Acute events in infancy including brief resolved unexplained event (BRUE)

INTRODUCTION — Infants who present with a history of an acute event (an unexpected change in an infant's breathing, appearance, or behavior), reported by their parent or caregiver, represent a heterogeneous group of patients of varying ages with diverse pathophysiology. It is not a specific diagnosis, but rather a "chief complaint" that brings an infant to medical attention. The clinical challenge is to identify the infants who may benefit from further testing and prolonged observation, based on factors that suggest an identifiable underlying diagnosis or risk for subsequent events, while avoiding unnecessary testing, monitoring, and hospital admission for the many other infants without these characteristics.

In the past, these events were termed "apparent life-threatening events" (ALTE). This term was broad and included a wide range of events and prognoses. Other previously used terms were "near-miss sudden infant death syndrome (SIDS)" or "aborted crib deaths," which were discarded because they incorrectly implied a direct association between these symptoms and SIDS [1,2].

A majority of these events are more precisely described as a "brief resolved unexplained event" (BRUE). This term was defined by consensus in 2016 and should be used instead of ALTE whenever the event is transient and remains unexplained after an appropriate medical evaluation [3]. Most but not all infants with BRUE are at low risk for recurrence or for having a serious underlying problem [4].

Because of the diverse presentations, causes, and prognoses of infants presenting with acute events, evaluation and management should be individualized. This topic review outlines the primary diagnostic considerations and a stepwise plan for evaluating infants presenting with this chief complaint.

DEFINITION

Brief resolved unexplained event (BRUE)

Clinical features — BRUE is not a specific diagnosis but a description of a sudden, brief, and now resolved episode in an infant that includes one or more of the following features (table 1) [3,5]:

●Cyanosis or pallor

●Absent, decreased, or irregular breathing

●Marked change in tone (hyper- or hypotonia)

●Altered level of responsiveness

The term should be applied only when the infant is asymptomatic on presentation and when there is no explanation for the episode after a focused history and physical examination. The estimated duration of the event is usually less than one minute (and typically <20 to 30 seconds).

Low-risk BRUE — Infants who have experienced BRUE are considered low risk if they have all of the following:

●Age >60 days.

●If premature, was born at gestational age ≥32 weeks and current postconceptional age is ≥45 weeks.

●Occurrence of only one BRUE (no prior BRUE, and BRUE did not occur in clusters).

●Duration of BRUE <1 minute.

●No cardiopulmonary resuscitation (CPR) by a trained medical provider was required – Resuscitation by an untrained caregiver is not used as an independent marker for medically significant BRUE, because the level of stimulation required is often difficult to determine from the history and, in some cases, the child probably resumed normal color, breathing, tone, and/or responsiveness after simply being picked up and patted.

●No concerning historical features – Concerning historical features include social risk factors for child abuse, respiratory illness or exposure, recent injury, other symptoms in days preceding the event (fever, fussiness, diarrhea, or decreased intake), administration or access to medications, history of episodic vomiting or lethargy, developmental delay or congenital anomalies, and family history of BRUE or sudden unexplained death in a sibling [5].

●No concerning physical examination findings – Concerning physical examination findings include any signs of injury, including bleeding, bruising (especially on the scalp, trunk, face, or ears), or bulging anterior fontanel; altered sensorium; fever or toxic appearance; respiratory distress; heart murmur or gallop; decreased pulses; hepatomegaly or splenomegaly; and abdominal distension or vomiting [5].

Infants who meet all of these criteria for low-risk BRUE after a focused history and physical examination require minimal additional evaluation or observation (see 'Initial evaluation' below and 'Management of low-risk BRUE' below). Infants who do not meet these low-risk criteria are thought to be at higher risk for a recurrence or serious underlying disorder and require more extensive evaluation [6]. (See 'Evaluation of infants not meeting low-risk criteria' below.)

Apparent life-threatening event (ALTE) — Apparent life-threatening event (ALTE) is a broader term that may include prolonged events or those that are explained by an underlying disorder. The term BRUE should be used instead of ALTE whenever possible (ie, when episodes are brief, resolved, and unexplained). For events that do not fit the definition of BRUE, guidelines encourage the use of event characteristics rather than the term "ALTE" to describe the event [3].

In this topic review, we will use ALTE when describing literature that used the broader definition, and "acute event" for the chief complaint prior to determination of whether it meets the definition of BRUE.

EPIDEMIOLOGY — Estimates of the incidence of BRUE in infants are not available, because most available studies focused on the broader and imprecisely defined category of apparent life-threatening event (ALTE); such studies estimated that ALTEs occur in 3:10,000 to 41:10,000 infants [7-12]. The wide range of prevalence probably represents different stringencies in the definition of ALTE and different case-finding strategies.

The main risk factors for acute events in infants described as BRUE or ALTE are feeding difficulties, recent upper respiratory symptoms, and age younger than two months, or a history of previous episodes [5,9,13]. Lesser risk factors include premature birth or low birth weight and maternal smoking [9,10]. Some studies also report that the rate of ALTE is higher among postmature infants or first-born infants, as compared with the general population [10]. In older studies focusing on the broad category of ALTE, the most commonly identified explanatory diagnoses included gastroesophageal reflux, neurologic problems (such as seizures), and respiratory infection [14]. However, it is likely that the distribution of explanatory diagnoses will change with implementation of the narrower diagnostic category BRUE [5].

INITIAL EVALUATION — The initial evaluation of an infant who has experienced BRUE is a focused history and physical examination. This information helps to identify infants who are at low risk for having a serious underlying disorder (table 1); such infants require minimal additional work-up or observation. (See 'Management of low-risk BRUE' below.)

The history and physical examination may also identify features that suggest a specific cause of the event (eg, choking/laryngospasm or an upper respiratory tract infection) or characteristics that suggest a higher risk for having a serious underlying disease (table 2). The clinical evaluation is supplemented by targeted testing in selected patients.

The importance of the focused history and physical examination was illustrated in a series of infants admitted to a tertiary center with apparent life-threatening event (ALTE). The cause of the event was diagnosed on the basis of the history and physical examination alone in 21 percent of cases [15]. The diagnosis was confirmed with testing prompted by the history and physical examination in an additional 49 percent. Eighteen percent of all tests ordered were positive and only 6 percent contributed to the diagnosis.

History — The most important diagnostic tool is a detailed description of the event and intervention obtained from the caretaker who witnessed the episode and any emergency personnel involved in the case. The key elements in the history are summarized in the table (table 3).

The history should include information about any previous apneic events, recent illnesses or symptoms, the pregnancy and perinatal period, the infant's usual behavior, sleep and feeding habits, a family history (including a history of siblings with similar episodes, sudden deaths, early deaths, genetic, metabolic, cardiac, and neurologic problems), a social history (including the presence of smoking, alcohol or substance use in the home, and a list of medications in the home) [5]. The family should be asked specifically about the possibility of accidental or intentional administration of poisons or medications, including over-the-counter cold preparations [16].

Features that suggest that the event was caused by gastroesophageal reflux (GER) and/or laryngospasm include gross emesis or oral regurgitation that occurred at the time of the event, and that the episode was characterized by obstructive apnea (ie, that the infant was making respiratory efforts but not successfully breathing). Acute events caused by laryngospasm typically occur during feeding, or shortly after feeding, especially if the infant is in a supine position. In an otherwise healthy infant, the presence of these features is reassuring because they suggest that the event was caused by choking, gagging, and/or laryngospasm, which are common and not life-threatening. If the events are recurrent and/or the infant has underlying neurologic or developmental abnormalities, further evaluation for swallowing dysfunction may be warranted. (See 'Gastroesophageal reflux or swallowing dysfunction' below.)

A respiratory tract infection should be suspected based on symptoms (eg, history of nasal congestion, cough, and/or fever). Features suggestive of seizures include loss of muscle tone and unresponsiveness during the episode, and no history of choking or gagging. (See 'Respiratory infection' below and 'Epilepsy or central nervous system disorder' below.)

A history of previous episodes of severe events should particularly prompt consideration of child abuse, especially if the events occurred in the presence of a single caretaker and required cardiopulmonary resuscitation (CPR). A history of acute events or unexplained death in siblings or a prior report for child maltreatment also raises this concern. Child abuse may involve intentional suffocation, abusive head trauma, or factitious illness. (See 'Child abuse' below.)

Examination — Infants presenting with a BRUE should undergo careful physical examination, with particular attention to abnormalities in the neurologic, respiratory, and cardiac systems [17]. The examination should include:

●Measurement of height, weight, and head circumference and comparison of these values to standards for age and sex

●Measurement of vital signs, including pulse oximetry

●Examination for physical signs of trauma (bruising, torn frenulum, subconjunctival or retinal hemorrhage, bulging anterior fontanel) (see 'Child abuse' below)

●Neurologic examination, including alertness and tone (see "Detailed neurologic assessment of infants and children")

●Evaluation for respiratory distress or upper airway obstruction, including assessment of facial dysmorphism [18,19]

●Cardiac examination, including for murmur, gallop, decreased pulses, or hepatomegaly (see "Identifying newborns with critical congenital heart disease", section on 'Clinical features')

●Developmental assessment, including assessment of developmental reflexes (see "Detailed neurologic assessment of infants and children")

Warning signs — The presence of the following warning signs increase the likelihood that the acute event is medically significant and may have a specific pathologic cause. Infants with these signs should be admitted to the hospital for observation with cardiorespiratory monitoring, with specific evaluation guided by the history, as outlined below.

●Symptoms at the time of evaluation, including toxic appearance, lethargy, unexplained recurrent vomiting, or respiratory distress.

●Significant physiologic compromise during the event, based on a detailed description by the caretaker. Concerning symptoms include generalized sustained cyanosis or loss of consciousness, and/or need for resuscitation by a trained CPR provider (more than just stimulation).

●Bruising or any other evidence of trauma.

●History of prior events in this patient, especially within the past 24 hours, or clusters of events.

●History of clinically significant events or unexpected death in a sibling.

●History that raises suspicion for the possibility of child maltreatment, such as an inconsistent description of the event, prior report for child maltreatment with the same family or caregiver, or a description that is inconsistent with the child's developmental stage.

●Dysmorphic features, congenital anomalies, and/or known syndrome.

MANAGEMENT OF LOW-RISK BRUE — For infants with low-risk characteristics (table 1), who are asymptomatic and have no concerning features identified on history and physical examination, little intervention is required. However, in a large retrospective multicenter study, only approximately 15 percent of infants presenting with BRUE meet all of these low-risk criteria [20]. These low-risk criteria are reasonably accurate for identifying infants who are unlikely to have a recurrent event but less accurate for excluding the possibility of a serious underlying condition, as discussed below.

The following steps are recommended, as outlined in guidelines from the American Academy of Pediatrics (algorithm 1) [3]:

●Recommended steps:

•Educate caregivers about BRUEs, and the low risk for infants with these characteristics.

•Offer resources for training in cardiopulmonary resuscitation (CPR).

•Engage in shared decision-making about further evaluation and disposition.

•Arrange for a follow-up check with a medical provider within 24 hours to identify infants with evolving medical concerns that would require further evaluation and treatment.

●Optional steps:

•A brief period of in-hospital observation (eg, one to four hours) with continuous pulse oximetry and serial observations.

•12-lead electrocardiogram with attention to QT interval. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Sudden infant death syndrome'.)

•Testing for pertussis (especially for infants with suggestive symptoms). Respiratory virus testing, such as for respiratory syncytial virus, is reasonable if a rapid testing method is available. However, this testing is not required in these low-risk infants, who by definition have no respiratory symptoms and are >2 months of age. (See 'Respiratory infection' below.)

In particular, the clinician should educate the family that there is no known association between BRUE (with low-risk characteristics) and the risk for sudden infant death syndrome (SIDS). It is reasonable to use this opportunity to remind the family of the routine measures that they should take to minimize the risk of SIDS, such as ensuring that the infant sleeps in a supine position with face free, and in a safe sleeping environment (avoiding adult or loose bedding, excessive clothing, extreme room temperatures), and eliminating prenatal and postnatal exposure to tobacco smoke [17]. Parents and caregivers should be specifically advised not to shake the infant in an effort to "resuscitate" him or her [11]. (See "Sudden infant death syndrome: Risk factors and risk reduction strategies", section on 'Prevention'.)

For these low-risk infants, there is no need for routine testing with a urinalysis, blood tests (glucose, bicarbonate, or lactic acid), or neuroimaging, or admission to the hospital solely for cardiorespiratory monitoring [3].

The American Academy of Pediatrics guideline specifically recommends against evaluating for systemic infection (white blood cell count, blood culture, or cerebrospinal fluid analysis or culture); laboratory testing for anemia; metabolic disease (electrolytes, calcium, ammonia, urine organic acids, plasma amino acids or acylcarnitines); respiratory disease (chest radiograph or blood gas testing); echocardiogram; electroencephalogram (EEG); or studies for gastroesophageal reflux (GER) [3]. Furthermore, home cardiorespiratory monitoring is not recommended for these infants. (See 'Home monitoring' below.)

EVALUATION OF INFANTS NOT MEETING LOW-RISK CRITERIA — Most infants presenting with BRUE fail to meet all of the low-risk criteria. In a large multicenter study, 87 percent had one or more high-risk characteristics [20]. The BRUE criteria were reasonably accurate for predicting a recurrent event in the emergency department or hospital (negative predictive value [NPV] 97 percent, positive predictive value [PPV] 14 percent) but less accurate for identifying the small minority with a serious underlying condition (NPV 97 percent, PPV 4 percent) [20]. The most common serious underlying causes were epilepsy/infantile spasms, airway abnormalities, and abusive head trauma. Because of the small but important risk of serious underlying causes, the complaint must be taken seriously even if the infant appears entirely well by the time they are evaluated.

Although this large retrospective study provides insights into the spectrum of presentations and outcomes of infants presenting to emergency departments with a potential BRUE, the methodology does not allow a full assessment evaluation of the performance of the BRUE risk criteria or algorithm as used prospectively in practice.

Initial screening evaluation — When the infant does not have the low-risk characteristics for BRUE described above (table 1), further evaluation is warranted.

If there are clinical features that suggest a specific diagnosis (eg, upper respiratory tract infection or child abuse), the evaluation may be targeted toward that concern. For those without clinical features suggesting a specific diagnosis, evidence is not available to provide a definitive approach for further evaluation. However, a reasonable, though not yet validated, framework has been published, which includes (algorithm 2) [6]:

●Pulse oximetry monitoring for at least four hours

●Electrocardiogram

●Hematocrit

●Blood glucose, bicarbonate or venous blood gas, lactic acid (to evaluate for inborn errors of metabolism)

●Respiratory virus testing panel (including respiratory syncytial virus)

●Testing for pertussis – If the infant has suggestive symptoms, has not been completely immunized, and/or has been exposed in an endemic region or outbreak (see 'Respiratory infection' below)

●Review of results of newborn screening tests (eg, for inborn errors of metabolism)

In addition, particularly if the infant has a change in sensorium, the evaluation should include a focused history and laboratory screening to detect accidental or intentional ingestions of poisons or medications, including over-the-counter cold preparations and ethanol [16,21]. (See "Approach to the child with occult toxic exposure" and "Ethanol intoxication in children: Clinical features, evaluation, and management".)

Targeted evaluation for specific disorders — Among infants presenting with acute events (using the broad definition of ALTE), a specific cause can be identified in more than 50 percent after a careful history, physical examination, and appropriate laboratory evaluation (table 2) [20,22]. Further specific diagnostic studies may be indicated in selected cases. The additional evaluation depends upon potential diagnoses suggested by the presenting symptoms and findings in the history, examination, and initial evaluation (algorithm 2) [17,23,24].

Gastroesophageal reflux (GER)/laryngospasm, neurologic problems (such as seizures), and respiratory infection account for the greatest number of episodes described in the literature as ALTE [22]. Child abuse is less common (reported in 0.4 to 11 percent of cases presenting as ALTE [25-30]), but a lower proportion of infants meeting the narrower definition of BRUE [5]. Infrequent causes of such events are cardiac disease, upper airway obstruction, metabolic disorders, anaphylaxis, and bacterial infections (including urinary tract infection), each accounting for 0.5 to 3 percent of ALTE [14,20,27,31]. In afebrile infants, bacterial infections are more likely in those presenting with multiple events on the day of admission, or in premature infants [32]. More rare causes of these events include disorders of ventilatory control, toxic ingestions, and other miscellaneous conditions [14,27,31].

Respiratory infection — Infants with upper respiratory symptoms (cough, nasal congestion) or those who are young (<60 days) or premature should be evaluated for respiratory infections, particularly pertussis and respiratory syncytial virus (RSV) infection. An upper or lower respiratory tract infection (including bronchiolitis) is ultimately diagnosed in approximately 20 percent of infants with acute events [14,15,33]. Pertussis and RSV infections are identified in approximately 10 percent of cases [14,24,33].

●Testing for pertussis is especially appropriate if the infant has any upper respiratory symptoms or if there is pertussis activity in the community. Testing of a nasopharyngeal specimen by polymerase chain reaction is typically used because it provides results promptly. (See "Pertussis infection in infants and children: Clinical features and diagnosis".)

●Testing for respiratory viruses (eg, RSV) is reasonable in infants with nasal congestion or other respiratory symptoms. Respiratory symptoms may be subtle (coryza), especially in young or premature infants. RSV has been associated with apnea in premature infants or those <60 days old, but such infants are by definition not in the low-risk category for BRUE. (See "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children".)

Child abuse — If the history or examination raises any concerns about child abuse, a thorough evaluation is warranted. This possibility should be particularly considered if the child has unexplained bruising or bleeding, a bulging fontanelle with or without recurrent vomiting and irritability, if the caretaker gives inconsistent or implausible descriptions of the event, or if there have been previous events that take place only in the presence of a single caretaker (especially severe events requiring cardiopulmonary resuscitation [CPR]), or siblings with unexplained events or deaths (table 4A-B). Child abuse may involve intentional suffocation, abusive head trauma, or factitious illness (Munchausen syndrome by proxy). (See "Physical child abuse: Recognition" and "Medical child abuse (Munchausen syndrome by proxy)".)

The evaluation may include radiographic evaluation for trauma, neuroimaging, social work screening, and/or hospitalization for observation and further assessment. To evaluate for retinal hemorrhage, a limited funduscopic examination can be performed using a direct ophthalmoscope with pupillary dilation, but this approach has low sensitivity. A definitive examination for retinal hemorrhage requires indirect ophthalmoscopy by an ophthalmologist and may require anesthesia. We also suggest querying the local child protection register to determine whether any relevant complaints have been recorded [14,34]. (See "Child abuse: Evaluation and diagnosis of abusive head trauma in infants and children" and "Child abuse: Eye findings in children with abusive head trauma (AHT)", section on 'Evaluation'.)

Gastroesophageal reflux or swallowing dysfunction — Transient choking or gagging during feeding can lead to an acute event in healthy infants and usually is benign. The likely mechanism is laryngospasm. Similarly, physiologic gastroesophageal reflux (GER) can cause laryngospasm and BRUE in healthy infants. The GER may have triggered the laryngospasm, but this does not mean that the infant has an abnormal degree of GER or that treatment of GER will prevent similar events in the future [35,36]. Clinical features that suggest this mechanism include:

●Gross emesis or oral regurgitation occurs at the time of the event

●Episodes occur while the infant is awake and supine

●The event is characterized by obstructive apnea (ie, the infant was making respiratory efforts, but not successfully breathing)

In infants with these characteristics who are otherwise healthy, low-risk medical interventions to reduce GER (eg, thickening of feeds, trial of a milk-free diet, and possibly acid suppression) may be used, but these interventions should not replace or delay an evaluation for other causes of acute events, especially in infants with warning signs that suggest a serious cause of the event [36] (see 'Warning signs' above). Because a causal association between GER and acute events rarely is established with certainty, and because the overall risk for death in these infants is low, invasive approaches such as antireflux surgery are rarely appropriate for this type of patient. (See "Gastroesophageal reflux in infants", section on 'Treatment options'.)

For infants with a history of recurrent difficulties while feeding (eg, observations of choking or repeated acute events), a videofluoroscopic swallowing study may be useful to evaluate for swallowing dysfunction. Infants with neurologic dysfunction, dysmorphic features, or known syndromes are at increased risk for swallowing dysfunction. (See "Aspiration due to swallowing dysfunction in children", section on 'Instrumental evaluation of swallowing'.)

Esophageal pH monitoring or multichannel intraluminal impedance monitoring is of limited value in evaluating infants with BRUE and suspected GER [37]. Abnormal results of esophageal monitoring do not confirm that GER caused the acute event, and normal results do not exclude GER as a cause. The test can only establish a causal association between GER and the acute event if another event occurs during the 24-hour monitoring period, and if the event is demonstrated to be temporally associated with a preceding episode of GER by using simultaneous polysomnography or continuous oxygen saturation monitoring. Barium esophagrams are neither sensitive nor specific for detecting pathologic GER in infants. (See "Gastroesophageal reflux in infants", section on 'Diagnostic tests'.)

Epilepsy or central nervous system disorder — An evaluation for seizures (electroencephalogram [EEG] and/or brain imaging) is warranted only if there is a strong clinical suspicion. This is because these tests have low sensitivity to predict which patients will ultimately be diagnosed with chronic epilepsy [27]. Clinical features that suggest the possibility of epilepsy or a central nervous system (CNS) disorder include recurrent events with loss of muscle tone and unresponsiveness, sustained or stereotyped events, and no history of choking or gagging [6,38]. Central apnea may be a symptom of CNS disorders, including brain injury (eg, from abusive head trauma or infection) or structural brain abnormalities (eg, hydrocephalus), or a disorder of ventilatory control (which is rare).

In several case series, a CNS disorder was ultimately diagnosed in 10 to 20 percent of infants who presented with an ALTE [14,15,24,33,38,39]. In most of these infants, the event was ultimately attributed to a seizure; a few others had ventricular hemorrhage or hydrocephalus. Of note, EEG performed after the event usually is normal, so the diagnosis of seizure in these series was based on a detailed history as reported by the caretakers.

Work-up for other disorders, by presenting symptoms — Rare causes of acute events include systemic infections, disorders of ventilatory control, inborn errors of metabolism, cardiac abnormalities, and toxic ingestions. Investigation for these disorders should be triggered by the presenting symptoms, as outlined below:

●Fever, toxic appearance, respiratory distress, hypoxemia, or clustered acute events – These signs or symptoms suggest the possibility of systemic infection and should be evaluated, as appropriate, to the infant's age and clinical presentation. Infants with symptoms of respiratory tract infection should be evaluated with a chest radiograph, as indicated by clinical symptoms (in addition to testing for Bordetella pertussis and RSV, as discussed above). Bacterial infections, including urinary tract infection, are uncommon causes of acute events but are more likely in infants presenting with multiple events on the day of admission, or in premature infants [32]. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation" and "Approach to the ill-appearing infant (younger than 90 days of age)".)

●Events that occur during sleep – Events that occur when the infant is supine or asleep raises the possibilities of:

•GER. (See 'Gastroesophageal reflux or swallowing dysfunction' above.)

•Epilepsy. (See 'Epilepsy or central nervous system disorder' above.)

•Apnea of prematurity – In infants younger than 44 weeks postmenstrual age.

•Sleep-related breathing disorder, ie, obstructive sleep apnea, or central sleep apnea. Central apnea may be due to brain malformations or a disorder of ventilatory control (which is rare). Findings that suggest a risk for a sleep-related breathing disorder include congenital malformations or a genetic syndrome, neuromuscular disorders, or craniofacial dysmorphism [18].

These disorders can be identified by performing polysomnography in selected infants, ie, those without apparent reflux and with recurrent events [40,41]. Multichannel polysomnography typically includes an EEG to evaluate the sleep-wake state of the infant, measurements of heart rate, respiratory effort, oxygen saturation, and airflow [17]. An expanded EEG montage can be added if a seizure disorder is suspected. Esophageal monitoring for reflux can be added if a temporal relationship between GER and apnea is strongly suspected. Multichannel polysomnograms are distinct from two-channel "pneumograms," which should not be used in the evaluation of an acute event. Pneumograms provide continuous 12- to 24-hour recordings of chest movement and heart rate but provide no data on oxygenation or airway obstruction. (See "Overview of polysomnography in infants and children".)

●Hypoglycemia, metabolic acidosis, vomiting, or lethargy – The clinical manifestations of metabolic disease (inborn errors of metabolism) may include findings in virtually every system and may be acute, recurrent, or chronic. Episodes may be triggered by fasting or an intercurrent illness. Neurologic and gastrointestinal manifestations are the most frequent.

Further evaluation for inborn errors of metabolism is warranted in any infant with hypoglycemia or other metabolic abnormalities on the initial laboratory screen (see 'Initial screening evaluation' above) and for infants whose current presentation, past history, or family history are suggestive of a possible metabolic disease. Newborn screening results should be reviewed but also verified by additional testing if there is a concern for metabolic disease. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and "Approach to hypoglycemia in infants and children".)

●Altered sensorium – An altered sensorium in an infant can be caused by a wide variety of processes. Such infants should be evaluated promptly with blood glucose and a toxicology screen (including ethanol levels), and the history should be carefully reviewed for any possible ingestion of drugs (over-the-counter, prescription or herbal; intentional or unintentional). In addition, they should be investigated for abusive head trauma, neurologic disease (seizures), infection, and metabolic disease (including testing for serum ammonia, lactate, and pyruvate).

Accidental or intentional poisoning may be responsible for a small number of acute events in some populations. In one institution, toxicology screens were performed in nearly one-half of the infants evaluated for ALTE. Of 274 results, 8 percent revealed clinically significant ingestions. Five percent of the infants screened positive for over-the-counter cold medications, although none of the parents admitted to administering these [16]. However, the extent to which the ingestion may have contributed to the episode is uncertain. Case reports identify ethanol ingestion as a cause of ALTE in young infants [21]. Clinical manifestations of ethanol ingestion in infants may include hypoglycemia, in addition to altered sensorium and respiratory depression.

●Cyanotic episodes, abnormal cardiac examination, or electrocardiogram abnormalities – Congenital heart diseases, both structural and ion channel defects, may present in a variety of ways including sudden death, cardiac arrest, syncope, and cyanotic episodes. The possibility of cardiac disease should be considered in infants with these features or with a family history of sudden death in a first- or second-degree relative <35 years old, if not otherwise explained; the scope of the cardiac evaluation is directed by the specific manner of presentation. These are infrequent causes of acute events. (See "Identifying newborns with critical congenital heart disease" and "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Sudden infant death syndrome'.)

Disposition — In-hospital observation with cardiorespiratory monitoring is indicated for infants whose initial evaluation (whether by history, examination, or other diagnostic studies) suggests physiologic compromise. This includes infants with a history of more than one acute event within the previous 24 hours or any other warning signs prompting additional evaluation [11,42] (see 'Warning signs' above). Other reasons to consider hospitalization include: suspicion of trauma, neglect, poisoning or abuse; an otherwise unwell-appearing infant (such as failure to thrive of unknown etiology); social risk factors; or perceived need to monitor and observe feedings.

For infants who do not meet criteria for low-risk BRUE (table 1), a brief period of in-hospital observation and monitoring (eg, for 24 hours) immediately after the event may provide important clinical information. This is because additional episodes may be witnessed by medical personnel during the observation period, providing additional detail about the nature of the event. In addition, serious underlying medical conditions (eg, hypoventilation or hypoxemia) may become apparent [23,24,43]. As an example, observations of apnea or bradycardia in association with clinical findings of inadequate respiratory effort, color change, or loss of tone will confirm the need for more specialized diagnostic studies (eg, extended Holter monitoring, esophageal pH monitoring, epilepsy monitoring, polysomnography, computed tomography or magnetic resonance imaging of the CNS, metabolic studies, or more invasive studies such as bronchoscopy).

Home monitoring — The diverse characteristics of infants with a history of an acute event preclude universal policies regarding the use of home cardiorespiratory (CR) monitoring. The decision should be made on a case-by-case basis after considering with the family the potential benefits, uncertainties, and stresses involved.

Studies of infants with a history of ALTE and who remain asymptomatic have failed to demonstrate a therapeutic benefit of home CR monitoring. Nonetheless, in selected cases, monitor recordings may provide some diagnostic value or may provide reassurance that clinically important events are not occurring. Infants who may particularly benefit from home monitoring include premature infants with recurrent episodes of apnea and bradycardia, or infants with unstable airways or chronic lung disease. Providers and families should recognize that home monitors typically detect only chest wall movement and heart rate. For some infants, particularly those in whom obstructive apnea is suspected, monitoring oxygen saturation by pulse oximetry may be more appropriate than CR monitoring. These issues are discussed in more detail in a separate topic review. (See "Use of home cardiorespiratory monitors in infants".)

PROGNOSIS

Risk of recurrence — The reported risk for recurrence varies with the patient population:

●For infants meeting the narrow criteria for BRUE (ie, was brief, resolved completely, and no explanation is found after a focused evaluation), the risk of recurrence is less than 10 percent [4,5]

●In a study of infants with BRUE that led to hospitalization, 65 percent had subsequent choking spells reported by caregivers, 10 percent had subsequent BRUE spells, and 15 percent had repeat emergency department visits or hospitalization [44]. The high recurrence rate in this study may be related to the characteristics of the events that prompted the hospitalizations, which were not reported in the paper.

●In studies of infants meeting historical criteria for apparent life-threatening events (ALTE), reported recurrence rates ranged from 10 to 25 percent [11,14,45-47].

Risk factors for clinically significant recurrences include prematurity (postmenstrual age <43 weeks), a history of multiple events preceding the hospital admission, event duration >1 minute, and a viral respiratory tract infection [27,48,49]. Although upper respiratory tract symptoms are associated with recurrent events, one series suggests that these events are not likely to be serious as long as the initial event was not severe and there were no other warning signs [47].

Apneic events that occur in infants with a history of prematurity usually represent an immaturity of respiratory control and generally resolve with maturation. In a longitudinal study that used home monitoring, preterm infants were at increased risk for "extreme" alarm events (defined as central apnea lasting more than 30 seconds, or extreme bradycardia or oxygen desaturation <80 percent lasting more than 10 seconds), and these events disappeared once the infants reached 43 weeks postconceptional age [49].

Infants who present with multiple acute events preceding the hospital admission are more likely to have an underlying disease as compared with those with single events. This may include an acute infection (viral illness or serious bacterial infection), metabolic disorder, or child abuse [27]. Whether the age of the infant predicts recurrence is unclear. Infants younger than two months of age require special attention because they are at increased risk for occult infection or undiagnosed congenital disorders [27,50]. On the other hand, acute events are uncommon after three months of age, so older infants are more likely to have an underlying cause (eg, seizure or child abuse) [9,27].

Death — The overall risk of subsequent death in infants who have experienced ALTE is estimated to be less than 1 percent, and substantially lower for those meeting the narrower criteria for BRUE [9,29,30,51,52]. Among infants who initially present with an ALTE and subsequently die, most have a specific cause for death. Causes of death may include child abuse, an underlying neurologic disorder, pneumonia, or metabolic disease [9,29,30,53].

Certain risk factors are associated with a greater mortality risk. Infants with recurrent events requiring cardiopulmonary resuscitation (CPR) have a very high risk of subsequent death, ranging from 10 to 30 percent [54,55]. In such infants, unusual diagnoses, including metabolic diseases, neurodegenerative problems, or intentional suffocation, should be considered. Infants subjected to child abuse presenting as BRUE-like events also have an increased mortality rate (9 percent in one case series [30]).

In the past, ALTE was thought to be a possible precursor to sudden infant death syndrome (SIDS) because prior ALTE events were reported in 5 percent of SIDS victims [56], and because early anecdotal reports described SIDS in infants with recurrent apnea [57]. However, the vast majority of SIDS victims do not experience acute events or apnea prior to death. Furthermore, studies over the past two decades have failed to confirm a causal relationship between preexisting apnea and SIDS [2]. (See "Sudden infant death syndrome: Risk factors and risk reduction strategies".)

Several other factors argue against a relationship between SIDS and ALTE:

●Over 80 percent of SIDS deaths occur between midnight and 6 AM [58], whereas 82 percent of ALTE episodes occur between 8 AM and 8 PM [59].

●The peak incidence of ALTE is during the first two months of life, whereas the peak incidence of SIDS is between two and four months of age [13].

●Interventions to prevent SIDS (eg, supine sleeping) have not resulted in a decreased incidence of ALTE [9].

●The risk factors for SIDS and ALTE differ [13,48]. In one prospective population-based study, prone sleeping, lack of breastfeeding, and maternal smoking were risks for SIDS, whereas behavioral characteristics (eg, previous episodes of apnea, pallor, cyanosis, or feeding difficulties) were risk factors for ALTE [9]. Prematurity and low birth weight are much stronger risk factors for SIDS than for ALTE [13].

Finally, ALTE is unlikely to be a predictor of SIDS because ALTE refers to a heterogeneous group of problems with different causes and severities, ranging from benign to near-fatal. Moreover, the case definition in ALTE (or BRUE) depends upon observations by the parent or caregiver, which have been shown to be unreliable in several studies [60-65].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Sudden infant death syndrome (SIDS) (The Basics)")

●Beyond the Basics topics (see "Patient education: Sudden infant death syndrome (SIDS) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions

•Brief resolved unexplained event (BRUE) – A BRUE is a description of a sudden, brief, and now resolved episode that includes one or more of the following features (table 1) and remains unexplained after an appropriate evaluation (see 'Definition' above):

-Cyanosis or pallor

-Absent, decreased, or irregular breathing

-Marked change in tone (hyper- or hypotonia)

-Altered level of responsiveness

•Apparent life-threatening event (ALTE) – ALTE is a broader term that may include prolonged events or those that were explained by an underlying disorder. The term BRUE should be used instead of ALTE whenever possible (ie, when episodes are brief, resolved, and unexplained). For events that do not fit the definition of BRUE, guidelines encourage the use of event characteristics rather than the term ALTE to describe the event. (See 'Apparent life-threatening event (ALTE)' above.)

●Initial evaluation – The initial evaluation of an infant who has experienced BRUE is a focused history and physical examination. The history includes a detailed description of the event by the caretaker who witnessed the episode (table 3). (See 'History' above and 'Examination' above.)

•Low-risk criteria – This information helps to identify infants who are at low risk for recurrence or for having a serious underlying disorder (table 1). Such infants require minimal additional work-up or observation (algorithm 1). These low-risk criteria are reasonably accurate for identifying infants who are unlikely to have a recurrent event in the emergency department but less accurate for excluding the possibility of a serious underlying condition. (See 'Low-risk BRUE' above and 'Management of low-risk BRUE' above.)

•Warning signs – Warning signs indicating that the event was medically significant and may have a specific pathologic cause include (see 'Warning signs' above):

-History of prior acute event in this patient (especially within the past 24 hours) or of an acute event or unexplained death in a sibling.

-Symptoms at the time of evaluation (toxic appearance, lethargy, fever, unexplained recurrent vomiting, or respiratory distress).

-Examination revealing bruising or any other evidence of trauma, dysmorphic features, congenital anomalies, and/or known syndrome.

-Significant physiologic compromise during the event, based on a detailed description by the caretaker. This may include generalized sustained cyanosis, loss of consciousness, or need for cardiopulmonary resuscitation (CPR) by caretaker or trained CPR provider (more than mere stimulation).

Infants with warning signs should be admitted to the hospital for observation and additional evaluation. (See 'Disposition' above.)

●Further evaluation – Infants with warning signs or those who do not meet low-risk criteria warrant further evaluation, which typically includes a basic screening evaluation. Further work-up depends upon the suspected disorder (algorithm 2). In some cases, the history and physical examination may identify features that suggest a specific cause of the event (eg, choking/laryngospasm or an upper respiratory tract infection) or other characteristics that suggest a higher risk for having a serious underlying disease (table 2). (See 'Evaluation of infants not meeting low-risk criteria' above and 'Targeted evaluation for specific disorders' above.)

●Specific considerations

•The role of gastroesophageal reflux (GER) in infants with acute events is uncertain. When an episode of GER appears to have immediately preceded the acute event, the direct cause of the respiratory event is probably laryngospasm. The GER may have triggered the laryngospasm, but this does not mean that the infant has an abnormal degree of GER or that treatment of reflux will prevent similar events in the future. Laryngospasm also may occur during feeding in the absence of GER. (See 'Gastroesophageal reflux or swallowing dysfunction' above.)

•The possibility of child abuse should be considered when an infant suffers recurrent, severe BRUE-like events requiring CPR that occur only in the presence of a single caretaker and a thorough diagnostic evaluation reveals no reasonable explanation for these dramatic repetitive events. These and other clues on history and physical examination are outlined in the tables (table 4A-B). (See 'Child abuse' above.)

●Prognosis – Approximately 4 percent of infants presenting with BRUE have a serious underlying cause. BRUE and ALTEs are not considered a precursor to, or risk factor for, SIDS. The vast majority of SIDS victims do not experience apnea prior to death, and the epidemiology and risk factors for SIDS are very different from those for BRUE and ALTE. (See 'Prognosis' above.)