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

Management of Apparent Life-Threatening Events in Infants: A Systematic Review Joel S. Tieder, MD, MPH1, Robin L. Altman, MD2, Joshua L. Bonkowsky, MD, PhD3, Donald A. Brand, PhD4,5, Ilene Claudius, MD6, Diana J. Cunningham, MLS, MPH, AHIP7, Craig DeWolfe, MD, Med8, Jack M. Percelay, MD, MPH9, Raymond D. Pitetti, MD, MPH10, and Michael B. H. Smith, MB, FRCPC, FRCPCH11 Objective To determine in patients who are well-appearing and without a clear etiology after an apparent lifethreatening event (ALTE): (1) What historical and physical examination features suggest that a child is at risk for a future adverse event and/or serious underlying diagnosis and would, therefore, benefit from testing or hospitalization? and (2) What testing is indicated on presentation and during hospitalization? Study design Systematic review of clinical studies, excluding case reports, published from 1970 through 2011 identified using key words for ALTE. Results The final analysis was based on 37 studies; 18 prospective observational, 19 retrospective observational. None of the studies provided sufficient evidence to fully address the clinical questions. Risk factors identified from historical and physical examination features included a history of prematurity, multiple ALTEs, and suspected child maltreatment. Routine screening tests for gastroesophageal reflux, meningitis, bacteremia, and seizures are low yield in infants without historical risk factors or suggestive physical examination findings. Conclusion Some historical and physical examination features can be used to identify risk in infants who are wellappearing and without a clear etiology at presentation, and testing tailored to these risks may be of value. The true risk of a subsequent event or underlying disorder cannot be ascertained. A more precise definition of an ALTE is needed and further research is warranted. (J Pediatr 2013;-:---).

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n apparent life-threatening event (ALTE) was defined at a consensus development conference convened in 1986 by the National Institutes of Health to address the relationship between sudden infant death syndrome (SIDS) and apnea.1 An ALTE was defined as “an episode that is frightening to the observer and that is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.” There are three significant challenges for clinicians managing patients who have experienced an ALTE. First, the infant is often asymptomatic at presentation. Second, although most ALTEs represent a benign event, they can signify a more serious illness, such as sepsis or child malFrom the Department of Pediatrics, Division of Hospital treatment. Third, the decision to perform tests or hospitalize a patient is fraught Medicine, Seattle Children’s Hospital and the University with uncertainties. Clinicians may hospitalize the infant to facilitate observation, of Washington, Seattle, WA; Department of Pediatrics, Division of General Pediatrics, New York Medical educate the parents, or complete tests. Yet, this approach may subject the patient College, Maria Fareri Children’s Hospital at Westchester Medical Center, Valhalla, NY; Department of Pediatrics, to unnecessary risk and increase parental anxiety without improving outDivision of Pediatric Neurology, University of Utah School 2,3 of Medicine, Salt Lake City, UT; Office of Health comes. Outcomes Research, Winthrop University Hospital, Given a lack of consensus regarding the management of infants who are iniMineola, NY; Department of Preventive Medicine, Stony Brook University School of Medicine, Stony Brook, NY; tially well-appearing and without a clear etiology, an ALTE expert panel systemDepartment of Emergency Medicine, Los Angeles County and University of Southern California (LAC+USC), atically reviewed the literature to answer two key questions: (1) What historical University of Southern California Keck School of and physical examination features on presentation suggest that an infant is at risk Medicine, Los Angeles, CA; New York Medical College, Valhalla, NY; Department of Pediatrics, Pediatric for a future adverse event and/or serious underlying diagnosis and would thereHospitalist Division, Children’s National Medical Center, George Washington University School of Medicine and fore benefit from diagnostic testing and hospitalization? and (2) What testing is Health Sciences, Washington, DC; E.L.M.O. Pediatrics, New York, NY; Sedation Services and Emergency indicated on presentation and during hospitalization? 1

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Department, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA; and 11Northern Ireland Clinical Research Network for Children, Department of Pediatrics, Craigavon Hospital, Craigavon, Northern Ireland

ALTE ED EEG GER RR SIDS URI

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

The Society of Hospital Medicine sponsored the conference calls and an online data management platform for this study; however, it was not involved in the study design, writing of the report, decision to submit the manuscript for publication, or collection, analysis, and interpretation of data. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.12.086

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

Results The review identified 37 studies. Fourteen studies investigated historical and physical examination features as potential indications for hospitalization or predictors of subsequent adverse events (Table I; available at www.jpeds. com). These studies evaluated age, sex, ethnicity, history of prematurity, occurrence of multiple ALTEs, concern for child maltreatment, concern for seizures, presence of upper respiratory tract (URI) symptoms, smoke exposure, severity of the ALTE event or need for cardiopulmonary resuscitation, prior diagnosis of gastroesophageal reflux (GER) or GER symptoms, birth order, and mode of delivery. Thirty-one studies evaluated diagnostic testing for GER, neurologic abnormalities, anemia, infections, toxic ingestions, metabolic disorders, and cardiac dysrhythmias (Table II; available at www.jpeds.com). All studies used an observational cohort design and only 4 studies used valid control groups. None of the studies completely addressed the clinical questions because of methodologic limitations. 2

Vol. -, No. These included insufficient samples sizes to detect rare events and limited generalizability of findings when patients were recruited from high risk referral centers. Heterogeneous outcomes and follow-up periods across different studies made it difficult to pool results. Predictors from History and Physical Examination Age and Prematurity. Five studies investigated the relationship between chronological age and a subsequent adverse event or a significant diagnosis following presentation to an emergency department (ED), and their findings conflicted (Table I). Two studies found younger age to be associated with higher risk. In 1 study, infants under 30 days of age and greater than 30 weeks gestational age were more likely (OR 3.3; P = .13) to have a recurrent ALTE or serious diagnosis during the hospitalization or within 48 hours after discharge from the ED.9 In another study, hospitalized infants less than 43 weeks post-conceptual age were more likely to have a subsequent event (relative risk [RR] 5.2; 95% CI 2.6-10.3) during the course of a hospitalization.10 In contrast, two studies with different study populations found younger age to be associated with lower risk. In 1 study of infants under 6 months presenting with 1 or more ALTE features (including some patients on home monitoring), those under 2 months old were less likely to experience a recurrent ALTE during hospitalization (RR = 0.12; 95% CI, 0.03-0.52).11 In another study of infants under 1 year of age and including some with an abnormal physical exam, age over 2 months was associated with higher risk for recurrent ALTE (RR 2.9; 95% CI, 1.36.8).12 Finally, in another study with a 5-year follow-up period, age was not associated with child abuse, adverse neurologic outcome, or chronic epilepsy.13 Four studies identified a history of prematurity as a risk factor for subsequent ALTEs or a serious underlying diagnosis. The first reported an OR of 14 (P = .009),9 and the 2 remaining studies reported RRs of 2.95 (95% CI, 1.0-8.7)11 and 6.3 (95% CI, 3.6-11),10 respectively, and the last 1 reporting risk attenuation at 48 weeks post-conceptual age.

Multiple ALTEs. Many studies report higher rates of underlying disorders in patients with multiple ALTEs (eg, child maltreatment and seizures), either occurring in clusters and/ or recurring after discharge.10-15 One study evaluated the risk conferred alone by a history of multiple ALTEs occurring during the 24 hours preceding ED presentation, and it demonstrated an increased likelihood (OR 4.0; P < .001) of recurrent ALTE or serious diagnosis during the hospitalization or within 48 hours after discharge from the ED.9

Suspected Child Maltreatment. Child maltreatment was reported in 0.4%-11% of well-appearing infants presenting to an ED or admitted to the hospital after an ALTE.13,14,1618 Documented types of child maltreatment reported to cause an ALTE included intentional smothering, intentional poisoning, non-accidental head trauma, other inflicted physical injury, emotional abuse, induced illness, and Munchausen by Tieder et al

- 2013 proxy syndrome.19,20 In a study with a 5-year follow-up period, suspicious physical findings, retinal hemorrhages, story discrepancy, parents calling emergency services for the ALTE, and the presence of vomiting or irritability at the time of presentation were associated with increased risk for abusive head injury.17 Other features associated with cases of maltreatment included multiple presentations of ALTEs (especially with a single witness), history of unresponsiveness, limpness, hypotonia, unexpected or sudden death of a sibling, and facial bruising or bleeding.16,19,20 A screening dilated fundoscopic exam was positive in some cases when there was an index of suspicion for non-accidental head trauma, but it was only 50% sensitive.16-18,21

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

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

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

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

Other. In studies that evaluated sex, ethnicity, severity of the ALTE event or need for cardiopulmonary resuscitation, prior diagnosis of GER or GER symptoms, smoke exposure, birth order, and mode of delivery, the evidence was inadequate to support a conclusion.9-14,18-22 Diagnostic Testing Six studies examined a standard approach to testing for all patients, regardless of presenting features (Table II).11,12,18,24-26 In an ED study, 2.5% of tests ordered resulted in a diagnosis (pertussis, anemia, and hypoglycemia) but the diagnosis was always suggested by a careful history.11 Another study found that testing contributed to the diagnosis in only 14% of patients with a negative history and physical exam.26 The conditions most frequently evaluated with testing were GER, neurologic abnormalities, anemia, infections, toxic ingestions, metabolic disorders, and cardiac dysrhythmias.

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

Infections. Four studies evaluated pertussis as a cause of an ALTE.11,12,26,37 Pertussis was diagnosed either clinically or by testing in 0.75%-7.0% of ALTE cases. Eight studies tested patients for serious bacterial infections.11,12,26,32,38-41 In afebrile and well-appearing patients, none had bacterial meningitis as the underlying cause of the ALTE and 0.7% had a urinary tract infection. Bacteremia was found in the context of afebrile infants only in premature patients or in those with multiple ALTEs on the day of admission.41 Toxic Ingestions. Three studies examined the role of a toxicology screen.12,42,43 One demonstrated that intentional poisoning presenting as an ALTE can be detected with a toxicology screen.42 Two studies evaluated toxicology screening in children evaluated in the ED.12,43 One study screened 54% of patients with a standard urine test for controlled substances and only 1 patient tested positive (for opioids discovered to be due to a prescribed cough medication).12 Another study tested 46% of patients with gas chromatography/mass spectrometry.43 Substances that could have caused the ALTE (eg, controlled substances or over-the-counter medication), but were not elicited by the history, were found in 8.4% of the cases. Details about the decision to screen and the context of the exposure (eg, intentional or not) were incomplete, and the role of the substance in the ALTE could not be proven (eg, no control population). Metabolic Disorders. Five studies addressed metabolic disorders.12,24,25,31,44 Routine screening in the absence of

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specific symptoms for serum chemistries, blood gases, and inborn errors of metabolism identified only 1 case of vitamin D deficient rickets.

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

Discussion None of the 37 studies identified in this systematic review satisfied a high level of evidence for diagnostic or prognostic investigations, and there was little consistency in study populations, outcomes, follow-up periods, and measurement.7,8 Nonetheless, after critical appraisal, we were able to identify some historical and physical exam features—prematurity, multiple ALTE, suspected child maltreatment—that are associated with risk for a future adverse event and/or serious underlying diagnosis. We found little evidence to support routine testing of patients without these historical risk factors. We found that a history of prematurity and multiple ALTEs are features associated with risk of recurrence and/ or an occult condition. The odds of an occult condition or adverse outcome in these patients may be 3 to 14 times higher than those without one of these historical features. An observation period to clarify features of the events, await testing results, or ensure that the cluster of events has ended may be appropriate. However, a larger prospective study is needed to determine the true magnitude of risk and determine the minimum duration of observation.7 We also found that child maltreatment may present as an ALTE. Even though the true prevalence of abuse in the wellappearing infant without a clear cause could not be determined, studies of high risk populations identified common historical and physical examination findings. These include recurrent ALTEs, historical discrepancies, a family history of unexplained sudden death or ALTE, parents calling emergency services, unexplained facial bruising or bleeding, and the presence of vomiting or irritability at the time of presentation.14,16,17 Many of these same findings were used in other studies to successfully establish an appropriate index of suspicion in ED and inpatient populations.19,20,46 Therefore, all ALTE patients warrant a thorough assessment for possible child maltreatment, and patients with any of the risk factors may benefit from a formal child maltreatment evaluation, inpatient observation, or further testing. Although age may be an important predictor, more research is needed because of conflicting evidence to determine what age group is at the highest risk of a subsequent adverse event. Nonetheless, children less than two months of age deserve special consideration due to neurological and immunologic immaturity and a relative increased risk for undiagnosed congenital 4

Vol. -, No. disorders. Clinicians should also consider the risk conferred by an URI or respiratory syncytial virus infection in younger infants which may cause apnea that can present either before or after the onset of upper respiratory symptoms.10,47,48 Although testing is common in patients who have experienced an ALTE, we found that routine testing for GER, seizures, meningitis, and bacteremia is highly unlikely to be helpful in patients who are well-appearing and have no other findings suggestive of a diagnosis.3 However, patients with a history of prematurity, multiple ALTEs, or concerns for child maltreatment may warrant targeted testing. This review found that routine GER testing is unnecessary in children with ALTEs, a finding consistent with previously published international recommendations.49 Because the prevalence of GER is high in infants, it is not surprising that GER testing would be positive in ALTE patients of the same age. A positive test does not necessarily inform management because causation cannot be established without a control group or the establishment of a temporal association between GER and the ALTE. Indeed, in 1 study, when 89% of the cases had radiographic evidence of GER, nearly one-half had another diagnosis that was thought to be more consistent with the presentation.12 Patients with recurrent ALTEs and GER symptoms failing medical management may benefit from pH esophageal monitoring in combination with symptom recording (and, in certain cases, polysomnography), to establish a cause and effect or consideration of another etiology. Although seizures cause up to 10% of all ALTEs, admission for testing to determine current or future risk of idiopathic epilepsy does not improve outcomes. EEGs and head imaging are neither sensitive nor predictive of patients ultimately diagnosed with chronic epilepsy. However, a head computed tomography is the most sensitive and specific test to evaluate for abusive head injury but it has associated risk and cost.50 In the studies reviewed, a thorough history and physical examination to detect child maltreatment nearly always created the index of suspicion to justify further testing. Nonetheless, the overall cost-effectiveness and safety profile of routine head imaging to detect abusive trauma in this population remains uncertain. Moreover, there is no evidence to recommend a routine complete blood count, serum glucose, chest radiograph, electrolytes, electrocardiograph, Holter monitor, or testing for pertussis, toxicology, or inborn errors of metabolism. Nonspecific tests, such as a complete blood count, were unlikely to reveal a clear cause or influence management. In fact, when the prevalence of disease is low, as is the case with ALTEs, such studies may complicate the management with high false-positive rates.51 Rates of meningitis and bacteremia are extremely low and, therefore, testing is not indicated. However, urinary tract infections can rarely present as an ALTE; therefore, pending future research, there may be benefit to performing urine screening in this population. The most significant limitation to this systematic review, indeed to all ALTE clinical care and research, is that the widely used National Institutes of Health definition is subjective and vague. Even after limiting this study to those infants Tieder et al

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ORIGINAL ARTICLES

who are well appearing and without a clear diagnosis, crossstudy comparisons and critical appraisal were challenging because of differences in ALTE classification, study populations, diagnostic testing, follow-up periods, outcomes, and determinations of causality. Second, all of the studies occurred at single centers and many lacked adequate control groups. Therefore, external validity of the findings could not always be determined, preventing the quantification of risk for other populations. Next, it is possible that relevant studies were not included in the final analysis, but this possibility was minimized by using a broad search strategy and a systematic approach for exclusions. Finally, most studies were not designed to detect the broad array of potential, yet rare, adverse outcomes. Despite the limitations, our findings likely represent a conservative evaluation of the well-appearing infant. Many of the relevant studies did not report the presence of symptoms upon presentation. The inability to identify and exclude all the symptomatic patients from the analysis, however, would lead our recommendations to overestimate the need for testing and rate of recurrent events. In order to improve the quality of care for patients with this common condition, a new definition is needed. The definition should distinguish: (1) the term ALTE as a description of a symptom from a diagnosis; (2) patients who have a clear etiology from those who do not; and (3) minor symptoms, such as spitting up followed by choking from more concerning symptoms, such as cessation of breathing followed by central cyanosis. Moreover, the definition should place in context the risk in terms of historical and physical examination features described in this study. For example, distinguishing first-time from recurrent ALTEs may assist in the development of tiered clinical guidelines. Following clarification of the definition, research should quantify the true risk for a subsequent event or a serious underlying disorder, and then identify the key historical and physical exam factors that determine the need for admission and scope of investigations. There is insufficient evidence to quantify risk of a subsequent event or underlying diagnosis in patients who have experienced an ALTE but are asymptomatic and/or without a clear etiology upon presentation. Although risk factors derived from the history and physical examination can help guide decisions to test or hospitalize patients, a more precise definition of ALTEs and further research are needed to improve the quality of care for this common condition. n Submitted for publication Aug 13, 2012; last revision received Nov 27, 2012; accepted Dec 27, 2012. Reprint requests: Joel S. Tieder, MD, MPH, Department of Pediatrics, Division of Hospital Medicine, Seattle Children’s Hospital and the University of Washington, 4800 Sand Point Way NE, Mail Stop M1-13, Seattle, WA 98105. E-mail: [email protected]

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24. Okada K, Miyako M, Honma S, Wakabayashi Y, Sugihara S, Osawa M. Discharge diagnoses in infants with apparent life-threatening event. Pediatr Int 2003;45:560-3. 25. Sunkaran K, McKenna A, O’Donnell M, Ninan A, Kasian G, Skwarchuk J, et al. Apparent life-threatening prolonged infant apnea in Saskatchewan. West J Med 1989;150:293-5. 26. Brand DA, Altman RL, Purtill K, Edwards KS. Yield of diagnostic testing in infants who have had an apparent life-threatening event. Pediatrics 2005;115:885-93. 27. Veereman-Wauters G, Bochner A, Van Caillie-Bertrand M. Gastroesophageal reflux in infants with a history of near-miss sudden infant death. J Pediatr Gastroenterol Nutr 1991;12:319-23. 28. Mousa H, Woodley FW, Metheney M, Hayes J. Testing the association between gastroesophageal reflux and apnea in infants. J Pediatr Gastroenterol Nutr 2005;41:169-77. 29. Kahn A, Rebuffat E, Sottiaux M, Blum D, Yasik EA. Sleep apneas and acid esophageal reflux in control infants and in infants with an apparent life-threatening event. Biol Neonate 1990;57:144-9. 30. Tirosh E, Jaffe M. Apnea of infancy, seizures, and gastroesophageal reflux: an important but infrequent association. J Child Neurol 1996;11: 98-100. 31. See CC, Newman LJ, Berezin S, Glassman MS, Medow MS, Dozor AJ, et al. Gastroesophageal reflux-induced hypoxemia in infants with apparent life-threatening event(s). Am J Dis Child 1989; 143:951-4. 32. Tsukada K, Kosuge N, Hosokawa M, Umezu R, Murata M. Etiology of 19 infants with apparent life-threatening events: relationship between apna and esophageal dysfunction. Acta Paediatr Jpn 1993;35: 306-10. 33. Genizi J, Pillar G, Ravid S, Shahar E. Apparent life-threatening events: neurological correlates and the mandatory work-up. J Child Neurol 2008;23:1305-7. 34. Tirosh E, Jaffe M. Apparent life-threatening event: a neurologic perspective. J Child Neurol 1995;10:216-8. 35. Poets CF, Samuels MP, Wardrop CA, Picton-Jones E, Southall DP. Reduced haemoglobin levels in infants presenting with apparent lifethreatening events—a retrospective investigation. Acta Paediatr 1992; 81:319-21. 36. Pitetti RD, Lovallo A, Hickey R. Prevalence of anemia in children presenting with apparent life-threatening events. Acad Emerg Med 2005; 12:926-31. 37. Crowcroft NS, Booy R, Harrison T, Spicer L, Britto J, Mok Q, et al. Severe and unrecognized: pertussis in UK infants. Arch Dis Child 2003;88: 802-6.

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Vol. -, No. 38. Tirosh E, Colin AA, Tal Y, Kolikovsky Z, Jaffe M. Practical approach to the diagnosis and treatment of apnea of infancy. Isr J Med Sci 1990;26:429-33. 39. Mittal MK, Shofer FS, Baren JM. Serious bacterial infections in infants who have experienced an apparent life-threatening event. Ann Emerg Med 2009;54:523-7. 40. Altman RL, Li KI, Brand DA. Infections and apparent life-threatening events. Clin Pediatr (Phila) 2008;47:372-8. 41. Zuckerbraun NS, Zomorrodi A, Pitetti RD. Occurrence of serious bacterial infection in infants aged 60 days or younger with an apparent lifethreatening event. Pediatr Emerg Care 2009;25:19-25. 42. Hickson GB, Altemeier WA, Martin ED, Campbell PW. Parental administration of chemical agents: a cause of apparent life-threatening events. Pediatrics 1989;83:772-6. 43. Pitetti RD, Whitman E, Zaylor A. Accidental and nonaccidental poisonings as a cause of apparent life-threatening events in infants. Pediatrics 2008;122:e359-62. 44. Penzien JM, Molz G, Wiesmann UN, Colombo JP, Buhlmann R, Wermuth B. Medium-chain acyl-CoA dehydrogenase deficiency does not correlate with apparent life-threatening events and the sudden infant death syndrome: results from phenylpropionate loading tests and DNA analysis. Eur J Pediatr 1994;153:352-7. 45. Woolf PK, Gewitz MH, Preminger T, Stewart J, Vexler D. Infants with apparent life threatening events. Cardiac rhythm and conduction. Clin Pediatr (Phila) 1989;28:517-20. 46. Samuels MP, McClaughlin W, Jacobson RR, Poets CF, Southall DP. Fourteen cases of imposed upper airway obstruction. Arch Dis Child 1992;67:162-70. 47. Ralston S, Hill V. Incidence of apnea in infants hospitalized with respiratory syncytial virus bronchiolitis: a systematic review. J Pediatr 2009; 155:728-33. 48. Schiller O, Levy I, Pollak U, Kadmon G, Nahum E, Schonfeld T. Central apnoeas in infants with bronchiolitis admitted to the paediatric intensive care unit. Acta Paediatr 2011;100:216-9. 49. Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 2009;49:498-547. 50. Campbell KA, Berger RP, Ettaro L, Roberts MS. Cost-effectiveness of head computed tomography in infants with possible inflicted traumatic brain injury. Pediatrics 2007;120:295-304. 51. Ober KP. Uncle Remus and the cascade effect in clinical medicine. Brer Rabbit kicks the Tar-Baby. Am J Med 1987;82:1009-13.

Tieder et al

Sample size

Control group (n, description)

Retrospective cohort

625

n/a

IP

14

Prospective cohort

243

n/a

Bonkowsky, 2008

13

Retrospective cohort

471

Bonkowsky, 2009

21

Retrospective cohort

Claudius, 2007

9

Curcoy, 2010

Author, year

Ref.

Study design

Al Kindy, 2009

10

Altman, 2003

Primary setting†

Age

Follow-up period

Exclusion criteria

Infant

Single ALTE (coded) no obvious cause

Significant PMH, likely alternative diagnosis

IP

0-12 m

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

Subsequent ALTE during study period

n/a

IP

0-12 m

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

Likely alternative diagnosis or suggestive PMH

2.5-7.5 y

Death Child abuse Chronic epilepsy Developmental delay

471

n/a

IP

0-12 m

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

Likely alternative diagnosis or suggestive PMH

2.5-7.5 y

Seizure, chronic epilepsy, and discharge diagnosis

Seizures, convulsions, abnormal movement, idiopathic

Prospective cohort

59

n/a

ED

0-12 m

ALTE (NIH definition)

Significant PMH, prematurity <30 wk

1 w-3 mo

Age Multiple ALTEs Prematurity

18

Prospective cohort

108

n/a

IP

15 d-2 y

ALTE (NIH definition)

Subsequent ALTE, intervention, or diagnosis mandating admission Retinal hemorrhage on fundoscopy

Davies, 2002

12

Prospective cohort

65

n/a

ED

0-10 m

DePiero, 2004

11

Retrospective cohort

150

n/a

IP

0-6 m

24 h

Hospital stay

Outcome or endpoint An “extreme event” within 24 h of admission defined as central apnea >30 s, bradycardia >10 s, and desaturation >10 s with pulse oximetry <80% Discharge diagnosis

Suspected child Hospital stay abuse, history of trauma, other causes of retinal hemorrhages ALTE (NIH definition), Febrile seizure 6 m (No death Significant diagnosis after fever, abnormal limb at 3 y) standardized evaluation movement

ALTE ($2: apnea, color, Bradycardia only on gag, choke, parental apnea alarm resuscitation, tone, single event within 24 h, stable vitals

Hospital stay

Positive test Significant medical intervention

Risk factors assessed*

Major findings reported

Major limitations or sources of biasz

Age pematurity URI

-Recurrent or “extreme events” -Only included hospitalized were associated with patients infants with URI symptoms, -Short follow-up period born premature, and <43 -Narrowly restricted wk post-conceptional age endpoint

Age Symptoms defining ALTE Suspicion for child maltreatment Age Prematurity Family history Previous event

-Wide spectrum of diagnoses -Child maltreatment in 2.5%

Age ALTE characteristics Multiple ALTEs

-Only included hospitalized patients -Short follow-up period

-Hospitalized ATLE patients are -Only included hospitalized patients (non-standard at risk for child abuse and admission criteria) neurologic disorders -IP neurologic evaluation is low yield -Only included hospitalized -Idiopathic epilepsy, cortical patients (non-standard dysplasia, complex partial admission criteria) seizures, and neurodegenerative disorders can present as ALTEs -Discharge diagnosis after ALTE hospitalization is poorly predictive of those who develop epilepsy -50% of patients who develop chronic epilepsy will be diagnosed with seizures within 1 week of their ALTE and a majority will be diagnosed within a month -Infants >30 d may be safely -Small sample size from discharged from the single tertiary care RC hospital -ALTEs do not cause retinal hemorrhage

-Excluded patients with suspected child abuse -Inadequate follow-up to detect child maltreatment Gestational age -History and Physical exam can -Small sample size Respiratory symptoms guide medical decision -“Standardized evaluation” making for tests not well defined Medications Family history of asthma, SIDS, child protection service involvement Age -A majority can be managed -Short follow-up period Pertussis symptoms with a limited ED diagnostic evaluation and period of observation (continued )

6.e1

ORIGINAL ARTICLES

Inclusion criteria

- 2013

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

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

Retrospective cohort

627

n/a

22

Retrospective cohort

6

Pitetti, 2002

16

Prospective cohort

Southall, 1997

19

Steinschneider, 1998

Truman, 2002

Study design

Guenther, 2010

17

Hewertson, 1994

Primary setting†

Follow-up period

Age

Inclusion criteria

Exclusion criteria

IP

0-12 m

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

Prematurity/ likely alternative diagnosis or suggestive PMH

0-5 y

n/a

RC

2-12 m

ALTE, EEG changes, preceding hypoxia

128

n/a

IP

0-24 m

ALTE (NIH definition)

Significant PMH, likely alternative diagnosis Evidence of abuse on exam

Retrospective cohort

36

46, Non-traumatic physiologic recurrent requiring CPR

RC/IP

2-4 m

Recurrent ALTEs requiring CPR, suspicion of abuse

None

15

Retrospective cohort

182

n/a

RC

0-6 m

ALTE (apnea, respiratory difficulty), home on apnea monitor

Insufficient time on home monitor

2m

20

Retrospective cohort

138

n/a

IP

2 d-4 y

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

Single admission, no FH of ALTE

$1 mo

Outcome or endpoint

Risk factors assessed*

Diagnosis of abusive head trauma

Suspicion for child maltreatment

n/a

Positive EEG associated with hypoxemia

Suspicion for seizures

1y

Positive fundoscopy by ophthalmologist

Suspicion for child maltreatment

IP observation Diagnosis of child period maltreatment from covert video

Prolonged apnea or bradycardia on home monitoring for 2 months

Diagnosis of child maltreatment

Suspect child maltreatment Age Prematurity Family history of SIDS ALTE characteristics

Recurrent ALTEs Facial blood ALTE/SIDS in sibling Suspected abuse

Major findings reported

Major limitations or sources of biasz

-Almost one-half of abusive -Only included hospitalized head trauma cases are patients (non-standard admission criteria) missed by ED management -1.4% diagnosed with abusive head trauma -Vomiting, irritability or 911 call risk factors for head trauma -Seizures can cause hypoxemic -Small sample size episodes -Only evaluated a high risk group -Evaluation should include -Sampling bias since only fundoscopic examination 57% of patients had fundoscopy -Unclear contributory value of history, PE, and CT head -ALTEs may be symptom of -Descriptive study of high child maltreatment risk population

-The clinical characteristics of -Descriptive study of high risk population without an ALTE cannot be used to comparison group determine the need for follow-up studies and/or home monitoring -Descriptive study of high The following are risk factors risk population without for child maltreatment: comparison group recurrent or poorly explained ALTE, same parent or caregiver as only witness, presence of blood on face or mouth, unexplained bruising, siblings with ATLES or SIDS

www.jpeds.com

Control group (n, description)

Ref.




Sample size

Author, year

THE JOURNAL OF PEDIATRICS

6.e2

Table I. Continued

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

Vol. -, No. -

Tieder et al

Author, year

Ref.

Study design

Sample size

Control group (n, description)

Primary setting*

Age

120

n/a

ED

0-12 m

Inclusion criteria

Exclusion criteria

32

Prospective cohort

Altman, 2008

40

Retrospective cohort

95

n/a

ED

0-12 m

Bonkowsky, 2008

13

Retrospective cohort

471

n/a

IP

0-12 m

Bonkowsky, 2009

21

Retrospective cohort

471 (25 patients with seizures)

n/a

IP

0-12 m

ALTE (breathing Likely alternative irregularity, color, diagnosis or mental status, suggestive PMH tone, movement)

Brand, 2005

25

Prospective cohort

243

n/a

ED

0-12 m

ALTE (color, tone, labored breathing, or altered mental status)

Previous ALTE admission

Crowcroft, 2003

37

Prospective cohort

142

n/a

ICU

0-5 m

ALTE, bradycardia, apnea

Significant pulmonary history

Curcoy, 2010

18

Prospective cohort

108

n/a

IP

15 d-2 y

Davies, 2002

12

Prospective cohort

65

n/a

ED

0-10 m

ALTE (NIH definition), Subsequent ALTE altered mental during study status period ALTE (color, tone, None labored breathing, Altered mental status), final infectious diagnosis ALTE (apnea, color, Likely alternative mental status, diagnosis or tone, movement) suggestive PMH

ALTE (NIH definition)

Outcome or endpoint

Test or condition assessed

Hospital stay Fundoscopy positive Fundoscopy for retinal hemorrhage Hospital stay Positive history or PE SBI Positive sepsis evaluation

2.5-7.5 y

2.5-7.5 y

Death Child abuse Chronic epilepsy Developmental delay Seizure, chronic epilepsy, and discharge diagnosis

Hospital Stay Positive test Positive test leading to diagnosis Positive history and PE leading to diagnosis

n/a

Positive test for pertussis (PCR, serology, or culture)

Neurologic imaging EEG

Neurologic imaging EEG

Neurologic imaging EEG Anemia Pertussis CBC and nonspecific testing Pertussis RSV

Suspected child Hospital stay Retinal hemorrhage Fundoscopy abuse, history of on fundoscopy Battery of tests trauma, other causes of retinal hemorrhages ALTE (NIH definition), Febrile seizure 6 m (No Significant diagnosis GER fever, abnormal death at after standardized Anemia limb movement 3 y) evaluation CBC SBI Toxicology EKG Metabolic Nonspecific testing

Major findings reported

Major Limitations or Sources of Bias†

-Fundoscopic examination can -Only patients seen by an help identify child abuse ophthalmologist included -Testing is low yield in well appearing patients with no signs suggestive of SBI, -CXR and urine culture may have benefits

-Short follow-up period -Clinical significance of positive urine culture and CXR uncertain

-Hospitalized ALTE patients are -Only included hospitalized at risk for child abuse and patients (non-standard neurological disorders admission criteria) -IP neurologic evaluation is low yield -Only included hospitalized -Idiopathic epilepsy, cortical patients (non-standard dysplasia, complex partial admission criteria) seizures, and neurodegenerative disorders can present as ALTEs -Discharge diagnosis after ALTE hospitalization is poorly predictive of those who develop epilepsy -50% of patients who develop chronic epilepsy will be diagnosed with seizures within 1 week of their ALTE and a majority will be diagnosed within a month -Likelihood of a positive result -Clinical significance of is low and the likelihood of positive tests uncertain a contributory result is even (eg, anemia on CBC or lower GER on fluoroscopy) -History and PE can lead to diagnosis in >70% of cases

Patients with ALTES and respiratory failure and low clinical suspicion of pertussis can have pertussis infections ALTEs do not cause retinal hemorrhages

-Only included patients with respiratory failure in ICU

-Excluded patients with suspected child abuse -Inadequate follow-up to detect child maltreatment -History and Physical exam can -Historical and PE features guide medical decision informing the decision to making for testing test are unclear -There were no abnormalities -Uncertain clinical in EKG, blood glucose, significance of positive metabolic screen CXR, reflux testing, and -CBC, urine culture, reflux anemia testing, pertussis, CXR were positive in some patients (continued )

6.e3

ORIGINAL ARTICLES

Altman, 2007

Follow-up period

- 2013

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

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

Author, year

Ref.

Study design

Sample size

Control group (n, description)

Primary setting*

Age

Retrospective cohort

150

n/a

IP

0-6 m

Genizi, 2008

33

Retrospective cohort

93

n/a

IP

0-12 m

Guenther, 2010

17

Retrospective cohort

627

n/a

IP

Hewertson, 1994

22

Retrospective cohort

6

n/a

Hickson, 1989 Kahn, 1990

42

Retrospective cohort Prospective cohort

9

Mittal, 2009

39

Mousa, 2005

Follow-up period

Outcome or endpoint

Test or condition assessed

Major findings reported

Major Limitations or Sources of Bias†

Pertussis SBI Nonspecific testing

-Positive tests in 2.5% of 122 patients with diagnostic tests (95%CI; 0.5-7.0)

-Short follow-up period

Neurologic imaging EEG

-Admission and diagnostic criteria were not standardized

0-12 m

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

Diagnosis of abusive head trauma

Neurologic imaging Fundoscopy Skeletal survey

RC

2-12 m

n/a

Unclear

5d-4 m

Positive EEG associated with hypoxemia Case report

Neurologic imaging EEG Toxicology

20

10, well infants

RC-sleep

4-25 w

n/a

Apnea with episodes of esophageal acidification

Polygraphic monitoring pH probe

Prospective cohort

189

n/a

ED

0-12 m

ALTE, EEG changes, Significant PMH, preceding likely alternative hypoxia diagnosis ALTE, evidence of None poisoning ALTE (apnea, limp, Significant PMH, color change), GER, vomiting, required vigorous alternative resuscitation diagnosis, prematurity ALTE (NIH definition) Febrile seizure, bronchiolitis

-Neurological impairment leading to seizures are relatively uncommon cause of ALTE -The history and PE still are the major diagnostic tools before resorting to extensive laboratory studies -Almost half of abusive head trauma cases are missed by ED management -Vomiting, irritability or 911 call are associated with increase risk for head trauma -Seizures can cause hypoxemic episodes

4w

Positive test for SBI

SBI

27

Prospective cohort

25

n/a

RC-GI

1-19 m

ALTE (NIH definition), None suspected GERD

n/a

Apnea and reflux on pneumography, esophageal pH and multichannel impedance monitoring

Okada, 2003

23

Prospective cohort

69

n/a

ED

9 d-11.1 m

ALTE (apnea, limp None color change), required vigorous resuscitation

Penzien, 1994

44

Retrospective cohort

197

55, Symptoms of metabolic disorders 72, close relatives of SIDS patients 5, siblings of ALTE patients

Ambulatory pediatric

2 d-108 m

ALTE or close None relative with SIDS or ALTE

28

Prematurity/ likely alternative diagnosis or suggestive PMH

0-5 y

n/a

n/a

Hospital stay Significant diagnosis after structured approach

n/a

Positive test for MCAD deficiency

-Only included hospitalized patients (non-standard admission criteria)

-Small sample size -Only evaluated a high risk group -Small case reports only

-Intentional poisoning can cause ALTE -Acidic esophageal reflux is not -Small sample size a cause of apnea -Only evaluated perceived high risk group

-SBI is extremely uncommon in -Sample size may be too patients presenting to the small to detect infection ED with ALTE in all age groups GER -Little association between -Only evaluated perceived Pneumo-graphy, apnea and total reflux, acid high risk group esophageal pH reflux or non-acid reflux -No comparison group and multichannel impedance monitoring GER testing GER can cause ALTE -GER was prevalent but not Neurological proven to be causative imaging SBI EKG Metabolic Nonspecific testing Metabolic -ALTE patients do not have -Unclear for study cohort or MCAD increased risk for MCAD comparison group

(continued )

Vol. -, No. -

Tieder et al

ALTE ($2: apnea, Bradycardia only on Hospital stay Positive test color, gag, choke, apnea alarm Significant medical parental intervention resuscitation, tone, single event within 24 h, stable vitals ALTE (NIH definition) None 1-7 y Neurologic etiology

www.jpeds.com

11

Exclusion criteria




DePiero, 2004

Inclusion criteria

THE JOURNAL OF PEDIATRICS

6.e4

Table II. Continued

Control group (n, description)

Primary setting*

Age

Inclusion criteria

Exclusion criteria

Prospective cohort

128

n/a

IP

0-24 m

ALTE (NIH definition)

Evidence of abuse on exam

36

Prospective cohort

108

ED

0-24 m

ALTE (NIH definition)

Prematurity, PMH

Pitetti, 2008

43

Prospective cohort

274

n/a

ED

0-24 m

ALTE (NIH definition)

None

Poets, 1992

35

Retrospective cohort

41

n/a

RC

2 w-12 m

See, 1989

30

Prospective cohort

16

6, GER-vomiting w/o apnea

RC/IP

Sunkaran, 1989

24

Retrospective cohort

111

n/a

Tirosh, 1990

38

Prospective cohort

23

Tirosh, 1995

34

Retrospective cohort

46

Ref.

Pitetti, 2002

16

Pitetti, 2005

Study design

Outcome or endpoint

Test or condition assessed

1 year

Positive fundoscopy by ophthalmologist

Fundoscopy Neurological imaging

1 year

Anemia on CBC

Anemia CBC

n/a

Positive toxicology screen

Toxicology

First/single ALTE, None required vigorous resuscitation, referred for home monitoring

None

Hemoglobin level below mean

Anemia CBC

1 w-10 m

ALTE

Prematurity, chronic cough/ wheeze

None

Positive pH probe with desaturation event

GER pH probe Continuous oximetry

RC

1-12 m

ALTE

Prolonged apnea, arrest

2-10 m

GER testing Nonspecific testing

n/a

RC-Apnea

6 d-9 m

Apnea with 1 or more None of following: color change, hypotonia, or LOC Plus stimulation

Significant diagnosis after “structural approach” Positive pneumogram Home monitor Not specified Significant diagnosis after “structural approach”

n/a

RC-apnea

108, Agematched

Not Apnea, color change, None specified and Change in tone

Follow-up period

Not specified Positive EEG Diagnosis of CNS disorder

Major findings reported

Major Limitations or Sources of Bias†

-Evaluation should include fundoscopic examination

-Sampling bias since only 57% of patients had fundoscopy -Unclear contributory value of history, PE, and CT head -Patients with recurrent ALTEs -Does not demonstrate have lower Hb, MCH, and increased risk or MCV than patients with causation without a single ALTE and agecomparison group -Unclear if treatment is matched control patients effective -Anemia in patients with -Relationship to oxygen recurrent ALTEs suggest carrying capacity not that iron deficiency may be associated with the addressed recurrence of events -A substantial number of -Does not demonstrate children presenting to an ED increased risk or for ALTE have positive causation without toxicology screens not comparison group consistent with parental reports -34 infants of 41 tested had -Does not demonstrate kemoglobin levels below increased risk or the mean causation without comparison group -Unclear if treatment is effective -Non-clinical GER is common -Non-valid control group in infants with ALTE -Small sample size -GER episodes may be directly -Only evaluated perceived associated with reflex high risk group hypoxemia -Intraesophageal pH monitoring should be considered -Theophylline improves -Only evaluated perceived pneumogram abnormalities high risk group

Nonspecific -In apparently healthy infants, -Only tested perceived high testing in-patient monitoring and risk group Polysomnographic evaluation is of much value study -Home monitors should be pH probe recommended in a selected -Home monitoring group of patients -Adequate follow-up and support system is essential -Inadequate study design EEG -EEG is recommended and Power to support Routinely that EEGs altered the -Even in the absence of clinical natural progression of clues CNS disorders should illness or that a period of be routinely ruled out observation would have been beneficial (continued )

6.e5

ORIGINAL ARTICLES

Sample size

Author, year

- 2013

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

Table II. Continued

Primary setting*

Age

Inclusion criteria

Prospective cohort

17

n/a

IP

3-37 w

ALTE with evidence of regurgitation

31

Retrospective case series

19

n/a

IP

23 d-13 m

VeeremanWauters, 1991

26

Retrospective cohort

?

ICU

2-36 w

ALTE (apnea, hypotonia, and color) <2 h after a feed, required vigorous resuscitation

Woolf, 1989

45

Prospective observational cohort

49 of 130 ALTE patients requiring vigorous stimulation 34 of 130 infants with GER and requiring vigorous stimulation 100

n/a

RC-Cardiac

0-12 m

Definition of ALTE is Significant PMH, unclear. Included prematurity infants with ALTE or siblings of patient with ALTE

1-32 m

Zuckerbraun, 2009

41

Retrospective cohort

182

n/a

IP

0-60 d

ALTE (NIH definition), Likely alternative afebrile, welldiagnosis appearing

6m

Tirosh, 1996

29

Tsukada, 1993

Study design

Exclusion criteria None

ALTE (NIH definition), None CNS imaging, EEG

Any PMH

Follow-up period

Outcome or endpoint

Test or condition assessed

Not specified Recurrent apnea after Seizure GER event on GER polygraphic study with pH probe Hospital stay only

Significant diagnosis after battery of test

None

Positive continuous esophageal pH monitoring and polygraphic recording

GER EEG EKG Metabolic Pertussis GER testing

EKG with dysrhythmia EKG or with sinus node Holter monitoring dysfunction requiring treatment

Positive SBI microbiologic test

Major findings reported

Major Limitations or Sources of Bias†

-There is no consistent -Small sample size temporal association between GER events and apnea -Seizures may cause apnea -Various identifiable diseases -Descriptive study of or conditions that can cause practice management of ATLEs a single center -Small sample size -Patients who have experienced an ALTE are more likely to have positive pH and polygraphic monitoring compared to controls

-No statistically significant association -Only tested high risk group -No causation -Non-blinded

-EKG and Holter monitoring in -Only tested perceived high infants with ALTE risk group infrequently determines therapy -Provides data linking theories of cardiac etiology of SIDS with actual clinical events -SBI occur in 2.7% of well-Sample size may be too appearing, afebrile infants small to detect infection in all age groups under 60 days with an ALTE -SBI higher with history of prematurity

www.jpeds.com

Control group (n, description)

Ref.




Sample size

Author, year

THE JOURNAL OF PEDIATRICS

6.e6

Table II. Continued

CBC, complete blood count; CNS, central nervous system; CXR, chest radiograph; EKG, electrocardiogram; ENT, otolaryngology; ICU, intensive care unit; LOC, loss of consciousness; MCAD, medium-chain acyl-CoA dehydrogenase; RSV, respiratory syncytial virus; SBI, serious bacterial infection. *Study setting [RC; IP; ICU; ED; ENT]; studies labeled “ED” also followed patients in the IP setting. †Not all limitations are listed. Nearly all studies had limited external validity due to small sample size (eg, wide CIs), different study population (eg, recruited from a sleep study center), different outcomes or endpoints (eg, underlying diagnoses vs recurrent event), and different follow-up periods (24 h vs 7 y).

Vol. -, No. -

Tieder et al