1 2 Intermittent Hypoxemia in 3 4 Preterm Infants 5 6 a, b b Juliann M. Di Fiore, BS *, Peter M. MacFarlane, PhD , Richard J. Martin, MD Q2 Q3 7 Q4 8 9 KEYWORDS 10 11 Intermittent hypoxemia Hypoxia Pulse oximetry Retinopathy of prematurity 12 Neurodevelopmental impairment Outcomes 13 14 KEY POINTS 15 16 Intermittent hypoxemia (IH) events are common in preterm infants during early postnatal 17 life. 18 In neonates, IH events have been associated with multiple morbidities, including retinop- 19 athy of prematurity, sleep disordered breathing, neurodevelopmental impairment, and death. 20 21 The relationship between IH and morbidity may depend on the pattern of the IH events, although this needs further investigation. 22 23 24 25 26 INTRODUCTION 27 28 Although maintaining adequate oxygenation is a fundamental aspect of newborn care, 29 clinicians are only beginning to appreciate how even subtle alterations in oxygen levels 30 can affect both short-term and long-term outcomes. Before the implementation of Q8 31 noninvasive technologies, oxygen assessment was limited to intermittent arterial sam- 32 pling, which only gave a glimpse of the true instability of oxygen levels that can occur 33 during early postnatal life. Current continuous recordings of oxygen saturation reveal a 34 much higher frequency of intermittent hypoxemia (IH) events that were previously un- 35 documented in medical charts and provide insight to high-risk patterns associated 36 with both short-term and long-term morbidity. This article summarizes what is 37 currently known about the technology used to assess oxygen levels, patterns of IH 38 during early postnatal life, underlying mechanisms associated with IH, and high-risk 39 IH patterns that may induce a pathologic cascade. 40 41 42 43 Disclosures: The authors have nothing to disclose. Q7 44 a Division of Neonatology, Case Western Reserve University, Rainbow Babies & Children’s 45 Hospital, Suite RBC 3100, Cleveland, OH 44106-6010, USA; b Case Western Reserve University, 46 Rainbow Babies & Children’s Hospital, 11100 Euclid Avenue, Suite RBC 3100, Cleveland, OH Q5 47 44106-6010, USA * Corresponding author. Q6 48 E-mail address: [email protected] Clin Perinatol - (2019) -–- https://doi.org/10.1016/j.clp.2019.05.006 perinatology.theclinics.com 0095-5108/19/ª 2019 Elsevier Inc. All rights reserved. CLP1106_proof ■ 14 June 2019 ■ 12:34 pm 2 Di Fiore et al 49 HISTORICAL PERSPECTIVE 50 51 Before the mid-1970s, intermittent arterial sampling formed the basis for assessing 52 and managing supplemental oxygen administration. There was no clear evidence 53 that arterial oxygen tension (PaO2) or arterial oxygen saturation (SaO2) showed frequent Q9 54 fluctuations in preterm infants even though apnea of prematurity was known to be a 55 problem. This situation changed with the advent of transcutaneous PO2 (TcPO2) mon- 56 itors, which were widely used during the 1980s. It was remarkable to observe how po- 57 sitional changes and associated procedures, such as spinal taps, could cause TcPO2 1 58 to decrease. This finding led to the widespread acceptance of gentle care for fragile 59 preterm infants. 60 However, TcPO2 electrodes (later combined with TcPCO2 electrodes) were cumber- some, required frequent recalibration, and resulted in site erythema from heating to 61 62 43 Cto44C. There was also the realization in the 1980s that TcPO2 increasingly 63 underestimated PaO2 with advancing postnatal age; this was especially a problem 2–4 64 with the increasing incidence of bronchopulmonary dysplasia (BPD). These patients 65 were a new population of extremely low birth weight infants who no longer had arterial 66 access. A solution was found in pulse oximetry and this technology has dominated 67 neonatology since approximately 1990. As a result, the available literature on IH epi- 68 sodes in preterm infants is almost exclusively based on pulse oximetry. 69 70 PULSE OXIMETRY 71 Because stabilization of oxygenation is one of the primary challenges in the neonatal 72 intensive care unit (NICU), pulse oximetry plays an important role in patient care. 73 Bedside discussions often include oximetry-based histogram data to note percentage 74 time in any given oxygen saturation range and/or nursing notation of IH events. How- 75 ever, treatment decisions based on medical chart documentation may be problematic 76 because they significantly underestimate the true incidence of even prolonged events.5 77 Adding to the confusion is that there is currently no criteria for a clinically relevant IH 78 event and, therefore, corresponding pulse oximeter alarm settings. Most research trials 79 have defined an IH event as a decrease less than 85% or 80%, but in the clinical setting 80 a low threshold alarm is determined by the individual NICU oxygen saturation target. 81 There is also wide variation in practice pertaining to the clinical significance of the dura- 82 tion of an IH event. For example, health care workers in some NICUs use a long pulse 83 oximeter alarm delay as a tool to minimize nuisance alarms caused by short self- 84 resolving IH, whereas others consider that even short events require intervention. 85 Correspondingly, alarm delay criteria can vary widely between NICUs depending on 86 the manufacturer (ranging from 0 to 15 seconds) and staff perception of the duration 87 needed for a clinically relevant desaturation event. 88 Pulse oximeters have the advantage of obtaining longitudinal documentation of ox- 89 ygen levels in a noninvasive and rapidly responding manner, but there are limitations 90 that may affect measurement accuracy. The most widely acknowledged disadvantage 91 of pulse oximetry is in the inability to detect hyperoxemia at levels of SpO2 (oxygen satu- 92 ration via pulse oximetry) exceeding approximately 97%.6 Additional factors, including 93 probe position, motion and ambient light interference, low perfusion, skin pigmenta- 94 tion, and variations in hemoglobin level, may result in delayed waveform recognition 95 and/or underestimation of oxygen saturation levels.7,8 Most manufacturers report an 96 overall error of Æ2% to 3% of full scale but, even under ideal conditions, accuracy 97 9 may diminish with decreasing SpO2. In a study of 1664 preterm infants, overall 98 mean differences between SaO2 and SpO2 (Masimo) were À1.8% Æ 2.9% but less 99 than 40% of infants were within 3% of the corresponding SaO2 when SpO2 decreased CLP1106_proof ■ 14 June 2019 ■ 12:34 pm Intermittent Hypoxemia in Preterm Infants Q1 3 100 less than 88%. During very low oxygen saturation levels of less than 70%, which are 101 impractical or unethical to target in infants, newborn lamb models have shown even 102 larger differences, ranging from 13% to 17%.10 Therefore, although pulse oximetry is 103 often used to identify periods of IH, treatment decisions based on the absolute SpO2 104 value should be made with caution, especially at low levels of oxygen saturation, as 105 can occur in cardiac patients. 106 107 INCIDENCE OF INTERMITTENT HYPOXEMIA EVENTS AND UNDERLYING 108 MECHANISMS 109 110 There is considerable current interest in the postnatal time course of IH events in pre- 111 term infants. This interest is precipitated by the fact that persistent IH events frequently 112 delay hospital discharge and may be perceived as increasing the vulnerability of these 113 infants. Barrington and colleagues11 documented more than 20 years ago that apneic 114 events of longer than 12 seconds are common in very low birth weight preterm infants 115 before discharge, many of which would, presumably, have been associated with IH. 116 Data for infants of 24 to 28 weeks’ gestation show a marked change in IH events 117 over time, with few hypoxemic episodes occurring during the first week of postnatal 118 life, a progressive increase in weeks 2 to 3, a plateau around weeks 4 to 6, and then 119 a decrease in weeks 6 to 812 (Fig. 1). It has been proposed that this postnatal increase 120 in IH events may be related to a documented postnatal increase in periodic breathing, 121 which is frequently associated with episodic desaturation.13 In a subsequent study, the 122 incidence of IH events was significantly increased in a low (85%–89%) versus high 14 123 (91%–95%) baseline SpO2 target. This finding is consistent with earlier data in pre- 124 term infants with BPD.15 More recently IH events (comprising a >10% decrease in 125 baseline SpO2) were reported in most preterm infants during home recordings of 16 126 SpO2, but declined between 36 and 44 weeks of postmenstrual age. 127 Immature respiratory control resulting in apnea and respiratory pauses, as well as 128 ineffective and/or obstructed inspiratory efforts, are the major precipitants of IH 129 events,17 but several physiologic parameters likely contribute to the resultant desatu- 130 ration. The most important of these is probably pulmonary oxygen stores, which may 131 reflect lung volume. Preterm infants are at risk for a low basal functional residual 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 Fig. 1. The progression of IH events during early postnatal life. Preterm infants have few IH 148 events during the first week of life, followed by an increase during weeks 2 to 4, and a decrease thereafter. (From Di Fiore JM, Bloom JN, Orge F, et al. A higher incidence of inter- 149 mittent hypoxemic episodes is associated with severe retinopathy of prematurity. The Jour- 150 nal of pediatrics. Jul 2010;157(1):69-73) CLP1106_proof ■ 14 June 2019 ■ 12:34 pm 4 Di Fiore et al 151 capacity because of both atelectasis and high chest wall compliance. Therapy with 152 continuous positive airway pressure (CPAP) clearly benefits these infants by splinting 153 the upper airway, stabilizing lung volume, and increasing baseline SpO2, thereby mini- 154 mizing the risk of desaturation.