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 behaviour), 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 "presenting 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 invasive testing, monitoring, and hospital admission for the many other infants without these characteristics.
 
The 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 (Apparent Life-Threatening Event) whenever the event is transient and remains unexplained after an appropriate medical evaluation. 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 Sudden Infant Death Syndrome (SIDS).
 
Most, but not all infants with BRUE are at low risk for recurrence or for having a serious underlying problem.
A BRUE refers to an episode in an infant less than 12 months old which is:
  • Duration <1 minute (typically 20-30 seconds)  
  • Sudden onset, accompanied by a return to a baseline state
  • Characterised by ≥1 of the following:
    • cyanosis or pallor
    • absent, decreased or irregular breathing
    • marked change in tone (hypertonia or hypotonia)
    • altered level of responsiveness
  • Not explained by identifiable medical conditions
If the above criteria are met, the assessing clinician should obtain a careful history & appropriate examination of the child to confirm the diagnosis of BRUE which in its self is a diagnosis of exclusion. If history and examination suggest features of other conditions/diagnosis, the clinician should proceed as appropriate for that identified condition and this guideline does not apply. Of note, gastro oesophageal reflux disease, feeding difficulties, food intolerances (specifically milk/soy protein) and non-accidental injury can present in this fashion and should be considered carefully.

Scope
This clinical guideline is applicable across all paediatric departments, both within the emergency department, and the paediatric ward.
 
The aim of this guideline is to identify and differentiate between patients who need further monitoring, invasive investigations and hospital admission and those who do not. 
Definitions​
These definitions apply to children under 12 months of age only, outside of this age bracket please consider alternative diagnosis
 
  • Brief Resolved Unexplained Event (BRUE):
    • An event lasting less than 60 seconds, characterised by 1 or more of the following: pallor or cyanosis, absent/reduced/irregular breathing, marked change in tone, altered level of consciousness which cannot be explained by a medical cause
​
  • Apparent Life-Threatening Event (ALTE):
    • The combination of clinical presentations such as apnoea, a marked change in skin and muscle tone, gagging, or choking
Guideline
History
A history should be ideally taken from someone who observed the infant during or immediately after the event. Key features of history should include:
Description of event, including any:
  • Choking or gagging
  • Breathing: including any shortness of breath, pauses or apnoea
  • Colour and colour distribution: normal, cyanosis, pallor, plethora
  • Any distress
  • Conscious state: responsive to voice, touch, or visual stimulus
  • Tone: stiff, floppy, or normal
  • Movement (including eyes): purposeful, repetitive
  • Duration of event
  • How the event stopped (self-resolved, repositioned, stimulation, CPR)
  • Recovery phase: rapid or gradual
Circumstances and environment prior to event
  • Awake or asleep
  • Relationship of the event to feeding and history of vomiting
  • Position (prone/supine/side)
  • Environment: sleeping arrangement, temperature, bedding
  • Objects nearby that could cause choking or suffocation
Other history
  • Past medical history including previous similar events
  • Preceding/intercurrent illness
  • Sick contacts
  • Family history of sudden death or significant childhood illness
  • Patient medications, medications or other drugs within the home (including any possibility of accidental or intentional adminstration of toxins or other drugs)
  • Social history including any safeguarding concerns, the presence of smoking, alcohol of substance use in the home
 
Examination
A detailed general physical examination is needed along with a full set of observations including temp, RR, HR, BP, AVPU and oxygen saturations. Plot height, weight and head circumference.
 
Warning signs indicating that the event was medically significant and may have a specific pathological cause include:
  • History of a 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 (lethargy, fever, unexplained recurrent vomiting, or respiratory distress).
  • Examination revealing bruising or any other evidence of physical trauma (e.g. torn frenulum, subconjunctival haemorrhages, bulging fontanelle), dysmorphic features, congenital anomalies, and/or known syndrome.
  • Significant physiological compromise during the event, based on a detailed description by the caretaker. This may include generalised sustained cyanosis, loss of consciousness, or need for cardiopulmonary resuscitation (CPR) by caretaker or trained CPR provider (more than mere stimulation).
 
Differential Diagnoses:
A BRUE is diagnosed after a thorough history and examination when there is no explanation for the event.
 
An exaggerated physiological airway protection reflex is the most common explanation. In young infants the laryngeal chemoreceptor cough reflex is immature and ingestion of saliva/feed/refluxed gastric contents into the larynx can sometimes trigger apnoea. This reflex appears to be more sensitive during upper respiratory tract infections.
 
Approximately half of presenting cases are idiopathic. Less commonly very serious illness such as sepsis or meningitis can be the underlying cause of the presentation and must always be considered.
 
Consider: Post vaccination HHE (Hypotonic Hyporesponsive Episode),
  • Awareness is low of this reaction which can appear quite alarming but also harmless and not a contraindication to further vaccination.
  • A hypotonic–hyporesponsive episode (HHE) is the sudden onset of hypotonia, hyporesponsiveness, and pallor or cyanosis that occurs within 48 hours after childhood immunizations.
  • Episodes are normally resolved by the time the child is seen in hospital and all that is needed is reassurance.
  • This syndrome has been primarily associated with pertussis-containing vaccines administered to children <2 years of age, and has been estimated to occur once every 1750 diphtheria-tetanus-pertussis (DTwP) vaccinations.
 
Of the group with an identifiable cause of the presentation, aetiology can include:
Airway

Cause
  • Airway obstruction, inhaled foreign body, laryngospasm, congenital abnormalities, infection
Presenting Features
  • Infants with upper respiratory symptoms (cough, nasal congestion) or those who are young (<60 days) or premature should be evaluated for viral respiratory infections, particularly pertussis and RSV infection.
Abdominal

Cause
  • GORD, intussusception, strangulated hernia, testicular torsion.
Presenting Features
  • GORD: Vomiting 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 apnoea.
    In infants with these characteristics who are otherwise healthy, low-risk medical interventions to reduce GOR (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
Neurological

Cause
  • Head injury, seizures, cerebral malformations
Presenting Features
  • Clinical features that suggest the possibility of epilepsy or CNS disorder include recurrent events with loss of muscle tone and unresponsiveness, sustained or stereotyped events, and no history of choking or gagging. Central apnoea may be a symptom of CNS disorders, including brain injury (e.g. from abusive head trauma or infection) or structural brain abnormalities (e.g. hydrocephalus), or a disorder of ventilatory control (which is rare)
Non-Accidental Injury
​
Presenting Features
  • (<5% of cases) – shaking, head injury, occlusion of airway, poisoning, Factitious Induced Illness
Cardiac

Cause
  • Congenital heart disease, vascular ring, arrhythmias, prolonged QT
Presenting Features
  • Cyanotic episodes, abnormal cardiac examination, or electrocardiogram abnormalities. Congenital heart disease (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
Infection

Cause
  • Pertussis, sepsis, pneumonia, meningitis.
Presenting Features
  • Fever, toxic appearance, respiratory distress, hypoxemia, or clustered acute events suggest the possibility of systemic infection and should be evaluated, as appropriate, to the infant's age and clinical presentation. 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
Metabolic

Cause
  • Hypoglycaemia, hypocalcaemia, hypokalaemia, other
Presenting Features
  • Inborn errors of metabolism: hypoglycemia, metabolic acidosis, vomiting, or lethargy. Episodes may be triggered by fasting or an intercurrent illness.
Toxins/Drugs/Ingestions

Cause
  • Accidental or non-accidental
Presenting Features
  • Accidental or intentional poisoning may be responsible for a small number of acute events. Altered level of consciousness and hypoglycaemia could be a presenting feature

Stratifying risk
Low risk (need to fulfil all below criteria) with no concerning history or examination:
  • Age >60 days
  • Born ≥32 weeks (and if preterm, now corrected gestational age ≥45 weeks age)
  • One episode only
  • No CPR given by medically trained professional
 
A low risk BRUE is unlikely to represent a presentation of a severe underlying disorder and is unlikely to recur.
 
The purpose of risk stratification with reference to BRUEs is to establish whether the evidenced based recommendations for low risk BRUEs are applicable. A lower risk BRUE is unlikely to represent a presentation of a severe underlying disorder and is unlikely to recur1,2,3. Risk stratification can be completed by thorough history, examination, and the above mentioned criteria. If deemed low risk, the patient may be suitable for limited observation, minimal or no investigations and discharge home, contrary to previous practice where many if not all were investigated heavily and admitted for prolonged observation.
 
The most recent, relevant and available evidence base as found on MEDLINE literature review (July 2019, see Appendix 4) concur that ‘low risk’ BRUEs are not associated with increased mortality rates. A recent meta analysis (n=3005, 13 studies over a 16 year period) supports the return-home approach for BRUE patients who have been evaluated in the emergency department and determined to be at lower risk, with the authors stating the risk of mortality being ‘about the same’ as baseline. Further specificity is limited by the varying definitions used in the studies included within the meta analysis, but the authors are clear they do not feel low risk BRUEs increase the risk of mortality, a opinion supported by further reviews of the meta analysis and a subsequent retrospective study where 87 low risk children who were admitted, were followed up for 5 years. 22% of these were readmitted in this period but of this, only 10% were for an event which could be classified as a BRUE on presentation (all were later confirmed as GORD).
 
Safeguarding and child protection
A long-term follow-up study in infants hospitalised with an ALTE showed that 11% were victims of child abuse, although using the slightly different definitions (ALTE rather than BRUE) this highlights the importance of keeping this at the forefront of the clinicians mind during assessment. A more recent study6 also highlights that occult head injuries can present very similarly to BRUEs and states that clinicians must consider non-accidental injury as an alternative diagnosis during history & examination.
 
Management

Low risk BRUE:
No investigations are necessary, but can consider:
  • A brief period of in-hospital observation (eg, one to four hours with continuous pulse oximetry and serial observations)
  • 12-lead ECG to assess QT interval.
  • NPA for respiratory virus +/- pertussis (especially if unimmunised infants with suggestive symptoms) 
 
Education for caregivers about BRUEs, and reassurance about the low risk for infants with these characteristics including that there is no known association between BRUEs and risk for SIDS.

Direct caregivers to where they can access infant CPR training - https://www.sja.org.uk/get-advice/first-aid-advice/paediatric-first-aid/ (St John’s also does a downloadable and free first aid app)
 
The infant can be discharged home, providing caregiver is reassured and capable for caring for the infant at home.
 
High risk BRUE:
Admit for observation and consider:
  • ECG to assess QT interval
  • NPA for respiratory virus testing +/- pertussis (especially if unimmunized infants with suggestive symptoms) 
  • Blood glucose, bicarbonate and lactic acid (to evaluate for inborn errors of metabolism)
  • Review of results of newborn screening tests (e.g. for inborn errors of metabolism)
  • FBC and UEs/ CRP if clinically indicated
Communication & Training Plans
This guideline will be made available regionally on the PIER Website.  Local leads for the paediatric emergency department will disseminate guideline and raise awareness locally
Process for Monitoring Compliance
The purpose of monitoring is to provide assurance that the agreed approach is being followed.  This ensures that we get things right for patients, use resources well and protect our reputation.  Our monitoring will therefore be proportionate, achievable and deal with specifics that can be assessed or measured.
References​
  • ​Tieder JS, Bonkowsky JL, Etzel RA, et al. Brief Resolved Unexplained Events (Formerly Apparent Life-Threatening Events) and Evaluation of Lower-Risk Infants. Pediatrics 2016; 137.
  • Colombo M, Katz ES, Bosco A, et al. Brief resolved unexplained events: Retrospective validation of diagnostic criteria and risk stratification. Pediatr Pulmonol 2019; 54:61.
  • Pitetti RD, Whitman E, Zaylor A. Accidental and nonaccidental poisonings as a cause of apparent life-threatening events in infants. Pediatrics 2008; 122:e359.
  • Kahn A, European Society for the Study and Prevention of Infant Death. Recommended clinical evaluation of infants with an apparent life-threatening event. Consensus document of the European Society for the Study and Prevention of Infant Death, 2003. Eur J Pediatr 2004; 163:108.
  • Sherman PM, Hassall E, Fagundes-Neto U, et al. A global, evidence-based consensus on the definition of gastroesophageal reflux disease in the pediatric population. Am J Gastroenterol 2009; 104:1278.
  • Zuckerbraun NS, Zomorrodi A, Pitetti RD. Occurrence of serious bacterial infection in infants aged 60 days or younger with an apparent life-threatening event. Pediatr Emerg Care 2009; 25:19.
  • Hall, D., Goodbye ALTE, Hello BRUE, RCEM Presentation, Evelina Children’s hospital April 2017.
  • McGovern MC, Smith MB. Causes of apparent life threatening events in infants: a systematic review. Arch Dis Child. 2004;89(11):1043–1048pmid:15499062
  • Bonkowsky, J., Guenther, E., Filloux, F. and Srivastava, R. (2008). Death, Child Abuse, and Adverse Neurological Outcome of Infants After an Apparent Life-Threatening Event. PEDIATRICS, 122(1), pp.125-131.
  • Puls, H., Anderst, J., Bettenhausen, J., Masonbrink, A., Markham, J., Plencner, L., Krager, M., Johnson, M., Walker, J., Greeley, C. and Hall, M. (2018). Potential Opportunities forPrevention or Earlier Diagnosis of Child Physical Abuse in the Inpatient Setting. Hospital Pediatrics, 8(2), pp.81-88.
  • Bommel, N. and Kannarkatt, S. (2017). Case 5: BRUE in an Infant Found to Have Feeding Difficulties. Pediatrics in Review, 38(11), pp.535-535.
  • Sankaran, J., Qureshi, A., Woodley, F., Splaingard, M. and Jadcherla, S. (2016). Effect of Severity of Esophageal Acidification on Sleep vs Wake Periods in Infants Presenting with Brief Resolved Unexplained Events. The Journal of Pediatrics, 179, pp.42-48.e1.
  • Jarasvaraparn, C., Belen Rojas Gallegos, M., Wang, B., Crissinger, K. and Gremse, D. (2018). The Characteristics of Esophageal Multichannel Intraluminal Impedance- Measurements in Infants Experiencing Brief Resolved Unexplained Events. Annals of gastroenterology and digestive disorders, 1(1), pp.1-8.
  • Jarasvaraparn, C., Gallegos, M., Mulekar, M., Bin Wang, Gremse, D. and Crissinger, K. (2018). Short article: The endoscopic and histologic findings of infants who have experienced brief resolved unexplained events. European Journal of Gastroenterology & Hepatology, 30(2), pp.195-200.
  • Zwemer, E., Claudius, I. and Tieder, J. (2017). Update on the Evaluation and Management of Brief Resolved Unexplained Events (Previously Apparent Life-Threatening Events). Reviews on Recent Clinical Trials, 12(4).
  • Brand, D. and Fazzari, M. (2018). Risk of Death in Infants Who Have Experienced a Brief Resolved Unexplained Event: A Meta-Analysis. The Journal of Pediatrics, 197, pp.63-67.
  • Tieder, J. (2018). Mortality Risk and Hospital Admission after a Brief Resolved Unexplained Event. The Journal of Pediatrics, 197, pp.12-13.
  • Ari, A., Atias, Y. and Amir, J. (2019). Long-Term Follow-Up of Infants After a Brief Resolved Unexplained Event–Related Hospitalization. Pediatric Emergency Care, p.1.
  • Vigo A, Costagliola G, Ferrero E, Noce S. Hypotonic-hyporesponsive episodes after administration of hexavalent DTP-based combination vaccine: A description of 12 cases. Hum Vaccin Immunother. 2017 Jun 3;13(6)
  • Tracy S. DuVernoy, M. Miles Braun, the VAERS Working Group; Hypotonic–Hyporesponsive Episodes Reported to the Vaccine Adverse Event Reporting System (VAERS), 1996–1998. Pediatrics October 2000; 106 (4): e52. 10.1542/peds.106.4.e52
Document Version: 
1.0

Lead Authors: 
Jillian Boden (ST6 PEM)
Kang Min Sun (ST7 Paediatrics)
Heba Hassan (ST6 Paediatrics)
​Sebastien Austin (Paediatric Consultant)
Approving Network:
Paediatric Emergency Medicine Network

Date of Approval: 
June 2023

Review Due:
June 2026