News

Apr 28, 2023

Executive Summary of the Second International Guidelines for... : Pediatric Critical Care Medicine

Emeriaud, Guillaume MD, PhD1; López-Fernández, Yolanda M. MD, PhD2; Iyer,

Emeriaud, Guillaume MD, PhD1; López-Fernández, Yolanda M. MD, PhD2; Iyer, Narayan Prabhu MBBS, MD3; Bembea, Melania M. MD, MPH, PhD4; Agulnik, Asya MD, MPH5; Barbaro, Ryan P. MD, MSc6; Baudin, Florent MD, PhD7; Bhalla, Anoopindar MD, MSCI8; Brunow de Carvalho, Werther MD9; Carroll, Christopher L. MD10; Cheifetz, Ira M. MD11; Chisti, Mohammod J. MD12; Cruces, Pablo MD13,14; Curley, Martha A. Q. RN, PhD, FAAN15,16; Dahmer, Mary K. PhD6; Dalton, Heidi J. MD, MCCM, FELSO17; Erickson, Simon J. MBBS18; Essouri, Sandrine MD, PhD1; Fernández, Analía MD19; Flori, Heidi R. MD6; Grunwell, Jocelyn R. MD, PhD20; Jouvet, Philippe MD, PhD1; Killien, Elizabeth Y. MD, MPH21; Kneyber, Martin C. J. MD, PhD, FCCM22; Kudchadkar, Sapna R. MD, PhD, FCCM4,23; Korang, Steven Kwasi MD, PhD8,24; Lee, Jan Hau MBBS, MRCPCH, MCI25; Macrae, Duncan J. MB ChB, FRCA, FFICM26; Maddux, Aline MD, MSCS27; Modesto i Alapont, Vicent MD, PhD28; Morrow, Brenda M. PhD, BSc PT29; Nadkarni, Vinay M. MD, MS30; Napolitano, Natalie MPH, RRT-NPS31; Newth, Christopher J. L. MD, ChB, FRACP, FRCPC8; Pons-Odena, Martí MD, PhD32; Quasney, Michael W. MD, PhD6; Rajapreyar, Prakadeshwari MD, MBA33; Rambaud, Jerome MD, PhD34; Randolph, Adrienne G. MD, MS35; Rimensberger, Peter MD36; Rowan, Courtney M. MD, MScr37; Sanchez-Pinto, L. Nelson MD, MBI38; Sapru, Anil MD, MAS39; Sauthier, Michael MD, PhD1; Shein, Steve L. MD11; Smith, Lincoln S. MD40; Steffen, Katerine MD41; Takeuchi, Muneyuki MD42; Thomas, Neal J. MD, MSc43; Tse, Sze Man MDCM, MPH1; Valentine, Stacey MD, MPH44; Ward, Shan MD45; Watson, R. Scott MD, MPH21,46; Yehya, Nadir MD, MSCE30; Zimmerman, Jerry J. MD, PhD, FCCM40,47; Khemani, Robinder G. MD, MsCI8; on behalf of the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) Group on behalf of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network

Emeriaud, Guillaume; López-Fernández, Yolanda M.; Khemani, Robinder G.; Iyer, Narayan Prabhu; Bembea, Melania; Korang, Steven Kwasi; Steffen, Katherine M.; Yehya, Nadir; Smith, Lincoln; Thomas, Neal J.; Zimmerman, Jerry J.; Erickson, Simon J.; Shein, Steven L.; Grunwell, Jocelyn R.; Dahmer, Mary K.; Sapru, Anil; Quasney, Michael W.; Flori, Heidi R.; Fernandez, Analia ; Alapont, Vicent Modesto i; Rimensberger, Peter; Cheifetz, Ira; Rowan, Courtney; Randolph, Adrienne G.; Kneyber, Martin; Valentine, Stacey; Kudchadkar, Sapna; Ward, Shan; Nadkarni, Vinay; Curley, Martha A.Q.; Bhalla, Anoopindar; Baudin, Florent; Takeuchi, Muneyuki; Cruces, Pablo; Carroll, Christopher L.; Napolitano, Natalie ; Pons-Odena, Marti; Essouri, Sandrine; Rambaud, Jérome; Barbaro, Ryan; Macrae, Duncan; Dalton, Heidi; Killien, Elizabeth; Maddux, Aline; Tse, Sze Man; Watson, Scott; Sanchez-Pinto, L. Nelson; Sauthier, Michaël; Rajapreyar, Prakadeshwari; Jouvet, Philippe; Newth, Christopher; Morrow, Brenda; Agulnik, Asya; de Carvalho, Werther Brunow; Chisti, Mohamod; Lee, Jan Hau; Lobner, Katie; Kysh, Lynn; Pincivy, Alix; Dodin, Philippe

1Department of Pediatrics, Sainte-Justine Hospital, Université de Montréal, Montréal, QC, Canada.

2Pediatric Intensive Care Unit, Department of Pediatrics, Cruces University Hospital, Biocruces-Bizkaia Health Research Institute, Bizkaia, Spain.

3Fetal and Neonatal Institute, Division of Neonatology, Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA.

4Departments of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

5Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN.

6Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, MI.

7Pediatric Intensive Care Unit, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Réanimation Pédiatrique, Lyon, France.

8Department of Anesthesiology and Critical Care Medicine, Children's Hospital Los Angeles. Keck School of Medicine, University of Southern California, Los Angeles, CA.

9Department of Pediatrics, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.

10Department of Pediatrics, Connecticut Children´s, Hartford, CT.

11Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH.

12Dhaka Hospital, International Centre for Diarrhoeal Disease Research, Bangladesh.

13Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile.

14Departamento de Pediatría, Unidad de Paciente Crítico Pediátrico, Facultad de Ciencias de la Vida, Hospital El Carmen de Maipú, Santiago, Chile.

15Department of Family and Community Health, School of Nursing, University of Pennsylvania, Philadelphia, PA.

16Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA.

17Department of Pediatrics and Heart and Vascular Institute, INOVA Fairfax Medical Center, Falls Church, VA.

18Department of Paediatric Critical Care, Perth Children's Hospital Western Australia, Perth, WA, Australia.

19Pediatric Intensive Care Unit, Emergency Department, Hospital General de Agudos "C. Durand" Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.

20Division of Critical Care, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.

21Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA.

22Department of Paediatrics, Division of Paediatric Critical Care Medicine, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

23Departments of Pediatrics, Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD.

24Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region of Denmark, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

25KK Women's and Children's Hospital, Singapore and Duke-NUS Medical School, Singapore.

26Cardiac Critical Care and ECMO, Sidra Medicine, Doha, Qatar.

27Department of Pediatrics, Section of Pediatric Critical Care Medicine, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO.

28Pediatric Intensive Care Unit, Hospital Universitari I Politècnic La Fe, València, Spain.

29Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.

30Department of Anesthesiology, Critical Care and Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

31Respiratory Therapy Department, Children's Hospital of Philadelphia, Philadelphia, PA.

32Immunological and Respiratory Disorders, Paediatric Critical Care Unit Research Group, Institut de Recerca Sant Joan de Déu, Pediatric Intensive Care and Intermediate Care Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.

33Department of Pediatrics, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, WI.

34Departement of Pediatric and Neonatal Intensive Care, Armand-Trousseau Hospital, Sorbonne University, Paris, France.

35Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, and Departments of Anaesthesia and Pediatrics, Harvard Medical School, Boston, MA.

36Division of Neonatology and Paediatric Intensive Care, University of Geneva, Geneva, Switzerland.

37Department of Pediatrics, Division of Pediatric Critical Care Medicine, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN.

38Departments of Pediatrics (Critical Care) and Preventive Medicine (Health & Biomedical Informatics), Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.

39Division of Pediatric Critical Care, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA.

40Department of Pediatrics, University of Washington, Seattle Children's Hospital, Seattle, WA.

41Department of Pediatrics, Division of Pediatric Critical Care, Stanford University, Palo Alto, CA.

42Department of Intensive Care Medicine, Osaka Women's and Children's Hospital, Osaka, Japan.

43Division of Pediatric Critical Care Medicine, Department of Pediatrics and Public Health Sciences, Penn State University College of Medicine, Hershey, PA.

44Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA.

45Department of Pediatrics, University of California San Francisco, Benioff Children's Hospitals, San Francisco and Oakland, CA.

46Center for Child Health, Behavior, and Development, Seattle Children's Research Institute Seattle, WA.

47Harborview Medical Center, University of Washington School of Medicine, Seattle, WA.

The views presented are those of the author and do not represent the views of the Society of Critical Care Medicine organization.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal).

Dr. Barbaro is currently receiving grant support (R01 HL153519; R01 HD015434) from the National Institutes of Health (NIH); he is currently Chair of the Extracorporeal Life Support Organization Registry. Dr. Bembea receives research funding to her institution from the NIH/National Institute of Neurological Disorders and Stroke (R01NS106292) and the Grifols Investigator Sponsored Research Grant. She serves as Chair of the Scientific Committee of the Pediatric Acute Lung Injury and Sepsis Investigators Research Network. Dr. Cheifetz is a medical consultant for Phillips and Medtronic. His institution receives research grant funding from the NIH. Dr. Cruces received funding from the Chilean Ministry of Sciences (Fondecyt 1220322). Dr. Curley received funding from the NIH (UH3HL141736, R01HD098269, R01HL149910, R01HL153519, R01HD104618). Dr. Dahmer received funding from the NIH (National Institute of Child Health and Human Development [NICHD], R21 HD097387; National Heart, Lung and Blood Institute [NHLBI] R01 HL149910). Dr. Dalton received funding from the Department of Defense (No. 13363072). She is a consultant for Innovative Extracorporeal Membrane Oxygenation Concepts, Hemocue, Entegrion, Medtronic, and advisory board member for Abiomed. Dr. Emeriaud's research program is supported by the Fonds de Recherche du Québec-Santé and the Quebec Respiratory Health Network. Dr. Emeriaud is leading a study, which is financially supported by Maquet. Dr. Jouvet's research program and salary is supported by the Fonds de Recherche du Québec-Santé and the Quebec Respiratory Health Network. Dr. Jouvet is leading studies, which is financially supported by VitalTracer, Dymedso and public financial agencies (Canadian Foundation for innovation, Institut TransMedTech, Quebec Ministry of Health, Sainte-Justine Hospital). Dr. Killien received funding from the NIH (NICHD K23HD100566). Dr. Kneyber received research funding from the NIH/NICHD (UG3 HL141736-01/U24 HL141723-01) and ZorgOnderzoek Nederland and the area Medical (848041002), Stichting Vrienden Beatrix Kinderziekenhuis, Fonds NutsOhra, University Medical Center Groningen, VU University Medical Center, and the Royal Academy of Dutch Sciences (TerMeulen stipend). Dr. Kneyber's research program is technically supported by Vyaire, Applied Biosignals, and Timpl. Dr. Kneyber received honoraria from Vyaire. Dr. Kneyber serves as consultant for Metran and served as consultant for Vyaire. Dr. Kudchadkar received funding to her institution from the NIH/NICHD (R01HD103811 & R21HD093369) and the Donaghue Foundation. Dr. López-Fernández is funded by an academic grant from the Instituto de Salud Carlos III, Madrid, Spain (PI19/00141). Dr. Maddux received funding to her institution from the NIH/NICHD (K23HD096018). Dr. Morrow has received honoraria for Continuing Medical Education presentations from EduPro Health. Her research is part-funded by the National Research Foundation of South Africa, through the Incentive Funding for Rated Researchers program. Dr. Nadkarni receives unrestricted research grants to his institution from the NIH, U.S. Department of Defense, Agency for Healthcare Research and Quality, Laerdal Foundation, RQI Partners, Zoll Medical, Defibtech, HeartHero, and Nihon-Kohden. Dr. Nadkarni is an elected member of the Executive Committee (Council) of the Society of Critical Care Medicine. Dr. Napolitano research and consulting relationships with: Drager, Timpel, VERO-Biotech, Actuated Medical, and Philips/Respironics. Dr. Pons has been on the speaker's bureau of Philips, ResMed and Fisher & Paykel; Hospital Sant Joan de Déu has received disposable material from these companies. Dr. Randolph receives funding from the Centers for Disease Control and Prevention, NIH (National Institute of Allergy and Infectious Diseases AI154470). Dr. Rowan receives funding from the NHLBI (NHLBI K23HL150244). Dr. Sanchez-Pinto received funding from the NIH (NICHD R01 HD105939). Dr. Sauthier research program and salary is supported by the Fonds de Recherche du Québec-Santé. Dr. Takeuchi receives funding from Japan Society for the Promotion of Science grant (KAKENHI 21K09063). Dr. Tse receives research funding to her institution from the Canadian Institute of Health Research and salary support from the Fonds de Recherche du Québec—Santé. Dr. Watson receives research funding to his institution from the NIH. Dr. Zimmerman received research funding from NIH and Biomedical Advanced Research and Development Authority; royalties from Elsevier Publishing. The remaining authors have disclosed that they do not have any potential conflicts of interest.

This Executive Summary has been endorsed by The World Federation of Pediatric Intensive & Critical Care Societies.

The Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) group members are listed in Appendix 1 (https://links.lww.com/PCC/C287).

For information regarding this article, E-mail: [email protected]

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

We sought to update our 2015 work in the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS), considering new evidence and topic areas that were not previously addressed.

International consensus conference series involving 52 multidisciplinary international content experts in PARDS and four methodology experts from 15 countries, using consensus conference methodology, and implementation science.

Not applicable.

Patients with or at risk for PARDS.

None.

Eleven subgroups conducted systematic or scoping reviews addressing 11 topic areas: 1) definition, incidence, and epidemiology; 2) pathobiology, severity, and risk stratification; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive respiratory support; 8) extracorporeal support; 9) morbidity and long-term outcomes; 10) clinical informatics and data science; and 11) resource-limited settings. The search included MEDLINE, EMBASE, and CINAHL Complete (EBSCOhost) and was updated in March 2022. Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to summarize evidence and develop the recommendations, which were discussed and voted on by all PALICC-2 experts. There were 146 recommendations and statements, including: 34 recommendations for clinical practice; 112 consensus-based statements with 18 on PARDS definition, 55 on good practice, seven on policy, and 32 on research. All recommendations and statements had agreement greater than 80%.

PALICC-2 recommendations and consensus-based statements should facilitate the implementation and adherence to the best clinical practice in patients with PARDS. These results will also inform the development of future programs of research that are crucially needed to provide stronger evidence to guide the pediatric critical care teams managing these patients.

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome, which contributes to high rates of mortality and long-term morbidities (1–3). For years, pediatric practitioners relied on adult-oriented criteria to diagnose ARDS in children, until the 2015 Pediatric Acute Lung Injury Consensus Conference (PALICC) published a specific definition for pediatric ARDS (PARDS) with guidelines for management and future research (2,4,5). There were 744 new cases of PARDS identified by the PALICC definition over the 10 study weeks, yielding an international PARDS incidence of 3.2% (95% CI 3.0, 3.4%) amongst PICU patients and 6.1% (95% CI 5.7, 6.5%) amongst those on MV (6).

In the last years, there has been a wealth of new knowledge regarding (P)ARDS, with emerging concepts in the pathobiology, lung protection (driving pressure, mechanical power, patient self-inflicted lung injury), and use of new technologies (high-flow nasal cannula [HFNC]) and healthcare systems (informatics, clinical decision support tools) (7–9). Notable gaps exist in defining PARDS in resource-limited settings (RLS), in addition to differences in the availability of supportive therapies. Furthermore, recent literature has highlighted that implementation of 2015 PALICC recommendations varies among PICUs (6,10), and nonadherence with recommendations is associated with higher mortality (11,12). This motivated refinement of the PARDS definition and an update from the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2). Two new sections focused on the use of informatics and data management strategies to help with implementation, as well as on modifications of the guidelines that may be needed in RLS.

In this executive summary, we briefly describe the methodology and present the set of recommendations and statements for the definition and the clinical management of PARDS. The full rationale and evidence-to-decision (EtD) framework for each recommendation, as well as detailed methods, are provided in accompanying articles published separately (13–24).

The process for generation of these guidelines involved: 1) systematic literature review with identification, assessment, and synthesis of evidence; 2) stratification of recommendations into categories using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology; 3) voting (up to three rounds) on recommendations and statements to achieve consensus; and 4) revision and harmonization of the recommendations and statements. The detailed methodology is reported in the accompanying supplement (13).

Panelists were selected based on research in specific aspects of PARDS over the preceding 10 years, with particular attention to increased diversity and international representation (Asia, Africa, South America). Final participants comprised a panel of 52 content and four methodology experts (24 women, 32 men) from multiple disciplines (52 physicians, one respiratory therapist, one nurse, one physical therapist, one PhD researcher) and geographic settings (15 countries). The panel worked with two guidelines methodologists (N.P.I., M.M.B.) along with an expert in meta-analysis (S.R.K.) and two experts in implementation science (R.P.B., K.S.).

Panelists were divided into 11 subgroups and each group was tasked with answering a key question, as listed in Table 1. In addition to their specific subgroup, a panelist from the RLS group also participated in each subgroup to ensure that RLS modifications were considered unless the group experts already included at least one expert from RLS regions.

Population, Intervention, Comparator, and Outcome questions were formulated based on topics addressed in the 2015 PALICC guidelines (2) as well as new key topics that were identified by each subgroup. Electronic searches were conducted by experienced medical librarians in Medline and Embase databases, as well as CINAHL, Cochrane, Scopus, and/or the Web of Science databases during November 2020–December 2020, with an update in March 2022–April 2022. For topics covered in the 2015 PALICC guidelines, searches were updated to include publications since 2013, while two new sections (i.e., key questions 10 and 11 on informatics and RLS, respectively) or new topics underwent literature review from 1980. We used a combination of medical subject heading terms and text words for concepts related to PARDS and each of the 11 sections. Search strategies are detailed in the methods article and supplemental digital files for each of the individual articles (13–24). References included in previous PALICC reviews were systematically added to the extracted evidence.

All titles and abstracts in each subgroup had single author review, and full-text article review and extraction was independently conducted by two reviewers. A third reviewer resolved differences at each stage. Risk of bias was assessed using the Cochrane risk of bias 2 (RoB2) tool for randomized clinical trials and the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for nonrandomized studies (25,26). Key data elements were extracted using electronic forms developed in the Research Data Electronic Capture (REDCap) browser (27) and exported into evidence tables. The protocol for the systematic reviews was registered on the International Prospective Register of Systematic Reviews (CRD42021236582).

Different types of recommendation or statements were generated (Table 2). The GRADE approach was used to summarize relevant evidence and develop recommendations for clinical practice (28,29). Where applicable, we performed meta-analyses to obtain pooled estimates from similar studies. The methodologists independently categorized the certainty of evidence of each recommendation using the GRADE framework (30). We used the EtD framework to facilitate transition from evidence to recommendations (31). Based on the certainty of evidence and the EtD framework, clinical practice recommendations (CR) were described as "strong" (with wording "we recommend") or "conditional" (using "we suggest") (29). The implications of the strength of recommendations for different stakeholders are provided in Table 3. Good practice statements (GPS) are a unique category recognized by GRADE. This was used when it was abundantly clear that there is a "large net positive impact" if the recommended course of action is implemented (32). Policy statements (PS) related to healthcare delivery, education, or ethics. In making such statements, we considered the impact of the implementation of the recommended course of action on patient centered outcomes. Relevant gaps in evidence were synthesized into future research initiatives and classified as "research statements (RS)." Definition statements (DS) were offered in the context of updating the definition of pediatric ARDS. DS were primarily based on analysis of data from observational studies and clinical trials that described the impact of different variables on patient centered outcomes. Clinical attributes and indices that had a major impact on prognosis were used in formulating the definition of pediatric ARDS. GPS, PS, RS, and DS were ungraded.

All recommendations, statements, their corresponding remarks, and their evidence were discussed by the entire panel utilizing multiple online webinars. Three co-chairs (G.E., Y.M.L.-F., R.G.K.) were responsible for leadership and coordination of the PALICC-2 meetings, oversight of the voting processes, and harmonization of recommendations/statements and manuscripts. Conflict of interest disclosures were completed by all panelists at the beginning, during the voting process, and at the time of journal submission. Three rounds of voting were conducted to achieve consensus using an online anonymous survey (Qualtrics, Provo, UT). Each recommendation/statement was scored on a 9-point Likert scale, ranging from strong disagreement (scored 1) to strong agreement (scored 9). Implementation science experts suggested revisions for recommendations/statements to each subgroup to improve clarity and to facilitate future implementation. After the first two rounds, recommendations and statements that did not meet 90% agreement (score ≥ 7) were reviewed based on comments from the full panel and resubmitted for voting. Remarks were used to provide clarification to some recommendations/statements and were included in the voting process.

The PALICC-2 Recommendations and Statements were endorsed by the World Federation of Pediatric Intensive and Critical Care Societies on June 17, 2022.

All the following recommendations and statements achieved the a priori specified 80% agreement threshold. There were 34 CR (one strong and 33 conditional). There were another 112 statements: 18 related to the definition of PARDS and patients at risk for PARDS, 55 GPS, seven PS, and 32 RS. The evidence tables and rationale supporting CR are presented in the corresponding subgroup manuscripts (13–24).

The revised PARDS definition is now summarized in Tables 4 and 5, and introduces key new concepts related to stratifying PARDS severity at least 4 hours after initial PARDS diagnosis for both invasive and noninvasive ventilation (NIV), allowing for the diagnosis of "possible PARDS" for children on nasal modes of support such as HFNC, and enabling modifications for RLS. Tables 6–9 summarize PALICC-2 recommendations and statements in the context of a patient's trajectory from diagnosis to follow-up.

Definition statement 1.1. All patients less than 18 years old without active perinatal lung disease should be diagnosed with PARDS using PALICC-2 criteria. (Ungraded DS, 94% agreement) (14).

Remarks: Practitioners can use either the PALICC-2 or neonatal definition (Montreux NARDS) for neonates and can use either the PALICC-2 or adult definition (Berlin ARDS) for young adults.

Definition statement 1.2. Symptoms of hypoxemia and radiographic changes must occur within 7 days of a known insult to qualify for PARDS. (Ungraded DS, 96% agreement).

Definition statement 1.3. Chest imaging findings of new opacity (or opacities) consistent with acute pulmonary parenchymal disease not explained by atelectasis or effusion are necessary to diagnose PARDS. (Ungraded DS, 90% agreement).

Oxygenation index (OI) or oxygen saturation index (OSI), in preference to Pao2/Fio2 or pulse oximeter oxygen saturation (Spo2)/Fio2, should be the primary metric of lung disease severity to define PARDS for all patients treated with invasive mechanical ventilation (IMV), with Pao2 used preferentially when available. (Ungraded DS, 90% agreement).

Definition statement 1.4.2. Pao2/Fio2 or Spo2/Fio2 should be used to diagnose PARDS and possible PARDS for patients receiving NIV or HFNC (Ungraded DS, 88% agreement).

Definition statement 1.4.3. Patients on a full-face interface of NIV (continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BiPAP]) with CPAP greater than or equal to 5 cm H2O or invasively ventilated should be considered as having PARDS if they meet timing, oxygenation, etiology/risk factor, and imaging criteria (Ungraded DS, 90% agreement).

Definition statement 1.4.4. Subjects with PARDS should be stratified into severity categories after a period of at least 4 hours (Ungraded DS, 85% agreement).

Definition statement 1.4.5. When applying Spo2 criteria to diagnose PARDS, oxygen should be titrated to achieve an Spo2 between 88% and 97%. (Ungraded DS, 96% agreement).

Definition statement 1.5.1. Patients on a nasal interface of NIV (CPAP or BiPAP) or on HFNC greater than or equal to 1.5 L/kg/min or greater than or equal to 30 L/min should be considered as having possible PARDS if they meet timing, oxygenation, etiology/risk factor, and imaging criteria (Ungraded DS, 87% agreement).

Definition statement 1.5.2. Patients who are missing imaging due to resource limitations should be considered as having possible PARDS if they otherwise meet timing, oxygenation, and risk factor criteria. (Ungraded DS, 90% agreement).

Definition statement 1.5.3. Defining a group of patients at risk for PARDS is necessary to determine the epidemiology of disease progression and potential avenues for disease prevention. (Ungraded DS, 96% agreement).

Definition statement 1.6.1. Patients with cyanotic congenital heart disease are considered to have PARDS if they fulfill standard PARDS criteria and have an acute deterioration in oxygenation (relative to baseline) not fully explained by the underlying cardiac disease. (Ungraded DS, 98% agreement).

Definition statement 1.6.2. Patients with left ventricular (LV) dysfunction who fulfill standard PARDS criteria are considered to have PARDS if acute hypoxemia and new chest imaging changes cannot be explained solely by LV heart failure or fluid overload. (Ungraded DS, 92% agreement).

Remarks: Cardiac ultrasonography and/or left atrial pressure may be useful in identifying hydrostatic pulmonary edema.

Definition statement 1.6.3. Patients with preexisting chronic lung disease treated with supplemental oxygen, NIV, or IMV via tracheostomy are considered to have PARDS if they demonstrate acute changes that fulfill standard PARDS criteria and exhibit an acute deterioration in oxygenation from baseline that meets oxygenation criteria for PARDS. (Ungraded DS, 96% agreement).

Definition statement 1.6.4. Patients with chronic lung disease who receive IMV at baseline or have cyanotic congenital heart disease with acute onset of illness that fulfills standard PARDS criteria should not be stratified by OI or OSI risk categories. Future studies are necessary to determine PARDS risk stratification of such patients with acute-on-chronic hypoxemic respiratory failure. (Ungraded DS, 90% agreement).

Definition statement 1.7.1. PARDS shall be defined using Table 4. (Ungraded DS, 84% agreement).

Definition statement 1.7.2. Possible and at risk for PARDS shall be defined using Table 5. (Ungraded DS, 94% agreement).

Remarks: Clinicians should consider treating patients with possible PARDS as if they have PARDS and apply other recommendations after considering the specific risks and benefits for that specific patient.

Dead-Space Fraction for Risk Stratification. Clinical recommendation 2.1. We suggest that in PARDS patients with arterial access, dead space to tidal volume ratio and/or end-tidal alveolar dead-space fraction should be measured, compared with not measured, at the onset of PARDS to assist in the bedside assessment of severity of illness and risk stratification. (Conditional CR, low certainty of evidence, 90% agreement).

Research statement 2.2. Studies should be conducted to examine whether there are differences in the progression and/or outcome of PARDS between adults and children across different age groups and between adults and children. (Ungraded RS, 96% agreement).

Research statement 2.3.1. Biomarker and genetic studies will provide insight into the pathobiology of PARDS. Future research requires increased integration of human studies and human model systems. (Ungraded RS, 96% agreement).

Research statement 2.3.2. The heterogeneity of PARDS should be defined using combinations of biomarkers (proteins, metabolites, gene transcripts, and genetics) to define phenotypes and endotypes of patients with PARDS for prognostic and predictive enrichment in studies (Ungraded RS, 84% agreement).

Research statement 2.4.1. Research studies evaluating trajectory of illness and recovery should use standardized, minimal datasets with operational definitions (Ungraded RS, 90% agreement).

Research statement 2.4.2. Studies measuring variables such as tidal volume, peak and plateau pressures, positive end-expiratory pressure (PEEP), or mean airway pressure should use explicit protocols and definitions to allow for reproducibility (Ungraded RS, 100% agreement).

Research statement 2.4.3. A validated measure of nonpulmonary organ system dysfunction should be included in studies of clinical risk factors associated with outcome in patients with PARDS (Ungraded RS, 98% agreement).

Research statement 3.1. We cannot make a recommendation on the specific ventilator mode preferred for PARDS patients. Future clinical studies should be conducted to assess controlled and assisted modes of ventilation on outcomes. (Ungraded RS, 94% agreement).

Remarks: There are no outcome data on the influence of mode (controlled or assisted, including airway pressure release ventilation and neurally adjusted ventilatory assist) during conventional mechanical ventilation (MV).

Clinical recommendation 3.2. We suggest the use of physiologic tidal volumes between 6 and 8 mL/kg in patients with PARDS compared with supraphysiologic tidal volumes (> 8 mL/kg). (Conditional CR, very low certainty of evidence, 98% agreement).

Remarks: Tidal volumes below 6 mL/kg should be used in patients if needed to stay below suggested plateau and driving pressure limits. Tidal volumes below 4 mL/kg should be used with caution.

Clinical recommendation 3.3.1. In the absence of transpulmonary pressure measurements, we suggest an inspiratory plateau pressure less than or equal to 28 cm H2O. (Conditional CR, very low certainty of evidence, 92% agreement).

Remarks: The plateau pressure may be higher (29–32 cm H2O) for patients with reduced chest wall compliance.

Clinical recommendation 3.3.2. We suggest limiting driving pressure to 15 cm H2O (as measured under static conditions) for patients with PARDS. (Conditional CR, very low certainty of evidence, 82% agreement).

Clinical recommendation 3.4.1. We suggest that PEEP should be titrated to oxygenation/oxygen delivery, hemodynamics, and compliance measured under static conditions compared with other clinical parameters or any of these parameters in isolation in patients with PARDS. (Conditional CR, very low certainty of evidence, 96% agreement).

Clinical recommendation 3.4.2. We recommend that PEEP levels should typically be maintained at or above the lower PEEP/higher Fio2 table from the ARDS Network protocol (33) (Supplemental Table 1, https://links.lww.com/PCC/C287) compared with PEEP levels lower than the lower PEEP/higher Fio2 table. (Strong CR, moderate certainty of evidence, 96% agreement).

Good practice statement 3.4.3. When adjusting PEEP levels to achieve the proposed oxygen target range for PARDS, attention to avoid exceeding plateau pressure and/or driving pressure limits is warranted. (Ungraded GPS, 100% agreement).

Clinical recommendation 3.5. We suggest that a lung protective ventilation bundle should be used compared with no bundle when caring for ventilated patients with PARDS. (Conditional CR, low certainty of evidence, 83% agreement).

Remarks: Lung protective bundles prioritize maintaining multiple ventilator settings (tidal volume, plateau pressure, driving pressure, PEEP) within the suggested limits as well as using detection algorithms and educational programs.

Clinical recommendation 3.6. We cannot suggest for or against the use of recruitment maneuvers in patients with PARDS. (Conditional CR, low certainty of evidence, 94% agreement).

Remarks: Careful recruitment maneuvers may be applied in the attempt to improve oxygenation by slow incremental and decremental PEEP steps. Sustained inflation maneuvers cannot be recommended.

Research statement 3.7. There is insufficient evidence to suggest the use of mechanical power calculations to guide pediatric MV. Future research is needed with regards to mechanical power calculations in children before clinical use. (Ungraded RS, 90% agreement).

Clinical recommendation 3.8.1. We cannot make a recommendation as to whether high-frequency oscillatory ventilation (HFOV) should be used instead of conventional ventilation in patients with PARDS. (Conditional CR, low certainty of evidence, 90% agreement).

Remark: HFOV may be considered in patients with PARDS in whom the ventilatory goals are not achieved with a lung protective strategy on conventional MV.

Good practice statement 3.8.2. When using HFOV, the optimal lung volume should be achieved by exploration of the potential for lung recruitment with a stepwise increase and decrease of the mean airway pressure under continuous monitoring of the oxygen and co2 response and hemodynamic parameters (Ungraded GPS, 90% agreement).

Clinical recommendation 3.9.1. We suggest that for mild/moderate PARDS, Spo2 be maintained between 92% and 97%. (Conditional CR, low certainty of evidence, 98% agreement).

Clinical recommendation 3.9.2. We suggest that for severe PARDS, after optimizing PEEP, Spo2 less than 92% can be accepted in order to reduce Fio2 exposure. (Conditional CR, low certainty of evidence, 88% agreement).

Good practice statement 3.9.3. Prolonged exposure to hypoxemic (< 88%) or high (> 97%) Spo2 targets should be avoided while on oxygen supplementation. (Ungraded GPS, 88% agreement).

Good practice statement 3.9.4. When Spo2 is less than 92%, central venous saturation and markers of oxygen delivery/utilization should be monitored. (Ungraded GPS, 94% agreement).

Clinical recommendation 3.10.1. We suggest allowing permissive hypercapnia (to a lower limit pH of 7.20) in patients with PARDS to remain within previously recommended pressure and tidal volume ranges. (Conditional CR, very low certainty of evidence, 100% agreement).

Remarks: Exceptions to permissive hypercapnia include, but are not limited to, intracranial hypertension, severe pulmonary hypertension, select congenital heart disease lesions, hemodynamic instability, and significant ventricular dysfunction.

Clinical recommendation 3.10.2. We suggest against the routine use of bicarbonate supplementation compared with selective use of bicarbonate in PARDS. (Conditional CR, low certainty of evidence, 96% agreement).

Remarks: Bicarbonate supplementation can be considered in situations where severe metabolic acidosis or pulmonary hypertension are adversely affecting cardiac function or hemodynamic stability.

Good practice statement 3.11. Cuffed endotracheal tubes should be used when ventilating a patient with PARDS. (Ungraded GPS, 100% agreement).

Clinical recommendation 4.1. We suggest against the routine use of inhaled nitric oxide (iNO) in PARDS compared with selective use of iNO in PARDS. (Conditional CR, low certainty of evidence, 98% agreement).

Remarks: There may be clinical benefit in the use of iNO in some phenotypes such as patients with documented pulmonary hypertension or severe right ventricular dysfunction. In addition, the use of iNO may be considered in patients with severe PARDS as a rescue from, or bridge to, extracorporeal life support. When used, assessment of benefit should be undertaken within the first 4 hours and serially to minimize toxicity and to eliminate continued use in the absence of established effect.

Clinical recommendation 4.2. We suggest against the routine use of surfactant therapy in PARDS compared with selective use of surfactant. (Conditional CR, low certainty of evidence, 100% agreement).

Remarks: There may be a role for selective use of surfactant in specific populations; however, there is insufficient evidence to guide which populations may benefit.

Clinical recommendation 4.3. There are insufficient data to support or refute the use of prone positioning in patients with PARDS. (Conditional CR, low certainty of evidence, 94% agreement).

Remarks: The use of prone positioning may be considered in patients with PARDS and hypoxemia not responding to other interventions. If used, improvement in oxygenation while in the prone position should be assessed. We cannot make recommendations on the duration of prone positioning.

Good practice statement 4.4.1. In intubated patients with PARDS, an unobstructed airway should be maintained. (Ungraded GPS, 98% agreement).

Remark: Endotracheal suctioning must be performed with caution to minimize the risk of derecruitment.

Research statement 4.4.2. We cannot make a recommendation on the use of a closed versus an open suctioning system. Future research should focus on the impact of closed and open suctioning systems on outcomes. (Ungraded RS, 90% agreement).

Remarks: In severe PARDS, consideration should be given to the technique of suctioning with careful attention to minimize the potential for derecruitment.

Good practice statement 4.4.3. The routine instillation of isotonic saline prior to endotracheal suctioning should not be used in patients with PARDS. (Ungraded GPS, 94% agreement).

Remarks: The instillation of isotonic saline prior to endotracheal suctioning may be considered for lavage to remove thick tenacious secretions.

Research statement 4.5. We cannot make a recommendation on the use of specific methods of airway clearance (such as chest physiotherapy and mucolytics) in patients with PARDS. Future research should focus on the impact of specific airway clearance methods on outcomes and on specific populations likely to benefit from these methods. (Ungraded RS, 96% agreement).

Clinical recommendation 4.6. We suggest against the routine use of corticosteroids in patients with PARDS compared with selective use of steroids. (Conditional CR, low certainty of evidence, 96% agreement).

Remarks: There may be some benefit in patients with PARDS caused by severe acute respiratory syndrome coronavirus 2; however, we cannot make recommendations regarding other specific populations for use.

Research statement 4.7. We cannot make a recommendation on the use of the following ancillary treatment in patients with PARDS: helium-oxygen mixture, inhaled or IV prostaglandins therapy, plasminogen activators, fibrinolytics or other anticoagulants, inhaled β-adrenergic receptor agonists or ipratropium, or IV N-acetylcysteine for antioxidant effects. Future research should focus on the impact of these treatments and on specific populations likely to benefit from them. (Ungraded RS, 96% agreement).

Good practice statement 5.1.1. Valid and reliable assessment scales for pain, sedation, delirium, and withdrawal should be used to monitor, target and titrate comfort therapies and to facilitate interprofessional communication. (Ungraded GPS, 100% agreement).

Good practice statement 5.1.2. In patients with PARDS, sedation (minimal yet effective) should be titrated to achieve the targeted MV strategy that facilitates oxygen delivery, oxygen consumption, and work of breathing goals. (Ungraded GPS, 96% agreement).

Good practice statement 5.1.3. Sedation monitoring, titration, and weaning should be managed by a goal-directed protocol with a daily sedation goal collaboratively established by the interprofessional team. (Ungraded GPS, 96% agreement).

Good practice statement 5.1.4. Patients with PARDS who are weaning from 5 or more days of sedation should be 1) assessed for symptoms of iatrogenic withdrawal syndrome using a validated instrument and 2) placed on a systematic plan that facilitates sedation weaning. (Ungraded GPS, 96% agreement).

Good practice statement 5.2.1. Patients with PARDS should be assessed daily for delirium using a validated pediatric delirium screening tool. (Ungraded GPS, 94% agreement).

Good practice statement 5.2.2. Patients with PARDS should receive multicomponent, nonpharmacologic interventions as first-line interventions to prevent and treat delirium through reduction of modifiable risk factors. (Ungraded GPS, 90% agreement).

Remarks: Measures include goal-directed, titrated, minimal but effective sedation, nighttime sleep promotion with noise and light optimization, augmentative and assistive communication, family engagement and activity and mobility as tolerated.

Research statement 5.2.3. We cannot make a recommendation regarding the use of typical or atypical antipsychotics, melatonin or other medications for routine prevention or treatment of delirium. Further studies are needed to evaluate the role of antipsychotic medications and melatonin in the treatment of delirium. (Ungraded RS, 98% agreement).

Clinical recommendation 5.3.1. We suggest that minimal, yet effective, neuromuscular blockade (NMB) be used in conjunction with sedation in comparison to the use of sedation alone if effective and protective MV cannot be achieved. (Conditional CR, very low certainty of evidence, 98% agreement).

Good practice statement 5.3.2. NMB should be monitored and titrated to the goal depth established by the interprofessional team. (Ungraded GPS, 94% agreement).

Remarks: Monitoring may include effective and protective ventilation, movement, and train-of-four response (if available).

Clinical recommendation 5.4.1. We suggest early initiation of enteral nutrition (< 72 hr) when feasible, over parenteral nutrition or delayed enteral nutrition in PARDS patients. (Conditional CR, very low certainty of evidence, 92% agreement).

Good practice statement 5.4.2. Patients with PARDS should receive a nutrition plan to facilitate their recovery, maintain their growth and meet their metabolic needs. (Ungraded GPS, 98% agreement).

Good practice statement 5.4.3. Enteral nutrition monitoring, advancement and maintenance should be managed by a goal-directed protocol that is collaboratively established by the interprofessional team. (Ungraded GPS, 96% agreement).

Clinical recommendation 5.4.4. We suggest a nutrition strategy that includes a minimum of 1.5 g/kg/d of protein compared with less than 1.5 g/kg/d of protein for PARDS patients. (Conditional CR, low certainty of evidence, 92% agreement).

Research statement 5.4.5. The reporting of the nutrition strategy, exposure and monitoring in clinical trials should be adequately explicit to allow comparison across studies (e.g., route, composition, calories delivered, time to reach nutrition goal). (Ungraded RS, 98% agreement).

Clinical recommendation 5.5. We suggest that patients with PARDS should receive fluids with the daily fluid goal collaboratively established by the interprofessional team to maintain optimal oxygen delivery and preserve end organ function, while preventing fluid overload. (Conditional CR, low certainty of evidence, 98% agreement).

Good practice statement 5.6.1. Critically ill patients with respiratory failure who have a hemoglobin concentration less than 5 g/dL should receive a packed RBC (pRBC) transfusion. (Ungraded GPS, 96% agreement).

Remark: This statement may not be appropriate for patients with hemolytic anemia.

Clinical recommendation 5.6.2. We suggest against transfusing pRBCs in critically ill patients if the hemoglobin concentration is greater than or equal to 7 g/dL and they are hemodynamically stable and do not have chronic cyanotic condition, severe PARDS or hemolytic anemia. (Conditional CR, low certainty of evidence, 98% agreement).

Research statement 5.6.3. We cannot make a recommendation regarding optimal pRBC transfusion threshold in critically ill patients with PARDS who are hemodynamically unstable or have severe hypoxemia. Further studies are needed to determine the risks, benefits and alternatives of transfusion in PARDS patients with severe hypoxemia. (Ungraded RS, 98% agreement).

Good practice statement 5.7.1. In patients with PARDS, day-night activity and rest patterns should be optimized with nonpharmacologic, multicomponent approaches. (Ungraded GPS, 94% agreement).

Good practice statement 5.7.2. In patients with PARDS, daily assessment and determination of activity and mobility goals based on clinical status should be made. (Ungraded GPS, 94% agreement).

Good practice statement 5.7.3. In patients with PARDS, a rehabilitation team (physiotherapy and/or occupational therapy) evaluation within 72 hours should be established for determination of baseline function, rehabilitation goals and readiness for intervention as appropriate and based on clinical status. (Ungraded GPS, 98% agreement).

Good practice statement 6.1.1. All patients with PARDS should receive the minimum clinical monitoring of continuous respiratory frequency, heart rate, pulse oximetry, and regular intermittent noninvasive blood pressure. (Ungraded GPS, 90% agreement).

Remarks: Pulse oximetry alarms should be set to identify parameters outside of PALICC-2 recommendations.

Good practice statement 6.1.2. Metrics using lung volumes (e.g., tidal volume, compliance of the respiratory system) should be interpreted after standardization to body weight. (Ungraded GPS, 94% agreement).

Remarks: The lesser of predicted body weight or actual body weight should be used.

Good practice statement 6.2.1. During invasive ventilation in patients with PARDS, the tidal volume should be continuously monitored. (Ungraded GPS, 96% agreement).

Good practice statement 6.2.2. Tidal volumes measured at the ventilator should be adjusted using compensation for circuit compliance, either by the ventilator or manually. (Ungraded GPS, 96% agreement).

Remarks: In infants and smaller children, monitoring the exhaled tidal volumes at the end of the endotracheal tube should be considered, with caution for additive dead space due to the flow sensor.

Good practice statement 6.2.3. Ventilatory inspiratory pressures including plateau pressure and driving pressure should be monitored in patients with PARDS. (Ungraded GPS, 90% agreement).

Remarks: Plateau pressure measurement should be made under static or quasi-static conditions.

Good practice statement 6.2.4. Flow-time, and pressure-time curves and intrinsic PEEP should be monitored to assess the accuracy of respiratory timings, including detection of expiratory flow limitation and patient-ventilator asynchrony. (Ungraded GPS, 96% agreement).

Good practice statement 6.2.5. Patient effort of breathing should be monitored, at least through clinical assessment. (Ungraded GPS, 96% agreement).

Remark: other more objective methods to assess patient effort might be appropriate when available.

Research statement 6.2.6. We cannot make a recommendation on routine monitoring of the following parameters of respiratory system mechanics: Flow-volume loop, pressure-volume loop, dynamic compliance and resistance, strain, stress index, esophageal manometry and transpulmonary pressure, functional residual capacity, ventilation index, mechanical power, mechanical energy, electrical activity of diaphragm, or thoraco-abdominal asynchrony quantification by respiratory inductance plethysmography. Future research should focus on specific populations likely to benefit from routine monitoring of these parameters. (Ungraded RS, 90% agreement).

Remarks: In some subgroups of patients, monitoring these metrics may help individualize MV management.

Good practice statement 6.3.1. Monitoring of Fio2, Spo2, and/or Pao2, mean airway pressure, and PEEP should be used to diagnose PARDS, to assess PARDS severity, and to guide the management of oxygenation failure. (Ungraded GPS, 96% agreement).

Good practice statement 6.3.2. Blood pH and Paco2 measurement frequency should be adjusted according to PARDS severity, noninvasive monitoring data, and stage of the disease. (Ungraded GPS, 92% agreement).

Good practice statement 6.3.3. Continuous monitoring of co2 should be used in patients with PARDS during invasive MV to assess adequacy of ventilation. (Ungraded GPS, 94% agreement).

Remarks: End-tidal co2/time curves or volumetric capnography should be used in patients with invasive conventional ventilation. Transcutaneous co2 measurements should be used in patients with nonconventional ventilation therapies such as HFOV.

Good practice statement 6.3.4. Dead space should be calculated and monitored in patients with PARDS when Paco2 and either end-tidal co2 pressure or mixed-expired co2 pressure are available during invasive MV. (Ungraded GPS, 94% agreement).

Good practice statement 6.4.1. Daily assessment of predefined clinical and physiologic criteria of extubation readiness should be performed to avoid unnecessary prolonged ventilation. In patients meeting extubation readiness criteria, a spontaneous breathing trial should be performed to test extubation readiness. (Ungraded GPS, 98% agreement).

Research statement 6.4.2. Spontaneous breathing trials and extubation readiness tests should be standardized when used in clinical research. (Ungraded RS, 98% agreement).

Good practice statement 6.5.1. Chest imaging is necessary for the diagnosis of PARDS, to detect complications such as air leak or equipment displacement, and to assess severity. (Ungraded GPS, 90% agreement).

Remarks: Frequency of chest imaging should be predicated on patient clinical condition and availability.

Research statement 6.5.2. We cannot make a recommendation on the routine use of chest CT scan, lung ultrasonography, and electrical impedance tomography. Future research should focus on specific populations likely to benefit from routine use of these imaging modalities. (Ungraded RS, 94% agreement).

Good practice statement 6.6.1. All patients with PARDS should receive hemodynamic monitoring to evaluate the impact of ventilation and disease on right and left cardiac function and to assess oxygen delivery. (Ungraded GPS, 92% agreement).

Good practice statement 6.6.2. Cumulative fluid balance should be monitored in patients with PARDS. (Ungraded GPS, 98% agreement).

Good practice statement 6.6.3. In patients with suspected cardiac dysfunction or severe PARDS, echocardiography should be performed when feasible for noninvasive evaluation of both left and right ventricular function, the preload status, and pulmonary arterial pressures. (Ungraded GPS, 94% agreement).

Remark: Frequency of assessment should be based on hemodynamic status.

Good practice statement 6.6.4. An arterial catheter should be considered in patients with severe PARDS for continuous monitoring of arterial blood pressure and arterial blood gas analysis. (Ungraded GPS, 92% agreement).

Research statement 6.6.5. We cannot make a recommendation on when to use the following hemodynamic monitoring devices: pulse contour with transpulmonary dilution technology, pulmonary artery catheters, alternative devices to monitor cardiac output (ultrasonic cardiac output monitoring, transesophageal aortic Doppler, noninvasive monitoring of cardiac output based on changes in respiratory co2 concentration caused by a brief period of rebreathing, indirect calorimetry Fick cardiac output), central venous pressure monitoring, and B-type natriuretic peptide measurements. Future research should focus on patient populations most likely to benefit from these monitoring modalities. (Ungraded RS, 100% agreement).

Clinical recommendation 7.1.1. We suggest that in patients with possible PARDS or at risk for PARDS on conventional oxygen therapy or HFNC who are showing signs of worsening respiratory failure, a time-limited trial of NIV (CPAP or BiPAP) should be used if there are no clear indications for intubation. (Conditional CR, very low certainty of evidence, 88% agreement).

Clinical recommendation 7.1.2. In patients on NIV who do not show clinical improvement within the first 6 hours of treatment or have signs and symptoms of worsening disease including increased respiratory/heart rate, increased work of breathing, and worsening gas exchange (Spo2/Fio2 ratio), we suggest that intubation be used in comparison to continuing NIV. (Conditional CR, very low certainty of evidence, 94% agreement).

Remark 1: This recommendation also includes patients who are at greater risk of complications from IMV (such as children with immunodeficiency).

Remark 2: We suggest that intubation be used earlier, in comparison to NIV, in patients with severe NIV PARDS or with other severe organ dysfunction.

Good practice statement 7.2. NIV should be delivered in a setting with trained experienced staff and where close monitoring is available to rapidly identify and treat deterioration. (Ungraded GPS, 96% agreement).

Good practice statement 7.3.1. When delivering NIV, the provider should choose the interface that provides the most efficient patient-ventilator synchronization for the child. (Ungraded GPS, 100% agreement).

Good practice statement 7.3.2. Patients receiving NIV should be closely monitored for potential problems such as skin breakdown, gastric distention, barotrauma, and conjunctivitis. (Ungraded GPS, 98% agreement).

Good practice statement 7.3.3. Heated humidification should be used for NIV and HFNC in patients at risk, or with possible or confirmed PARDS. (Ungraded GPS, 96% agreement).

Good practice statement 7.3.4. For patients with poor tolerance to NIV, sedation can be used to improve tolerance. (Ungraded GPS, 92% agreement).

Remarks: The level of sedation should be adjusted to ensure adequate ventilatory drive and airway protective reflexes.

Good practice statement 7.3.5. When patients with PARDS are managed on NIV, inspiratory pressure augmentation with pressure support should be used to reduce inspiratory muscle effort. CPAP alone may be suitable for those patients who are unable to attain patient-ventilator synchrony or when using nasal interface. (Ungraded GPS, 96% agreement).

Research statement 7.4. We cannot make a recommendation on when to use HFNC in patients at risk of or with possible PARDS. Further studies are needed to identify clinical indications for HFNC in patients at risk or with possible PARDS. (Ungraded RS, 94% agreement).

Clinical recommendation 7.5.1. In RLS, we suggest the use of CPAP or HFNC over standard oxygenation therapy in patients at risk for PARDS. (Conditional CR, very low certainty of evidence, 92% agreement).

Remark: The use of CPAP should be conducted under physician oversight.

Clinical recommendation 7.5.2. We suggest the use of CPAP over HFNC in RLS in patients with possible PARDS. (Conditional CR, very low certainty of evidence, 83% agreement).

Remarks: The use of CPAP should be conducted under physician oversight. Depending on availability of equipment or physician oversight, HFNC should still be preferred over standard oxygenation therapy.

Clinical recommendation 8.1.1. We suggest that patients with a potentially reversible cause of severe PARDS should be evaluated for extracorporeal membrane oxygenation (ECMO) when lung protective strategies result in inadequate gas exchange. (Conditional CR, very low certainty of evidence, 96% agreement).

Remarks: There is no evidence to support strict criteria for the selection of patients who will benefit from ECMO in PARDS.

Good practice statement 8.1.2. Decisions to institute ECMO should be based on a structured evaluation of case history and clinical status by an established expert team. (Ungraded GPS, 94% agreement).

Clinical recommendation 8.1.3. We suggest that serial evaluation compared with a single time point of assessment be used to guide decisions about ECMO eligibility. (Conditional CR, low certainty of evidence, 98% agreement).

Clinical recommendation 8.1.4. We suggest the use of venovenous ECMO over venoarterial ECMO in patients with PARDS who have adequate cardiac function. (Conditional CR, low certainty of evidence, 94% agreement).

Good practice statement 8.1.5. Transfer to an ECMO center should be considered in patients with PARDS who are failing to stabilize with optimal non-ECMO therapies. (Ungraded GPS, 96% agreement).

Policy statement 8.2.1. All personnel directly caring for the patient should understand the ECMO circuit and the physiologic interactions between it and the patient. Competencies for clinicians with primary patient care duties and ECMO specialists should be required. Simulation may be useful in training. (Ungraded PS, 94% agreement).

Policy statement 8.2.2. Centers providing ECMO support for PARDS should report all ECMO data to Extracorporeal Life Support Organization or a similar organization in order to benchmark outcomes of mortality and complications. (Ungraded PS, 94% agreement).

Clinical recommendation 8.3.1a. We suggest maintaining normal Pao2 compared with hyperoxia in patients with PARDS supported on ECMO. (Conditional CR, very low certainty of evidence, 96% agreement).

Clinical recommendation 8.3.1b. We suggest slow decrease in Paco2 compared with rapid decrease of Paco2 in patients with PARDS supported on ECMO, especially in the setting of hypercapnia. (Conditional CR, very low certainty of evidence, 88% agreement).

Clinical recommendation 8.3.2. In patients with PARDS supported by ECMO, we suggest mechanical ventilator pressures comply with the lung protective limits previously identified, compared with exceeding these limits, to avoid additional lung injury. (Conditional CR, low certainty of evidence, 98% agreement).

Research statement 8.4. We cannot make a recommendation on when to use extracorporeal carbon dioxide removal (ECco2R) technology in patients with PARDS. Further studies are needed to identify clinical indications for ECco2R in patients with PARDS. (Ungraded RS, 92% agreement).

Good practice statement 8.5. All pediatric ECMO survivors should receive short- and long-term neurodevelopmental and physical functioning evaluations to assess for impairment. (Ungraded GPS, 90% agreement).

Good practice statement 9.1.1. In patients with PARDS, the patient's primary care providers should be advised to screen for post-ICU morbidities within 3 months of discharge from the hospital. (Ungraded GPS, 90% agreement).

Good practice statement 9.1.2. A stepwise approach to clinical evaluation of post-ICU morbidities should be used with initial screening by a primary care provider or electronic/telephonic screen. (Ungraded GPS, 96% agreement).

Remark: Full assessment, initial management, and serial re-evaluations of impairments should be made by a primary care provider if appropriate and referral to a specialist if deficits persist or are not in the scope of practice of the primary care provider. Location-specific resources should be considered, including availability of dedicated post-ICU follow-up clinics or remote consultation.

Good practice statement 9.2.1. Patients with PARDS should be screened for pulmonary function abnormalities within the first three months after hospital discharge. (Ungraded GPS, 90% agreement).

Remarks: The screening should include a minimum of a respiratory symptom questionnaire, a respiratory examination, and pulse oximetry.

Good practice statement 9.2.2. Patients with PARDS who are of sufficient developmental age and capabilities should also be assessed by spirometry to screen for pulmonary function abnormalities within the first three months after discharge. (Ungraded GPS, 94% agreement).

Remarks: A follow-up assessment within the first year should be added if spirometry is abnormal.

Good practice statement 9.2.3. Patients should be referred to a specialist (pediatrician or pediatric pulmonologist) when deficits in pulmonary function are identified for further assessment, treatment, and long-term pulmonary follow-up. (Ungraded GPS, 94% agreement).

Good practice statement 9.3.1. For patients who survive PARDS, health-related quality of life, physical, neurocognitive, emotional, family, and social function should be evaluated within three months of hospital discharge. (Ungraded GPS, 100% agreement).

Good practice statement 9.3.2. For infants and toddlers who survive PARDS, additional evaluation of health-related quality of life, physical, neurocognitive, emotional, family, and social function should be performed prior to entering school, for example, at 4–6 years old. (Ungraded GPS, 90% agreement).

Good practice statement 9.3.3. Patients with identified abnormalities should be treated or referred for more in-depth assessment and treatment by appropriate subspecialists and educators. (Ungraded GPS, 98% agreement).

Research statement 9.4.1. When feasible, pre-ICU baseline status for each outcome measure should be established or estimated when evaluation of post-ICU morbidity is anticipated. (Ungraded RS, 98% agreement).

Research statement 9.4.2. We cannot make a recommendation regarding the use of alternative postdischarge endpoints. Given declining mortality among patients with PARDS, additional studies are needed to evaluate potential alternative postdischarge endpoints for clinical trials. (Ungraded RS, 96% agreement).

Remarks: Potential postdischarge endpoints to evaluate may include hospital and PICU readmissions (e.g., within 30 d of discharge), unplanned health resource use, health-related quality of life, and physical, pulmonary, neurocognitive, emotional, family, and social function.

Research statement 9.4.3. Clinical studies should be designed to evaluate the association between short-term outcomes (e.g., new or progressive organ dysfunction) and longer-term postdischarge outcomes for patients with PARDS. (Ungraded RS, 100% agreement).

Research statement 9.4.4. Further studies are needed to determine factors that may affect the trajectory of recovery following PARDS. (Ungraded RS, 100% agreement).

Remarks: Additional research should include demographic characteristics, clinical factors, PICU exposures, social determinants of health, and access to care.

Research statement 9.4.5. Practices to optimize follow-up (e.g., incentives, multimodal evaluations) should be used to minimize bias due to differential loss-to-follow-up when conducting post-ICU outcomes research. (Ungraded RS, 96% agreement).

Clinical recommendation 10.1. We suggest that clinicians implement electronic tools to automatically screen critically ill patients to help identify those with PARDS or at significant risk of developing PARDS compared with nonelectronic screening or no standardized screening. (Conditional CR, very low certainty of evidence, 96% agreement).

Clinical recommendation 10.2. We suggest automatic monitoring of compliance with PALICC-2 clinical practice guidelines for lung protective strategies, compared with no monitoring of compliance. (Conditional CR, low certainty of evidence, 96% agreement).

Remarks: Automatic monitoring should incorporate measures of gas exchange and MV and provide feedback to clinicians in real-time with user-friendly interfaces.

Policy statement 10.3. Healthcare organizations should provide human and material resources to help clinicians develop, implement, and use electronic tools to improve the management of patients with PARDS or at significant risk of developing PARDS. (Ungraded PS, 96%).

Research statement 10.4. Collaborative networks should be developed to share clinical data and develop, test, and implement electronic tools to improve the diagnosis, management, monitoring, and prognosis of patients with PARDS. (Ungraded RS, 100% agreement).

Research statement 10.5. Electronic tools should be developed to improve the management of PARDS and designed to maximize generalizability, reproducibility, and dissemination. (Ungraded RS, 100% agreement).

Good practice statement 11.1. Healthcare providers working in RLS should be mindful of precipitating factors for PARDS (including dengue, malaria, measles, scrub typhus, leptospirosis) and concurrent comorbidities (e.g., HIV and associated opportunistic infections, malnutrition, chronic anemia) that are not commonly encountered in high-income countries. (Ungraded GPS, 100% agreement).

Definition statement 11.2. In RLS where all the criteria for PARDS cannot be fulfilled, the term "Possible PARDS" should be used when the patient has history and physical examination findings consistent with known precipitating factors and clinical features of PARDS. (Ungraded DS, 92% agreement).

Remarks: In these settings, the use of Spo2/Fio2 or OSI (as per PALICC-2 PARDS cut-offs) is appropriate and may be preferred over Pao2/Fio2 or OI.

Remarks: Imaging is recommended to diagnose possible PARDS and can include ultrasound or chest radiograph demonstrating parenchymal disease; however, there is no absolute need for imaging criteria to diagnose "Possible PARDS" if timing, oxygenation and risk factor criteria are present.

Research statement 11.3. Future studies conducted in RLS should apply the PALICC-2 definition to identify patients with possible PARDS or PARDS. Future studies are needed to determine the sensitivity and specificity, positive predictive value, negative predictive value, and accuracy of the PALICC-2 definition for possible PARDS or PARDS in RLS. (Ungraded RS, 96% agreement).

Research statement 11.4. Collaborative networks should engage and include sites in RLS to allow sharing of clinical data and research results related to respiratory support in PARDS. (Ungraded RS, 98% agreement).

Policy statement 11.5. All hospitals in RLS should implement locally adapted protocols for starting, maintenance, and weaning of MV and for extubation of patients with PARDS. (Ungraded PS, 94% agreement).

Policy statement 11.6. All members of the multidisciplinary team involved in the care of a patient with PARDS should be provided with regular MV training and education. (Ungraded PS, 100% agreement).

Policy statement 11.7. While using pulmonary and nonpulmonary ancillary therapies in RLS, current overall evidence (as provided by PALICC-2) as well as availability and costs of these therapies locally, should be taken into consideration. (Ungraded PS, 98% agreement).

Research statement 11.8. More research should be conducted regarding the use of NIV in patients with respiratory failure including PARDS in RLS. (Ungraded RS, 100% agreement).

Research statement 11.9. Further research is needed in RLS to determine the optimal use, applications, safety and efficacy of nonpulmonary ancillary therapies and monitoring in patients with PARDS. (Ungraded RS, 100% agreement).

Remarks: Ancillary therapies that are easily adopted within RLS and not prohibited by cost should be considered a priority for research.

Policy statement 11.10. For long-term outcomes of PARDS patients in RLS, alignment with PALICC-2 recommendations should be kept wherever possible and according to available resources. (Ungraded PS, 98% agreement).

Research statement 11.11. Research in RLS is warranted to inform development of relevant recommendations pertaining to PARDS that are appropriate to these settings. (Ungraded RS, 98% agreement).

These guidelines are the result of a large international panel's review of the existing evidence and our interpretation of how that evidence should be applied in clinical practice. As highlighted in the recommendations and statements, the risk-benefit profile for many therapies change as a function of PARDS severity, although lack of evidence in most areas prevent clear cut points to delineate when a specific therapy should or should not be implemented. A framework highlighting several key PARDS therapies or management strategies with assessment of the balance of risk and benefits in most versus select patients with PARDS is presented in Figure 1.

While most recommendations align with PALICC, the PALICC-2 process systematically considered new evidence, and applied an EtD framework for all recommendations, seeking to ensure the language of recommendations was unambiguous. There are several changes to the definition of PARDS. These include a delayed marker of oxygenation severity (at least 4 hr after initial diagnosis) to improve risk stratification. PARDS severity groups have been simplified to classify patients into one of four severity groupings based on ventilation type (invasive vs noninvasive) and oxygenation severity (mild/moderate vs severe). The definition also creates a "possible PARDS" category, to capture the increasing use of nasal modes of respiratory support such as HFNC and to be able to better capture patients who likely have PARDS in RLS. Full rationale for these changes are found in the corresponding justification manuscript for Section 1 (14).

Other substantial changes with PALICC-2 include two new sections focused on informatics and data science (23), as well as implementation in RLS (24). The informatics section provides specific recommendations on systems to screen for PARDS and monitor compliance with lung protective ventilation recommendations. The RLS section highlights how to adapt PALICC-2 recommendations for defining and treating PARDS in circumstances where availability of diagnostic testing, equipment, or training may be limited. New concepts are addressed in ventilatory management and monitoring related to mechanical power, driving pressure, and patient-self-inflicted lung injury (16). Heterogeneity of treatment effect and the importance of precision medicine approaches, which embrace biological phenotypes has also been an area of focus, with growing pediatric data that are described in section 2 (15).

In summary, the development of PALICC-2 recommendations was based on a rigorous and systematic assessment of available evidence, supported by transparent methodology using GRADE and the EtD framework. Overall, high-quality randomized studies are lacking in PARDS, making all but one of our clinical recommendations conditional. Nevertheless, we believe these clinical practice guidelines will be valuable at the bedside, as we took into consideration feasibility, safety, equity, and implementation for all recommendations. Detailed considerations for all of these recommendations can be found in the supplemental articles (13–24). These guidelines have also identified many gaps that offer opportunities for the future PARDS research agenda. Many important questions remain to be answered to improve the certainty of evidence and strength of recommendations for patients with PARDS.

We thank Katie Lobner (Johns Hopkins University), Lynn Kysh (University of South California), Alix Pincivy and Philippe Dodin (Université de Montréal) for assisting with literature searches. We also thank Justin Hotz for technical support and Ariana Lane for administrative assistance.

acute respiratory distress syndrome; best practice/evidenced-; based; guidelines; pediatric acute respiratory distress syndrome/children; pediatric critical care; systematic review