a2 receptors targeted by clonidine and

the m receptors targeted by opioids, the constellation of symptoms that have been

described with clonidine toxicity largely resemble an opioid toxidrome [47,48].

Symptoms include altered mental status, somnolence, respiratory depression,

miosis, bradycardia, and hypotension. Dose-related responses have been documented,

with cardiovascular effects seen with ingestions between 0.01 and

0.02 mg/kg and respiratory depression occurring with ingestions greater that

20 mg/kg [47,49]. Apnea and respiratory depression are common when the dose

exceeds 0.02 mg/kg [49]. Most children will have signs or symptoms of toxicity

within 30 to 90 minutes after ingestion [47]. The toddler may respond somewhat

differently than older children, presenting in a deeply comatose state, with apnea

and bradycardia. However when stimulated, the toddler may respond with increased

respiration and pulse, with an improved level of consciousness. If the

child is not stimulated, she may quickly return to the previous state or even slip

into cardiopulmonary arrest [47]. Although they are rare, seizures can occur with

significant overdoses.

Management

The management of suspected clonidine overdose remains largely supportive.

Careful attention must be focused on the establishment and maintenance of a

patent airway. Because of the risks of bradycardia, heart block, and hypotension,

continuous cardiac monitoring and a 12-lead EKG should be used. Activated

charcoal should be administered if the patient presents within 1 hour of ingestion.

The rapid absorption profile of clonidine precludes recommendations for multiple

dosing of charcoal [47].

Naloxone has been used with variable success in treating severe clonidine

overdose. It has been shown to reverse both cardiovascular and respiratory depression

in up to 50% of case reports [47,50–54]. This is likely caused by opioid

receptor overlap, as described above. Suggested naloxone dosing is 0.1 mg, up to

a maximum of 10 mg [47,52,54]. Refractory cases of bradycardia will usually

respond to atropine. Hypotension should be managed with aggressive fluid resuscitation.

Dopamine is recommended by most authorities as the vasopressor of

choice, starting at 5 mg/kg/min and increasing in 5-mg/kg/min increments as

needed. Norepinephrine should be added if more than 20 mg/kg/min of dopamine

is needed. At moderate doses, dopamine may provide sufficient blood pressure

support, while its chronotropic properties may mitigate clonidine-induced

bradycardia [47].

Admission to the pediatric ICU is always appropriate in patients who manifest

altered mental status, respiratory depression, or cardiac abnormality. Patients who do not show signs

of toxicity within 6 to 8 hours after ingestion are usually safe

for discharge after a 6- to 8-hour observation period [50,55–57].

----------

Clonidine kilde: Pediatr Ann. 2005 Dec;34(12):964-8.

One pill can kill: assessing the potential for fatal poisonings in children.

Matteucci MJ.

Source

Division of Medical Toxicology, University of California San Diego Medical Center, CA 92103-8925,

USA. mmatteucci@cox.net

Abstract

Antimalarials, camphor, clonidine, methyl salicylates, and sulfonylureas all may result in serious

poisonings and are potentially fatal in small doses in toddlers. Early recognition and appropriate

management, including antidotal and supportive care, may prevent poor outcomes in these patients.

Toxicity

Clonidine

Toxicity in 30 to 90 minutes

May persist for 1 to 3 days

Children most at risk for bradycardia, respiratory depression, intermittent apnea

Cases

Clonidine

Case series: 80 children admit for clonidine ingestion

Average time to onset of symptoms: 35 minutes

Most common presenting sign or symptom: reduced level of consciousness (96%)

Nichols MH, et al. Ann Emerg Med 1997;29:511

Cases

Clonidine

Six required intubation

No deaths reported

54% of the clonidine belonged to patients’ grandmothers

Nichols MH, et al. Ann Emerg Med 1997;29:511

Cases

Clonidine

21-month-old girl: coma, bradycardia, hypotension after ingesting 0.3-mg tablet

6-year-old girl: obtundation, bradycardia after applying patch she mistook for bandage

Killian CA, et al. Pediatr Emerg Care 1997; 13:340–1.

Neuvonen PJ, et al. Clin Toxicol 1979;14:369–74.

Cases

Clonidine

9-month-old boy lethargic 90 minutes after sucking on a discarded clonidine patch

2-year-old child bradycardic, recurrent apnea after ingesting 5 mL apraclonidine

Everson G, et al. J Toxicol Clin Toxicol 1999; 37:629.

Caravati EM, et al. Ann Emerg Med 1988;17:175

Management

Imidazoline: supportive

Symptomatic patients respond variably to naloxone up to a total of 10 mg

Retrospective review: 39 / 80 patients (49%) got naloxone

o Positive response in 4 patients

Nichols MH, et al. Ann Emerg Med 1997;29:511

Clonidine

Management

Symptomatic bradycardia: start with atropine

Hypotension unresponsive to fluid resuscitation or complicated by persistent bradycardia:

dopamine

Maggi JC, et al. Clin Paediatr 1986;25:453–5.

Clonidine

Clonidine and related imidazoline poisoning (kilde I hyperlink)

Author

Kevin C Osterhoudt, MD, MS

Section Editor

Michele Burns Ewald, MD

Deputy Editor

James F Wiley, II, MD, MPH

Disclosures

Last literature review version 19.2: mai 2011 | This topic last updated: mars 23, 2011 (More)

INTRODUCTION — A rapid overview summarizes the important clinical features and initial

management of clonidine poisoning (table 1).

Clonidine, an alpha-2 adrenergic agonist, is a biochemical derivative of imidazoline that was

initially introduced as a topical nasal decongestant over 40 years ago [1]. Subsequently,

clonidine has been primarily utilized for its potent antihypertensive effect. Related

imidazolines are found in topical eye and nose decongestants and in the antispasticity agent,

tizanidine.

The clinical features, evaluation, and management of clonidine and related imidazoline

intoxication will be reviewed here. The clinical approach to the poisoned patient is discussed

separately. (See "General approach to drug poisoning in adults" and "Approach to the child

with occult toxic exposure".)

EPIDEMIOLOGY — In the United States, about 7000 calls regarding clonidine exposure are

made annually to regional poison control centers, and serious clinical findings are common

[2,3]. Clonidine poisoning may occur from exploratory ingestion by young children,

transdermal exposure from a clonidine patch, malicious drug administration, suicidal

ingestion, or therapeutic error.

Although clonidine exposure is frequently symptomatic in children, deaths due to pediatric

exploratory ingestion of clonidine are rare, with only one reported in a poison control center

cohort of 10,060 exposures [4].

PHARMACOLOGY AND CELLULAR TOXICOLOGY

Indications — Clonidine is indicated for the treatment of hypertension in adults, but is also

used for anesthetic premedication, spinal anesthesia, opioid detoxification, alcohol

withdrawal, smoking cessation, and amelioration of postmenopausal hot flashes [5-9]. In

children, it is used in the treatment of attention deficit disorder with hyperactivity, refractory

conduct disorder, and Tourette's syndrome [10-12]. In a mail survey of pediatricians,

clonidine was also the second-most commonly prescribed (off-label) medication for treating

sleep disturbances in children [13].

Guanabenz and guanfacine are related alpha-2 adrenergic agonist medications used for

hypertension. In addition, guanfacine is used for the treatment of behavioral disturbance in

children [14].

Imidazoline derivatives, such as tetrahydrozoline, naphazoline, oxymetazoline, and

xylometazoline, are found in commercial topical eye and nose decongestants.

Brimonidine and apraclonidine are prescribed for treatment of glaucoma. Tizanidine is a

muscle relaxant used for the treatment of spasticity. Ingestion or systemic absorption of small

amounts of these agents can produce toxicity syndromes strikingly similar to that produced by

clonidine [15-17].

Formulation — Clonidine is supplied as 0.1, 0.2, and 0.3 mg tablets and in transdermal patch

delivery systems containing 2.5, 5, or 7.5 mg of drug. Clonidine is also available in a

combination product containing the diuretic agent chlorthalidone.

Toxic dose — No globally applicable minimum toxic dose of clonidine has been established.

A review of low-dose clonidine poisonings among children details eight children who

developed some combination of central nervous system, cardiovascular, or respiratory

depression after alleged exposure to just one or two tablets [18]. In contrast, survival has been

documented after 1000-fold overdoses in both children and adults [19,20]. Topical

imidazoles, though structurally similar to clonidine, are more polar than clonidine and less

likely to cross the blood-brain barrier. Still, they have been implicated in pediatric poisoning

after ingestion of small amounts of drug or after therapeutic use [15].

Mechanism of action — The pharmacological mechanisms through which clonidine lowers

blood pressure and causes sedation are complex and still await full characterization [21-23].

Clonidine stimulates alpha-2 adrenergic receptors and imidazoline receptors which are located primarily in the rostral ventrolateral medulla. This effect leads to decreased sympathetic outflow from the central nervous system and reduced plasma norepinephrine levels [22].

Endothelialium-derived nitric oxide (NO) also plays a role in the antihypertensive effects of clonidine [21].

Further sedative effects may occur from the stimulation of alpha-2 adrenergic receptors in the locus coeruleus, by augmented release of gamma-aminobutyric acid (GABA), and by interaction with opioid and serotonergic receptor systems [21].

Stimulation of alpha-2 adrenergic receptors located in peripheral vascular smooth muscle causes vasoconstriction. This action explains the utility of imidazoline compounds as topically applied vasoconstrictors and the early and transient hypertension that is occasionally seen following clonidine overdose [23].

KINETICS — The absorption, distribution, and elimination of clonidine vary depending upon

the formulation of clonidine and route of exposure.

Clonidine tablets — The pharmacokinetics for oral ingestion of clonidine tablets are as

follows [24-26]:

Bioavailability is 75 to 100 percent. Peak plasma clonidine concentrations occur at approximately 2 hours, and absorption is

complete by 2.5 hours in hypertensive, fasting adults [24]. Maximal blood pressure reduction occurs between three and eight hours after a routine daily

dose [25]. Clonidine in the bloodstream is 20 to 40 percent protein bound and has an apparent volume

of distribution of 3.2 to 5.6 L/kg. Elimination half-life in therapeutic use ranges from 6 to 24 hours with more than half

excreted unchanged in the urine [26].

Clonidine patch — Clonidine patch formulations are available in doses of 2.5, 5, and 7.5 mg

contained in a timed matrix delivery system [27].

Clonidine is delivered at a constant rate over seven days. The elimination half life while the patch is adherent varies from 26 to 55 hours. Up to 75 percent of the total dose may remain in a clonidine patch after seven days of use.

CLINICAL FEATURES OF OVERDOSE — Diagnosis of clonidine poisoning relies on a

careful history and physical examination. A rapid overview summarizes the important clinical

features and initial management of clonidine poisoning (table 1).

History — Data obtained should include the specific agent, amount ingested, time of

ingestion, and any coingestions. Any possible witnesses and emergency medical services

(EMS) personnel who may have recovered pill bottles at the scene should be contacted. The

patient's pharmacy may provide valuable information regarding prescribed medications, the

date of the most recent refill, and the total number of pills dispensed.

If the ingestant is unknown, a history of glaucoma or hypertension in an adult patient or

household member suggests a possible clonidine exposure as does a patch medication

prescribed for behavioral disturbance in a pediatric patient or sibling. (See "Approach to the

child with occult toxic exposure".)

The circumstances that led to the poisoning should be considered, as suicidal or malicious

overdoses may warrant involvement of social services. It is also important to review the

medical history for conditions which may predispose patients to the toxic effects of clonidine,

such as airway compromise or preexisting cardiac conduction abnormalities.

A detailed knowledge of the patient's coingestants and chronic medications is important, as

clonidine exacerbates the hypotension of coingested antihypertensive medications (eg, beta

blockers, calcium channel blockers) and the lethargy or coma following ingestion of ethanol,

barbiturates, and other sedative hypnotics (eg, benzodiazepines, zolpidem, chloral hydrate).

The clinical approach to the poisoned patient is discussed separately. (See "General approach

to drug poisoning in adults" and "Approach to the child with occult toxic exposure".)

Physical examination — The classic toxic syndrome, or "toxidrome," associated with

clonidine consists of central nervous system depression, bradycardia, hypotension, respiratory

depression, and small pupil size [28-30].

Up to 60 percent of clonidine exposures that are reported to regional poison control centers

result in symptoms [4]. However, clinical presentations can vary [4,29,30]. The relative

frequency of findings in children and adults poisoned with clonidine are shown in the table

(table 2).

Signs of toxicity are seen within one hour of clonidine tablet ingestion and new findings

rarely appear more than four hours after exposure [29,30].

Clonidine patch exposure through ingestion or self application to the skin may result in signs

of toxicity beyond four hours [31,32]. A full body search for adherent transdermal patches is

an important aspect of the physical examination.

Depressed mental status, ranging from lethargy to coma, is the most common finding after

clonidine poisoning [4,29,30]. Miosis, hyporeflexia, and hypotonia often accompany the

alteration in mental status and making the differentiation of clonidine poisoning from opioid

toxicity difficult (table 3). Transient responsiveness to painful stimuli is more frequently seen

in patients poisoned with clonidine than with opioids.

Respiratory depression and apnea accompany clonidine poisoning in a significant number of

patients, especially children, and may require immediate airway support [4,29,30]. Children

will often resume breathing upon tactile stimulation.

Bradycardia and hypotension are prominent signs of clonidine and related imidazoline

toxicity. Sinus bradycardia is the usual rhythm although atrioventricular [AV] block and sinus

arrest have been described [33,34]. Second-degree AV block or complete AV dissociation are

uncommon and should prompt consideration of toxicity from other cardioactive agents, such

as digoxin, beta blockers, or calcium channel blockers (figure 1 and figure 2).

Hypertension occurs transiently in many patients with clonidine overdose, particularly after a

large ingestion [21,29]. In addition, hypertension has been reported in patients with clonidine

poisoning who receive naloxone. Hypertension progressing to hypotension has also been

reported after guanfacine overdose [35]. Hypertensive emergency requiring treatment is very

rare [36].

Pallor, hypothermia, and dry mouth may also be seen following clonidine poisoning [29,37].

DIFFERENTIAL DIAGNOSIS — There are many causes of coma that deserve consideration

when evaluating the patient with suspected clonidine poisoning (table 4). In the poisoned

patient, it is especially important to consider hypoglycemia and potential traumatic brain

injury. (See "Evaluation of stupor and coma in children" and "Stupor and coma in adults".)

As in all poisonings, careful consideration should be given to the potential for coingested

toxic agents. Clonidine exacerbates the lethargy or coma following ingestion of ethanol,

barbiturates, and other sedative hypnotics (eg, benzodiazepines, zolpidem, chloral hydrate).

(See "Approach to the child with occult toxic exposure".)

Among toxic agents that may cause coma, other centrally acting, though chemically distinct,

antihypertensive medications, including methyldopa, guanfacine, and guanabenz, also

decrease sympathetic outflow and mimic clonidine's toxic effects.

The combination of central nervous system depression and pupillary miosis closely resembles

the toxic syndrome seen with opioid intoxication, which may be further confused by the

variable response of clonidine poisoning to naloxone (table 3). Many other sedative-hypnotic

and psychoactive agents may also produce somnolence and bradycardia. (See "Opioid

intoxication in adults" and "Opioid intoxication in children and adolescents".)

LABORATORY EVALUATION — Quantitative and qualitative testing for clonidine is

available from dedicated toxicology reference laboratories with methodology, such as gas

chromatography or mass spectroscopy. However, the results usually cannot be obtained in

time to be useful for patient management. Thus, specific measurement of clonidine in the

urine or other fluids is typically performed for forensic or other nonclinical purposes.

Further laboratory evaluation of clonidine poisoning varies depending on the circumstances of

exposure. A witnessed exploratory ingestion in a toddler or a known therapeutic error in a

hospitalized patient may merit little laboratory investigation whereas an unwitnessed suicidal

overdose may lead to more extensive testing, especially if clonidine is not the definite cause

of symptoms. Other ancillary studies may be indicated in selected patients in whom trauma,

infection, or other etiologies besides poisoning are suspected. (See "Evaluation of stupor and

coma in children" and "Stupor and coma in adults" and "Approach to the child with occult

toxic exposure" and "General approach to drug poisoning in adults".)

We suggest the following tests in adolescent and adult patients with altered mental function

and suspected clonidine overdose:

Bedside glucose determination, to exclude hypoglycemia as the cause of reduced consciousness.

Arterial blood gas evaluation or venous blood gas measurement combined with pulse oximetry to assess adequacy of ventilation in patients with serious and persistent respiratory depression.

Serum acetaminophen level in patients who ingest clonidine with suicidal intent. Serum ethanol level, to identify patients at a higher risk for coma and respiratory depression

due to coingestion of clonidine and ethanol. Electrocardiogram (ECG), to evaluate for drug-induced cardiac electrical dysfunction. Chest radiography, if the history or exam suggests the possibility of pulmonary aspiration.

Other studies that may be helpful in selected patients include:

Serum electrolyte determination, in the setting of likely coingestants, to assess for electrolyte disturbance or metabolic acidosis and to calculate the anion.

Serum blood urea nitrogen and creatinine to identify patients with renal insufficiency who may have delayed elimination of clonidine after overdose.

Rapid urine pregnancy test in postmenarchal women.

MANAGEMENT — Consultation with a clinical toxicologist is available to provide guidance

in managing individual patients. To obtain emergent consultation with a medical toxicologist,

call the United States Poison Control Network at 1-800-222-1222, or access the World Health

Organization's list of international poison centers

(www.who.int/ipcs/poisons/centre/directory/en).

The management for clonidine and related imidazoline intoxications is the same. (See

'Formulation' above.) Almost all clonidine poisoned patients will have good outcomes with

attentive supportive care alone. A rapid overview summarizes the important clinical features

and initial management of clonidine poisoning (table 1).

No randomized controlled trials exist to guide specific care. The recommendations for

gastrointestinal decontamination and potential antidotal therapy given below are based upon

individual reports and case series.

Basic measures — Management begins with assessment and stabilization of the airway,

breathing, and circulation.

Respiratory depression often responds transiently to tactile stimulation of the patient. However, clinicians should proceed with endotracheal intubation and mechanical ventilation if there is any doubt about the patient's ability to breathe adequately on their own or if pulmonary aspiration poses a significant risk.

Bradycardia is typically mild, but may respond to atropine [29,38]. Isolated hypotension may initially be treated with Trendelenburg positioning and rapid administration of intravenous isotonic crystalloid fluids (normal saline or Ringer's lactate solution). Dopamine, or similar pressor agents, may be useful in the minority of patients whose bradycardia or hypotension that does not respond to stimulation, intravenous atropine administration and rapid intravenous infusion of isotonic fluids.

Hypertension may be noted early after clonidine overdose. As hypertension is typically of short duration and is often followed by hypotension, use of antihypertensive therapy is only warranted when there are signs of hypertensive emergency, a rare event after clonidine poisoning. (See "Malignant hypertension and hypertensive encephalopathy in adults".) In the unlikely event that hypertension must be treated, a short-acting, easily titratable agent, such as nitroprusside is advised. Beta adrenergic antagonist agents should be avoided as they may lead to unopposed alpha adrenergic action with worsening of hypertension.

Hypothermic patients merit external warming. (See "Accidental hypothermia in adults" and "Treatment of hypothermia in children".)

External decontamination — Any adherent transdermal patches found on diligent search of

the patient's skin during exposure should be removed.

Gastrointestinal decontamination — Clonidine and related imidazolines bind well to activated

charcoal (AC), the primary means of decontamination in overdose. The recommendation of

AC administration following clonidine overdose derives from indirect evidence of benefit in

volunteers, animal studies, and evidence of benefit following ingestions of other medications

[39]. Because of adverse effects, such as vomiting and dehydration, the combination of a

cathartic (eg, sorbitol) and AC should be used sparingly, if at all, and only a single dose of a

cathartic should be given to any patient.

We do not recommend gastric emptying by gastric lavage or by syrup of ipecac induced

emesis in patients who ingest clonidine or related imidazolines based on randomized

controlled trials showing minimal benefit and possible risk to patients who undergo gastric

emptying after poisoning. (See "Decontamination of poisoned adults" and "Decontamination

of poisoned children".)

Tablet or liquid preparation

We suggest that patients who present within one to two hours of a known or suspected

ingestion of clonidine tablet, related imidazoline tablet, or imidazoline liquid preparation

receive AC (1 gm/kg, maximum dose 50 grams) by mouth or nasogastric tube. Great care

must be taken to ensure that the airway is not compromised prior to administration and that

pulmonary aspiration risk be minimized. Patients with respiratory depression or coma should

first have their airway secured, as needed based on clinical evaluation, prior to AC

administration.

In patients who present for care more than two hours after ingestion of clonidine tablet,

related imidazoline tablet, or imidazoline liquid preparation, we suggest that AC not be given

because the likelihood of preventing medication absorption is low and is outweighed by the

risk of pulmonary aspiration.

Clonidine patch

We suggest the nasogastric administration of whole bowel irrigation (WBI) (500 mL to 1 L of

polyethylene glycol per hour) after oral administration of AC (1 gm/kg, maximum dose 50

grams) in patients who have ingested clonidine transdermal patches. In this setting, AC may

also prevent delayed absorption of clonidine when administered more than one hour after

ingestion. Safe administration of WBI requires attention to the following provisions [40]:

The patient should have bowel sounds present and no evidence of gastrointestinal obstruction.

Airway adequacy must be assessed and secured, if necessary, prior to the procedure. Nasogastric tube placement must be radiographically confirmed prior to initiation of whole

bowel irrigation. The patient should be maintained in an upright position (minimum 45 degree elevation of

the head) throughout the procedure.

Gastrointestinal decontamination is discussed in detail separately. (See "Decontamination of

poisoned adults" and "Decontamination of poisoned children".)

Specific treatment measures and antidotal therapy — No true antidote for clonidine or related

imidazoline intoxication exists. Naloxone and alpha adrenergic antagonists have been utilized

to treat seriously poisoned patients with inconsistent results.

Naloxone — In case reports and case series, naloxone administration has reversed signs of

clonidine and tizanidine poisoning in some patients [28-30,41]. Intravenous doses ranging

from 0.05 to 0.1 mg/kg (maximum 10 mg) have been used. Experience with naloxone

administration for related imidazolines is limited [30].

Based on results from case reports and retrospective case series, we suggest that

clonidine poisoned patients with marked CNS depression and apnea receive intravenous

naloxone (0.1 mg/kg, maximum dose: 2 mg; may be repeated every one to two minutes up to

10 mg total dose). This treatment should not delay the timely provision of aggressive

supportive care in patients who do not respond. Patients who improve after naloxone

administration still warrant hospital admission and intensive monitoring for recurrence of

symptoms.

Many patients who respond to the initial dose of naloxone do not require additional doses

[29]. However, if altered mental status and respiratory depression recur, we suggest the

administration of additional intermittent doses as needed rather than a continuous infusion.

Naloxone therapy for clonidine overdose has been rarely associated with the onset of acute

hypertension [42].

Alpha adrenergic antagonists — The nonselective alpha adrenergic antagonist, tolazoline, and

the specific alpha-2 adrenergic antagonist, yohimbine, have been proposed as potential

antidotes to clonidine poisoning [43,44], but the risk associated with these agents exceeds any

expected benefit [29,43,45,46]. Thus, the use of these agents for treatment of clonidine

poisoning is strongly discouraged. Selective alpha-1 adrenergic antagonists would be

expected to promote hypotension and should also be avoided.

Indications for extracorporeal removal — Clonidine is not amenable to extracorporeal

removal (eg, multiple dose AC, hemodialysis, hemoperfusion).

Disposition — Further management depends on presence of symptoms and reason for

ingestion.

Symptomatic patients — All patients displaying clonidine or related imidazoline toxicity

warrant hospital admission and intensive medical care regardless of their response to

naloxone. These patients typically fully recover within 24 to 48 hours.

Asymptomatic patients — Disposition of asymptomatic patients depends on the

clonidine formulation ingested:

Oral imidazoline preparations - Patients who remain asymptomatic at six hours after exploratory or inadvertent ingestion of clonidine tablets, imidazoline tablets, or imidazoline liquids may be discharged home as long as close observation and ability to rapidly return for medical care, if needed, is assured. An extended release formulation of guanfacine is now marketed, and may warrant longer observation periods.

Clonidine patch preparations - Asymptomatic patients who ingest a clonidine transdermal patch should be admitted and closely monitored because signs of poisoning may be delayed for up to 24 hours in this setting [31].

Suicidal overdose — Patients who ingest clonidine or related imidazolines with intent of self-

harm warrant mental health consultation, measurement of serum acetaminophen levels, and

careful evaluation for other coingestants. (See 'Laboratory evaluation' above.)

Patients should be evaluated by the mental health provider before discharge from medical

care. Psychiatric evaluation should be deferred in symptomatic patients until after they have

recovered. (See "Approach to the child with occult toxic exposure" and "General approach to

drug poisoning in adults".)

ADDITIONAL PEDIATRIC CONSIDERATIONS — Clonidine is frequently prescribed for

behavior problems in children. Clonidine exposure often involves young children who ingest

their own medication or that of another child in the household [29,47]. Ingestion of as little as

one clonidine tablet or one swallow of imidazoline containing eye drops can cause life-

threatening toxicity in children.

In addition to routine anticipatory guidance regarding poisoning prevention, clinicians should

counsel caretakers about measures to prevent clonidine or imidazoline poisonings as follows:

Used transdermal clonidine patch preparations contain a significant amount of clonidine. These patches should be carefully discarded so that young children cannot find them in the trash. Caretakers should be alerted to the serious toxicity these patches pose if ingested or reapplied to the skin.

Topical imidazoline preparations, which are tasteless and highly potent after ingestion, often do not have child-resistant closures and need to be maintained out of reach of children. (See "Prevention of poisoning in children".)

RESOURCES — Regional poison control centers in the United States are available at all

times for consultation on patients who are critically ill, require admission, or have clinical

pictures that are unclear (1-800-222-1222). In addition, some hospitals have clinical and/or

medical toxicologists available for bedside consultation and/or inpatient care. Whenever

available, these are invaluable resources to help in the diagnosis and management of

ingestions or overdoses. The World Health Organization provides a listing of international

poison centers at its website: www.who.int/ipcs/poisons/centre/directory/en.

SUMMARY AND RECOMMENDATIONS — A rapid overview summarizes the important

clinical features and initial management of clonidine poisoning (table 1).

Clinical features

Clonidine, an alpha 2 agonist, is a biochemical derivative of imidazoline that causes lethargy, coma, small pupils (miosis), bradycardia, hypotension, transient hypertension, and respiratory depression in overdose. (See 'Clinical Features of overdose' above.)

Ingestion of as little as one clonidine tablet or one swallow of imidazoline containing eye drops can cause life-threatening toxicity in children. (See 'Additional pediatric considerations' above.)

Most signs of toxicity are seen within one hour of ingestion of clonidine tablets and new findings rarely appear more than four hours after exposure. Clonidine patch exposure through ingestion or self application to the skin may develop signs of toxicity beyond four hours. (See 'Clinical Features of overdose' above.)

Management

Supportive care

Almost all clonidine poisoned patients will have good outcomes with attentive supportive care of airway, breathing, and circulation. (See 'Basic measures' above.)

Decontamination

The patient should be fully exposed and any adherent transdermal patches should be removed. (See 'External decontamination' above.)

We suggest that patients who ingest clonidine tablets or related imidazoline preparations and who present within the one to two hours of known or suspected clonidine ingestion receive activated charcoal (AC) (1 gm/kg, maximum dose 50 grams) by mouth or nasogastric tube. (Grade 2C). Charcoal should be withheld in patients who are sedated and may not be able to protect their airway, unless endotracheal intubation is performed first. However, endotracheal intubation should not be performed solely for the purpose of giving charcoal. (See 'Gastrointestinal decontamination' above.)

Because the likelihood of preventing medication absorption is low and is outweighed by the risk of pulmonary aspiration, we suggest that patients who seek care more than two hours after known or suspected clonidine tablet or related imidazoline preparation ingestion not receive AC. (See 'Gastrointestinal decontamination' above.)

We suggest that patients who ingest clonidine transdermal patches and who present within the first hour receive a single oral dose of AC (Grade 2C). In this setting, AC may also prevent delayed absorption of clonidine when administered more than one hour after ingestion. We suggest that AC be followed by nasogastric whole bowel irrigation with polyethylene glycol (Grade 2C). Endotracheal intubation may be necessary in symptomatic patients to avoid aspiration. In addition, gastrointestinal integrity must be assured before initiation of whole bowel irrigation. (See 'Gastrointestinal decontamination' above.)

We recommend not emptying the stomach by gastric lavage or syrup of ipecac induced emesis (Grade 1B). (See 'Gastrointestinal decontamination' above.)

Specific therapy

We suggest that patients poisoned with clonidine or related imidazolines with marked CNS depression and apnea receive intravenous naloxone (Grade 2C). This treatment should not delay the timely provision of aggressive supportive care in patients who do not respond. (See 'Specific treatment measures and antidotal therapy' above.)

Disposition

We admit the following patients with clonidine or related imidazoline ingestion:

All symptomatic patients All patients who ingest transdermal patches

Patients who are suicidal warrant psychiatric evaluation prior to discharge and should also be carefully evaluated for coingestions, including the measurement of an acetaminophen level

Patients who are asymptomatic for six hours after ingestion of clonidine or related imidazoline tablets or liquid, and who are not suicidal, may be discharged home as long as close observation and the ability to return rapidly if care is needed are assured. (See 'Disposition' above.)

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