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PEDIATRICS Vol. 108 No. 3 September 2001, p. e52
From the Department of Pediatrics, Johns Hopkins School of
Medicine, Baltimore, Maryland.
Over-the-counter (OTC) cough and cold medications
are marketed widely for relief of common cold symptoms, and yet studies have failed to demonstrate a benefit of these medications for young
children. In addition, OTC medications can be associated with
significant morbidity and even mortality in both acute overdoses and
when administered in correct doses for chronic periods of time.
Physicians often do not inquire about OTC medication use, and parents
(or other caregivers) often do not perceive OTCs as medications. We
present 3 cases of adverse outcomes over a 13-month period
ABSTRACT
Top
Abstract
Discussion
Conclusion
References
including 1 deathas a result of OTC cough and cold medication use. We
explore the toxicities of OTC cough and cold medications, discuss
mechanisms of dosing errors, and suggest why physicians should be more vigilant in specifically inquiring about OTCs
when evaluating an ill child.
Colds, coughs, and upper respiratory infections are common
childhood illnesses. The average child suffers from 6 to 10 colds per
year, and each cold can last from 10 to 14 days, providing several days
and nights of discomfort for the child as well as for his/her
caregiver.1 Many times parents will turn to one of many
hundreds of cough and cold preparations for relief. However,
over-the-counter (OTC) cough and cold preparations Case 1
A 36-month-old boy was transferred to the pediatric emergency
department (ED) from an outside hospital for lethargy and vomiting. Several hours earlier, the child's mother had given her son an unspecified amount of Dimetapp (Whitehall-Robins, Madison, NJ) cold
syrup containing PPA (12.5 mg/5 mL) and brompheniramine (2 mg/5 mL).
His past medical history was remarkable for prematurity and
hydrocephalus with ventriculoperitoneal shunt placement as a result of
child abuse.
On arrival to the ED, the patient was lethargic, bradycardic,
tachypneic, and hypertensive. Physical examination revealed equal, but
sluggishly reactive pupils, and slightly increased tone. Shunt survey
showed no evidence of shunt disruption, and computerized tomography
scan of the head was within normal limits. A pediatric neurosurgeon
evaluated the patient, and determined He was admitted to the pediatric intensive care unit (PICU) for
additional observation, where he was given intravenous fluids and close
monitoring. His activity level and mental status improved spontaneously
over the next several hours. He was discharged from the hospital from
the PICU with a diagnosis of mental status change secondary to
antihistamine and sympathomimetic ingestion.
Case 2
A 35-month-old boy was seen at a community ED with a chief
complaint of fever to 104°F. A complete blood (cell) count (CBC) revealed a white blood cell (WBC) count of 8400 with 33% bands and
27% neutrophils. A blood culture was sent, and a chest radiograph obtained, which was read as findings consistent with a left lobe infiltrate and cardiomegaly. He was treated with intramuscular ceftriaxone and discharged from the hospital with instructions to
follow-up with his pediatrician the next day.
In his primary care clinic the next day, his parents reported that he
had had intermittent fevers for 3 weeks, along with cough and
rhinorrhea, prompting the ED visit. He had been eating and drinking
well. When asked about medications, his parents said he was only taking
Tylenol (McNeil Consumer Healthcare, Fort Washington, PA) as instructed
for fever. His vital signs were: temperature, 37.3°C axillary; pulse,
150 beats per minute (bpm); and respirations, 40 breaths per minute. He
was tired-appearing, but cooperative. His physical examination was
notable for mild yellow rhinorrhea and tachycardia on heart examination
without murmurs, gallops, or rubs.
A chest radiograph was repeated because of the report of cardiomegaly.
His heart size was within normal limits and there was no evidence of a
focal infiltrate. An electrocardiogram was obtained for persistent
tachycardia in the absence of fever, and demonstrated only sinus
tachycardia. An echocardiogram was performed to further evaluate the
etiology of tachycardia, and it revealed a mildly dilated left
ventricle and moderate left ventricular dysfunction. He was admitted to
the cardiology service for additional evaluation of possible
myocarditis or cardiomyopathy, and was scheduled for cardiac
catheterization.
The patient continued to have persistent tachycardia in the hospital.
His parents repeatedly denied administering any medications other than
Children's Tylenol (McNeil Consumer Healthcare, Fort Washington, PA),
and also denied the possibility of ingestion of any other preparations.
However, when his parents produced the bottle of Tylenol, which they
had been using for fever, the bottle was labeled Children's Tylenol:
Cold, which contains acetaminophen (160mg/5 mL),
chlorpheniramine (1mg/5 mL), dextromethorphan (5mg/5 mL), and
pseudoephedrine (15mg/5 mL). His urine toxicology screen revealed 2 metabolites of chlorpheniramine. His tachycardia slowly resolved before
discharge on hospital day 3. His left ventricular function as
determined by echocardiogram improved during the hospitalization, and
had returned to within normal range 2 weeks after discharge.
Case 3
A 9-month-old boy was referred to the ED by his primary care
physician for evaluation of persistent crying and fever. His mother
stated that the symptoms had started 6 days previously with a fever to
102°F, although the child had had a cough without rhinorrhea for
several weeks. Throughout the week, the child had been fussy and
nonconsolable, according to the mother, and had not slept at all for
the 3 nights before being seen in the ED. His mother denied diarrhea,
but reported emesis 3 times per day. His mother reported only giving
him 3/4 dropper of Motrin (Pharmacia Upjohn, Peapack, NJ).
Vital signs on arrival in the ED were: temperature, 39.5°C; pulse,
208 bpm; respirations, 40 breaths per minute; and blood pressure,
121/78 mm Hg. Physical examination was notable for a screaming infant,
immobile, erythematous tympanic membranes, tachycardia without murmur,
and brisk capillary refill. Because of his persistent irritability and
fever, an evaluation for meningitis/sepsis was performed, and was
normal (WBC of 7600, urine analysis with 3-5 WBCs and cerebrospinal
fluid with 8 WBC per high-power field and negative Gram stain). Several
hours after presentation, the infant was noted to be alert, active, and
playful, and tolerating oral liquids. He was given intramuscular
ceftriaxone and was discharged from the hospital with instructions to
return to the ED the following day for reevaluation.
Approximately 12 hours after discharge, the infant was brought back to
the ED in full cardiopulmonary arrest. By report he had gone to bed at
4 am, and had been sleeping with his grandmother. When the grandmother
awakened at 11:30 am, the child was blue and apneic. The paramedics
were called and he was brought to the ED with cardiopulmonary
resuscitation in progress. On arrival, the child was cyanotic, cold,
and slightly stiff. Initial temperature was 35°C rectally; no other
vital signs could be obtained. Blood pH was 6.35; glucose, 20 mg/dL;
serum sodium, 167 mEq/L; and potassium, 10.5 mEq/L. Advanced life
support was conducted for approximately 20 minutes, but was
unsuccessful, and the child was pronounced dead.
An autopsy by the medical examiner revealed no gross abnormalities of
any organs including the brain and heart, and no evidence of traumatic
injuries. Postmortem urine toxicology testing revealed acetaminophen, pseudoephedrine, chlorpheniramine,
dextromethorphan, and PPA. Postmortem blood analysis from the heart
revealed markedly elevated levels of several substances. The level of
pseudoephedrine was 10.0 mg/L; PPA, 1.4 mg/L; and dextromethorphan, 0.6 mg/L. Postmortem liver analysis showed a concentration of
pseudoephedrine of 14.0 mg/L and PPA of 0.5 mg/L. After review of the
autopsy findings and tests, the medical examiner determined the cause of death as mixed drug intoxication secondary to ingestion of these
drugs. Additional investigation and questioning of the caretakers revealed numerous doses of OTC cough and cold preparations had been
given to the infant. A criminal investigation ensued; however, it was
determined that the OTC cough and cold medicines were not intentionally
given in toxic doses.
OTC cough and cold preparations are nearly ubiquitous, and are
marketed for the relief of those most irritating symptoms of the common
cold: rhinorrhea and cough. Although they may alleviate some symptoms
in adolescents and adults,2 many studies have demonstrated
that OTC cough and cold preparations do not achieve such claims in the
younger pediatric population.2-6 In fact, studies in
children of the immediate,5 short-term4 (within 48 hours), and long-term3 (after 72 hours) effects of cough and cold preparations showed no significant difference between
OTC medications and placebo in the reduction of cough. In addition, OTC
cough and cold medications are associated with potentially serious side
effects.7-20
In 1997, the American Academy of Pediatrics (AAP) issued a statement on
the use of codeine- and dextromethorphan-containing cough remedies in
children, concluding that physicians should clearly educate parents
about the known risks and lack of benefits of these
medications.6 We chose to report these cases because they
represent the range of severity of adverse outcomes that can be seen
with OTC cough and cold preparations. In addition, a review of the
recent literature does not reveal reports of heart failure or death
attributable to such medications. Finally, our case reports from a
single institution reflect 3 episodes in just over 1 year that required
admission, and most likely only represent the "tip of the iceberg"
of adverse outcomes attributable to OTC cough and cold preparations.
The potential toxicities of cough and cold medicines vary with their
composition. Many products contain multiple substances including a
decongestant, cough suppressant, antihistamine, and/or antipyretic/analgesic. Pseudoephedrine and PPA are sympathomimetics that reduce nasal congestion by stimulating the A comprehensive review of >100 case reports of adverse drug effects
involving PPA described 24 cases of intracranial hemorrhage Many cough and cold preparations even include antihistamines such as
chlorpheniramine and brompheniramine although histamine has not been
shown to contribute to the symptoms seen in the common cold.15 Adverse effects and clinical toxicity of
antihistamines are characterized by a spectrum of anticholinergic
symptoms and CNS depression. Tachycardia, blurred vision, agitation,
hyperactivity, toxic psychoses, and seizures may be evident. Cardiac
dysrhythmias including torsades de pointes have also been
reported.15,18 Dextromethorphan, an antitussive, has also
been associated with toxic side effects such as lethargy, stupor,
hyperexcitability, ataxia, abnormal limb movements, and
coma.18
We cannot definitively prove that OTC cough and cold preparations were
the cause of the symptoms in all cases. In the first 2 cases, other
causes of the patients' symptoms were excluded based on diagnostic
testing, repeated clinical evaluations, specialty consultation, and the
resolution of symptoms over time without specific interventions.
Although the presence of the antihistamines in the urine toxicology
test does not establish toxicity, the symptoms and their resolution
correlate with adverse effects from the drug and timing of its
metabolism. There have been no previous reports of cardiac dysfunction
in children specifically with the use of OTC sympathomimetic agents.
However, there has been good evidence that demonstrates cardiomyopathy
and valvular abnormalities, as well as cardiac dysrhythmias and
conduction abnormalities can result from exposure to amphetamines that
are also sympathomimetic agents.19,20 We hypothesize that
the patient in the second case developed left ventricular dysfunction
because of sustained tachycardia from the ingested sympathomimetic and antihistamine agents.
In the third case, postmortem drug concentrations from the heart
revealed elevated concentrations of pseudoephedrine and PPA. However,
therapeutic and toxicity data on serum and postmortem drug
concentrations in children is limited. Therapeutic blood concentrations
of pseudoephedrine are reported to be between 0.21 and 0.77 mg/L.21 In 1 report, a 2-year-old child believed to have
ingested a large amount of pseudoephedrine tablets was found dead with
a postmortem blood level of 66.0 mg/L.22 Another fatal
overdosage demonstrated a pseudoephedrine concentration of 19.0 mg/L in
the blood and 33.0 mg/L in the liver.23 For PPA,
therapeutic concentrations in males have been reported to be between
0.11 and 0.40 mg/L.24 Fatal cases of PPA ingestions have
reported postmortem blood concentrations of 2.0 mg/L and 4.6 mg/L.22 Similarly, for dextromethorphan, therapeutic drug
concentrations vary widely and have been reported to average from 2.4 µg/L to 207 µg/L.25 Two fatalities in adults reported
dextromethorphan concentrations of 3.3-9.2 µg/L in
blood.26 Although there are limitations in interpreting postmortem drug concentrations in the blood and determining cause of
death Cough and cold medicines, therefore, are not administered without risk.
In 1 analysis of poison control reports of 249 038 exposures to cough
and cold preparations in children <6 years old, there were 72 "major
events" and 4 deaths.27 These numbers are probably
falsely low resulting from reliance of this data on voluntary
reporting. Other children may have adverse outcomes from cough and cold
preparation use, but may not be reported to the poison control centers
due to self-limited reactions, failure to recognize the reaction (eg,
the child slept through the sedation), lack of reporting by the medical
facility, or a lack of acknowledgment that OTC medications had been
administered.
In addition to side effects of the various ingredients, OTC cough and
cold preparations also present potential hazards due to dosing errors.
The first and third case reports demonstrate negative outcomes
attributable to acute and chronic dosing errors. Little published data
exists on levels of OTC cough and cold preparations in infants and
children; thus, dosing guidelines historically have been extrapolated
from adult data, making them imprecise for children.6 In 2 studies, caregivers reported that they primarily followed dosing
guidelines on the medication package28,29; however, this
too allows for many potential errors. They can misunderstand the
recommended dose, frequency or length of therapy, use an incorrect measuring device, or even give the wrong preparation.30,31 In our second case report, well-intentioned parents were giving their
child what they perceived to be only an antipyretic; however, because
of package labeling Some parents may intentionally give children supratherapeutic doses of
cough and cold preparations, exceeding either the recommended dose
amount or length of therapy. When appropriate doses of pediatric formulations don't achieve the desired outcome, parents may increase the dose, or give adult preparations that may be perceived as stronger.32 Kapasi et al28 noted in a study of acetaminophen use, that a significant percentage of
poisonings from acetaminophen were secondary to excessive
dosing, rather than unintentional ingestion. In the third case report,
the child tragically died from an overdose of cough and cold
medications that likely had been persistently administered because of
continued symptoms in the child.
Other parents, while recognizing that OTC cough and cold medications do
not relieve the cold symptoms, may continue to use these medications
for 1 of the side effects Despite the risks of OTC cough and cold medicines, many parents believe
they should treat their children's cold symptoms with medication.4 Cold remedies are a formidable industry; in
1990 alone, nearly $2 billion was spent on OTC cough and cold preparations nationwide.33 In 1991, Hutton et
al4 conducted a randomized, controlled trial evaluating
the efficacy of an antihistamine-decongestant preparation versus
placebo, and noted that parents reported greater symptom improvement in
children who received medicine even if it was a placebo. This parental observational bias suggests that parents in this study felt the need to
treat their children's cold symptoms, and perceived more improvement
when they received therapy.
The opportunity for physician-providers to educate parents about OTC
medications is tremendous; but it is often missed. Many times,
physicians fail to ask specifically about OTC medication use in the
evaluation process, presuming that when asked about medicine use
parents will include all medicines. However, most parents perceive
questions about medications as pertaining to prescription medications
only, and not OTC medications. This was evident in the third case
report, where the parent revealed antipyretic use, but not the use of a
cough and cold medicine, and the issue was not further explored. It is
possible that some physicians are concerned that inquiring about OTC
medicines and other, alternative therapies, may offend their patients;
however, this has not been substantiated. One study of OTC medicine use
and provider attitudes concluded that providers should routinely ask
their patients about OTC use, and that patients would be appreciative
of their providers' inquiries.34
Many providers fail to give specific instructions on OTC cough and cold
medication use even when they are aware that the patient is using
them.29 In addition, some providers have a lack of
knowledge regarding the various ingredients in cough and cold
preparations. Finally, not only are many physicians unsuccessful in
educating parents about the risks of OTC cough and cold preparations, some physicians continue to prescribe them for their patients Three cases of children experiencing significant adverse effects
and toxicity from OTC cough and cold preparations are presented. Health
care providers have the opportunity to intervene by inquiring specifically about OTC cough and cold medication use, and by educating parents on the lack of demonstrated benefit and known risks in the
pediatric populationalthough generally
safehave no demonstrated benefit. No studies have proven the efficacy
of cough and cold preparations in facilitating recovery from these
illnesses,2-6 and most children will eventually improve
on their own. However, a small number of children may suffer
significant adverse effects from the administration of the very cough
and cold formulations they were given in an attempt to relieve their
symptoms. For example, the Food and Drug Administration recently issued
an advisory to remove phenylpropanolamine (PPA)a common constituent
of OTC decongestantsfrom those products because of concern for
increased risk of hemorrhagic stroke.7,8 We present 3 cases of children who suffered significant morbidity from OTC cough and
cold preparations requiring admission and treatment in a tertiary care
hospital during a 13-month period; they ranged from a self-limited
reaction requiring an intensive care unit admission to death in 1 patient. Because no cases of death or heart failure attributable to OTC
cough and cold preparations have been reported in recent literature,
these cases are presented to serve as points for additional discussion
on the risks of OTC cough and cold preparations in children.
CASE REPORTS
without tapping his shuntthat
shunt malfunction was not the source of the child's altered mental
status. Urine toxicology testing demonstrated the presence of
brompheniramine, while all other laboratory investigations were normal.
DISCUSSION
Top
Abstract
Discussion
Conclusion
References
-andrenergic receptors on vascular smooth muscles. Clinical toxicity presents with
central nervous system (CNS) stimulation, hypertension, and tachycardia
with ephedrine or pseudoephedrine ingestion, and bradycardia with PPA
ingestion.10-12 CNS stimulation can manifest as extreme
agitation, restlessness, insomnia, psychosis, and seizures. Serious
complications after decongestant ingestions and/or overdoses include
hypertension, tachycardia, bradycardia, seizures, stroke, and cerebral
hemorrhage.1013-14 Dysrhythmias, myocardial infarction,
and ischemic bowel infarction have also been
reported.9,11,12,16,17
8 with
seizures and 8 fatalitiesbetween 1965 and 1990.11 PPA
toxicity may present with agitation, psychosis, seizures, chest pain,
or headache.12 Hypertension is common after overdose and
some patients may also present with confusion and altered mental status
as a result of hypertensive encephalopathy. Many reports of severe
hypertension after therapeutic and toxic doses of PPA have been
published, some of which resulted in intracranial hemorrhage and
death.7,13,14 Reflex bradycardia may accompany the
hypertension, which distinguishes toxicity from this drug and other
sympathomimetics. Toddlers may be at increased risk for hypertensive
episodes with unintentional ingestions because of the relatively
significant mg/kg dose ingested. Recently, the Food and Drug
Administration (FDA) started taking steps to remove PPA from all drug
products and has requested that all drug companies discontinue
marketing products containing PPA,8 after results of a
study found an increased association between PPA use and hemorrhagic
stroke in women.7 Although this risk of stroke is very
low, the FDA has significant concerns resulting from the seriousness of
this adverse event and the inability to currently predict who is at
risk for this complication.
especially in the context of limited data in childrenthe values in our report are elevated and definitely confirm that multiple
substances were present in this infant's body at the time of death.
Furthermore, we are unaware of any OTC cough and cold preparation that
contains both pseudoephedrine and PPA, again confirming that this
infant had been given at least 2 different preparations. Given the
child's age, the circumstances of his death, and the finding of
significantly elevated levels of these drugs, other diagnoses such as
sudden infant death syndrome are unlikely. With evidence of at least 2 cough and cold preparations in his system, it is possible that this
infant suffered a dysrhythmia from these drugs, which led to his death.
the Cold portion of the name Children's Tylenol:
Cold was in much smaller printthey did not realize that what they had
actually been giving was a cough and cold preparation.
sedation.5,33 Additionally,
many parents may simply be unaware of the potentially serious side
effects of OTC cough and cold medications.28
despite their lack of demonstrated efficacy. Gadomski and Horton33 described 2 such cases where a physician-prescribed cough and cold
preparation produced an adverse outcome in the patient because of
inappropriate dosing by the parents. Although the AAP guidelines do not
state that physicians should not prescribe OTC cough and cold
preparations, they do clearly state that physicians have a
responsibility to educate parents about the lack of benefit and known
risks of OTC cough and cold preparations. It is our belief that for
those families who insist on using OTC cough and cold preparations,
physicians should negotiate to discontinue use in 2 days if there is no
appreciated benefit.
CONCLUSION
Top
Abstract
Discussion
Conclusion
References
as recommended by the AAP.
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FOOTNOTES |
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Received for publication Oct 16, 2000; accepted Apr 16, 2001.
Address correspondence to Veronica L. Gunn, MD, Johns Hopkins Hospital, Department of Pediatrics, CMSC 2-124, Baltimore, MD 21287. E-mail: gunnvl{at}mail.jhmi.edu
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ABBREVIATIONS |
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OTC, over-the-counter; PPA, phenylpropanolamine; ED, emergency department; PICU, pediatric intensive care unit; CBC, complete blood (cell) count; WBC, white blood cell (count); bpm, beats per minute; AAP, American Academy of Pediatrics; CNS, central nervous system; FDA, Food and Drug Administration.
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REFERENCES |
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Top
Abstract
Discussion
Conclusion
References
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 J. M. Crandell and W. A. Ware Cardiac Toxicity From Phenylpropanolamine Overdose in a Dog J. Am. Anim. Hosp. Assoc., November 1, 2005; 41(6): 413 - 420. [Abstract] [Full Text] [PDF]
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