CLINICAL REPORT

Guidance for the Clinician in Rendering Pediatric Care

Eric C. Eichenwald, MD, FAAP, COMMITTEE ON FETUS AND NEWBORN Apnea of prematurity is one of the most common diagnoses in the NICU. abstract Despite the frequency of apnea of prematurity, it is unknown whether recurrent apnea, bradycardia, and in preterm infants are harmful. Research into the development of respiratory control in immature animals and preterm infants has facilitated our understanding of the pathogenesis and treatment of apnea of prematurity. However, the lack of consistent definitions, monitoring practices, and consensus about clinical significance leads to significant variation in practice. The purpose of this clinical report is to review the evidence basis for the definition, epidemiology, and treatment of apnea of prematurity as well as discharge recommendations for preterm infants diagnosed with recurrent apneic events.

BACKGROUND This document is copyrighted and is property of the American Academy of and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Apnea of prematurity is one of the most common diagnoses in the NICU. Pediatrics has neither solicited nor accepted any commercial Despite the frequency of apnea of prematurity, it is unknown whether involvement in the development of the content of this publication. recurrent apnea, bradycardia, and hypoxemia in preterm infants are Clinical reports from the American Academy of Pediatrics benefit from expertise and resources of liaisons and internal (AAP) and external harmful. Limited data suggest that the total number of days with apnea reviewers. However, clinical reports from the American Academy of and resolution of episodes at more than 36 weeks’ postmenstrual age Pediatrics may not reflect the views of the liaisons or the organizations or government agencies that they represent. (PMA) are associated1,2 with worse neurodevelopmental outcome in preterm infants. However, it is difficult to separate any potential The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking adverse effects of apnea from the degree of immaturity at birth, because3 into account individual circumstances, may be appropriate. the incidence of apnea is inversely proportional to gestational age. All clinical reports from the American Academy of Pediatrics Research into the development of respiratory control in immature automatically expire 5 years after publication unless reaffirmed, animals and preterm infants has facilitated our understanding of the revised, or retired at or before that time. pathogenesis and treatment of apnea of prematurity (Table 1). However, DOI: 10.1542/peds.2015-3757 the lack of consistent definitions, monitoring practices, and consensus4–6 PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). about clinical significance leads to significant variation in practice. The purpose of this clinical report is to review the evidence basis for Copyright © 2016 by the American Academy of Pediatrics the definition, epidemiology, and treatment of apnea of prematurity as well as discharge recommendations for preterm infants diagnosed with To cite: Eichenwald EC and AAP COMMITTEE ON FETUS recurrent apneic events. AND NEWBORN. Apnea of Prematurity. Pediatrics. 2016;137(1):e20153757

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38 weeks’ PMA is higher in infants Preterm infants with resolved apnea who were 24 to 26 weeks’ gestational also may have clinically unapparent An apneic spell is usually defined ≥ age at birth compared with those intermittent events. In a as a cessation of for 20 8 born at 28 weeks’ gestation. recent study in former preterm seconds or longer or a shorter pause Infants with bronchopulmonary infants after discontinuation of accompanied by bradycardia (<100 dysplasia may have delayed medical therapy for apnea, the mean beats per minute), , or pallor. maturation of respiratory control, number of seconds/hour of In practice, many apneic events in which can prolong apnea for as long saturation less than 80% was 20.3 preterm infants are shorter than 20 8 as 2 to 4 weeks beyond term PMA. at 35 weeks’ PMA, decreasing to 6.8 seconds, because briefer pauses in 12 In most infants, apnea of prematurity seconds/hour at 40 weeks’ PMA. airflow may result in bradycardia follows a common natural history, or hypoxemia. On the basis of MONITORING FOR APNEA/ with more severe events that require respiratory effort and airflow, BRADYCARDIA intervention resolving first. Last to apnea may be classified as central resolve are isolated, spontaneously (cessation of breathing effort), resolving bradycardic events of obstructive (airflow obstruction 8 uncertain clinical significance. Most infants in NICUs are usually at the pharyngeal level), continuously monitored for or mixed. The majority of apneic heart rate, , and episodes in preterm infants are Most studies examining the time oxygen saturation. Cardiac alarms mixed events, in which obstructed course to resolution of apnea are most commonly set at 100 airflow results in a central apneic of prematurity have relied on beats per minute, although lower pause, or vice versa. nurses' recording of events in the medical record; however, alarm settings are acceptable in EPIDEMIOLOGY AND TIME COURSE TO convalescent preterm infants. RESOLUTION several studies have shown a lack Apnea alarms are generally set of correlation with9,10 electronically recorded events. Standard at 20 seconds. However, apnea NICU monitoring techniques are detection by impedance monitoring In an observational study, 3 unable to detect events that are is potentially misleading. Impedance Henderson-Smart reported that primarily obstructive in nature. With monitoring is prone to artifact the incidence of recurrent apnea continuous electronic recording, attributable to body movement or increased with decreasing gestational ≤ it is evident that some preterm cardiac activity and is unable to age. Essentially, all infants born infants continue to have clinically detect obstructive apnea. Practices at 28 weeks’ gestation were unapparent apnea, bradycardia, and differ as to when continuous diagnosed with apnea; beyond 28 oxygen desaturation events even oximetry is discontinued. In a study weeks’ gestation, the proportion of after discharge. The Collaborative investigating the age at last recorded infants with apnea decreased, from Home Infant Monitoring Evaluation apnea and age at discharge from the 85% of infants born at 30 weeks’ Study examined the occurrence of hospital in 15 different NICUs, the gestation to 20% of those born at 34 apnea/bradycardia events in >1000 duration of use of was weeks’ gestation. This relationship preterm and healthy term infants significantly5 different among hospital has important implications for NICU 11 monitored at home. “Extreme sites. Later discontinuation of pulse policy, because infants born at less events” (apnea >30 seconds and/or oximetry was associated with a later than 35 weeks’ gestation generally heart rate <60 beats per minute for PMA at recorded last apnea and require cardiorespiratory monitoring >10 seconds) were observed most longer length of stay, suggesting that after birth because of their risk frequently in former preterm infants, oximetry may detect events that of apnea. As expected with a decreasing dramatically until about cardiorespiratory monitoring does developmental process, some infants 43 weeks’ PMA. After 43 weeks’ PMA, not. born at 35 to 36 weeks’ gestation “extreme events” in both preterm There are no data to suggest that a may have respiratory control and term infants were very rare. diagnosis of apnea of prematurity is instability, especially when placed in 7 TABLE 1 Factors Implicated in the Pathogenesis of Apnea of Prematurity a semiupright position. Central Mechanisms Peripheral Reflex Pathways In Henderson-Smart’s study, apneic Decreased central chemosensitivity Decreased carotid body activity spells stopped by 37 weeks’ PMA in Hypoxic ventilatory depression Increased carotid body activity 92% of infants and by 40 weeks’3 PMA Upregulated inhibitory neurotransmitters Laryngeal chemoreflex in more than 98% of infants. The Delayed central nervous system development Excessive bradycardic response proportion of infants with apnea/ bradycardia events persisting beyond Downloaded from www.aappublications.org/news by guest on September 30, 2021 e2 FROM THE AMERICAN ACADEMY OF PEDIATRICS associated with an increased risk of with resultant excitation of gestation who do not require sudden infant syndrome (SIDS) respiratory neural output, as well as positive pressure support, one γ or that home monitoring can prevent blockade of excitatory adenosine A2A reasonable approach would be

SIDS in former preterm infants. receptors located on -aminobutyric to await the occurrence of20 apnea Although infants born preterm have acidergic neurons. Specific before initiating therapy. In the a higher risk of SIDS, epidemiologic 1 2A Caffeine for Apnea of Prematurity polymorphisms in the A and A ≥ and physiologic data do not support a adenosine receptor genes have been Trial, earlier treatment with caffeine causal link with apnea of prematurity. associated with a higher risk of apnea (<3 days) compared with later ( 3 The mean PMA for SIDS occurrence days) was associated with a shorter of prematurity as well as variability15 for infants born between 24 and in response to xanthine therapy. duration of , 28 weeks’ gestation is estimated These observations may help explain although it is not clear whether to be 47.1 weeks, compared 13with apparent genetic susceptibility infants started earlier on caffeine 53.5 weeks for term infants. to apnea of prematurity, high were assessed to21 be more likely to be Apnea of prematurity resolves at concordance of its diagnosis in extubated soon. In a retrospective a PMA before which most SIDS cohort study in 62 056 infants with twins, and variability16 in response to occur; in the Collaborative xanthine therapy. very low birth weight discharged Home Infant Monitoring Evaluation between 1997 and 2010, early Study, extreme events in former The largest trial of caffeine citrate caffeine therapy compared with later preterm infants11 resolved by 43 (Caffeine for Apnea of Prematurity therapy was associated with a lower weeks’ PMA. As such, routine home Trial) randomly assigned 2006 incidence of bronchopulmonary monitoring for preterm infants with infants with birth weights between dysplasia (23.1% vs 30.7%; odds resolved apnea of prematurity is not 500 and 1250 g to caffeine or ratio: 0.68; 95% confidence interval: recommended. Cardiorespiratory placebo in the first 10 postnatal 0.69–0.80) as well as a shorterP monitoring after hospital discharge duration of mechanical ventilation 22 days to prevent or treat17 apnea or may be prescribed for some preterm to facilitate extubation. Dosing (mean difference: 6 days; < .001). infants with an unusually prolonged of caffeine citrate in this study Further trials are needed to assess course of recurrent, extreme apnea. included a loading dose of 20 mg/kg the safety and the potential benefits Current evidence suggests that if followed by maintenance of 5 mg/ of early prophylactic caffeine in such monitoring is elected, it can be infants who require mechanical kg per day, which could be increased discontinued in most infants after 43 ventilation. to 10 mg/kg per day for persistent weeks’ PMA unless indicated by other 14 apnea. Caffeine-treated infants had significant medical conditions. a shorter duration of mechanical No trials have addressed when to discontinue xanthine treatment in TREATMENTS ventilation, lower incidence of preterm infants; however, timely bronchopulmonary dysplasia, and Xanthine Therapy discontinuation is advised to avoid improved neurodevelopmental 18 unnecessary delays in discharge. outcome at 18 months. Differences Because of variability in when in neurodevelopmental outcome Methylxanthines have been the apnea resolves, the use of any were less evident at 5 years but mainstay of pharmacologic treatment specific gestational age may result in favored the caffeine-treated 4,5,8 of apnea for decades. Adverse 19 unnecessarily continuing therapy. subjects. The study did not collect effects include tachycardia, emesis, One approach might be a trial off data on the frequency of apnea and and jitteriness. Both theophylline therapy after a clinically significant therefore did not directly address and caffeine are used, but caffeine apnea-free period (off positive the effect of caffeine on apnea; citrate is preferred because of its pressure) of 5 to 7 days or 33 to 34 however, the data indicated that longer half-life, higher therapeutic weeks’ PMA, whichever comes first. caffeine therapy, as used clinically index, and lack of need for drug-level However, there may be significant in this trial, is safe and may have monitoring. Xanthines have multiple effects of caffeine on respiratory additional benefits by yet unknown effects on , including control in preterm infants with mechanisms. However, the use increased minute ventilation, clinically resolved apnea. A recent of prophylactic caffeine solely for improved sensitivity, study in preterm infants who had decreased periodic breathing, and potential neurodevelopmental been treated with caffeine for apnea decreased hypoxic depression of benefits requires additional study. showed a decrease in the frequency breathing. Their primary mechanism The optimal time to start caffeine of intermittent hypoxia episodes of action is thought to be blockade of therapy in infants at risk of apnea in those who received a prolonged inhibitory adenosine A1 receptors, is not known. In infants >28 weeks’ course of therapy compared with a Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 137, number 1, January 2016 e3 12 25,26 usual-care group. Further study of caregivers. A recent study that incidence of necrotizing enterocolitis, is necessary to determine the used a novel computer algorithm late-onset sepsis, and death) of implicationsNasal Continuous of this Positive finding. Airway to detect apnea, bradycardia, and medications to reduce33 gastric acidity Pressure oxygen desaturation in continuously in preterm infants. recorded physiologic data from 67 DISCHARGE CONSIDERATIONS preterm infants showed decreased Nasal continuous positive airway apnea for the 3 days after pressure (NCPAP) at pressures of 4 transfusions27 compared with 3 days to 6 cm H2O, usually in conjunction before. These authors also reported Practice and management with treatment with a xanthine, is that the probability of an apnea surrounding discharge decisions for effective in reducing the frequency event in a 12-hour epoch was higher infants with apnea of prematurity with a lower hematocrit, adjusted vary widely, but most physicians and severity23 of apnea in preterm infants. It appears to work by for PMA. These results suggest that require infants to be apnea/ splinting open the upper airway and anemia may increase the likelihood bradycardia free for a period of of apnea of prematurity and that time before discharge. In 1 survey, decreasing23 the risk of obstructive apnea. NCPAP may also decrease blood transfusions may result in the majority of neonatologists the depth and duration of oxygen a short-term reduction in apnea. (approximately 75%) required 4a desaturation during central apneas However, there are no data to 5- to 7-day observation period. by helping maintain a higher end- indicate that blood transfusion Common practice is to initiate this expiratory volume. Limited results in any long-term reduction countdown period a few days after in apnea. evidence suggests that variable-flow Gastroesophageal Reflux Treatment discontinuation of caffeine therapy continuous (caffeine half-life,34 approximately (CPAP) devices may be more 50–100 hours) and to include effective in the reduction in apnea only spontaneously occurring events than conventional delivery Preterm infants have a hyperreactive (ie, not feeding-related) events. laryngeal chemoreflex response Limited information exists about the systems for CPAP24 (ventilator or bubble CPAP). that precipitates apnea when recurrence of apnea or bradycardia stimulated. In addition, almost all after a specific event-free period. ≤ Humidified high-flow nasal preterm infants show some degree In a retrospective cohort of 1400 cannula or nasal intermittent of gastroesophageal reflux (GER). infants born35 at 34 weeks’ gestation, positive-pressure ventilation These 2 physiologic observations Lorch et al reported that a 5- to may be acceptable substitutes for have led to speculation that GER can 7-day apnea-free period successfully NCPAP. However, larger studies precipitate apnea in preterm infants predicted resolution of apnea in that specifically examine the and that pharmacologic treatment 94% to 96% of cases. However, advantages and disadvantages of of GER might decrease the incidence the success rate was significantly nasal intermittent positive-pressure or severity of apnea. Despite the lower for infants born at younger ventilation and high-flow nasal frequent coexistence of apnea and gestational ages. A 95% success ≥ cannula versus conventional NCPAP GER in preterm infants, several rate threshold was 1 to 3 apnea-free on the incidence and severity of studies examining the timing of days for infants born at 30 weeks’ Bloodrecurrent Transfusion apnea are needed. reflux episodes in relation to apneic gestation, 9 days for those born at

events indicate that28,29 they are rarely 27 to 28 weeks’ gestation, and 13 temporally related. Additional days for infants born at <26 weeks’ An increase in respiratory drive data indicate that GER does not gestation. Similar gestational age resulting from increased oxygen- prolong30 or worsen concurrent effects were observed in another carrying capacity, total content of apnea. There is no evidence that smaller retrospective36 study by oxygen in the blood, and increased pharmacologic treatment of GER with Zupancic et al. These results tissue oxygenation is the proposed agents that decrease gastric acidity or suggested that the specified event- mechanism for red blood cell that promote gastrointestinal motility free period need not be uniform for transfusions to reduce apnea of decreases the risk of31,32 recurrent apnea all infants, and shorter durations prematurity. Retrospective and in preterm infants. Indeed, some may be considered for older prospective studies of the effects of studies have shown a coincident gestational ages. However, such blood transfusions on the incidence increase in recorded events with 32 recommendations are based on and severity of recurrent apnea pharmacologic treatment of GER. In observed events, which may not in preterm infants are conflicting, addition, recent data suggest harmful be accurate, and the prescribed perhaps because of a lack of blinding effects (including an increased event-free periods do not Downloaded from www.aappublications.org/news by guest on September 30, 2021 e4 FROM THE AMERICAN ACADEMY OF PEDIATRICS ≥ preclude the possibility that a new 36 to 37 weeks’ PMA in infants bradycardia/desaturation events circumstance (eg, intercurrent born at 28 weeks’ gestation. as well as the duration of the illness) may result in the period of observation before 2. Infants born at <28 weeks’ re-emergence of apnea. discharge. gestation may have apnea that Discharge considerations are usually persists to or beyond term 9. A clinically significant apnea based on nursing observation and gestation. event–free period before recording of apnea or bradycardia 3. Individual NICUs are encouraged discharge of 5 to 7 days is events, which may not always to develop policies for commonly used, although a correlate with those events that are 9,10 cardiorespiratory monitoring longer period may be suitable electronically recorded. Preterm for infants considered at risk of for infants born at less than infants with a history of apnea apnea of prematurity. 26 weeks’ gestation. The specific who are otherwise deemed ready event-free period may need for discharge may have clinically 4. Initial low heart rate alarms are to be individualized for some unsuspected apnea, bradycardia, most commonly set at 100 beats infants depending on the and/or hypoxemia events if archived per minute. Lower settings for gestational age at birth and convalescent preterm infants continuous electronic37 recording is the nature and severity of interrogated. There is no evidence, older than 33 to 34 weeks’ PMA recorded events. however, that such events predict the may be reasonable. 10. Interrogation of electronically recurrence of clinically significant 5. Caffeine citrate is a safe and archived monitoring data may events on discharge, SIDS, or the effective treatment of apnea of reveal clinically unsuspected need for readmission to the hospital. prematurity when administered events of uncertain significance. As such, more intensive monitoring at a 20-mg/kg loading dose Such events do not predict or pneumogram recordings in and 5 to 10 mg/kg per day subsequent outcomes, including convalescent preterm infants maintenance. Monitoring routine recurrent clinical apnea or SIDS. approaching discharge may not be serum caffeine levels usually is LEAD AUTHOR useful. However, standardizing the not contributory to management. Eric C. Eichenwald, MD, FAAP documentation and clinical approach A trial off caffeine may be to apnea within individual NICUs considered when an infant has COMMITTEE ON FETUS AND NEWBORN, may reduce38 the variation in discharge been free of clinically significant 2014–2015 timing. apnea/bradycardia events off Kristi L. Watterberg, MD, FAAP, Chairperson Infants born preterm may develop positive pressure for 5 to 7 Susan Aucott, MD, FAAP apnea and other signs of respiratory days or at 33 to 34 weeks’ PMA, William E. Benitz, MD, FAAP control instability with certain whichever comes first. James J. Cummings, MD, FAAP Eric C. Eichenwald, MD, FAAP stresses, including general anesthesia 6. Evidence suggests that GER is Jay Goldsmith, MD, FAAP and viral illnesses. Additional close not associated with apnea of Brenda B. Poindexter, MD, FAAP monitoring in these situations may prematurity, and treatment of Karen Puopolo, MD, FAAP be indicated in preterm infants presumed or proven GER solely Dan L. Stewart, MD, FAAP until 44 weeks’ PMA, including for the reduction in apnea events Kasper S. Wang, MD, FAAP former preterm infants readmitted is not supported by currently for elective surgical procedures, available evidence. such as hernia repair. In addition, LIAISONS the exacerbation of apnea has 7. Brief, isolated bradycardic Wanda D. Barfield, MD, MPH, FAAP – Centers for been reported in very preterm episodes that spontaneously Disease Control and Prevention infants after their initial 2-month resolve and feeding-related James Goldberg, MD – American College of immunizations or ophthalmologic events that resolve with Obstetricians and Gynecologists examinations, and rarely after the interruption of feeding are Thierry Lacaze, MD – Canadian Pediatric Society 4-month immunizations, while still in common in convalescent Erin L. Keels, APRN, MS, NNP-BC – National 39 Association of Neonatal Nurses the NICU. preterm infants and generally need not delay discharge. Tonse N.K. Raju, MD, DCH, FAAP – National CLINICAL IMPLICATIONS Institutes of Health 8. Individual units are encouraged to develop policies and STAFF 1. Apnea of prematurity reflects procedures for caregiver Jim Couto, MA immaturity of respiratory assessment, intervention, control. 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