Management of Apparent Life-Threatening Events in Infants: A Systematic Review

PEPO-214; No. of Pages 15 pediatria polska xxx (2014) xxx–xxx

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Original research article/Artykuł oryginalny Reprint/Przedruk

Management of Apparent Life-Threatening Events in Infants: A Systematic Review Joel S. Tieder 1,*, Robin L. Altman 2, Joshua L. Bonkowsky 3, Donald A. Brand 4,5, Ilene Claudius 6, Diana J. Cunningham 7, Craig DeWolfe 8, Jack M. Percelay 9, Raymond D. Pitetti 10, Michael B.H. Smith 11 1 Department of Pediatrics, Division of Hospital Medicine, Seattle Children's Hospital and the University of Washington, Seattle, WA 2 Department of Pediatrics, Division of General Pediatrics, New York Medical College, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, NY 3 Department of Pediatrics, Division of Pediatric Neurology, University of Utah School of Medicine, Salt Lake City, UT 4 Office of Health Outcomes Research, Winthrop University Hospital, Mineola, NY 5 Department of Preventive Medicine, Stony Brook University School of Medicine, Stony Brook, NY 6 Department of Emergency Medicine, Los Angeles County and University of Southern California (LAC+USC), University of Southern California Keck School of Medicine, Los Angeles, CA 7 New York Medical College, Valhalla, NY 8 Department of Pediatrics, Pediatric Hospitalist Division, Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC 9 E.L.M.O. Pediatrics, New York, NY 10 Sedation Services and Emergency Department, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA 11 Northern Ireland Clinical Research Network for Children, Department of Pediatrics, Craigavon Hospital, Craigavon, Northern Ireland

Przedrukowano z The Journal of Pediatrics 163 (2013) s. 94–99, za zgoda Elsevier.

article info

Reprinted from The Journal of Pediatrics 163 (2013) pp. 94–99, with permission from Elsevier.

abstract Objective: To determine in patients who are well-appearing and without a clear etiology after an apparent life-threatening event (ALTE): (1) What historical and physical examination features suggest that a child is at risk for a future adverse event and/or serious underlying diagnosis and would, therefore, benefit from testing or hospitalization? and (2) What testing is indicated on presentation and during hospitalization? Study design:

DOI of original article: http://dx.doi.org/10.1016/j.jpeds.2012.12.086 * Corresponding author. Department of Pediatrics, Division of Hospital Medicine, Seattle Children's Hospital and the University of Washington, 4800 Sand Point Way NE, Mail Stop M1-13, Seattle, WA 98105. E-mail address: [email protected] (J.S. Tieder). http://dx.doi.org/10.1016/j.pepo.2014.04.008 0031-3939/© 2013 Mosby Inc. All rights reserved.

Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

PEPO-214; No. of Pages 15

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Systematic review of clinical studies, excluding case reports, published from 1970 through 2011 identified using key words for ALTE. Results: The final analysis was based on 37 studies; 18 prospective observational, 19 retrospective observational. None of the studies provided sufficient evidence to fully address the clinical questions. Risk factors identified from historical and physical examination features included a history of prematurity, multiple ALTEs, and suspected child maltreatment. Routine screening tests for gastroesophageal reflux, meningitis, bacteremia, and seizures are low yield in infants without historical risk factors or suggestive physical examination findings. Conclusion: Some historical and physical examination features can be used to identify risk in infants who are well-appearing and without a clear etiology at presentation, and testing tailored to these risks may be of value. The true risk of a subsequent event or underlying disorder cannot be ascertained. A more precise definition of an ALTE is needed and further research is warranted. (J Pediatr 2013;163:94-9). © 2013 Mosby Inc. All rights reserved.

Methods ALTE ED EEG GER RR SIDS URI

Apparent life-threatening event Emergency department Electroencephalogram Gastroesophageal reflux Relative risk Sudden infant death syndrome Upper respiratory tract

An apparent life-threatening event (ALTE) was defined at a consensus development conference convened in 1986 by the National Institutes of Health to address the relationship between sudden infant death syndrome (SIDS) and apnea [1]. An ALTE was defined as ‘‘an episode that is frightening to the observer and that is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.’’ There are three significant challenges for clinicians managing patients who have experienced an ALTE. First, the infant is often asymptomatic at presentation. Second, although most ALTEs represent a benign event, they can signify a more serious illness, such as sepsis or child maltreatment. Third, the decision to perform tests or hospitalize a patient is fraught with uncertainties. Clinicians may hospitalize the infant to facilitate observation, educate the parents, or complete tests. Yet, this approach may subject the patient to unnecessary risk and increase parental anxiety without improving outcomes [2, 3]. Given a lack of consensus regarding the management of infants who are initially well-appearing and without a clear etiology, an ALTE expert panel systematically reviewed the literature to answer two key questions: (1) What historical and physical examination features on presentation suggest that an infant is at risk for a future adverse event and/or serious underlying diagnosis and would therefore benefit from diagnostic testing and hospitalization? and (2) What testing is indicated on presentation and during hospitalization?

Pertinent articles were identified using the stepwise approach specified in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement [4]. PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane Library databases were searched to identify articles published in the English-language from January 1970 through May 2011 that addressed ALTEs in children less than 24 months of age. We conducted keyword searches to identify articles with at least one of the following terms in the title or abstract: ALTE, apparent life-threatening event, life-threatening event, near-miss sudden infant death syndrome, near-miss SIDS, aborted sudden infant death syndrome, aborted SIDS, aborted crib death, or aborted cot death. Additional articles were identified by examining the cited references of review articles published between January 2000 and December 2010. Next, at least 2 reviewers independently scored abstracts (on a Likert scale) for relevance to the clinical questions using a validated methodology [5, 6]. Then two independent reviewers critically appraised the full text of the identified article using a structured data collection form based on published guidelines for evaluation of the medical literature and recorded the study's relevance to the given clinical question, research design, setting, time period covered, sample size, patient eligibility criteria, data source, variables collected, key results, study limitations, potential sources of bias, and stated conclusions [7, 8]. If at least 1 reviewer judged an article to be relevant based on the full text, then 2 reviewers critically appraised the article and determined by consensus what evidence, if any, should be cited in the systematic review. The lead author or another panel member served as third reviewer to resolve disagreements. The search initially identified 1388 articles, of which 1351 were systematically excluded.

Results The review identified 37 studies. Fourteen studies investigated historical and physical examination features as potential

Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

PEPO-214; No. of Pages 15 pediatria polska xxx (2014) xxx–xxx

indications for hospitalization or predictors of subsequent adverse events (Table I; available at www.jpeds.com). These studies evaluated age, sex, ethnicity, history of prematurity, occurrence of multiple ALTEs, concern for child maltreatment, concern for seizures, presence of upper respiratory tract (URI) symptoms, smoke exposure, severity of the ALTE event or need for cardiopulmonary resuscitation, prior diagnosis of gastroesophageal reflux (GER) or GER symptoms, birth order, and mode of delivery. Thirty-one studies evaluated diagnostic testing for GER, neurologic abnormalities, anemia, infections, toxic ingestions, metabolic disorders, and cardiac dysrhythmias (Table II; available at www.jpeds.com). All studies used an observational cohort design and only 4 studies used valid control groups. None of the studies completely addressed the clinical questions because of methodologic limitations. These included insufficient samples sizes to detect rare events and limited generalizability of findings when patients were recruited from high risk referral centers. Heterogeneous outcomes and follow-up periods across different studies made it difficult to pool results.

Predictors from History and Physical Examination Age and Prematurity Five studies investigated the relationship between chronological age and a subsequent adverse event or a significant diagnosis following presentation to an emergency department (ED), and their findings conflicted (Table I). Two studies found younger age to be associated with higher risk. In 1 study, infants under 30 days of age and greater than 30 weeks gestational age were more likely (OR 3.3; P = .13) to have a recurrent ALTE or serious diagnosis during the hospitalization or within 48 hours after discharge from the ED [9]. In another study, hospitalized infants less than 43 weeks post-conceptual age were more likely to have a subsequent event (relative risk [RR] 5.2; 95% CI 2.6-10.3) during the course of a hospitalization [10]. In contrast, two studies with different study populations found younger age to be associated with lower risk. In 1 study of infants under 6 months presenting with 1 or more ALTE features (including some patients on home monitoring), those under 2 months old were less likely to experience a recurrent ALTE during hospitalization (RR = 0.12; 95% CI, 0.03-0.52) [11]. In another study of infants under 1 year of age and including some with an abnormal physical exam, age over 2 months was associated with higher risk for recurrent ALTE (RR 2.9; 95% CI, 1.3-6.8) [12]. Finally, in another study with a 5-year follow-up period, age was not associated with child abuse, adverse neurologic outcome, or chronic epilepsy [13]. Four studies identified a history of prematurity as a risk factor for subsequent ALTEs or a serious underlying diagnosis. The first reported an OR of 14 (P = .009), [9] and the 2 remaining studies reported RRs of 2.95 (95% CI, 1.0-8.7) [11] and 6.3 (95% CI, 3.6-11) [10], respectively, and the last 1 reporting risk attenuation at 48 weeks post-conceptual age.

3

seizures), either occurring in clusters and/or recurring after discharge [10–15]. One study evaluated the risk conferred alone by a history of multiple ALTEs occurring during the 24 hours preceding ED presentation, and it demonstrated an increased likelihood (OR 4.0; P < .001) of recurrent ALTE or serious diagnosis during the hospitalization or within 48 hours after discharge from the ED [9].

Suspected Child Maltreatment Child maltreatment was reported in 0.4%-11% of well-appearing infants presenting to an ED or admitted to the hospital after an ALTE [13, 14, 16–18]. Documented types of child maltreatment reported to cause an ALTE included intentional smothering, intentional poisoning, non-accidental head trauma, other inflicted physical injury, emotional abuse, induced illness, and Munchausen by proxy syndrome [19, 20]. In a study with a 5-year follow-up period, suspicious physical findings, retinal hemorrhages, story discrepancy, parents calling emergency services for the ALTE, and the presence of vomiting or irritability at the time of presentation were associated with increased risk for abusive head injury [17]. Other features associated with cases of maltreatment included multiple presentations of ALTEs (especially with a single witness), history of unresponsiveness, limpness, hypotonia, unexpected or sudden death of a sibling, and facial bruising or bleeding [16, 19, 20]. A screening dilated fundoscopic exam was positive in some cases when there was an index of suspicion for non-accidental head trauma, but it was only 50% sensitive [16–18, 21].

Suspected Seizures Three studies of ALTEs as a manifestation of seizures reported an occurrence rate of up to 10% of the patients evaluated [13, 21, 22]. A long-term follow-up study concluded that when seizures were suspected, inpatient management after the event did not establish the diagnosis or improve outcome [13, 22].

URI Symptoms One study reported an increased risk of subsequent ALTEs in patients presenting with URI symptoms (RR = 11.2; 95% CI, 6.7-18.9) compared with patients presenting with ALTEs from another or an unidentified cause [10].

Other In studies that evaluated sex, ethnicity, severity of the ALTE event or need for cardiopulmonary resuscitation, prior diagnosis of GER or GER symptoms, smoke exposure, birth order, and mode of delivery, the evidence was inadequate to support a conclusion [9–14, 18–22].

Multiple ALTEs

Diagnostic Testing

Many studies report higher rates of underlying disorders in patients with multiple ALTEs (eg, child maltreatment and

Six studies examined a standard approach to testing for all patients, regardless of presenting features (Table II) [11, 12,

Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

Al Kindy, 2009

Altman, 2003

Bonkowsky, 2009

[10]

[14]

[13]

[21]

Study design

Retrospective cohort

Prospective cohort

Retrospective cohort

Retrospective cohort

Sample size

625

243

471

471

Control group (n, description)

n/a

n/a

n/a

n/a

Primary settingy

IP

IP

IP

IP

Age

Infant

0-12 m

0-12 m

0-12 m

Inclusion criteria

Single ALTE (coded) no obvious cause

ALTE (color, tone, labored breathing, altered mental status) ALTE (apnea, color, mental status, tone, movement)

Exclusion criteria

Significant PMH, likely alternative diagnosis

Subsequent ALTE during study period

Likely alternative diagnosis or suggestive PMH

ALTE (breathing irregularity, color, mental status, tone,

Likely alternative diagnosis or suggestive

movement)

PMH

Follow-up period

24 h An

Hospital stay

2.5-7.5 y

2.5-7.5 y

Outcome or endpoint

‘‘extreme event’’ within 24 h of admission defined as central apnea >30 s, bradycardia >10 s, and desaturation >10 s with pulse oximetry <80% Discharge diagnosis

Death Child abuse Chronic epilepsy Developmental delay

Seizure, chronic epilepsy, and discharge diagnosis

Risk factors

Major findings

Major limitations

assessed*

reported

or sources of biasz

-Recurrent or ‘‘extreme events’’ were associated with infants with URI symptoms, born premature, and <43

-Only included hospitalized patients -Short follow-up period -Narrowly

wk postconceptional age

restricted endpoint

Age Symptoms defining ALTE Suspicion for

-Wide spectrum of diagnoses -Child

-Only included hospitalized patients

child maltreatment Age Prematurity Family history Previous event

maltreatment in 2.5% -Hospitalized ATLE patients are at risk for child abuse and neurologic disorders -IP neurologic

-Short follow-up period -Only included hospitalized patients (nonstandard admission

evaluation is low yield -Idiopathic epilepsy, cortical dysplasia, complex partial seizures, and

criteria)

Age pematurity URI

Seizures, convulsions, abnormal movement, idiopathic

neurodegenerative disorders can present as ALTEs -Discharge diagnosis after ALTE hospitalization is poorly predictive of

-Only included hospitalized patients (nonstandard admission criteria)

those who develop epilepsy -50% of patients who develop chronic epilepsy will be diagnosed with

Claudius, 2007

[9]

Prospective cohort

59

n/a

ED

0-12 m

ALTE (NIH definition)

Significant PMH, prematurity <30 wk

1 w-3 mo

Subsequent ALTE, intervention, or

Age Multiple ALTEs

seizures within 1 week of their ALTE and a majority will be diagnosed within a month -Infants >30 d may be safely discharged

diagnosis mandating admission

Prematurity

from the hospital

-Small sample size from single tertiary care RC

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Bonkowsky, 2008

Ref.

PEPO-214; No. of Pages 15

Author, year

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Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

Table I – Studies included in systematic review that address the historical and physical examination features suggesting risk for a future adverse event (n = 14)

Prospective cohort

108

n/a

IP

15 d-2 y

ALTE (NIH definition)

Suspected child abuse, history of trauma, other causes

Hospital stay

Retinal hemorrhage on fundoscopy

Age ALTE characteristics Multiple ALTEs

-ALTEs do not cause retinal hemorrhage

of retinal hemorrhages Davies, 2002

DePiero,

[12]

[11]

2004

Guenther, 2010

Hewertson,

Southall, 1997

Retrospective

65

150

n/a

n/a

ED

IP

0-10 m

0-6 m

cohort

[17]

[22]

1994

Pitetti, 2002

Prospective cohort

Retrospective cohort

Retrospective

627

6

n/a

n/a

IP

RC

0-12 m

2-12 m

cohort

[16]

[19]

Prospective cohort

Retrospective cohort

128

36

n/a

46, Non-traumatic physiologic recurrent requiring CPR

IP

RC/IP

0-24 m

2-4 m

ALTE (NIH definition), fever, abnormal limb movement

Febrile seizure

ALTE ($2: apnea,

Bradycardia

color, gag, choke, parental resuscitation, tone, single event within 24 h, stable vitals

only on apnea alarm

ALTE (apnea, color, mental status, tone, movement)

Prematurity/ likely alternative diagnosis or suggestive PMH

ALTE, EEG

Significant

changes, preceding hypoxia ALTE (NIH definition)

PMH, likely alternative diagnosis Evidence of abuse on exam

Recurrent ALTEs requiring CPR, suspicion of abuse

None

6 m (No death at 3 y)

Hospital stay

0-5 y

n/a

1y

IP observation period

-Excluded patients with suspected child abuse -Inadequate

Significant diagnosis after standardized evaluation

Gestational age Respiratory symptoms Medications

-History and Physical exam can guide medical decision making for

follow-up to detect child maltreatment -Small sample size -‘‘Standardized evaluation’’ not

tests

well defined

Positive test

Family history of asthma, SIDS, child protection service involvement Age Pertussis

-A majority can be

-Short follow-up

Significant medical intervention

symptoms

managed with a limited ED diagnostic evaluation and period of observation

period

Diagnosis of abusive head trauma

Suspicion for child maltreatment

-Almost one-half of abusive head trauma cases are missed by ED management -1.4% diagnosed with abusive head

-Only included hospitalized patients (nonstandard admission criteria)

Positive EEG

Suspicion for

trauma -Vomiting, irritability or 911 call risk factors for head trauma -Seizures can cause

associated with hypoxemia

seizures

hypoxemic episodes

Positive fundoscopy by ophthalmologist

Suspicion for child maltreatment

-Evaluation should include fundoscopic examination

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[18]

-Small sample

pediatria polska xxx (2014) xxx–xxx

Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

Curcoy, 2010

size -Only evaluated a high risk group -Sampling bias since only 57% of patients had fundoscopy

Diagnosis of child maltreatment from

Suspect child maltreatment

-ALTEs may be symptom of child

-Unclear contributory value of history, PE, and CT head -Descriptive study of high

covert video

Age Prematurity Family history of SIDS

maltreatment

risk population

5

Ref.

Study design

Sample size

Steinschneider,

[15]

Retrospective

182

Truman, 2002

n/a

Primary settingy

RC

Age

0-6 m

cohort

[20]

Retrospective cohort

138

n/a

IP

2 d-4 y

Inclusion criteria

Exclusion criteria

ALTE (apnea,

Insufficient

respiratory difficulty), home on apnea monitor

time on home monitor

Idiopathic suffocation, choking, pacemaker, recurrent apnea, bradycardia, cyanosis, late

Single admission, no FH of ALTE

apnea, arrest

Follow-up period

2m

$1 mo

Outcome or endpoint

Risk factors assessed*

Major findings reported

Major limitations or sources of biasz

Prolonged apnea or

ALTE

-The clinical

-Descriptive

bradycardia on home monitoring for 2 months

characteristics

characteristics of an ALTE cannot be used to determine the need for followup studies and/or home monitoring

study of high risk population without comparison group

Diagnosis of child maltreatment

Recurrent ALTEs Facial blood ALTE/SIDS in sibling Suspected abuse

The following are risk factors for child maltreatment: recurrent or poorly explained ALTE, same parent or caregiver as only

-Descriptive study of high risk population without comparison group

witness, presence of blood on face or mouth, unexplained bruising, siblings with ATLES or SIDS

CPR, cardiopulmonary resuscitation; CT, computed tomography; FH, family history; IP, inpatient; n/a, not applicable; NIH, National Institutes of Health; PE, physical exam; PMH, past medical history; RC, referral center. * Sex, ethnicity, severity of the ALTE event or need for CPR, prior diagnosis of GER or GER symptoms, birth order and route, and smoke exposure were evaluated, but there was inadequate evidence to support a conclusion.9-15,18-21 y Study setting [RC; IP; ED]; studies labeled ‘‘ED’’ also followed patients in the IP setting. z Not all limitations are mentioned. Nearly all studies had limited external validity due to small sample size (eg, wide CI), different study population (eg, recruited from a sleep study center), different outcomes or endpoints (eg, underlying diagnoses vs recurrent event), and different follow-up periods (24 h-7 y).

pediatria polska xxx (2014) xxx–xxx

1998

Control group (n, description)

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Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

Table I (Continued ) Author, year

Study

design

2003

Crowcroft,

[25] Prospective

Brand, 2005

cohort

[37] Prospective

cohort

cohort

Subsequent ALTE

criteria

Exclusion

suggestive PMH

status, tone,

142

243

n/a

n/a

ICU

ED

0-5 m

0-12 m

testing

leading to

apnea

pulmonary history

ALTE, bradycardia, Significant

on fluoroscopy) contributory result is

low clinical suspicion of pertussis can have

serology, or culture)

pertussis infections

respiratory failure and

Patients with ALTES and

cases

to diagnosis in >70% of

-History and PE can lead

ICU

with respiratory failure in

-Only included patients

(eg, anemia on CBC or GER

likelihood of a even lower

-Clinical significance of positive tests uncertain

-Likelihood of a positive result is low and the

month

will be osed within a

their ALTE and a majority

seizures within 1 week of

will be diagnosed with

develop chronic epilepsy

-50% of patients who

who develop epilepsy

poorly predictive of those

ALTE hospitalization is

-Discharge diagnosis after

ALTEs

pertussis (PCR,

Positive test for

Pertussis RSV

nonspecific

history and PE

n/a

CBC and

diagnosis Positive

diagnosis

Anemia Pertussis

leading to

labored breathing, status)

Neurologic

and neurodegenerative

or altered mental

Stay

admission

Positive test

criteria)

complex partial seizures,

imaging EEG

Hospital

Previous ALTE

(non-standard admission

cortical dysplasia,

disorders can present as

hospitalized patients

-Idiopathic epilepsy,

-Only included

criteria)

(non-standard admission

hospitalized patients

-Only included

imaging EEG

is low yield

-IP neurologic evaluation

neurological disorders

child abuse and

patients are at risk for

CXR uncertain

positive urine culture and

-Clinical significance of

-Short follow-up period

ophthalmologist included

-Only patients seen by an

of Biasy

or Sources

Neurologic

imaging EEG

Positive test

ALTE (color, tone,

tone, movement)

seizures)

diagnosis

discharge

suggestive PMH

mental status,

with

Seizure, chronic epilepsy, and

2.5-7.5 y

delay

Developmental

Chronic epilepsy

diagnosis or

movement)

diagnosis or

color, mental

-Hospitalized ALTE

may have benefits

ALTE (apnea,

Death Child abuse Neurologic

with no signs suggestive

well appearing patients

-Testing is low yield in

identify child abuse

examination can help

-Fundoscopic

reported

diagnosis

SBI

Fundoscopy

assessed

Major Limitations

Major findings

-CXR and urine culture

evaluation

PE Positive sepsis

Positive history or

hemorrhage

positive for retinal

Test or condition

of SBI

2.5-7.5 y

stay

Hospital

stay

Fundoscopy

endpoint

or

Outcome

infectious Likely alternative

None

period

Hospital

period

Follow-up

status), final

Altered mental

labored breathing,

ALTE (color, tone,

mental status

definition), altered during study

ALTE (NIH

criteria

Inclusion

irregularity, color,

0-12 m

0-12 m

0-12 m

0-12 m

Age

patients

IP

IP

ED

ED

setting*

Primary

Likely alternative

n/a

n/a

n/a

n/a

(n, description)

group

Control

ALTE (breathing

[21] Retrospective 471 (25

cohort

[13] Retrospective 471

cohort

size

Sample

120

[40] Retrospective 95

cohort

[32] Prospective

Ref.

2009

Bonkowsky,

2008

Bonkowsky,

2008

Altman,

2007

Altman,

year

Author,

Table II – Studies included in systematic review that address testing at presentation and during hospitalization (n = 31)

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Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

1989

Hickson,

1994

Hewertson,

2010

Guenther,

2008

Genizi,

2004

Study

65

108

cohort

[42] Retrospective 9

cohort

[22] Retrospective 6

cohort

[17] Retrospective 627

cohort

[33] Retrospective 93

cohort

size

Sample

[11] Retrospective 150

cohort

[12] Prospective

cohort

[18] Prospective

design

n/a

n/a

n/a

n/a

n/a

n/a

n/a

(n, description)

group

Control

Unclear

RC

IP

IP

IP

ED

IP

setting*

Primary

5d-4 m

2-12 m

0-12 m

0-12 m

0-6 m

0-10 m

15 d-2 y

Age

fundoscopy

causes of retinal

diagnosis or suggestive PMH

status, tone, movement)

likely alternative ALTE, evidence of

None

preceding hypoxia diagnosis

changes,

Significant PMH,

alternative

color, mental

ALTE, EEG

Prematurity/likely

None

ALTE (apnea,

definition)

ALTE (NIH

vitals

within 24 h, stable

tone, single event

n/a

n/a

0-5 y

1-7 y

Case report

hypoxemia

associated with

Positive EEG

trauma

abusive head

Diagnosis of

etiology

Neurologic

intervention

Significant medical

stay

Positive test

resuscitation,

on apnea alarm

Hospital

parental

color, gag, choke,

ALTE ($2: apnea,

evaluation

diagnosis after

Significant

movement

at 3y)

Battery of tests

Fundoscopy

endpoint

or

Outcome

standardized

Bradycardia only

Febrile seizure

6 m (No death

hemorrhage on

hemorrhages

stay Retinal

trauma, other

Hospital

period

Follow-up

abuse, history of

Suspected child

criteria

Exclusion

abnormal limb

definition), fever,

ALTE (NIH

definition)

ALTE (NIH

criteria

Inclusion

Test or

Toxicology

imaging EEG

Neurologic

Skeletal survey

Fundoscopy

imaging

Neurologic

imaging EEG

Neurologic

testing

Nonspecific

can cause ALTE

-Intentional poisoning

hypoxemic episodes

-Seizures can cause

head trauma

with increase risk for

911 call are associated

-Vomiting, irritability or

management

missed by ED

head trauma cases are

-Almost half of abusive

studies

extensive laboratory

tools before resorting to

are the major diagnostic

-The history and PE still

-Small case reports only

risk group

-Only evaluated a high

-Small sample size

criteria)

(non-standard admission

hospitalized patients

-Only included

not standardized

relatively uncommon cause of ALTE

diagnostic criteria were

leading to seizures are

-Neurological impairment -Admission and

0.5-7.0)

diagnostic tests (95%CI;

122 patients with

-Positive tests in 2.5% of

patients

were positive in some

testing, pertussis, CXR

-Short follow-up period

CXR, reflux testing, and anemia

screen

Pertussis SBI

significance of positive

blood glucose, metabolic -CBC, urine culture, reflux

-Uncertain clinical

abnormalities in EKG,

unclear

-There were no

testing

decision to test are

features informing the

-Historical and PE

of Biasy

or Sources

testing

decision making for

exam can guide medical

-History and Physical

detect child maltreatment

-Inadequate follow-up to

suspected child abuse

-Excluded patients with

reported

Major Limitations

Major findings

Nonspecific

EKG Metabolic

SBI Toxicology

GER Anemia CBC

hemorrhages

cause retinal

ALTEs do not

assessed

condition

8

DePiero,

2002

Davies,

2010

Curcoy,

year

Ref.

Table II (Continued )

Author,

PEPO-214; No. of Pages 15 pediatria polska xxx (2014) xxx–xxx

Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

2005

Pitetti,

2002

Pitetti,

1994

Penzien,

2003

Okada,

2005

Mousa,

2009

Mittal,

1990

Kahn,

69

25

189

20

cohort

[36] Prospective

cohort

[16] Prospective

cohort

108

128

[44] Retrospective 197

cohort

[23] Prospective

cohort

[27] Prospective

cohort

[39] Prospective

cohort

[28] Prospective

matched

Age-

108,

n/a

ALTE

siblings of

patients 5,

of SIDS

close relatives

disorders 72,

of metabolic

Symptoms

55,

n/a

n/a

n/a

infants

10, well

ED

IP

pediatric

diagnosis,

resuscitation

monitoring

impedance

0-24 m

0-24 m

-Small sample size

small to detect infection

-Sample size may be too

high risk group

-Only evaluated perceived

-Only evaluated perceived

definition)

ALTE (NIH

definition)

ALTE (NIH

or ALTE

relative with SIDS

ALTE or close

PMH

Prematurity,

1 year

Anemia on CBC

ophthalmologist

exam

Positive fundoscopy by

1 year

abuse on

Evidence of

MCAD deficiency

Anemia CBC

imaging

Neurological

Fundoscopy

have increased risk for

MCAD

-Unclear for study cohort

comparison group -Unclear if treatment is effective -Relationship to oxygen carrying capacity not addressed

ALTE and age-matched control patients -Anemia in patients with recurrent ALTEs suggest that iron deficiency may recurrence of events

be associated with the

causation without patients with a single

increased risk or

-Does not demonstrate

CT head

value of history, PE, and

-Unclear contributory

fundoscopy

57% of patients had

-Sampling bias since only

comparison group

MCH, and MCV than

ALTEs have lower Hb,

-Patients with recurrent

examination

include fundoscopic

-Evaluation should

MCAD

-ALTE patients do not

testing Metabolic

Nonspecific

approach

resuscitation Positive test for

Metabolic

structured

required vigorous

n/a

causative

imaging SBI EKG

diagnosis after

color change),

None

not proven to be

Neurological

Significant

-GER was prevalent but

-No comparison group

high risk group

stay

GER can cause ALTE

acid reflux

reflux, acid reflux or non-

between apnea and total

-Little association

ALTE

presenting to the ED with in all age groups

uncommon in patients

-SBI is extremely

is not a cause of apnea

-Acidic esophageal reflux

Hospital

GER testing

impedance

and multichannel

None

and multichannel

monitoring

esophageal pH

esophageal pH

graphy,

GER Pneumo-

SBI

pneumography,

Apnea and reflux

SBI

Positive test for

probe

monitoring pH

Polygraphic

suspected GERD

n/a

4w

acidification

esophageal

episodes of

Apnea with

on

None

bronchiolitis

Febrile seizure,

n/a

definition),

ALTE (NIH

definition)

prematurity

alternative

required vigorous

ALTE (NIH

GER, vomiting,

color change),

ALTE (apnea, limp, Significant PMH,

9 d-11.1 m ALTE (apnea, limp

1-19 m

0-12 m

4-25 w

Ambulatory 2 d-108 m

ED

RC-GI

ED

RC-sleep

PEPO-214; No. of Pages 15 pediatria polska xxx (2014) xxx–xxx

9

Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

1995

Tirosh,

1990

Tirosh,

1989

Sunkaran,

Study

16

23

cohort

[34] Retrospective 46

cohort

[38] Prospective

cohort

[24] Retrospective 111

cohort

[30] Prospective

cohort

size

Sample

274

[35] Retrospective 41

cohort

[43] Prospective

design

n/a

n/a

RC-apnea

RC-Apnea

RC

specified

Not

6 d-9 m

1-12 m

assessed

Positive pH probe

below mean

Hemoglobin level

screen

GER

Anemia CBC

increased risk or

-Does not demonstrate

of Biasy

or Sources

CNS disorder

Positive

Change in tone

Not specified

EEGDiagnosis of

None

change, and

Apnea, color

value

evaluation is of much

EEG

causation without

increased risk or

-Does not demonstrate

comparison group

progression of illness or that a period of observation would have

disorders should be routinely ruled out

been beneficial

EEGs altered the natural clinical clues CNS

and Power to support that

-Inadequate study design

risk group

-Only tested perceived

high risk group

-Only evaluated perceived

high risk group

-Only evaluated perceived

-Small sample size

-Non-valid control group

effective

-Even in the absence of

Routinely

-EEG is recommended

essential

support system is

-Adequate follow-up and

selected group of patients

be recommended in a

-Home monitoring -Home monitors should

pH probe

study approach’’

hypotonia, or LOC Plus stimulation

Polysomnographic monitoring and

‘‘structural

infants, in-patient

-In apparently healthy

abnormalities

pneumogram

-Theophylline improves

considered

color change,

Significant

Home monitor

pneumogram

Positive

Nonspecific

testing

‘‘structural approach’’

Nonspecific

GER testing

diagnosis after

Significant

monitoring should be

-Intraesophageal pH

reflex hypoxemia

testing

Not specified

2-10 m

-GER episodes may be

oximetry

directly associated with

ALTE

common in infants with

Continuous

pH probe

diagnosis after

None

arrest

Prolonged apnea,

event

with desaturation

more of following:

Apnea with 1or

ALTE

ALTE

-Non-clinical GER is

below the mean

had kemoglobin levels

-34 infants of 41 tested

reports

consistent with parental

toxicology screens not

ED for ALTE have positive causation without

children presenting to an

-A substantial number of

reported

Major Limitations

Major findings

-Unclear if treatment is

cough/wheeze

n/a

Test or condition

Positive toxicology Toxicology

endpoint

or

Outcome

comparison group

None

None

n/a

period

Follow-up

monitoring Prematurity,

None

None

criteria

Exclusion

referred for home

resuscitation,

required vigorous

First/single ALTE,

definition)

ALTE (NIH

criteria

Inclusion

w/o apnea

1 w-10 m

2 w-12 m

0-24 m

Age

chronic

RC/IP

RC

ED

setting*

Primary

vomiting

6, GER-

n/a

n/a

(n, description)

group

Control

10

See, 1989

1992

Poets,

2008

Pitetti,

year

Ref.

Table II (Continued )

Author,

PEPO-214; No. of Pages 15 pediatria polska xxx (2014) xxx–xxx

Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

17

cohort

0-60 d 6m

actual clinical events well-appearing, afebrile

-SBI occur in 2.7% of

-SBI higher with history of

with an ALTE

SBI

appearing

microbiologic test

Positive

infants under 60 days

diagnosis

Likely alternative

afebrile, well-

definition),

ALTE (NIH

theories of cardiac

[41] Retrospective 182

-Provides data linking

treatment

with ALTE

etiology of SIDS with

determines therapy

with ALTE infrequently

monitoring

requiring

monitoring in infants

Holter

dysfunction

-EKG and Holter

EKG

siblings of patient

IP

EKG with dysrhythmia or

with ALTE or

n/a

1-32 m with sinus node

prematurity

Significant PMH,

Included infants

Definition of ALTE

compared to controls

polygraphic monitoring

positive pH and

more likely to have

experienced an ALTE are

-Patients who have

in all age groups

small to detect infection

-Sample size may be too

high risk group

-Only tested perceived

-Non-blinded

-No causation

group

-Only tested high risk

significant association

-No statistically

-Small sample size

single center

practice management of a

that can cause ATLEs

-Descriptive study of

diseases or conditions

-Small sample size

-Various identifiable

apnea

cohort

0-12 m

recording

polygraphic

GER testing

Pertussis

Metabolic

EKG

EEG

GER

is unclear.

100

stimulation

vigorous

requiring

GER and

infants with

RC-Cardiac

resuscitation

stimulation

n/a

vigorous

vigorous

34 of 130

feed, required

requiring monitoring and

esophageal pH

Positive

color) <2 h after a

None

patients

Any PMH

battery of test

imaging, EEG

ALTE (apnea,

diagnosis after

Hospital stay only Significant

definition), CNS

ALTE (NIH

apnea -Seizures may cause

between GER events and

temporal association

-There is no consistent

with pH probe

Seizure

polygraphic study

Recurrent apnea

regurgitation

Not specified after GER event on GER

None

None

evidence of

ALTE with

continuous

2-36 w

23 d-13 m

3-37 w

hypotonia, and

ICU

IP

IP

ALTE

?

n/a

n/a

observational

[45] Prospective

cohort

[26] Retrospective 49 of 130

case series

[31] Retrospective 19

cohort

[29] Prospective

event), and different follow-up periods (24 h vs 7 y).

yNot all limitations are listed. Nearly all studies had limited external validity due to small sample size (eg, wide CIs), different study population (eg, recruited from a sleep study center), different outcomes or endpoints (eg, underlying diagnoses vs recurrent

*Study setting [RC; IP; ICU; ED; ENT]; studies labeled ‘‘ED’’ also followed patients in the IP setting.

virus; SBI, serious bacterial infection.

CBC, complete blood count; CNS, central nervous system; CXR, chest radiograph; EKG, electrocardiogram; ENT, otolaryngology; ICU, intensive care unit; LOC, loss of consciousness; MCAD, medium-chain acyl-CoA dehydrogenase; RSV, respiratory syncytial

2009

Zuckerbraun,

Woolf, 1989

Wauters, 1991

Veereman-

Tsukada, 1993

Tirosh, 1996

PEPO-214; No. of Pages 15 pediatria polska xxx (2014) xxx–xxx

11

Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

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pediatria polska xxx (2014) xxx–xxx

18, 24–26]. In an ED study, 2.5% of tests ordered resulted in a diagnosis (pertussis, anemia, and hypoglycemia) but the diagnosis was always suggested by a careful history [11]. Another study found that testing contributed to the diagnosis in only 14% of patients with a negative history and physical exam [26]. The conditions most frequently evaluated with testing were GER, neurologic abnormalities, anemia, infections, toxic ingestions, metabolic disorders, and cardiac dysrhythmias.

testing in 0.75%-7.0% of ALTE cases. Eight studies tested patients for serious bacterial infections [11, 12, 26, 32, 38–41]. In afebrile and well-appearing patients, none had bacterial meningitis as the underlying cause of the ALTE and 0.7% had a urinary tract infection. Bacteremia was found in the context of afebrile infants only in premature patients or in those with multiple ALTEs on the day of admission [41].

GER

Three studies examined the role of a toxicology screen [12, 42, 43]. One demonstrated that intentional poisoning presenting as an ALTE can be detected with a toxicology screen [42]. Two studies evaluated toxicology screening in children evaluated in the ED [12, 43]. One study screened 54% of patients with a standard urine test for controlled substances and only 1 patient tested positive (for opioids discovered to be due to a prescribed cough medication) [12]. Another study tested 46% of patients with gas chromatography/mass spectrometry [43]. Substances that could have caused the ALTE (eg, controlled substances or over-the-counter medication), but were not elicited by the history, were found in 8.4% of the cases. Details about the decision to screen and the context of the exposure (eg, intentional or not) were incomplete, and the role of the substance in the ALTE could not be proven (eg, no control population).

Five studies used polygraphic recordings to evaluate the association between ALTE and a variety of GER related outcomes. None found a correlation between apnea or recurrent ALTEs and the frequency, duration, or acidity of GER episodes [27–31]. One study found a correlation between GER episodes and oxygen desaturations to less than 89% [31]. Four studies reported ALTE patients to have an increased incidence of GER episodes compared with controls. Two studies found high rates of GER (87% [31] and 89% [12]), but the latter concluded that 48% of the ALTEs in those cases were caused by other concurrent diagnoses. Two other studies found a rate of GER to be less than 32% [25, 32].

Neurologic Three studies reported inflicted brain injury, collectively ranging from 0.4% to 2.3% of infants hospitalized without obvious physical exam findings of abuse, upon presentation to the ED after an ALTE [16, 17, 21]. In this population, head computed tomography was 100% sensitive in diagnosing inflicted head trauma, whereas a dilated fundoscopic exam was only 50% sensitive [16]. Five studies examined the role of brain imaging to evaluate seizures [13, 22, 23, 26, 33]. In two studies, abnormal central nervous system imaging in previously-well hospitalized ALTE patients had a sensitivity of only 6.7% for predicting the development of epilepsy over the 5-year follow-up period [13, 22]. All head imaging was normal in 2 other studies [23, 33]. Seven studies addressed the role of electroencephalograms (EEGs) to evaluate seizures [13, 24, 26, 32–34]. Abnormal readings occurred in 0%-15% of patients. EEG during the hospitalization after ALTE presentation had a low positive predictive value (33.0%; 95% CI 4.3-77.0) for predicting a diagnosis of epilepsy during a 5-year follow-up period [13].

Toxic Ingestions

Metabolic Disorders Five studies addressed metabolic disorders [12, 24, 25, 31, 44]. Routine screening in the absence of specific symptoms for serum chemistries, blood gases, and inborn errors of metabolism identified only 1 case of vitamin D deficient rickets.

Cardiac Arrhythmias Five studies evaluated electrocardiographs or 24-hour Holter monitors [12, 24, 26, 31, 45]. An abnormality that resulted in treatment was identified in 1.4% of ALTE cases. In 1 study, a 24-hour Holter monitor identified a sinus node dysfunction requiring treatment in 2% of patients referred to an apnea clinic. It is unclear, however, if the pH probes used with monitoring increased the vagal stimulus in these patients [45].

Discussion

Anemia Four studies documented anemia in 13%-24% of evaluated ALTE patients [12, 26, 35, 36]. The rate of anemia (hemoglobin level 11.6 g/dL vs 13.1, P = .018) in patients with recurrent ALTEs was higher (22%) than age-matched controls with either a single ALTE (17%) or no ALTEs (9%) [36]. None of the studies reported a causal role of anemia or evaluated the effect of treatment.

Infections Four studies evaluated pertussis as a cause of an ALTE [11, 12, 26, 37]. Pertussis was diagnosed either clinically or by

None of the 37 studies identified in this systematic review satisfied a high level of evidence for diagnostic or prognostic investigations, and there was little consistency in study populations, outcomes, follow-up periods, and measurement [7, 8]. Nonetheless, after critical appraisal, we were able to identify some historical and physical exam features—prematurity, multiple ALTE, suspected child maltreatment—that are associated with risk for a future adverse event and/or serious underlying diagnosis. We found little evidence to support routine testing of patients without these historical risk factors. We found that a history of prematurity and multiple ALTEs are features associated with risk of recurrence and/or

Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

PEPO-214; No. of Pages 15 pediatria polska xxx (2014) xxx–xxx

an occult condition. The odds of an occult condition or adverse outcome in these patients may be 3 to 14 times higher than those without one of these historical features. An observation period to clarify features of the events, await testing results, or ensure that the cluster of events has ended may be appropriate. However, a larger prospective study is needed to determine the true magnitude of risk and determine the minimum duration of observation [7]. We also found that child maltreatment may present as an ALTE. Even though the true prevalence of abuse in the wellappearing infant without a clear cause could not be determined, studies of high risk populations identified common historical and physical examination findings. These include recurrent ALTEs, historical discrepancies, a family history of unexplained sudden death or ALTE, parents calling emergency services, unexplained facial bruising or bleeding, and the presence of vomiting or irritability at the time of presentation [14, 16, 17]. Many of these same findings were used in other studies to successfully establish an appropriate index of suspicion in ED and inpatient populations [19, 20, 46]. Therefore, all ALTE patients warrant a thorough assessment for possible child maltreatment, and patients with any of the risk factors may benefit froma formal child maltreatment evaluation, inpatient observation, or further testing. Although age may be an important predictor, more research is needed because of conflicting evidence to determine what age group is at the highest risk of a subsequent adverse event. Nonetheless, children less than two months of age deserve special consideration due to neurologic and immunologic immaturity and a relative increased risk for undiagnosed congenital disorders. Clinicians should also consider the risk conferred by an URI or respiratory syncytial virus infection in younger infants which may cause apnea that can present either before or after the onset of upper respiratory symptoms [10, 47, 48]. Although testing is common in patients who have experienced an ALTE, we found that routine testing for GER, seizures, meningitis, and bacteremia is highly unlikely to be helpful in patients who are well-appearing and have no other findings suggestive of a diagnosis [3]. However, patients with a history of prematurity, multiple ALTEs, or concerns for child maltreatment may warrant targeted testing. This review found that routine GER testing is unnecessary in children with ALTEs, a finding consistent with previously published international recommendations [49]. Because the prevalence of GER is high in infants, it is not surprising that GER testing would be positive in ALTE patients of the same age. A positive test does not necessarily inform management because causation cannot be established without a control group or the establishment of a temporal association between GER and the ALTE. Indeed, in 1 study, when 89% of the cases had radiographic evidence of GER, nearly one-half had another diagnosis that was thought to be more consistent with the presentation [12]. Patients with recurrent ALTEs and GER symptoms failing medical management may benefit from pH esophageal monitoring in combination with symptom recording (and, in certain cases, polysomnography), to establish a cause and effect or consideration of another etiology. Although seizures cause up to 10% of all ALTEs, admission for testing to determine current or future risk of

13

idiopathic epilepsy does not improve outcomes. EEGs and head imaging are neither sensitive nor predictive of patients ultimately diagnosed with chronic epilepsy. However, a head computed tomography is the most sensitive and specific test to evaluate for abusive head injury but it has associated risk and cost [50]. In the studies reviewed, a thorough history and physical examination to detect child maltreatment nearly always created the index of suspicion to justify further testing. Nonetheless, the overall costeffectiveness and safety profile of routine head imaging to detect abusive trauma in this population remains uncertain. Moreover, there is no evidence to recommend a routine complete blood count, serum glucose, chest radiograph, electrolytes, electrocardiograph, Holter monitor, or testing for pertussis, toxicology, or inborn errors of metabolism. Nonspecific tests, such as a complete blood count, were unlikely to reveal a clear cause or influence management. In fact, when the prevalence of disease is low, as is the case with ALTEs, such studies may complicate the management with high false-positive rates [51]. Rates of meningitis and bacteremia are extremely low and, therefore, testing is not indicated. However, urinary tract infections can rarely present as an ALTE; therefore, pending future research, there may be benefit to performing urine screening in this population. The most significant limitation to this systematic review, indeed to all ALTE clinical care and research, is that the widely used National Institutes of Health definition is subjective and vague. Even after limiting this study to those infants who are well appearing and without a clear diagnosis, crossstudy comparisons and critical appraisal were challenging because of differences in ALTE classification, study populations, diagnostic testing, follow-up periods, outcomes, and determinations of causality. Second, all of the studies occurred at single centers and many lacked adequate control groups. Therefore, external validity of the findings could not always be determined, preventing the quantification of risk for other populations. Next, it is possible that relevant studies were not included in the final analysis, but this possibility was minimized by using a broad search strategy and a systematic approach for exclusions. Finally, most studies were not designed to detect the broad array of potential, yet rare, adverse outcomes. Despite the limitations, our findings likely represent a conservative evaluation of the well-appearing infant. Many of the relevant studies did not report the presence of symptoms upon presentation. The inability to identify and exclude all the symptomatic patients from the analysis, however, would lead our recommendations to overestimate the need for testing and rate of recurrent events. In order to improve the quality of care for patients with this common condition, a new definition is needed. The definition should distinguish: (1) the term ALTE as a description of a symptom from a diagnosis; (2) patients who have a clear etiology from those who do not; and (3) minor symptoms, such as spitting up followed by choking from more concerning symptoms, such as cessation of breathing followed by central cyanosis. Moreover, the definition should place in context the risk in terms of historical and physical examination features described in this study. For example, distinguishing first-time from recurrent ALTEs

Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008

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may assist in the development of tiered clinical guidelines. Following clarification of the definition, research should quantify the true risk for a subsequent event or a serious underlying disorder, and then identify the key historical and physical exam factors that determine the need for admission and scope of investigations. There is insufficient evidence to quantify risk of a subsequent event or underlying diagnosis in patients who have experienced an ALTE but are asymptomatic and/or without a clear etiology upon presentation. Although risk factors derived from the history and physical examination can help guide decisions to test or hospitalize patients, a more precise definition of ALTEs and further research are needed to improve the quality of care for this common condition.

Conflict of interest/Konflikt interesu The Society of Hospital Medicine sponsored the conference calls and an online data management platform for this study; however, it was not involved in the study design, writing of the report, decision to submit the manuscript for publication, or collection, analysis, and interpretation of data. The authors declare no confiicts of interest.

r e f e r e n c e s / p i s m i e n n i c t w o

[1] National Institutes of Health Consensus Development Conference on Infantile Apnea and Home Monitoring, Sept 29 to Oct 1, 1986. Pediatrics 1987; 79:292-9. [2] Green M. Vulnerable child syndrome and its variants. Pediatr Rev 1986;8:75–80. [3] Tieder JS, Cowan CA, Garrison MM, Christakis DA. Variation in inpatient resource utilization and management of apparent life-threatening events. J Pediatr 2008;152:629–635. e1-2. [4] Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. Ann Intern Med 2009;151:264–269. [5] Haynes RB, Cotoi C, Holland J, Walters L, Wilczynski N, Jedraszewski D, et al. McMaster Premium Literature Service (PLUS) Project. Second-order peer review of the medical literature for clinical practitioners. JAMA 2006;295:1801–1808. [6] Lokker C, McKibbon KA, McKinlay RJ, Wilczynski NL, Haynes RB. Prediction of citation counts for clinical articles at 2 years using data available within 3 weeks of publication: retrospective cohort study. BMJ 2008;336:655– 657. [7] Jaeschke R, Guyatt G, Sackett DL. Users' guides to the medical literature. III. How to use an article about a diagnostic test. A. Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA 1994;271:389–391. [8] Laupacis A, Wells G, Richardson WS, Tugwell P. Users' guides to the medical literature. V. How to use an article about prognosis. Evidence-Based Medicine Working Group. JAMA 1994;272:234–237. [9] Claudius I, Keens T. Do all infants with apparent lifethreatening events need to be admitted? Pediatrics 2007;119:679–683.

[10] Al-Kindy HA, Gelinas JF, Hatzakis G, Cote A. Risk factors for extreme events in infants hospitalized for apparent lifethreatening events. J Pediatr 2009;154:332–337. e1-2. [11] De Piero AD, Teach SJ, Chamberlain JM. ED evaluation of infants after an apparent life-threatening event. Am J Emerg Med 2004;22:83–86. [12] Davies F, Gupta R. Apparent life threatening events in infants presenting to an emergency department. Emerg Med J 2002;19:11–16. [13] Bonkowsky JL, Guenther E, Filloux FM, Srivastava R. Death, child abuse, and adverse neurological outcome of infants after an apparent life-threatening event. Pediatrics 2008;122:125–131. [14] Altman RL, Brand DA, Forman S, et al. Abusive head injury as a cause of apparent life-threatening events in infancy. Arch Pediatr Adolesc Med 2003;157:1011–1015. [15] Steinschneider A, Richmond C, Ramaswamy V, Curns A. Clinical characteristics of an apparent life-threatening event (ALTE) and the subsequent occurrence of prolonged apnea or prolonged bradycardia. Clin Pediatr (Phila) 1998;37:223–229. [16] Pitetti RD, Maffei F, Chang K, Hickey R, Berger R, Pierce MC. Prevalence of retinal hemorrhages and child abuse in children who present with an apparent life-threatening event. Pediatrics 2002;110:557–562. [17] Guenther E, Powers A, Srivastava R, Bonkowsky JL. Abusive head trauma in children presenting with an apparent lifethreatening event. J Pediatr 2010;157:821–825. [18] Curcoy AI, Trenchs V, Morales M, Serra A, Pou J. Retinal hemorrhages and apparent life-threatening events. Pediatr Emerg Care 2010;26:118–120. [19] Southall DP, Plunkett MC, Banks MW, Falkov AF, Samuels MP. Covert video recordings of life-threatening child abuse: lessons for child protection. Pediatrics 1997;100:735–760. [20] Truman TL, Ayoub CC. Considering suffocatory abuse and Munchausen by proxy in the evaluation of children experiencing apparent life-threatening events and sudden infant death syndrome. Child Maltreat 2002;7:138–148. [21] Altman RL, Forman S, Brand DA. Ophthalmologic findings in infants after an apparent life-threatening event. Eur J Ophthalmol 2007;17:648–653. [22] Bonkowsky JL, Guenther E, Srivastava R, Filloux FM. Seizures in children following an apparent life-threatening event. J Child Neurol 2009;24:709–713. [23] Hewertson J, Poets CF, Samuels MP, Boyd SG, Neville BG, Southall DP. Epileptic seizure-induced hypoxemia in infants with apparent life-threatening events. Pediatrics 1994;94(2 Pt 1):148–156. [24] Okada K, Miyako M, Honma S, Wakabayashi Y, Sugihara S, Osawa M. Discharge diagnoses in infants with apparent life-threatening event. Pediatr Int 2003;45:560–563. [25] Sunkaran K, McKenna A, O'Donnell M, Ninan A, Kasian G, Skwarchuk J, et al. Apparent life-threatening prolonged infant apnea in Saskatchewan. West J Med 1989;150:293– 295. [26] Brand DA, Altman RL, Purtill K, Edwards KS. Yield of diagnostic testing in infants who have had an apparent lifethreatening event. Pediatrics 2005;115:885–893. [27] Veereman-Wauters G, Bochner A, Van Caillie-Bertrand M. Gastroesophageal reflux in infants with a history of nearmiss sudden infant death. J Pediatr Gastroenterol Nutr 1991;12:319–323. [28] Mousa H, Woodley FW, Metheney M, Hayes J. Testing the association between gastroesophageal reflux and apnea in infants. J Pediatr Gastroenterol Nutr 2005;41:169–177. [29] Kahn A, Rebuffat E, Sottiaux M, Blum D, Yasik EA. Sleep apneas and acid esophageal reflux in control infants and in infants with an apparent life-threatening event. Biol Neonate 1990;57:144–149.

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[30] Tirosh E, Jaffe M. Apnea of infancy, seizures, and gastroesophageal reflux: an important but infrequent association. J Child Neurol 1996;11:98–100. [31] See CC, Newman LJ, Berezin S, Glassman MS, Medow MS, Dozor AJ, et al. Gastroesophageal reflux-induced hypoxemia in infants with apparent life-threatening event (s). Am J Dis Child 1989;143:951–954. [32] Tsukada K, Kosuge N, Hosokawa M, Umezu R, Murata M. Etiology of 19 infants with apparent life-threatening events: relationship between apna and esophageal dysfunction. Acta Paediatr Jpn 1993;35:306–310. [33] Genizi J, Pillar G, Ravid S, Shahar E. Apparent lifethreatening events: neurological correlates and the mandatory work-up. J Child Neurol 2008;23:1305–1307. [34] Tirosh E, Jaffe M. Apparent life-threatening event: a neurologic perspective. J Child Neurol 1995;10:216–218. [35] Poets CF, Samuels MP, Wardrop CA, Picton-Jones E, Southall DP. Reduced haemoglobin levels in infants presenting with apparent life-threatening events—a retrospective investigation. Acta Paediatr 1992;81:319–321. [36] Pitetti RD, Lovallo A, Hickey R. Prevalence of anemia in children presenting with apparent life-threatening events. Acad Emerg Med 2005;12:926–931. [37] Crowcroft NS, Booy R, Harrison T, Spicer L, Britto J, Mok Q, et al. Severe and unrecognized: pertussis in UK infants. Arch Dis Child 2003;88:802–806. [38] Tirosh E, Colin AA, Tal Y, Kolikovsky Z, Jaffe M. Practical approach to the diagnosis and treatment of apnea of infancy. Isr J Med Sci 1990;26:429–433. [39] Mittal MK, Shofer FS, Baren JM. Serious bacterial infections in infants who have experienced an apparent lifethreatening event. Ann Emerg Med 2009;54:523–527. [40] Altman RL, Li KI, Brand DA. Infections and apparent lifethreatening events. Clin Pediatr (Phila) 2008;47:372–378. [41] Zuckerbraun NS, Zomorrodi A, Pitetti RD. Occurrence of serious bacterial infection in infants aged 60 days or younger with an apparent life-threatening event. Pediatr Emerg Care 2009;25:19–25. [42] Hickson GB, Altemeier WA, Martin ED, Campbell PW. Parental administration of chemical agents: a cause of

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

15

apparent life-threatening events. Pediatrics 1989;83: 772–776. Pitetti RD, Whitman E, Zaylor A. Accidental and nonaccidental poisonings as a cause of apparent lifethreatening events in infants. Pediatrics 2008;122:e359–e362. Penzien JM, Molz G, Wiesmann UN, Colombo JP, Buhlmann R, Wermuth B. Medium-chain acyl-CoA dehydrogenase deficiency does not correlate with apparent life-threatening events and the sudden infant death syndrome: results from phenylpropionate loading tests and DNA analysis. Eur J Pediatr 1994;153:352–357. Woolf PK, Gewitz MH, Preminger T, Stewart J, Vexler D. Infants with apparent life threatening events. Cardiac rhythm and conduction. Clin Pediatr (Phila) 1989;28: 517–520. Samuels MP, McClaughlin W, Jacobson RR, Poets CF, Southall DP. Fourteen cases of imposed upper airway obstruction. Arch Dis Child 1992;67:162–170. Ralston S, Hill V. Incidence of apnea in infants hospitalized with respiratory syncytial virus bronchiolitis: a systematic review. J Pediatr 2009;155:728–733. Schiller O, Levy I, Pollak U, Kadmon G, Nahum E, Schonfeld T. Central apnoeas in infants with bronchiolitis admitted to the paediatric intensive care unit. Acta Paediatr 2011;100:216–219. Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ES-PGHAN). J Pediatr Gastroenterol Nutr 2009;49:498–547. Campbell KA, Berger RP, Ettaro L, Roberts MS. Costeffectiveness of head computed tomography in infants with possible inflicted traumatic brain injury. Pediatrics 2007;120:295–304. Ober KP, Uncle. Remus and the cascade effect in clinical medicine. Brer Rabbit kicks the Tar-Baby. Am J Med 1987;82:1009–1013.

Please cite this article in press as: Tieder JS, et al. Management of Apparent Life-Threatening Events in Infants: A Systematic Review. Pediatr Pol. (2014), http://dx.doi.org/10.1016/j.pepo.2014.04.008