Ethanol Ingestion in Two Infants Under 2 Months Old: A Previously Unreported Cause of ALTE

Article (PDF Available)inPEDIATRICS 131(2) · January 2013with12 Reads
DOI: 10.1542/peds.2012-1652 · Source: PubMed
Abstract
The differential diagnosis for the infant presenting with an apparent life-threatening event (ALTE) is broad. Toxic ingestions are a relatively uncommon cause of an ALTE, although several over-the-counter, prescription, and illicit drugs have been implicated. We present 2 cases of ethanol intoxication in infants as a previously unreported cause of an ALTE. Additionally, serial ethanol levels for these patients offer novel insight into the pharmacokinetics of ethanol metabolism in infants. Ethanol ingestion may be an underrecognized cause of an ALTE and should be considered if the history or physical examination is suggestive.

Figures

Ethanol Ingestion in Two Infants Under 2 Months Old:
A Previously Unreported Cause of ALTE
abstract
The differential diagnosis for the infant presenting with an apparent
life-threatening event (ALTE) is broad. Toxic ingestions are a relatively
uncommon cause of an ALTE, although several over-the-counter, pre-
scription, and illicit drugs have been implicated. We present 2 cases
of ethanol intoxication in infants as a previously unreported cause of
an ALTE. Additionally, serial ethanol levels for these patients offer novel
insight into the pharmacokinetics of ethanol metabolism in infants.
Ethanol ingestion may be an underrecognized cause of an ALTE and
should be considered if the history or physical examination is sugges-
tive. Pediatrics 2013;131:e604e607
AUTHORS: Taylor McCormick, MD, Michael Levine, MD,
Oma Knox, MD, and Ilene Claudius, MD
Department of Emergency Medicine, Los Angeles County and
University of Southern California, Los Angeles, California
KEY WORDS
apparent life-threatening event, ALTE, ethanol, alcohol,
intoxication, poisoning, ingestion, toxic ingestion, toxicology,
emergency medicine, infant
ABBREVIATIONS
ALTEapparent life-threatening event
DCFSDepartment of Children and Family Services
EDemergency department
Dr McCormick collected data, drafted the initial manuscript,
reviewed and revised subsequent drafts, and approved the nal
manuscript as submitted; Dr Levine analyzed the ethanol
pharmacokinetic data, created the ethanol elimination gure,
drafted the kinetics portion of the discussion section, reviewed
and revised the manuscript, and approved the nal manuscript
as submitted; Dr Knox participated in data compilation, drafted
the initial abstract, and approved the nal manuscript as
submitted; and Dr Claudius conceptualized the report, critically
reviewed and revised the manuscript through its many drafts,
and approved the nal manuscript as submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2012-1652
doi:10.1542/peds.2012-1652
Accepted for publication Aug 17, 2012
Address correspondence to Taylor McCormick, MD, LAC1USC
Department of Emergency Medicine, 1200 N State St, Ste 1011, Los
Angeles, CA 90033. E-mail: taylormccormick@gmail.com
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2013 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no nancial relationships relevant to this article to disclose.
FUNDING:No external funding.
e604 McCORMICK et al by guest on August 7, 2016Downloaded from
An apparent life-threatening event
(ALTE) is dened as an episode that is
frightening to the observer and char-
acterized by some combination of ap-
nea, color change, change in muscle
tone, and choking or gagging.
1
The
potential causes of an ALTE range
widely from a minor choking episode to
a life-threatening arrhythmia, and in
25% of cases, no denitive cause is
identied.
2,3
Child maltreatment is
a well-recognized cause of an ALTE,
whether in the form of physical abuse,
Munchausens by proxy, suffocation, or
poisoning, with abusive head injury
identied in 1.4% to 2.7% of infants
presenting with an ALTE.
47
Toxic in-
gestion is a recognized, but uncom-
mon, cause of an ALTE. Case reports
and small studies have implicated
opioids, phenothiazines, benzodiaze-
pines, barbiturates, cocaine, cough
and cold preparations, and colic
medications as potential causes of an
ALTE.
811
However, there are no pre-
viously published cases of ethanol in-
toxication as the cause of an ALTE.
Although toxicology screens are often
recommended in the evaluation of
a patient presenting with an ALTE, most
standard toxicology screens do not in-
clude ethanol and would have been of
little use in the cases described here.
Failure to identify ethanol as the cause of
an ALTE leads to unnecessary diagnostic
evaluation and, more importantly, could
have signicant consequences for the
future health and safety of the child. We
also present the pharmacokinetics and
clinical course of ethanol intoxication in
infants, which thus far have been poorly
described.
In our inner city, academic, pediatric
emergency department (ED) with a yearly
census of 22 186, an ethanol level was
sent 6 times between July 2010 and No-
vember 2011 for patients ,15 months
old. We identied 3 patients with a de-
tectable ethanol level. One case involved
an unintentional witch hazel ingestion in
an asymptomatic 25-day-old with a se-
rum ethanol level of 97 mg/dL. Two
patients presented with an ALTE and the
cases are described here.
PATIENT PRESENTATIONS
Case 1: Ethanol Concentration of
278 mg/dL
A 2-month-old, 3.8-kg full-term male
infant was brought in via ambulance for
ALTE at home. His mother reported the
infant had been fussy early in the
evening, and she called 911 after no-
ticing apnea, labored respirations, and
limpness without color change while he
was sleeping. Paramedics reported the
infant was unresponsive on their arrival
but had a partial improvement in
mental status after an intramuscular
injection of naloxone 0.5 mg. In addition,
the paramedics expressed concern
about the condition of the home and
erratic demeanor of the family on their
arrival, but they were unable to provide
specics. According to the mother, the
infant had been a term delivery at 3.2 kg
with an unremarkable prenatal and
past medical history and with normal
development. He had been formula-fed
without exposures to tobacco or drugs
and resided with his 21-year-old
mother, uncles, and paternal grand-
mother. The father, who was involved,
had a history of mental illness and
substance abuse, and the couple had 2
additional children who were reported
to be visiting family in Sacramento. The
patient arrived in the ED with a tem-
perature of 98.0°F, heart rate of 131
beats per minute, blood pressure of
79/39 mm Hg, respiratory rate of 30
breaths per minute, and oxygen satu-
ration of 100% on room air. He initially
appeared well and was vigorous with
an unremarkable physical examina-
tion; however, he fell asleep when not
stimulated. Blood glucose was 111 mg/
dL. Based on the paramedicsconcerns
about the home and the childsre-
sponse to naloxone, a toxicological
workup revealed a serum ethanol
concentration of 278 mg/dL, as mea-
sured with an enzymatic test. Other
laboratory test results were white
blood cells 18 310
3
/mm
3
, hemoglobin
10.1 g/dL, hematocrit 29.1%, sodium
142 mEq/L, potassium 5 mEq/L, chlo-
ride 108 mmol/L, bicarbonate 19
mmol/L, serum urea nitrogen 5 mg/dL,
creatinine 0.23 mg/dL, glucose 108 mg/
dL, salicylates ,2 mg/dL, acetamino-
phen ,5mg/mL, and lactate 5.2 mmol/
L. Urine toxicology screen for opiates,
cocaine, amphetamines, barbiturates,
and benzodiazepines was negative. Al-
though the possibility of a narcotic in-
gestion cannot be completely excluded
based on the urine toxicology screen,
12
it is most likely that the painful in-
jection, not the naloxone itself, awoke
the patient. The Department of Children
and Family Services (DCFS) was noti-
ed, and the child was admitted to the
PICU for ethanol intoxication and fail-
ure to thrive (weight ,5% with 12 g/
d gain). He remained stable as his se-
rum ethanol level approached zero
over the next 12 hours. He was dis-
charged to foster care 8 days later with
normal neurologic function.
Case 2: Ethanol Concentration of
405 mg/dL
An 8-week-old full-term male infant was
brought in via ambulance for ALTE at
home. The babysitter witnessed 30
minutes of abnormal respirations with
periods of apnea and gasping, de-
pressed level of consciousness, and
minimal response to vigorous stimula-
tion. The childshistorywassignicant
for suspected in utero cocaine and
phencyclidine exposure, but he had
been healthy and exclusively formula-
fed since birth, with no additional to-
bacco or drug exposure. He resided
with the father exclusively, although the
mother had monitored visitation rights,
and his development had been normal.
On arrival to the ED, vital signs included
temperature of 96.6°F, heart rate of 168
CASE REPORT
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beats per minute, blood pressure of
101/71 mm Hg, respiratory rate of 48
breaths per minute, oxygen saturation of
98% on room air, and weight of 5.6 kg
(65%). The infant had normal color and
respirations but a weak cry and oppy
muscle tone alternating with right-sided
facial twitching and upper extremity
movements concerning for seizure. He
was not visually tracking and did not
respond to intravenous line placement,
and the emergency physician noted the
smell of alcohol. His blood glucose was
168 mg/dL and his serum ethanol con-
centration was 405 mg/dL. This level was
initially measured via an enzymatic ap-
proach but was conrmed via gas
chromatographyame ionization de-
tection. Other laboratory test results
were white blood cells 11.3 310
3
/mm
3
,
hemoglobin 10.1 g/dL, hematocrit 28.3%,
sodium 140 mEq/L, potassium 4.5 mEq/L,
chloride 106 mmol/L, bicarbonate 18
mmol/L, serum urea nitrogen 7 mg/dL,
creatinine 0.17 mg/dL, glucose 159
mg/dL, salicylates ,2mg/dL,acet-
aminophen ,5mg/mL, and lactate 5.7
mmol/L. When approached regarding
the ethanol level, the father stated that
he accidentallymixed the babysfor-
mula with gin instead of water. The DCFS
was notied and the patient was ad-
mitted to the PICU, where he was intu-
bated because of concern for apnea. The
patient had a prolonged hospital course
secondary to respiratory complications.
After 2 normal electroencephalograms
and a thorough neurology consult, the
twitching movements were ultimately
deemed not to represent seizure activity.
He was eventually discharged to foster
care in stable condition with outpatient
occupational therapy for risk of de-
velopmental delay.
DISCUSSION
The differential diagnosis for the infant
with an ALTE or neurologic abnormalities
is broad, and toxic ingestions remain an
uncommon cause. However, we identi-
ed 2 infants presenting with an ALTE
secondary to ethanol intoxication in
a several-month period. This suggests
that ethanol ingestion may be an un-
derrecognized cause of these symp-
toms, because of a lack of recognition on
the part of the practitioner or because of
hesitation to publish information re-
gardingrecognized cases. Ethanol levels
would not be advised as part of a stan-
dard ALTE or altered mental status
workup; however, the possibility should
be considered and pursued if the history
or physical examination is supportive.
Ethanol intoxication in infants produces
similar clinical effects as seen in adults:
central nervous system and respiratory
depression. However, 2 important dis-
tinctions are known. First, because of
poor glycogen stores in infants and the
ability of ethanol to inhibit gluconeo-
genesis, hypoglycemia is relatively com-
mon in pediatric ethanol ingestions,
FIGURE 1
Plot of ethanol (ETOH) concentrations (mg/dL) versus time (hr) for subjects 1 and 2. The horizontal line represents the closest approximation of where
elimination order appears to have changed.
e606 McCORMICK et al by guest on August 7, 2016Downloaded from
although both infants described here
maintained normal blood glucose
concentrations.
13,14
Second, infants
appear to metabolize ethanol faster
than adults.
15
It is likely that this ac-
celerated metabolism is the result of
different elimination kinetics.
In adults, ethanol is primarily metab-
olized by alcohol dehydrogenase to
acetaldehyde, which is subsequently
converted to acetate by acetaldehyde
dehydrogenase. Because alcohol de-
hydrogenase is a saturable enzyme,
ethanol metabolism follows Michaelis-
Menten kinetics, with rst-order elim-
ination at low concentrations and zero-
order elimination at a rate of 20 mg/
dL/h at concentrations exceeding 20
mg/dL.
16
There is some suggestion that
the infant liver has 10-fold less alcohol
dehydrogenase and an equal or greater
amount of catalase compared with adult
livers.
17
Therefore, ethanol metabolism
may follow rst-order elimination in
infants at higher concentrations than
observed in adults. Serial ethanol levels
were available for both of the infants
described here. Based on these 2
patients, it appears that ethanol follows
Michaelis-Menten kinetics, with a change
from rst-order elimination to zero-
order elimination at 225 mg/dL (Fig 1).
Both cases resulted in DCFS involvement.
While reporting of suspected child abuse
should commence based on clinical
suspicion, nal legal judgment may re-
quire some level of certainty of the validity
of the test. Previously, high lactate ($14
mmol/L) or high lactate dehydrogenase
($682 IU/L) levels have been shown to
cause false elevations of ethanol con-
centrations from 17 to 138 mg/dL when
measured by enzymatic assays but not
by gas chromotography.
18
Our 2 infants
had levels well above this range; how-
ever, in patients with lower levels and no
contributory history, conrmation by gas
chromatography or measurement of the
lactate and lactate dehydrogenase might
be helpful in conrming child abuse or
neglect.
These patients both presented with
ALTEs without a history of ingestion.
Although toxicology screening is pro-
bably unnecessary in the evaluation of
all patients presenting with an ALTE,
maltreatment should always be con-
sidered in the differential diagnosis. In
cases where there is concern for
maltreatment, toxic ethanol ingestion
should be considered, and appropriate
diagnostic testing should be obtained.
The correct diagnosis of this rare but
serious ingestion as a cause of an ALTE
has the potential to improve patient
outcomes.
ACKNOWLEDGMENT
We thank Dale Bikin, PharmD (Department
of Pharmacy, Banner Good Samaritan
Medical Center, Phoenix, AZ), for his as-
sistance in the kinetic calculations.
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CASE REPORT
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DOI: 10.1542/peds.2012-1652
; originally published online January 14, 2013; 2013;131;e604Pediatrics
Taylor McCormick, Michael Levine, Oma Knox and Ilene Claudius
Cause of ALTE
Ethanol Ingestion in Two Infants Under 2 Months Old: A Previously Unreported
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Cause of ALTE
Ethanol Ingestion in Two Infants Under 2 Months Old: A Previously Unreported
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    • "Previously published reports on infant kinetics suggest that infants may follow first-order elimination kinetics or a percent of concentration per unit time [3, 10, 12]. McCormick et al. demonstrated a transition from 1st-order to zeroorder kinetics at a blood ethanol level of approximately 225 mg/dL in the two infants they observed [11]. Our patient appeared to follow a constant elimination rate consistent with zero-order kinetics given the linear trendline with a coefficient of determination (í µí±… 2 ) value of 0.9787. "
    [Show abstract] [Hide abstract] ABSTRACT: Primary ethanol metabolism occurs through alcohol dehydrogenase, but minor metabolic pathways such as the P450 enzymes CYP2E1 and CYP1A2 and the enzyme catalase exist. These enzymes have distinct developmental stages. Elimination kinetics of ethanol in the infant is limited. We report the elimination kinetics of ethanol in a 5-week-old African-American male who had a serum ethanol level of 270 mg/dL on admission. A previously healthy 5-week-old African-American male was brought to the ED with a decreased level of consciousness. His initial blood ethanol level was 270 mg/dL. Serial blood ethanol levels were obtained. The elimination rate of ethanol was calculated to be in a range from 17.1 to 21.2 mg/dL/hr and appeared to follow zero-order elimination kinetics with a R (2) = 0.9787. Elimination kinetics for ethanol in the young infant has been reported in only four previously published reports. After reviewing these reports, there appears to be variability in the elimination rates of ethanol in infants. Very young infants may not eliminate ethanol as quickly as previously described. Given that there are different stages of enzyme development in children, caution should be used when generalizing the elimination kinetics in young infants and children.
    Full-text · Article · Dec 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Alcohol ingestion in the pediatric patient can be life threatening. Younger patients consume larger volumes per body weight with accidental ingestions, and children have more serious adverse effects at lower blood alcohol levels. Complications of alcohol poisoning can include hypothermia, hypoglycemia, seizures, coma, and death. We present the course of a 9-month-old female infant who became unresponsive at home and presented to the emergency department comatose. When her blood alcohol level registered 489 mg/dL, it was revealed that she had accidentally been given a bottle of formula mixed with vodka rather than water. The infant required intubation for severely depressed level of consciousness and aggressive fluid resuscitation for hemodynamic instability. She had a peak lactate level of 24 mmol/L and a peak blood alcohol level of 524 mg/dL. Based on the severity of her initial presentation, preparations were made for hemodialysis. The infant responded to supportive measures including mechanical ventilation, fluids, and dextrose, and hemodialysis was not necessary. Her alcohol clearance followed zero-order kinetics at an average rate of 28.6 mg/dL per hour over 15.5 hours from her peak level of 524 mg/dL to the lowest measured value of 80 mg/dL. The kinetics of ethanol clearance at this level of toxicity, which is the highest reported in an infant to date, enhance our knowledge of ethanol metabolism and will assist in management decisions in cases of severe intoxication.
    Article · Oct 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Introduction Ethanol has been used for years in neonatal and infant liquid medications, yet the pharmacokinetics, pharmacodynamics, and safety of ethanol in this vulnerable population have not been well characterized. The purpose of this review is to raise awareness of ethanol use as an excipient in neonatal and infant medications and to provide insight, based on the available evidence, into clearance rates of ethanol in babies. We also discuss ethanol pharmacokinetics in adults, theoretical pharmacokinetic changes in neonates and infants as it may apply to ethanol disposition, and case reports involving ethanol exposure in neonates and infants. Materials and methods This study was a narrative review in which relevant papers were selected using databases and scientific search engines such as PubMed with the key words ethanol, infant, and newborninfant. Results It remains unclear what ethanol exposure is safe for neonates and infants. The Food and Drug Administration and American Academy of Pediatrics have both taken action, by either setting limits of ethanol content in over-the-counter medications or by recommending restricted exposure to ethanol-containing pediatric formulations. Conclusions Until the short- and long-term health effects of chronic ethanol administration can be further characterized, ethanol-containing medications should be used with caution.
    Full-text · Article · Dec 2014
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