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Multiple Organ Dysfunction in Children Mechanically Ventilated Saritha Pediatric Critical Care Medicine Multiple Organ Dysfunction in Children Mechanically 10.1097/PCC.0000000000001091 Ventilated for Acute Respiratory Failure* 1529-7535 Scott L. Weiss, MD, MSCE1; Lisa A. Asaro, MS2; Heidi R. Flori, MD3; Geoffrey L. Allen, MD4; Pediatr Crit Care Med David Wypij, PhD2,5,6; Martha A. Q. Curley, PhD, RN7,8; for the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) Study Investigators Weiss et al *See also p. 383. Objectives: The impact of extrapulmonary organ dysfunction, inde- 1Department of Anesthesiology and Critical Care, The Children’s Hospital pendent from sepsis and lung injury severity, on outcomes in pedi- of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. atric acute respiratory failure is unclear. We sought to determine the 2Department of Cardiology, Boston Children’s Hospital, Boston, MA. frequency, timing, and risk factors for extrapulmonary organ dysfunc- 3Division of Pediatric Critical Care, C.S. Mott Children’s Hospital, Univer- tion and the independent association of multiple organ dysfunction sity of Michigan, Ann Arbor, MI. syndrome with outcomes in pediatric acute respiratory failure. 4Division of Critical Care, Department of Pediatrics, Children’s Mercy Hos- Design: Secondary observational analysis of the Randomized Evalu- pitals and Clinics, Kansas City, MO. ation of Sedation Titration for Respiratory Failure cluster-random- 5Department of Biostatistics, Harvard T.H. Chan School of Public Health, ized prospective clinical trial conducted between 2009 and 2013. Boston, MA. Setting: Thirty-one academic PICUs in the United States. 6Department of Pediatrics, Harvard Medical School, Boston, MA. Patients: Two thousand four hundred forty-nine children mechani- 7School of Nursing, University of Pennsylvania, Philadelphia, PA. cally ventilated for acute respiratory failure enrolled in Random- 8Critical Care and Cardiovascular Program, Boston Children’s Hospital, Boston, MA. ized Evaluation of Sedation Titration for Respiratory Failure. The Randomized Evaluation of Sedation Titration for Respiratory Failure Measurements and Main Results: Organ dysfunction was defined Study Investigators are listed in Appendix 1. using criteria published for pediatric sepsis. Multiple organ dysfunc- Drs. Wypij and Curley have full access to all of the data in the study and tion syndrome was defined as respiratory dysfunction one or more take responsibility for the integrity of the data and the accuracy of the data extrapulmonary organ dysfunctions. We used multivariable logistic analysis. regression to identify risk factors for multiple organ dysfunction syn- Supplemental digital content is available for this article. Direct URL cita- tions appear in the printed text and are provided in the HTML and PDF drome, and logistic or proportional hazards regression to compare versions of this article on the journal’s website (http://journals.lww.com/ clinical outcomes. All analyses accounted for PICU as a cluster pccmjournal). variable. Overall, 73% exhibited extrapulmonary organ dysfunction, The Randomized Evaluation of Sedation Titration for Respiratory Failure including 1,547 (63%) with concurrent multiple organ dysfunction study was supported by grants from the National Heart, Lung, and Blood Institute and the National Institute of Nursing Research, National Insti- syndrome defined by onset on day 0/1 and 244 (10%) with new xxx tutes of Health (U01 HL086622 to Dr. Curley and U01 HL086649 to Dr. multiple organ dysfunction syndrome with onset on day 2 or later. Wypij). Dr. Weiss is also supported by K23GM110496. Most patients (93%) with indirect lung injury from sepsis presented April Dr. Weiss received funding from ThermoFisher Scientific (honorarium for with concurrent multiple organ dysfunction syndrome, whereas lecture unrelated to current study topic); his institution received fund- ing from National Institute of General Medical Science K23GM110496; patients with direct lung injury had both concurrent (56%) and new 2017 and he received support for article research from the National Institutes (12%) multiple organ dysfunction syndrome. Risk factors for con- of Health (NIH). Dr. Asaro’s institution received funding from the NIH/ current multiple organ dysfunction syndrome included older age, National Heart, Lung, and Blood Institute (NHLBI), and she received support for article research from the NIH. Dr. Flori received support illness severity, sepsis, cancer, and moderate/severe lung injury. 18 for article research from the NIH, and she disclosed that her site par- Risk factors for new multiple organ dysfunction syndrome were ticipated in the parent RESTORE trial funded by the NHLBI. Dr. Allen’s moderate/severe lung injury and neuromuscular blockade. Both 4 institution received funding from the NIH, and he received support for article research from the NIH. Dr. Wypij’s institution received funding concurrent and new multiple organ dysfunction syndrome were from the NIH/NHLBI, and he received support for article research from associated with 90-day in-hospital mortality (concurrent: adjusted 2017 the NIH. Dr. Curley’s institution received funding from the NIH (NHLBI odds ratio, 6.54; 95% CI, 3.00–14.25 and new: adjusted odds and National Institute of Nursing Research), and she received support for article research from the NIH. ratio, 3.21; 95% CI, 1.48–6.93) after adjusting for sepsis, moder- 319 For information regarding this article, E-mail: [email protected] ate/severe lung injury, and other baseline characteristics. Copyright © 2017 by the Society of Critical Care Medicine and the World Conclusions: Extrapulmonary organ dysfunction was common, gen- 329 Federation of Pediatric Intensive and Critical Care Societies erally occurred concurrent with respiratory dysfunction (especially DOI: 10.1097/PCC.0000000000001091 Pediatric Critical Care Medicine www.pccmjournal.org 319 Copyright © 2017 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. Unauthorized reproduction of this article is prohibited Weiss et al in sepsis), and was a major risk factor for mortality in pediatric acute invasive mechanical ventilation for children with acute respira- respiratory failure. (Pediatr Crit Care Med 2017; 18:319–329) tory failure compared with usual care. All care, other than the Key Words: mortality; multiple organ failure; pediatrics; respiratory sedation protocol at intervention PICUs, was at the discretion distress syndrome of the clinical team. Details of the RESTORE methodology and primary results have been published (16). Population cute respiratory failure requiring invasive mechanical We included all patients enrolled in the RESTORE trial. Patients ventilation is a common reason for admission to the were 2 weeks to 17 years old with new invasive mechanical APICU (1, 2). Prior studies have reported mortality rates ventilation for acute airways and/or parenchymal lung disease. between 11% and 34% for children with moderate to severe Excluded were patients expected to be extubated within 24 pediatric acute respiratory distress syndrome (PARDS) (3–10). hours, transferred from an outside PICU with sedative exposure Previously reported risk factors for death include high ventila- greater than 24 hours, or with unrepaired cyanotic heart disease, tory requirements, severe hypoxemia, immune deficiency, fluid primary pulmonary hypertension, chronic ventilator-depen- overload, indirect lung injury (most commonly sepsis), and dence, and neuromuscular respiratory failure. Written informed extrapulmonary organ dysfunction (3–5, 7, 9, 11, 12). consent was obtained from the legal guardian of each patient. As in other critical illnesses, multiple organ dysfunction syndrome (MODS) is often present at death in mechanically Data Collection ventilated children (3–5, 7, 9, 10, 13). However, the timing Patient characteristics included demographic data, base- and impact of extrapulmonary organ dysfunction and MODS line Pediatric Cerebral Performance Category and Pediatric on the outcomes of children with acute respiratory failure is Overall Performance Category (17), Pediatric Risk of Mortal- not clear. An important challenge has been to separate the ity (PRISM) III-12 score (18), primary etiology of lung dis- independent role of MODS on outcome from the impact of ease, and comorbid conditions. Acute respiratory failure due either sepsis or PARDS severity, since extrapulmonary organ to sepsis was defined as a nonpulmonary systemic infection. dysfunction is more likely to be present in these two scenar- Although pneumonia is often included as sepsis, for the pur- ios than in other cases of acute respiratory failure (7). Prior poses of differentiating direct from indirect etiologies of lung studies of extrapulmonary organ dysfunction in children with disease in this study, pneumonia and extrapulmonary sepsis acute respiratory failure have been limited by small sample size were considered separately. PARDS severity on day 0/1 was (< 350 patients) and have predominantly focused on PARDS defined using the 2015 PALICC criteria. The 2015 PALICC (3–5, 7, 9, 10, 13). In addition, most prior pediatric studies have defined PARDS severity as 1) at-risk (oxygenation index [OI], relied on the 1994 American European Consensus Conference < 4.0 or oxygenation saturation index [OSI], < 5.0), 2) mild adult definitions of ARDS, whereas the Pediatric Acute Lung (OI, 4.0 to < 8.0 or OSI, 5.0 to < 7.5), 3)
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