Too Much of a Good Thing: Hyperoxia and Pediatric Respiratory Illnesses Shawn L. Ralston, MD, MS,a Julia A. Lonhart, MD,b Alan R. Schroeder, MDb

The advent of pulse oximetry as a widely adopted technology has transformed the overall clinical assessment of children with acute respiratory illness. One result of this transformation is a stronger clinical focus on treating hypoxemia in young children hospitalized with common respiratory illnesses, such as bronchiolitis, asthma, and pneumonia. For example, in acute viral bronchiolitis, international guidelines provide lower-limit oxygen saturation thresholds despite a weak evidence base and lack of consensus on the specific values. Nonetheless, advice to keep oxygen saturations above a precise threshold can be found in almost every bronchiolitis order set or hospital pathway. On the other hand, there has not been much debate about the opposite end aSchool of Medicine, Johns Hopkins University, Baltimore, Maryland; b of the spectrum: an upper saturation boundary once supplemental oxygen and School of Medicine, Stanford University, Palo Alto, California is administered for these common pediatric conditions. Pulse oximetry Dr Ralston conceptualized the perspective and drafted the readings of 100% are not generally treated as abnormal, but they can manuscript; Drs Lonhart and Schroeder drafted the manuscript; and all authors approved the final manuscript as represent a wide variety of PaO2 values and tissue oxygen delivery; thus, some readings of 100% while on supplemental oxygen will likely submitted. constitute tissue hyperoxia. Furthermore, nebulized therapies given in the DOI: https://doi.org/10.1542/peds.2019-3343 hospital setting are typically driven by the flow of 100% oxygen from Accepted for publication Jan 2, 2020 centralized supply lines, thus providing another source of exposure, which Address correspondence to Shawn L. Ralston, MD, MS, Division can be substantial for patients on continuously nebulized treatments. of Quality and Safety, Johns Hopkins Children’s Center, 1800 N Nevertheless, there is a dearth of pediatric research on the scope of the Orleans St, Baltimore, MD 21287. E-mail: [email protected] exposure and the potential for harm from excess oxygen outside of the PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098- neonatal period. 4275). Recently, the risk of excessive supplemental oxygen has garnered Copyright © 2020 by the American Academy of Pediatrics significant attention in adult patients. In a comprehensive systematic FINANCIAL DISCLOSURE: The authors have indicated they have fi review involving 16 000 patients in 25 randomized controlled trials, no nancial relationships relevant to this article to disclose. researchers compared liberal and conservative oxygen strategies in adults FUNDING: No external funding. with sepsis, critical illness, stroke, trauma, myocardial infarction, cardiac POTENTIAL CONFLICT OF INTEREST: The authors have arrest, or emergency surgery.1 Liberal oxygen use increased both in- indicated they have no potential conflicts of interest to hospital and out-of-hospital mortality. The largest increase in risk was disclose. seen with in-hospital mortality (relative risk, 1.21; 95% confidence interval, 1.03–1.43), translating to a number needed to harm of 71. To cite: Ralston SL, Lonhart JA, Schroeder AR. Too Much of Findings were consistent across populations and interventions (nasal a Good Thing: Hyperoxia and Pediatric Respiratory Illnesses. Pediatrics. 2020;146(2):e20193343 cannula, face masks, invasive ventilation). These findings have already

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 146, number 2, August 2020:e20193343 PEDIATRICS PERSPECTIVES begun to inform adult guidelines for States.5 The Oxy-PICU trial is an eventually overturned by Lavoisier. It many different conditions in several ongoing study of liberal (.94%) was Lavoisier who chose the word countries, with “goalposts” (eg, versus conservative (88%–92%) oxygene in French, which meant “acid saturation targets between 90% and saturation targets for patients generating,” because he believed 96%) suggested rather than simply receiving respiratory support in PICU oxygen was necessary for acid a lower threshold for initiation.1 in Britain, with pilot feasibility data formation, a theory also overturned published to date and a full trial by later scientists. Thus, the history of We propose that similar research on scheduled to begin in early 2020.6 the name for the element oxygen supplemental oxygen use warrants itself contains a history of scientific consideration in pediatric acute Hyperoxia has a multitude of paradigm shifts. respiratory illness. For years, the proposed pathophysiological potential harms of excessive mechanisms, which may exacerbate Similar paradigm shifts routinely supplemental oxygen have been respiratory disease in children. Both occur in medicine, and our thinking recognized in neonatology, in which temporary and permanent about supplemental oxygen may be there has been a sustained effort to morphologic changes to lung tissue amid such a shift. In the recent past, achieve a balance between preventing secondary to hyperoxia can occur few would have questioned oxygen as the negative effects of both hypoxia within hours of exposure. Free-radical a first-line therapy in a patient and hyperoxia in preterm neonates. species damage the capillary suspected of having a myocardial Hyperoxia is associated with endothelium, creating a state of infarction, yet this practice has increased risk of retinopathy of hyperpermeability, which can trigger undergone reevaluation and reversal. prematurity, bronchopulmonary pulmonary edema, and modulations We hope that the next frontier in dysplasia, and intraventricular to coagulation and fibrinolysis pediatric research will investigate the hemorrhage, whereas hypoxemia is pathways lead to deposition of fibrin possibility that supplemental oxygen, associated with poor growth and and platelet accumulation, altering like other drugs, has the potential 7 higher mortality rates. Theoretically, the alveolar-capillary membrane. for harm when used in excess. the premature infant’s limited Distortion of cell signaling alters Specifically, we suggest that a bell- defense mechanisms against antioxidant mechanisms, hastening shaped dose-response curve is likely 7 oxidative stress underlie the negative necrosis and apoptosis. Perhaps an to be present for other pediatric 2 sequelae associated with hyperoxia. even more relevant potential harm in conditions, consistent with the recent In term infants, there is now an pediatrics, in which viral lower adult literature. understanding that hyperoxia respiratory tract infections commonly contributes to negative outcomes in result in mucus plugging and alveolar The recent Nobel Prize awarded for neonatal resuscitation, resulting in collapse because of smaller airway work elucidating how the body recommendations for room air size, is a phenomenon known as responds to hypoxia provides an resuscitation of depressed term resorption atelectasis. Pressure opportunity to marvel at the complex neonates and tighter oxygen gradients between alveoli and and tightly regulated physiology of saturation targets by hour of life in pulmonary capillary beds increase as oxygen delivery in the human body. It the most recent American Heart higher concentrations of oxygen are also provides an opportunity to note Association resuscitation guidelines.3 inspired such that atelectasis distal to that such evolutionarily refined obstructed airways can hasten when mechanisms likely do not exist for There is evidence of emerging breathing oxygen rather than air. hyperoxia. Hyperoxia only became pediatric interest in this question in Much of our understanding of this possible with the development of the intensive care literature. In concept comes from the anesthesia supplemental oxygen for clinical use a 2016 systematic review of mortality literature, in which substantial effects in the modern era; thus, it stands to in children who were critically ill, on atelectasis may occur even with reason that there is still much we do researchers evaluated 6 observational changes in fractional inspired oxygen not know about its physiology. studies and could not draw strong from 21% to 30%.8 Children may be conclusions about any association Although pulse oximetry is limited in even more susceptible to these effects between hyperoxia and mortality.4 In its ability to assess the exact degree of given baseline lower tidal volumes a larger, more recent observational hyperoxia in patients receiving and/or smaller airway diameters. study involving .6000 patients, supplemental oxygen, invasive researchers concluded that severe Joseph Priestley initially named the measurement of arterial oxygenation hyperoxemia (PaO2 level . 300 element oxygen “dephlogisticated air.” is challenging in patients outside of mm Hg) was independently That name, which sounds somewhat the ICU. Furthermore, saturation associated with mortality in a large ridiculous to us today, referenced the (rather than PaO2) targets have been quaternary PICU in the United phlogiston theory of combustion, widely accepted as proxies for

Downloaded from www.aappublications.org/news by guest on September 24, 2021 2 RALSTON et al oxygenation in pediatric and adult a systematic review and meta-analysis. 5. Ramgopal S, Dezfulian C, Hickey RW, et al. trials. While awaiting definitive Lancet. 2018;391(10131):1693–1705 Association of severe hyperoxemia events and mortality among patients studies to determine the relationship 2. Kayton A, Timoney P, Vargo L, Perez JA. A admitted to a pediatric intensive care between high oxygen saturation review of oxygen physiology and unit. JAMA Netw Open. 2019;2(8):e199812 levels, tissue hyperoxia, and appropriate management of oxygen outcomes, strategies to avoid levels in premature neonates. Adv 6. Peters MJ, Jones GAL, Wiley D, et al; excessive doses of oxygen when Neonatal Care. 2018;18(2):98–104 Oxy-PICU Investigators for the saturations are high may be Paediatric Intensive Care Society Study 3. Wyckoff MH, Aziz K, Escobedo MB, et al. Group (PICS-SG). Conservative versus warranted. Practitioners should Part 13: neonatal resuscitation. 2015 liberal oxygenation targets in critically consider not only when to use American Heart Association Guidelines ill children: the randomised multiple- oxygen to treat hypoxemia but also update for cardiopulmonary centre pilot Oxy-PICU trial. Intensive how to titrate the dose more resuscitation and emergency Care Med. 2018;44(8):1240–1248 judiciously. cardiovascular care. Circulation. 2015; 132(18 Suppl 2):S543-60 7. Walsh BK, Smallwood CD. Pediatric REFERENCES oxygen therapy: a review and update. 4. Raman S, Prince NJ, Hoskote A, Ray S, Respir Care. 2017;62(6):645–661 1. Chu DK, Kim LH-Y, Young PJ, et al. Peters MJ. Admission PaO2 and mortality Mortality and morbidity in acutely ill in critically ill children: a cohort study 8. Magnusson L, Spahn DR. New concepts of adults treated with liberal versus and systematic review. Pediatr Crit Care atelectasis during general anaesthesia. conservative oxygen therapy (IOTA): Med. 2016;17(10):e444–e450 Br J Anaesth. 2003;91(1):61–72

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Downloaded from www.aappublications.org/news by guest on September 24, 2021 Too Much of a Good Thing: Hyperoxia and Pediatric Respiratory Illnesses Shawn L. Ralston, Julia A. Lonhart and Alan R. Schroeder Pediatrics originally published online July 23, 2020;

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