CME Review

Apparent life-threatening events: Assessment, Risks, Reality

Naif Al Khushi, Aurore Cote *
Department of Pediatrics and Respiratory Medicine Division, The Montreal Childrens Hospital, McGill University Health Centre, Montreal Canada
INTRODUCTION
There has been quite an evolution in the understanding and
management of Apparent life-threatening events (ALTEs) over the
past few decades. In the late 1970s, as investigators were
exploring the possible causes of Sudden Infant Death Syndrome
(SIDS), a commonly held hypothesis was that infants who
succumbed to SIDS might have presented episodes prior to the
nal event. Such episodes, characterized by an acute and
unexpected change in behaviour, with or without perceived
apnoea, were then referred to as near-miss for sudden infant death
syndrome.
1
The term apparent life-threatening event (ALTE) was
later proposed and subsequently endorsed in 1987 by the National
Institute of Child Health and Human Development
2
. In the 1980 s
through the mid-1990 s, studies investigated numerous physio-
logical, biochemical and metabolic variables in infants having
presented with an ALTE in the hope of elucidating the cause of SIDS
or to identify risk factors. A possible link between ALTE and SIDS
has never been proven and there is now ample evidence that the
two conditions might not be related.
3
Between the mid 1990 s and
the year 2000, more studies looked at various diagnoses found
during the investigation of ALTE. Finally, in recent years, a few
studies have appeared that explore the risk factors for serious
diseases that could present as ALTE.
Although ALTEs might not be the precursor of death, these acute
unexpected events represent a frightful experience for the
observer, often one of the childs parents, and they lead to medical
consultation, often in an Emergency Department (ED). Studies
have revealed that ALTEs represent between 0.6% to 1.7% of all ED
visits of infants below 1 year of age
47
and more often than not
Paediatric Respiratory Reviews 12 (2011) 124132
A R T I C L E I N F O
Keywords:
Apparent life threatening event [ALTE]
serious bacterial infection
seizures
investigations
literature review
S U M M A R Y
Apparent life-threatening events (ALTEs), because of their prevalence as well as their potential to hide
serious diseases and consume signicant medical resources, remain a challenge for physicians caring for
infants. In this review, we focused on the assessment of the well-appearing infant for the most serious
diagnoses, namely serious bacterial infections, seizure disorders, child abuse, metabolic disorders and
severe apnoea with hypoxemia. Our extensive review of the literature has highlighted the difculties
physicians are facing in this evaluation, especially for the youngest infants (aged less than 2 months).
Large-scale prospective studies are needed to identify risk factors and to guide physicians as to who
should be investigated and the minimal investigation needed to avoid missing such conditions as serious
bacterial infection, abusive head injury or repeated severe cardiorespiratory events. While infants with
severe forms of metabolic disorders typically present with evident signs and symptoms, less severe
forms of metabolic disorders, seizure disorders, and some forms of child abuse will often be diagnosed
only when recurrent events are investigated.
2010 Elsevier Ltd. All rights reserved.
LEARNING OBJECTIVES
The reader will feel condent to:
Consider the likelihood of serious bacterial infection in an infant presenting with an ALTE.
Realise that the majority of ALTEs are not associated with a serious underlying condition
Differentiate between the more likely conditions presenting with a single ALTE as opposed to recurrent ALTEs.
Appreciate the limited evidence-based information available to guide management practices of infants with an ALTE.
* Corresponding author. Respiratory Medicine Division, D-380, The Montreal
Childrens Hospital, 2300 Tupper, Montreal, Canada, H3H 1P3.
E-mail address: aurore.cote@muhc.mcgill.ca (A. Cote ).
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
1526-0542/$ see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.prrv.2010.10.004
leads to an admission; the admission rate for ALTE is usually higher
than 75% and even 100% in some centers.
4,6,8,9
The many causes of ALTE have been reviewed in numerous
excellent publications.
1015
Considering the variety of diagnoses
leading to ALTE it is important for the clinicians, faced with a well-
appearing infant following an ALTE, to take a decision concerning
admission and investigation. Our aim is to review the most
important diagnoses, meaning those that should not be missed
during the evaluation for ALTE. We will therefore focus, rst, on
serious diseases that might present as anALTE inthe rst year of life.
These include serious bacterial infections, seizures, child abuse,
metabolic disorders and severe apnoea with hypoxemia. We will
then review the few studies that have looked at risk factors for
serious diseases in order to give physicians caring for children some
guidelines as to who should have a thorough investigation and be
admitted to the hospital following an ALTE. Throughout the text, we
provide clinical vignettes, chosen from our experience with infants
presenting with ALTE, to illustrate the important points made.
ASSESSMENT FOR SERIOUS DISEASES IN THE INFANT
PRESENTING WITH ALTE
The assessment of any infant having presented with an ALTE
has been reviewed thoroughly in recent publications.
1215
Briey,
the evaluation should always start with a careful history of the
event from the observer, a review of the past medical history
followed by a physical examination looking for any evidence of an
underlying process that might have caused or contributed to the
ALTE. When the event corresponds to the denition of an ALTE
2
the
baseline investigation should include complete blood count, blood
gases analysis with serum bicarbonate and lactate (ideally as soon
as possible after the event), blood glucose, serum electrolytes
including calcium and urinalysis. Other tests will depend on the
condition of the infant and the information already gathered. In
most reviews, a chest radiograph and tests to identify common
respiratory viruses are recommended. In the next sections, we will
focus on the indication of additional assessment for serious
diseases in the well-appearing infant following an ALTE.
Review of the literature
We did a literature search in order to identify all studies
published in English, French or Spanish and reporting on causes of
ALTEs. MEDLINE and EMBASE databases (1966-2010) were
searched using the PubMed and Ovid interfaces. As well, reference
lists from identied studies were hand-searched in order to add
any published studies missed by the database search. We were
careful to identify different publications reporting on the same
database to avoid duplication of data in our report of studies.
From all the identied studies, we read the abstracts to exclude
irrelevant studies, reviews on ALTE including systematic reviews
of the literature and case reports. We then obtained the full
publication on all remaining studies identied. We were particu-
larly interested in studies reporting on the investigation during the
rst admission for an ALTE in infants that appeared well when rst
evaluated in the ED. This information, however, was not always
available and some studies did not mention the clinical state of the
infants and some others included infants admitted more than once
for ALTE. After excluding publications that did not present original
research data and case series on a particular diagnosis, we were left
with 23 publications with 20 different cohorts that came fromnine
different countries with a total number of 6849 infants presenting
with ALTE. The countries represented are: Australia
16
, Austria
17,18
,
Belgium
10,19
, Brazil
20
, Canada
6
, Israel
21,22
, Japan
23,24
, UK
4,5,7
, and
USA
7,9,14,2531
. The data is presented in Table 1. We also report data
from our own cohort of 625 infants with ALTE from which
information as to the cause of ALTE has not been fully reported in a
publication except for the presence of severe cardiorespiratory
events
6
.
Serious bacterial infection
Case 1: 1-month-old male, born at term. Episodes of limpness
and pallor were noticed by the parents and the infant was given
strong stimulation. The infant was well-appearing when later
evaluated in the ED. The initial investigation which included urine
analysis was suggestive of urinary tract infection and the infant did
develop fever while waiting for admission. The urine culture was
positive for E. coli (obtained by catheterization) and the
investigation subsequently revealed right vesico-ureteral reux
grade III with hydronephrosis..
Key point: Well-appearing afebrile infants aged less 2 months
may have a serious bacterial infection.
For this review, we considered as serious bacterial infection the
diagnoses of bacterial meningitis, bacteriemia/septicemia, urinary
tract infection and Pertussis. We did not retain the diagnosis of
pneumonia for two reasons: a) in most studies where it was
reported, the diagnosis of pneumonia was based on a positive chest
radiograph in asymptomatic infants putting in doubt the diagnosis
of bacterial pneumonia; or b) the infants were sick with fever and
respiratory distress and should not have posed any problem for
diagnosis.
We identied 7 studies
5,7,18,23,26,31,32
that provided enough data
on the rate of severe bacterial infection. The details of the studies
are given in Table 1 where the rates provided in the publications
have been corrected to include only the diagnoses of bacterial
meningitis, bacteriemia/septicemia, urinary tract infection and
Pertussis. Three studies looked specically at infections as the
cause of an ALTE
7,26,31
and two of these three studies
7,31
provided
details on follow-up of all the ALTEs to discover if any of the infants
had been sick and diagnosed with bacterial infection post-
discharge. The proportion of ALTEs due to serious bacterial
infection varied from 0 to 18.5% and the pooled data on 1442
infants yielded a 3.2% incidence of serious bacterial infection. In
Table 2, we present the proportion of various diagnoses identied.
Clearly, Pertussis and urinary tract infection are much more
prevalent than meningitis or sepsis.
ALTEs are certainly more prevalent in the younger age group. In
our series of 625 infants admitted for investigation of ALTE, 453
(72%) were less than 60 days (corrected age). These young infants
could present with a paucity of signs and symptoms and no fever
despite having an ongoing bacterial infection. The investigation for
serious bacterial infection is invasive and includes blood culture,
cerebrospinal uid collection and urine culture (catheterization
recommended). What is the rate of serious bacterial infectioninthat
age group? Zuckerbraun et al.
31
focused solely on infants aged less
than 2 months and found 5 of 182 infants (2.7%) with serious
bacterial infection (three with bacteriemia/septicemia, one with
urinary tract infection and one with Pertussis). In our own cohort, of
the 453 infants aged less than 2 months (corrected age)
32
, 12 (2.9%)
hada serious bacterial infection(sixwithPertussis, vewithurinary
tract infection, one with bacteriemia). Brand et al.
14
looked at the
yield of testing ininfants admittedwithALTE. Althoughthey did not
report specically on infants less than 2 months of age, of the 72
infants who had no contributory ndings on history and physical
examination, 3infants hadaserious bacterial infection(urinarytract
infection). Their recommendation for well-appearing infants was
therefore to do a urine culture, not a full septic workup. In the study
of Altman et al.
26
the four well-appearing infants with severe
bacterial infection (all urinary tract infection) were respectively 10
day-old, 10 week-, 12 week- and 3.5 month-old, therefore only one
infant was less than 60 days (gestational age was not mentioned).
N. Al Khushi, A. Cote / Paediatric Respiratory Reviews 12 (2011) 124132 125
Table 2
Diagnoses identied in cases of serious bacterial infection
First author N Meningitis Bacteriemia / septicemia Urinary tract infection Pertussis
Okada
23
69 1 2 0 4
Davies
5
65 0 0 5 7
Kurtz
18
60 0 1 0 1
Altman
25
243 0 0 4 0
Cote
32
625 1 1 7 7
Zuckerbraun
31
182 0 3 1 1
Mittal
7
198 0 0 0 0
Total 1442 2 (0.1%) 7 (0.5%) 17 (1.2%) 20 (1.4%)
Table 1
Studies reporting on serious conditions as the cause of ALTE
First author Years of study Duration of study State/Country Type of study Age group N N with diagnosis (%) Follow-up
Serious bacterial infection
Okada
23
1991 2000 9 years Japan Prospective < 12 m 69 7 (10.1%) No
Davies
5
1996 1998 1 year UK Prospective < 12 m 65 12 (18.5%)
1
6 m
Kurz
18
NA
2
NA Austria Prospective 1-45 wks 60 2 (7%) Y, NA
3
Altman
25
1996 1999 2.7 years USA Prospective < 12 m 243 4 (1.6%)
4
No
Cote
32
1996 2006 10.5 years Canada Retrospective < 12 m 625 16 (2.6%) No
Zuckerbraun
31
2002 2005 3.5 years USA Prospective < 2 m 182 5 (2.7%) 6 m
Mittal
7
2006 2007 1 year USA Prospective < 12 m 198 0 1 m
Pooled data 1442 46 (3.2%)
Seizures
Rahilly
16
1982 1985 3.3years Australia Prospective NA 340 25 (7.3%) 19 m
5
Kahn
10
1983 1990 7 years Belgium Retrospective < 12 m 3799 150 (3.9%) NA
Veereman-Wauters
19
1984 1986 2.7 years Belgium Retrospective 2-36 wks 130 5 (4%) Y, NA
Tsukada
24
1986 1991 5.2 years Japan Retrospective up to 13 m 19 1 (5%) No
Okada
23
1991 2000 9 years Japan Prospective < 12 m 69 1 (1.4%) No
Gray
4
1993 1 year UK Retrospective < 12 m 130 40 (25%)
6
18 m
Tal
21
1993 1995 NA Israel Retrospective 1-6 m 65 3 (4.6%) 12 m
Sheikh
29
1993 1997 5 years USA Retrospective < 12 m 74 3 (4%) No
Kiechl-Kohlendorfer
17
1993 2001 8 years Austria Prospective < 12 m 164 1% No
Davies
5
1996 1997 1 year UK Prospective < 12 m 65 6 (9%) 6 m
Altman
26
1996 1999 2.7 years USA Prospective < 12 m 243 12 (4.9%) No
Pitetti
28
1997 1999 2 years USA Prospective < 24 m 128 4 (3.1%) At 1 year
Bonkowsky
27
1999 2003 5 years USA Retrospective < 12 m 471 25 (5.3%) 5 years
7
Anjos
20
2004 2006 1.5 years Brazil Prospective < 24 m 30 1 (3.3%) Y, NA
Genizi
22
2000 2006 6 years Israel Retrospective < 12 m 93 15 (16%) Y, 2007
8
Kurz
18
NA NA Austria Prospective 1-45 wks 60 4 (6.7%) Y, NA
Pooled data 5880 296 (5.0%)
Child abuse
Rahilly
16
1982 1987 3.3 years Australia Prospective NA 340 2 (0.5%) 19 m
Kahn
10
1983 1991 7 years Belgium Retrospective < 12 m 3799 8 (< 0.1%) NA
Davies
5
1996 1998 1 year UK Prospective < 12 m 65 2 (3%) 6 m
Altman
25
1996 1999 2.7 years USA Prospective < 12 m 243 6 (2.5%) No
Pitetti
28
1997 1999 2 years USA Prospective < 24 m 128 3 (2.3%)
9
At 1 year
10
Vellody
30
2001 2002 2 years USA Retrospective < 12 m 92 0
11
No
Pooled data 4667 21 (0.4%)
Metabolic disorder
Kahn
10
1983 1990 7 years Belgium Retrospective < 12 m 3799 6 (< 0.1%) NA
Veereman-Wauters
19
1984 1986 2.7 years Belgium Retrospective 2-36 wks 130 1 (0.7%) Y, NA
Kiechl-Kohlendorfer
17
1993 2001 8 years Austria Prospective < 12 m 164 1%
12
No
Altman
25
1996 1999 2.7 years USA Prospective < 12 m 243 1 (0.4%) No
Cote
32
1996 2006 10 years Canada Retrospective < 12 m 625 1 (< 0.1%) No
Kurz
18
NA NA Austria Prospective 1-45 wks 60 2 (3.3%) Y, NA
Pooled data 5021 13 (0.3%)
Severe cardiorespiratory events
Al-Kindy
6
1996 2006 10.5 years Canada Retrospective < 12 m 625 46 (7.4%) No
1
No cases of bacteriemia/septicemia and meningitis.
2
Dates of the study not available anywhere in the publication.
3
Y, NA = Follow-up mentioned, other details not available from the publications.
4
The reported rate was higher but all cases of meningitis, bacteriemia and pertussis and one of the case with urinary tract infection were sick on initial evaluation.
5
The range was 6 months to 42 months
6
The % is calculated on the number of admissions and some infants had more than one admission.
7
Follow-up continued for 2 years after the end of the study. The average was 5.1 years for all patients.
8
The medical records were screned up to 2007.
9
First event in two infants, recurrent ALTE in the other.
10
One year after the initial evaluation for ALTE.
11
Four cases were reported, all were symptomatic (lethargy and full fontanelle or bruies) and the diagnosis was made before the admission.
12
The percentage only was reported. NA: not available; m: months; Y: yes.
N. Al Khushi, A. Cote / Paediatric Respiratory Reviews 12 (2011) 124132 126
Zuckerbraun et al.
31
who focused solely on infants aged less
than 2 months sought to determine the risk factors associated with
serious bacterial infection. They identied prematurity as a risk
factor. In our own cohort,
32
if only well-appearing prematurely
born infants aged less than 60 days (corrected age) had a full septic
work-up we would have identied only one infant with serious
bacterial infection and missed 12. Clearly, our results differ from
those of Zuckerbraun et al. but the difference cannot be explained
as the design of the two studies was very similar except that infants
with fever were excluded in the study of Zuckerbraun et al. and we
did not report the presence of fever in ours.
Recommendations. Clearly there is a need for a large
prospective preferably multi-centered study evaluating risk
factors and the yield of a full septic work-up on well-appearing
infants who presents with an ALTE and are less than 2 months of
age, taking into account premature birth.
Presently, fromall the reviewed data, it is difcult to make clear
evidence-based recommendations. The case of infants who are not
well on arrival, those who have fever or physical ndings pose no
problem as an investigation is easily targeted to the ndings or
broadened to include septic work-up. As well, for infants older than
2 months, the likelihood of a meningitis or septicemia when they
are well-appearing is unlikely and urine analysis and culture might
be the only additional test as suggested by Brand et al.
14
For well-appearing infants younger than 60 days (corrected
age), we have seen that a serious bacterial infection could occur in
2% to 3%. Although low, this rate cannot be ignored as a serious
bacterial infection could lead to a rapid deterioration. A full septic
work-up should be considered in all these infants.
Seizure disorder
Case 2: Three-month-old female in prior good health and born at
term. Two episodes were reported at a 1 week interval before the
1
st
admission for investigation. On both occasions, the child was
found unconscious, limp and responded slowly to stimulation. No
diagnosis was identied during the initial investigation. The
episodes repeated themselves over a period of 2 months and
became clearer: the parents noticed a few episodes characterized
by a sudden loss of consciousness with head drop and loss of tone.
The repeated investigation was normal including search for a
metabolic disease and prolonged video and EEG recording (no
events occurred during recording). One event was later observed in
hospital and clearly suggestive of a seizure. The infant was treated
for one year with anti-epileptic medication and there was no
recurrence of events.
Key points: Ensure adequate follow-up for idiopathic ALTE and
re-evaluation for recurrent ALTE.
We identied 16 studies which looked at the proportion of ALTE
with a diagnosis of seizures.
4,5,10,1625,2729
The proportion varied
widely from 1.4% and 25%. The pooled data on 5880 infants with
ALTE showed a proportion of 5.0% (296 infants) with seizures.
There are several potential explanations for this wide variance.
Many studies report the discharge diagnosis following the rst
admission for ALTE. This does not give a precise estimation of who
really has a seizure disorder and rates can be either lower or higher.
Indeed, Bonkowsky et al.
27
showed that discharge diagnosis at the
time of the apparent life-threatening event was poorly predictive
of those who developed seizures.
Two very well done studies with long follow-up information
looked specically at seizures as the cause of ALTE
22,27
and
reported a rate of 5.3% and 16%. Important information can be
derived from these studies and be of use as guidelines for
physicians. First, neurological evaluation at the time of the initial
admission had low yield for predicting those who would develop a
seizure disorder. Second, most diagnoses of seizure disorders in
these two studies were not done at the rst evaluation and EEG
was usually normal or non-contributory. In addition, Bonkowsky
et al.
27
found that a majority of infants who later developed
seizures following an apparent life-threatening event present
within 1 month of their initial hospitalization. This put emphasis
on the necessity of a well organized follow-up for the infants who
have no diagnosis following an initial ALTE. Organized follow-up
includes contact with the primary care physician and plan for
follow-up appointment. Finally, studies reporting on recurrent
ALTEs have often identied a seizure disorder as one of the
causes.
3335
Recommendations. EEGshould not be routinely done as part of
the evaluation of a rst admission for ALTE. Close follow-up should
be organized for infants for whom no cause of ALTE has been
identied as a diagnosis of seizure could become evident only with
recurrence of events.
Child abuse
Case 3: Three-month-old female, born at term. Over a period of
one month, the infant presented with repeated episodes of
choking with xed gaze, movements of the arms and legs and
eventually change in colour and loss of consciousness and slow
recuperation. The investigation was negative, including EEG,
except for the presence of clinical gastro-oesophageal reux
(GER) but with a 24hr oesophageal pH recording within normal
limits. During prolonged video-recording and EEG, she presented
two events that were clearly observed to be obstructive apnoea
apparently triggered by GER followed by movements of the
extremities, profound cyanosis and heart deceleration but with no
change on the EEG suggesting seizures. She was treated with anti-
reux medication with improvement in hospital and disappear-
ance of the events before being discharged home on a cardior-
espiratory monitor. The mother reported numerous apparently
serious clinical events over the next several weeks, none of which
were captured on monitor. Re-admission for investigation was
negative on two occasions. Factitious illness was suspected and the
mother was confronted with the diagnosis and increased
psychosocial support provided. No clinical events recurred
(follow-up of two years).
Key point: Consider factitious illness with recurrent clinical
events, even if there was an identied diagnosis for the initial
events.
Six studies
5,10,16,25,28,30
reported data on the rate of child abuse
in infants presenting with ALTE. The rate of child abuse ranged
from0 to 3% with pooled data on 4667 infants giving a rate of 0.4%.
It is likely that this represents an underestimation of the true rate
of child abuse. Indeed, prospective studies that have specically
looked for child abuse report approximately 2%.
25,28
Despite the lowrate of child abuse in infants presenting with an
ALTE, the consequences are often very serious. The question then
arises: Should every infant presenting for ALTE be investigated for
possible child abuse? There is no easy answer to this question.
Pitetti et al.
28
have recommended that the evaluation of ALTE
should always include a dilated fundoscopic examination. In their
study, one out of 73 infants (1.4%) had retinal hemorrhages.
Importantly also, of the three reported infants with child abuse in
that study, two were asymptomatic including the one with retinal
hemorrhages who was later discovered to have multiple fractures.
The search for retinal hemorrhages will specically identify a
subset of infant victims of abusive head injury. Fundoscopic
examination will not help in cases of imposed suffocation and
parental reports of factitious illness. In these two instances, it is
usually the recurrence of events that leads the medical teamto the
diagnosis. Not surprisingly, the rate of child abuse is much higher
in studies looking specically at causes of recurrent ALTEs. We and
N. Al Khushi, A. Cote / Paediatric Respiratory Reviews 12 (2011) 124132 127
others have reported on this condition in a population of infants
with recurrent ALTE
33,34,36
and the proportion of child abuse
(factitious illness or imposed suffocation) varied from 10.6 to
16.7%.
Recommendations. We recommend that clinicians caring for
infants presenting with an ALTE consider including dilated
fundoscopy in their evaluation protocol even in well-appearing
infants as the diagnosis of abusive head injury is a serious one that
could be overlooked on standard physical examination. Again here,
careful organization of follow-up with the primary care physician
is essential as the diagnosis of some forms of child abuse become
evident with recurrent events.
Metabolic disorders
Case 4: 11-day-old male, born at term. There was one episode of
limpness of short duration, but three episodes of vomiting reported
by the parents. The infant was well appearing when rst evaluated
in the ED, but was admitted to the hospital for observation. He was
found to be progressively lethargic over the next few hours with
metabolic acidosis which progressed rapidly to a cardiac arrest
from which he was resuscitated. He was found to have
cardiomegaly (cardiomyopathy) and an enlarged liver and was
eventually diagnosed with glutaric aciduria type II.
Key point: Vomiting and development of lethargy in a newborn
can be the typical presentation of a metabolic disorder.
We identied 6 studies
10,1719,25,32
that reported the proportion
of metabolic disorders in infants presenting with ALTE. The
incidence was usually quite low, varying from less than 0.1% to 3%
with pooled data on 5021 ALTE at 0.3%. However, metabolic
investigation might not be done in all cases of ALTE and can
account for the low incidence. Most disorders described in the
studies where a cause was identied are disorders that should lead
to impairment of consciousness upon presentation with ALTE,
namely disorders of urea cycle, severe forms of fatty acid oxidation
defects and lactic acidosis disorders. Unfortunately, the studies
that looked at the rate of metabolic disorders at the initial
admission for ALTE did not report on the state of the infant when
rst evaluated.
As reported for a seizure disorder or child abuse, it is often with
the recurrence of events that the diagnosis of metabolic disorder is
made. Arens et al.
37
reported ve cases of metabolic disorders in 65
infants with recurrent ALTEs (7.7%), a proportion much higher that
the pooled data of 0.3%. Of importance, most infants had increased
ammonia levels.
Recommendations. For the rst episode of ALTE in well-
appearing infants with normal initial biochemistry we do not
recommend a full metabolic disease work-up. If the state of
consciousness is not normal, in the presence of hypoglycemia or
increased lactate level, blood ammonia should be obtained and a
metabolic work-up considered. Afull metabolic work-up should be
mandatory for the assessment of recurrent ALTEs.
Severe recurrent apnoea
Case 5: 45-day-old male, born at 32 weeks gestation. This infant
had been discharged from the Neonatal Intensive Care Unit three
weeks prior to the event. Episodes of respiratory pauses (reported
Table 3
Risk factors for serious disease in infants presenting with an ALTE
First Author
Country
Years of study
Type of study
N
Inclusion criteria Exclusion criteria Factors explored Group comparison Results
De Piero
8
USA
19941998
Retrospective
150
age < 6 m,
single episode,
had to be
stable when
presenting to ED
None Age, prematurity and
positive medical history
Infant with vs.
without signicant
medical intervention
Lower risk for signicant
medical interventions:
Infants less than 60 days
of age and full term
infants without a
signicant medical
history.
Davies
5
UK
19961997
Prospective
65
age < 12 m,
could be
recurrent ALTE
Fever, working
diagnosis of febrile
seizures, abnormal
limb movements,
all with age over
6 months
Age, nding on initial
examination
Single episode,
idiopathic ALTE vs.
diagnosis found
and/or recurrent
episodes
Infants with either a
recurrent ALTE or a
denitive diagnosis were
more likely to be older
than 2 months at
presentation or have
abnormal ndings on
initial clinical examination.
Al-Kindy
6
Canada
19962006
Retrospective
625
age < 12 m, 1st
consultation
for ALTE
Pre-existing problems:
control-of-breathing,
airway anomalies,
cyanotic heart diseases,
arrhythmias; patients
already on
cardiorespiratory
monitors or tracheotomy
Prematurity, male gender,
age less than 43 weeks,
season
Infants with severe
cardiorespiratory
events vs. infants
with no extreme event
Post-conceptional age
<43 weeks, premature
birth, and the presence
of URTI symptoms
increased the likelihood
of having severe
cardiorespiratory events
(P < .0001).
Claudius
9
USA
20022005
Prospective
59
age < 12 m,
could be
recurrent ALTE
Gestational age < 30wks,
uncorrected cardiac disease,
known seizure disorder,
signicant developmental
delay, or chronic lung
disease requiring
treatment
Family history of SIDS,
moderate prematurity
(gestational age 30-37 wks),
previous ALTEs, patient age,
presence of upper
respiratory infection
symptoms, color
and tone during the ALTE,
duration of the ALTE,
interventions required,
appearance of the child in
the ED, suspicion of child
abuse, multiple ALTEs
within 24hours.
High risk vs. low risk.
Classication as high
risk was based on
subsequent events,
signicant interventions,
or nal diagnoses that
would have mandated
admission to the hospital
Patients in the high risk
group were more likely
to have a history of
multiple ALTEs
and be premature
N. Al Khushi, A. Cote / Paediatric Respiratory Reviews 12 (2011) 124132 128
as < 10 s) were noticed by the parents and the infant was given
strong stimulation. There was a history of nasal congestion for two
days. During the observation in the ED the infant appeared well
and the physical examination was normal. Within a few hours,
there were repeated episodes of central apnea with bradycardia
and marked desaturations (below 80%) which lead to intensive
care unit admission. Low ow oxygen was administered by nasal
canula and continued over 3 days. The investigation revealed the
presence of Respiratory Syncytial Virus infection.
Key point: Well-appearing young infants born prematurely
may developed severe apnea with viral respiratory infection.
We are the only group that reported on the prevalence of
severe cardiorespiratory events in a cohort of 625 infants
presenting with an ALTE.
6
For that study, we dened severe
cardiorespiratory events as central apnoea >30 seconds, brady-
cardia >10 seconds, and desaturation >10 seconds at hemoglo-
bin-oxygensaturationvalue <80%. We identied 46 infants (7.4%)
with these events usually within 24 hours of hospital admission.
Nine infants had RSV infection, two had Pertussis and the others
had a variety of diagnoses including one metabolic disorder. Most
infants did not have a specic diagnosis but had symptoms of an
upper respiratory tract infection and the cardiorespiratory events
resolved rapidly (median 4 days). The most frequent events were
severe desaturations (43/46 infants). Prematurity, postmenstrual
age less than 43 weeks and symptoms of a viral respiratory
infection were all associated with an increased risk of severe
events. All of the 46 infants with severe cardiorespiratory events
were aged less than 2 months (corrected age for prematurity) at
the time of the ALTE.
Recommendations. It is difcult to make recommendations
based on only one study. As for serious bacterial infections, the
younger infants were more at risk for severe cardiorespiratory
events. Clearly, a period of observation with monitoring by a pulse
oximeter should identify the infants with these events. There is a
denite need for a large prospective study on the risk factors for
serious diseases.
RISKS FACTORS FOR SIGNIFICANT DISEASE
We identied 4 studies
5,6,8,9
that looked specically at some
risk factors and the data is presented in Table 3. The results are
difcult to interpret due to different factors being evaluated,
different study designs, and infants experiencing recurrent ALTEs
being included in some studies. Three studies
6,8,9
identied
prematurity as a risk factor for a serious diagnosis or the need
for a medical intervention. Zuckerbraun et al.
31
also identied
prematurity as a risk factor for a serious bacterial infection. In
contrast, Davies et al.
5
found that infants with either a recurrent
ALTE or a denitive diagnosis were more likely to be older than 2
months at presentation or have abnormal ndings on initial
clinical examination. As already mentioned, there is a need for a
large-scale prospective study evaluating the risk factors for serious
disease presenting as ALTE and including the evaluation of the role
of prematurity and age less than 2 months.
Comparison of risk factors for ALTE vs. SIDS. We identied 5
studies
17,3841
in addition to our own data that looked specically at
comparison between ALTE and SIDS, taking into account the known
risk factors for SIDS (Table 4). Two major differences emerged from
those studies, 1) the incidence of ALTE did not change over time
while the incidence of SIDS decreased in all regions of the world
where the ALTE studies were undertaken; and 2) the age at events
was younger for ALTE (except in one study
38
). In the studies where
Table 4
Comparisons of risk factors, ALTE vs. SIDS
First author
Country
Years of study
Type of study
N for ALTE
SIDS group
13
Years of data
Comparison ALTE vs. SIDS
Risk factors evaluated Results
Kahn
38
Belgium
19771982
Prospective on
69 ALTE and
150 SIDS
SIDS cases referred
to same institution
19771982
353 items from questionnaire to parents
and concerning sociodemographics of
the family, prenatal and postnatal history,
child care practices, behaviour o the infant
and circumstances surrounding the event
(ALTE or SIDS).
Age at the time of event not different.
Signicantly less frequent in ALTE:
young maternal age, smoking during
pregnancy, prone sleeping.
Mitchell
39
New Zealand
19861994
Retrospective
4858
SIDS cases from a
National study
19871990
Incidence of ALTE and SIDS, chronological
age at the event.
14
1) Incidence of ALTE did not change
over time, SIDS decreased
2) Age at events was younger for ALTE
Tirosh
40
Israel
1991-2000
Retrospective
245
National SIDS data
19911998
Incidence of idiopathic ALTE and SIDS Incidence of idiopathic ALTE did not
change over time, SIDS decreased
Esani
41
USA
19941998
Prospective
153
SIDS in case-control
studies from different
countries
19941998
Male predominance, gestational age, low
birth weight, very low birth weight,
incidence of small for gestational age (SGA),
age at the event, multiparity, maternal age,
smoking.
In infants with ALTE:
fewer infants with low birth weight
and SGA at birth, fewer teenage
pregnancies, and younger infant
age at ALTE
Kiechl-Kohlendorfer
17
Austria
19932001
Prospective
164
SIDS cases in the
same region
1993-2001
Infants data: age, sex, birth weight, and gestation.
Sociodemographic background: maternal
educational level, marital status. Pregnancy
characteristics: mothers age at delivery, number
of previous pregnancies, maternal smoking habits
during pregnancy. Postnatal factors: infant medical
history and child care practices such as usual
sleeping position, feeding practices. Infant
behaviour: apnoea, repeated cyanotic episodes,
remarkably pallid, profuse sweating during night.
Incidence of ALTE did not change
over time, SIDS decreased
Age at events was younger for ALTE
Cote
15
Canada
19962006
Retrospective
625
All SIDS cases in the
province
1996-2006
Prematurity, Chronological age at the event,
PMA at the event
Age at events was younger for ALTE
13
In all but one study, the infants who died of SIDS had a complete autopsy. In the study of Tirosh, the autopsy rate was 30%.
14
This study looked principally at parental reported apnea and risk factors for these reported apnea.
15
Current publication. ALTE cases presenting to a tertiary pediatric Centre in Montreal, province of Quebec
6
; SIDS cases from the province, data from this cohort already
published.
4649
N. Al Khushi, A. Cote / Paediatric Respiratory Reviews 12 (2011) 124132 129
maternal smoking during pregnancy was evaluated, the risk was
present for infants with ALTE and victims of SIDS. These results
highlight more differences than similarities between the two
conditions.
RECOMMENDATIONS FOR INITIAL ASSESSMENT FOR ALTE
Protocols have been published dealing with the initial
evaluation of infants presenting with ALTE.
8,12,13,43
These protocols
rarely take into account the age of the infant and some do not
target specically the identication of serious diseases. We provide
our recommendations for the initial assessment of an infant
presenting with an ALTE in Figure 1, based on our review of the
literature. Depending on the results of this initial investigation,
further testing can be organized as indicated.
It is also very important to remember that when discharge is
planned, parental anxiety should always have been addressed, the
primary physician should have been contacted and follow-up
organized. Whether a diagnosis has been identied or not,
recurrence of events needs careful re-evaluation and possibly an
admission.
GENERAL PERSPECTIVES ON ALTE AND LESSONS LEARNED
FROM RESEARCH
We have reviewed the signicant diagnoses that could present
as ALTE and made some recommendations based on the current
literature. We focused on the well-appearing infant when rst
evaluated as symptomatic infants, especially those with altered
level of consciousness, respiratory distress or those with specic
physical ndings pose less of a problem for physicians. The reality
remains that evidence-based clinical guidelines are not yet
available to limit costly investigation but also for reducing the
risk of missing serious diseases that could be life-threatening.
Our review of the literature has highlighted the difculties
physicians are facing in evaluating the well-appearing youngest
infant (aged less than 2 months). Clearly, large scale prospective
studies are needed to identify risk factors for serious illnesses and
the yield of different tests, especially for the evaluation of serious
bacterial infection, abusive head injury or repeated severe
cardiorespiratory events. In the mean time, there is still enough
justication for physicians to order diagnostic tests to rule out
those serious diagnoses.

Group I
First, short, self-correcting episode with
feeding or in awake state
Careful history with observer of the event
Group II - ALTE
Long episode, Repetitive episodes
Perceived need of strong stimulation
Discharge home
Address parental anxiety
Advise primary care physician
Ensure follow-up
Advise to reconsult if recurrent
Well appearing infant, afebrile,
Normal physical examination
Baseline investigation
CBC and differential
Glucose, Electrolytes
Magnesium, calcium
CBG, Serum lactate
Urinalysis
Chest radiography
ECG
Consider dilated fundoscopy
Investigate and manage as
clinically indicated
Physical examination is normal?
Yes No
Prepare admission
Cardiorespiratory and
Hb-O2 saturation monitoring
Include:
Full septic work-up
Age 48 wks
(PMA)
Include:
Brain imaging
Blood ammonia level
Consider full metabolic work-up
Fever and/or Lethargy and/or
Abnormal physical
examination
Figure 1. Initial evaluation for ALTE
CBC = complete blood count; CBG = capillary blood gases; ECG = electrocardiogram; PMA = postmenstrual age.
N. Al Khushi, A. Cote / Paediatric Respiratory Reviews 12 (2011) 124132 130
It is nevertheless the reality that most ALTEs do not lead to a
serious diagnosis and a large proportion of ALTEs occur in the
rst two months of life. Diagnoses such as gastro-oesophageal
reux (GER), immaturity of the swallowing mechanism or vagal
response, make a large part of the identied causes of ALTE, and
especially GER.
10,12
These diagnoses are also most frequent in
young infants pointing to a relationship between immaturity
and ALTE. It should be remembered that infants respond to
airway stimuli differently from older children. Much research
from that eld has shown that premature infants will respond to
laryngeal stimuli, for instance, with a central apnoea, brady-
cardia and diminished tone instead of coughing.
4244
This
reaction is also common in the rst few weeks of life in full
term infants. In fact, although not usually termed ALTEs, these
events are frequently witnessed by nurses and physicians in
neonatal intensive care units and their description by the
observer resembles closely that of ALTE.
2
A similar or less
severe reaction to reux material to the level of the pharynx,
which is a normal protective reaction, will certainly alert
parents and make them believe that their child was in danger. A
single episode in a very young infant should not precipitate a
lengthy investigation.
Research has also taught us that ALTEs should not be linked to
SIDS. This has been an important lesson and gave rise to many
important studies aimed at identifying the various causes of ALTE.
Finally, research has taught us other important lessons concerning
follow-up of infants having presented with ALTE. First, close
follow-up should always be organized after an evaluation for ALTE
to identify infants with recurrent events who need further
evaluation to reach a diagnosis. Second, cardiorespiratory home
monitoring, which has been a recommendation of the past for
idiopathic ALTE
2
is not recommended anymore
3
. This is not to say
that home monitoring is not indicated in selected cases. It has been
our experience and that of others
45
that in cases of idiopathic ALTE,
a short period of monitoring might be especially helpful for infants
with recurrent but infrequent clinical events not captured during a
hospital admission.
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CME SECTION
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TRUE AND FALSE QUESTIONS
Theme 1. General information on ALTE
The management of ALTE has changed signicantly over the
past few decades
There have been major changes, in the past 30 years, in the
causes identied for ALTE.
The most prevalent diagnosis, when a cause for ALTE is
identied, is gastro-oesophageal reux.
There is no proof of a link between ALTE and SIDS.
The evaluation of ALTE should always start with a thorough
review of the symptoms and physical examination as it is
important to differentiate well appearing infants with normal
physical examination from symptomatic infants.
Theme 2. Serious diagnoses found with the investigation
of ALTE
Serious bacterial infection is most frequent in infants less
than 2 months of age.
Included in the serious bacterial infections that could present
as an ALTE in a well appearing infant are meningitis,
bacteriemia/septicemia, urinary tract infection and pneumo-
nia.
Bacteriemia/septicemia and urinary tract infection are the
two most prevalent serious bacterial infection identied with
investigation.
Abusive head injury may be difcult to diagnose as infants can
be well appearing on initial presentation.
Metabolic disorders usually present with lethargy or other
important ndings on history or physical examination.
Theme 3. Risk factor for a serious diagnosis in infants
presenting with ALTE
Prematurity is identied as a risk factor in most studies
Maternal smoking during pregnancy is a risk factor.
Age at presentation less than 2 months is a risk factor.
Young age at presentation is a risk factor for SIDS but not
ALTE.
Risk factors for recurrent ALTE have not been studied.
Theme 4. Investigation of ALTE
Septic work-up should be considered in all infants less than 2
months of age.
Complete blood count, electrolytes and calcium, capillary
blood gases and chest radiograph are some of the recom-
mended initial tests for an infant presenting in the Emergency
department with a history suggestive of ALTE.
A search for the various forms of child abuse is indicated on
the initial investigation.
With recurrent ALTEs, the investigation should focus on
diagnoses such as child abuse and seizures.
A cause for the ALTE is almost always found after investiga-
tion (including repeated events)
Theme 5. Follow-up
The primary care physician of the child should always be
notied of the visit for ALTE
A seizure disorder is usually diagnosed with recurrence of
events, not on initial presentation.
Metabolic disorders and child abuse may be diagnosed only
after recurrent ALTE
It is recommended that infants be re-evaluated within one
month after the initial investigation for ALTE.
Home monitoring is no longer recommended for the follow-
up of ALTE.
N. Al Khushi, A. Cote / Paediatric Respiratory Reviews 12 (2011) 124132 132