Brief Resolved Unexplained Events (Apparent Life-Threatening Events)

The following statement is from the National Institutes of Health ^[1] :

"An apparent life-threatening event (ALTE) is defined as an episode that is frightening to the observer and is characterized by some combination of apnea (central or obstructive), color change (cyanotic, pallid, erythematous or plethoric) change in muscle tone (usually diminished), and choking or gagging. In some cases, the observer fears that the infant has died. Previously used terminology such as near-miss sudden infant death syndrome (SIDS) or aborted crib death should be abandoned because their use implies a possibly misleading close association between this type of spell and SIDS." This original description was established by expert consensus in 1986.

In 2016, the American Academy of Pediatrics (AAP) released a new clinical practice guideline that recommended the replacement of the term ALTE with a new term, brief resolved unexplained event (BRUE). The authors define BRUE as an event observed in infants younger than 1 year during which an observer reports a sudden, brief (less than one minute), but then resolved episode including at least one of the following: cyanosis or pallor; absent, decreased, or irregular breathing; marked change in muscle tone (hyper- or hypotonia); or altered responsiveness. The guidelines also add that a BRUE is diagnosed only when there is no explanation for a qualifying event after completion of a thorough history and physical examination. Infants younger than 1 year who present with a BRUE are categorized either as (1) a lower-risk patient on the basis of history and physical examination for whom evidence-based recommendations for evaluation and management are offered or, (2) a higher-risk patient whose history and physical examination suggest the need for further investigation and treatment but for whom recommendations are not offered.  This clinical practice guideline is structured to promote a patient- and family-centered approach to care, reduce unnecessary and potentially costly medical interventions, improve patient outcomes, and enhance efforts at future research. ^{[2, 3]}

Because of marked variability in the clinical presentations of brief resolved unexplained events (BRUEs), the true frequency is unknown.

The estimated frequency of apparent life-threatening events among healthy term infants widely varies (0.5–6% of all newborns), reflecting figures derived from older retrospective reviews of hospital records. ^[4]

A systematic review reported that apparent life-threatening events accounted for 0.6-0.8% of all emergency department visits among children younger than 1 year, was noted in 2.27% of hospitalized children, and had an incidence of 0.6 cases per 1,000 live-born infants. ^[5]

A prospective population-based study of apparent life-threatening events conducted in Austria reported an incidence of 2.46 cases per 1,000 live births. ^[6]  A population based infant cohort in Italy suggesting a cumulative incidence of 4.1 per 1,000 live births in the study area. ^[40]

Esani et al (2008) compared the epidemiologic features of apparent life-threatening events and sudden infant death syndrome (SIDS). ^[7] Infants who experienced an apparent life-threatening event were younger at the time of clinical presentation. In this study, 74% of patients who experienced an apparent life-threatening event presented when younger than 2 months. By contrast, approximately 25% of SIDS victims are younger than 2 months at the time of death, according to several epidemiologic studies of SIDS. The apparent life-threatening event cohort also included more female infants and fewer infants who were small for gestational age and who had low birth weight when compared with infants who experienced SIDS in other studies. The risk of subsequent death in the apparent life-threatening event group was 0.6%.

The cause of brief resolved unexplained events (BRUEs) in infants reflects a differential diagnosis that includes an array of congenital or acquired disorders. Approximately 10-25% of apparent life-threatening events may remain unexplained following a thorough evaluation.

From retrospective studies, apparent life-threatening events have been associated with gastroesophageal reflux disease, viral lower respiratory tract infection, pertussis, sepsis and/or meningitis, seizures, metabolic disorders, toxic ingestion, cardiac dysrhythmia (eg, long QT syndrome, supraventricular tachycardia), anemia, nonaccidental trauma, or structural CNS, cardiac (ductal-dependent lesion), or airway anomaly.

Davies and Gupta (2002) conducted a prospective study of infants who presented to an emergency department with an apparent life-threatening event over a 1-year period. ^[8] The results of this prospective study suggest that a standardized approach to evaluation identifies a specific cause in most presentations. Each infant was subject to a standardized evaluation protocol upon admission; only 23% of patients had no diagnosis after evaluation. The apparent life-threatening events were associated with the following:

• Gastroesophageal reflux disease - 26%

• Pertussis - 9%

• Lower respiratory tract infection - 9%

• Seizure - 9%

• Urinary tract infection - 8%

• Factitious illness including medical child abuse - 3%

• Miscellaneous - 11%

Medical child abuse occurs when a child receives unnecessary and harmful, or potentially harmful, medical care at the instigation of a caretaker through exaggeration, falsification, or induction of symptoms of illness in a child. Neurological manifestations including false reports of BRUE or seizure are common with this type of maltreatment particularly among instances of recurrent BRUE. ^[42]

Parker and Pitetti (2011) reviewed the children presenting to an emergency department of a large children’s hospital with a diagnosis of BRUE, looking at follow up mortality. They found a mortality rate of 0.5%; however, in those children who were victims of nonaccidental trauma, the subsequent mortality rate was 9%. ^[9]

Hasenstab and Jadcherla present data that some respiratory events in infants with BRUEs are caused by atypical regulation of esophageal and airway function. As a result, therapies should not be directed to treat gastroesophageal reflux if there is no factual evidence, but instead target the coordination of airway and swallowing functions. ^{[10, 11]}

The evaluation and disposition of an infant following a brief, resolved unexplained event (BRUE or ALTE) is directed by a thorough history of the event and a careful physical examination. In most cases, the infant is free of symptoms by the time medical evaluation occurs, allowing for a systematic approach to history-taking and physical examination.

History

Key questions related to the history of the episode include the following:

• Who observed the event? Recognize that second-hand accounts may vary from the history provided by direct observers who were present at the time.

• What was the description of the event? A caregiver’s description of the infants’ color, respiration, and muscle tone is key. Care must be taken to distinguish central cyanosis (lips and oral mucous membranes) from acrocyanosis (hands and feet). Infants who are coughing, choking, or gagging may exhibit a ruddy or plethoric facial color that may be interpreted as “turning blue.” Determine whether apnea was present, and, if so, whether it appeared to be central (lack of respiratory effort) or obstructive (respiratory effort with inadequate airflow). Distinguish apnea that lasted more than 15-20 seconds from periodic breathing, in which respiratory rate and tidal volumes fluctuate and are accompanied by brief pauses in breathing that typically last less than 5-10 seconds.

• Was the infant limp, or was muscle tone increased during or after the event?

• Were any seizurelike movements observed?

• Was any resuscitation required, or did the event spontaneously resolve? Recall that caregivers may provide mouth-to-mouth resuscitation to spontaneously breathing infants with intact perfusion, fearing that the infant’s life is threatened.

• Was the infant born at term, or was the infant premature?

• Does the infant have any other significant health issues?

• Were any pregnancy or labor and delivery complications reported?

• Are any factors that predispose to neonatal sepsis noted?

• Has the infant previously exhibited symptoms of gastroesophageal reflux or aspiration of thin liquids? These symptoms may include coughing, choking, or gagging during or after feeding; frequent or excessive spitting-up; persistent nasal stuffiness; or frequent hiccups. Acid reflux disease is suggested by excessive irritability, arching, and straining behaviors displayed during or following a feeding.

• Are the newborn metabolic screening findings normal?

• Does the family have a history of seizures, metabolic disorders, previous sudden infant death syndrome (SIDS), or unexplained death in infancy or childhood?

Physical examination

A complete physical examination begins by obtaining a full set of vital signs, including pulse oximetry.

• A full head-to-toe examination of the skin should be performed to look for skin lesions or signs of trauma.

• The head and neck examination should note the characteristics of the anterior fontanelle (ie, normal, bulging, or sunken). Nondilated funduscopic examination should be performed. If retinal hemorrhages are suspected, a formal dilated indirect examination may be necessary for further characterization. ^[12] The nose and mouth should be examined for the presence of blood or formula.

• The respiratory examination should include the respiratory rate, pattern of breathing, and adequacy of air exchange. The presence of stridor, wheezes, or crackles should be noted.

• The cardiovascular examination should reveal whether murmurs are present and the adequacy and symmetry of pulses. In young infants, suspicion for ductal-dependent cardiovascular lesions may be heralded by a differential in blood pressure findings, oximetry findings, or both in the right upper extremity compared with measurements obtained from the lower extremities.

• Abdominal distension or tenderness may indicate acute intestinal obstruction. Inguinoscrotal examination should evaluate for incarcerated inguinal hernia or testicular torsion.

• Neurologic assessment begins with assessment of the infants’ responsiveness. Determine whether lethargy is persistent or resolved and whether the muscle tone and reflexes are appropriate for age. Also, determine if any focal or lateralizing findings are present.

• The skin should be carefully examined for bruises. The bones should be carefully palpated for signs of trauma.

The laboratory evaluation of an infant following a brief resolved unexplained event (BRUE) is directed by a thorough history of the event and careful physical examination. Recent BRUE guidelines for evaluation and disposition are now focused on risk stratification. Low risk infants meet the following: age greater than 60 days; gestational age greater than 32 weeks and post-conceptual age greater than 45 weeks, a negative history and normal physical examination; a single BRUE without a "BRUE cluster"; event duration less than one minute; no CPR by a trained provider. Infants meeting these criteria do not need to undergo laboratory testing or imaging studies.

Altman et al (2007) noted that signs or symptoms indicative of acute infection are typically present among infants with apparent life-threatening events who are subsequently shown to have bacterial infection. ^[13] However, in this study, some infants with urinary tract infection or pneumonia lacked conventional signs or symptoms, suggesting the need to consider these types of infections in infants with apparent life threatening events.

Zuckerbraun et al (2009) determined that serious bacterial infections (SBIs) occurred in 2.7% of afebrile, well-appearing infants younger than 60 days who experienced an apparent life-threatening event. ^[14] Infants with a history of prematurity were more likely to have a SBI than infants born at term (6.7% vs 0.8%; P = .04), suggesting the need for added vigilance in screening premature infants for SBI following an apparent life-threatening event.

Diagnostic evaluation for symptomatic infants or infants falling outside of the BRUE "low-risk" group may include the following ^[15] :

• A CBC count to screen for the presence of systemic viral or bacterial infection or anemia ^[16]

• Serum chemistry levels to assess for hypoglycemia, hyponatremia, hyperkalemia, acidemia, hypocalcemia, or elevation of serum lactate and pyruvate

• ABG to assess for acidosis or retention of carbon dioxide

• Serum and/or urine toxicology studies for possible ingestions

• Specific bacterial or viral cultures to assess for respiratory syncytial virus (RSV), pertussis, bacteremia, or urinary tract infection

• ECG to assess for long QT syndrome and preexcitation that suggests supraventricular tachycardia or other dysrhythmia

• EEG to assess for epileptiform activity

• Upper GI contrast studies to assess for swallowing dysfunction, thin liquid aspiration, or upper-intestinal anatomic malformations

• Impedance pH monitoring to assess for gastroesophageal reflux disease

• Neuroimaging to assess for hemorrhage or structural CNS abnormality

• Polysomnography to assess for sleep-based disturbances in cardiorespiratory control

Hoki et al (2012) report an ALTE cohort followed longitudinally, revealing significant cardiac disease in less than 1% of patients. ^[17] Two patients were identified with significant cardiac disease (cardiomyopathy, ventricular pre-excitation). During 7.7 years of follow-up, 3 additional significant cardiac diagnoses (ventricular pre-excitation, frequent ventricular ectopy, moderate aortic stenosis) were identified. In this group, ECG was sensitive for identifying significant cardiac disease. In general, however, all cardiac tests had low positive predictive value. Significant cardiac disease was associated with prematurity (22% vs 80%, P =.002), but not age, sex, prior ALTE, or rescue breaths.

A Japanese study sought to determine the association between ALTE and inborn errors of metabolism, particularly organic acidemia and fatty acid oxidation disorders. The majority of the infants in this study group with subsequently identified inborn error of metabolism had a history of poor feeding and somnolence during the neonatal period, and symptoms of infection such as cough, fever or vomiting precipitating an acute metabolic crisis manifesting as an ALTE. Many of these infants had active symptoms at the time of their acute evaluation in contrast to the typical BRUE presentation.  The study concluded that when ALTE is encountered in the emergency unit, samples such as urine, serum, and filter paper blood specimens should be considered for tandem mass spectrometry of organic acids and acylcarnitines, to identify inborn metabolic disorders. ^[18]

In-hospital observation has traditionally been suggested for most infants following a brief resolved unexplained event (BRUE). The initial evaluation of some infants reveals active ongoing symptoms or examination findings clearly suggesting the need for hospitalization for purposes of further evaluation and treatment (eg, sepsis). However, ALTEs that are the result of a self-resolving episode of choking or gagging associated with feedings in well-appearing infants may be observed in an outpatient setting. ^[46]

Claudius and Keens (2007) noted that infants younger than 1 month or those who had a history of multiple apparent life-threatening events at the time of presentation were at higher risk for additional events or eventual diagnoses that required further in-hospital evaluation. ^[16] This study suggests that well-appearing infants older than 30 days who have experienced a single ALTE and who have normal initial screening findings may be safely discharged from the hospital with proper outpatient follow-up.

Doshi et al (2012) report a series of 300 infants admitted following an ALTE. ^[19] Forty-six percent of these infants were diagnosed with gastroesophageal reflux as the cause of the event. Of the infants diagnosed with gastroesophageal reflux disease, only 6% experienced additional events while in the hospital. Most of these infants were younger than age 30 days or had histories of premature birth.

Mittal et al (2012) report a prospective cohort series of infants admitted following an ED diagnosis of ALTE. ^[20] Following admission, 12% of infants required significant intervention. Logistic regression identified prematurity, abnormal result in the physical examination, color change to cyanosis, absence of symptoms of upper respiratory tract infection, and absence of choking as predictors for significant intervention. These variables were used to create a clinical decision rule, based on which, 184 infants (64%) could be discharged home safely from the ED, reducing the hospitalization rate to 102 (36%). The model yielded a negative predictive value of 96.2% (range, 92-98.3%).

In a multicenter study of 832 ALTE patients presenting to ED, ^[21] 16.5% met criteria mandating admission (eg, need for supplemental oxygen or antibiotics). Regression-tree analysis identified 2 additional historical factors predicting need for admission: significant medical history and more than 1 ALTE within 24 hours of presentation. For these 2 factors, sensitivity was 89% (95% confidence interval, 83.5-92.9%) and specificity was 61.9% (95% confidence interval, 58-65.7%).

Based on these studies, approximately 10-15% of ALTE patients seen in ED benefit from admission, owing to the risk for further deterioration or identification of a significant underlying diagnosis. Study data suggest that infants younger than age 1 month, preterm infants, infants with a significant medical history, infants experiencing multiple events, or infants with episodes not associated with choking are at higher risk for additional events or significant diagnoses warranting hospitalization. Additional low-risk infants and their families may benefit from the reassurance provided by an observational stay.

Documenting cardiorespiratory monitors should be reserved for preterm infants who are at high risk for recurrent apnea or bradycardia and for infants who depend on technology because they have specific disorders of cardiorespiratory control. ^[22]

A study by Ueda et al reported that symptoms of respiratory tract infection were more frequent in patients who experienced a brief resolved unexplained event recurrence (44% vs 14%). ^[45]

Updated BRUE guidelines for evaluation and disposition are now focused on risk stratification.  Low risk infants meet the following: age greater than 60 days; gestational age greater than 32 weeks and post-conceptual age greater than 45 weeks, a negative history and normal physical examination; a single BRUE without a "BRUE cluster"; event duration less than one minute; no CPR by a trained provider. Infants meeting these criteria do not need to undergo laboratory testing or imaging studies.

A meta-analysis of the risk of death following BRUE/ALTE revealed no higher risk for death than the baseline rate of mortality for infants under one year of age. This meta-analysis supports the return-home approach advocated in the recently published clinical practice guideline for BRUE patients who have been evaluated in the emergency department and determined to be at lower risk. ^[51]

In discussing the updated BRUE guidelines with parents, care providers should anticipate the likelihood of parental concern regarding management plans which include an option for discharge to home.  Brand et al conducted structured interviews of parents of infants diagnosed with BRUE. ^[48]   Interview transcripts revealed a near-universal fear about the child's well-being, ambivalence about the best course of action following the evaluation in the emergency department, and the need for reassurance about the unlikelihood of a recurrence. Parental attitudes toward the "return-home scenario" ranged from unthinkable to extreme relief. Two-thirds of parents expressed at least some reservations about the idea of returning home.