Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children

Scott L Weiss, Mark J Peters, Waleed Alhazzani, Michael S D Agus, Heidi R Flori, David P Inwald, Simon Nadel, Luregn J Schlapbach, Robert C Tasker, Andrew C Argent, Joe Brierley, Joseph Carcillo, Enitan D Carrol, Christopher L Carroll, Ira M Cheifetz, Karen Choong, Jeffry J Cies, Andrea T Cruz, Daniele De Luca, Akash Deep, Saul N Faust, Claudio Flauzino De Oliveira, Mark W Hall, Paul Ishimine, Etienne Javouhey, Koen F M Joosten, Poonam Joshi, Oliver Karam, Martin C J Kneyber, Joris Lemson, Graeme MacLaren, Nilesh M Mehta, Morten Hylander Møller, Christopher J L Newth, Trung C Nguyen, Akira Nishisaki, Mark E Nunnally, Margaret M Parker, Raina M Paul, Adrienne G Randolph, Suchitra Ranjit, Lewis H Romer, Halden F Scott, Lyvonne N Tume, Judy T Verger, Eric A Williams, Joshua Wolf, Hector R Wong, Jerry J Zimmerman, Niranjan Kissoon, Pierre Tissieres, Scott L Weiss, Mark J Peters, Waleed Alhazzani, Michael S D Agus, Heidi R Flori, David P Inwald, Simon Nadel, Luregn J Schlapbach, Robert C Tasker, Andrew C Argent, Joe Brierley, Joseph Carcillo, Enitan D Carrol, Christopher L Carroll, Ira M Cheifetz, Karen Choong, Jeffry J Cies, Andrea T Cruz, Daniele De Luca, Akash Deep, Saul N Faust, Claudio Flauzino De Oliveira, Mark W Hall, Paul Ishimine, Etienne Javouhey, Koen F M Joosten, Poonam Joshi, Oliver Karam, Martin C J Kneyber, Joris Lemson, Graeme MacLaren, Nilesh M Mehta, Morten Hylander Møller, Christopher J L Newth, Trung C Nguyen, Akira Nishisaki, Mark E Nunnally, Margaret M Parker, Raina M Paul, Adrienne G Randolph, Suchitra Ranjit, Lewis H Romer, Halden F Scott, Lyvonne N Tume, Judy T Verger, Eric A Williams, Joshua Wolf, Hector R Wong, Jerry J Zimmerman, Niranjan Kissoon, Pierre Tissieres

Abstract

Objectives: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction.

Design: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process.

Methods: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate.

Results: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 49 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 52 research priorities were identified.

Conclusions: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.

Keywords: Evidence-based medicine; Grading of Recommendations Assessment, Development and Evaluation criteria; Guidelines; Infection; Pediatrics; Sepsis; Septic shock; Surviving Sepsis Campaign.

Conflict of interest statement

Drs. Weiss and Peters served as arbiters for conflict interest management and adjudication throughout the guidelines process following standard operating procedures set forth by Society of Critical Care Medicine (SCCM) and endorsed by European Society of Intensive Care Medicine. Dr. Weiss participates in Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) and Shock Society. Dr. Peters participates in the UK PICS study group (vice-chair) and has testified as an expert witness in cases of clinical negligence, causation of injuries. Dr. Agus participates in the American Academy of Pediatrics (AAP), Pediatric Academic Societies (PAS), American Pediatric Society, Society for Pediatric Research, and The American Society for Clinical Investigation, and he has testified as an expert witness in cases related to ICU and/or endocrinology in children. Dr. Flori participates in American Thoracic Society (ATS) State Chapter (Executive Board Member—Michigan and California State Chapters) and PALISI Network, Grant funding from Gerber Foundation (Steering committee member for various studies being implemented through the Network from intramural funding, governmental or other Foundation Grant funding). Dr. Nadel received funding form La Jolla Pharmaceutical (consulting), and he participates in the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) (Medical President). Dr. Brierley participates in the ESPNIC. Dr. Carrol participates in National Institute for Health and Care Excellence (NICE) (Diagnostic Advisory Committee panel) and National Institutes for Health Research (two scientific panels, i4i and DTF). Dr. Cheifetz participates in American Association for Respiratory Care and ATS (volunteer activities) and has testified as an expert witness for medical malpractice cases, he is an advisor to Philips, and a contributor to Up-to-Date. Dr. Cies received funding from Allergan, Merck, Thermo Fisher Scientific, and Atlantic Diagnostic Laboratories (consultant), and he participates in Pediatric Pharmacy Advocacy Group (multiple positions), Society of Infectious Diseases Pharmacists (Vice-Chair of the Inter-organizations Liaison Committee), and the American College of Clinical Pharmacists (member and fellow). Dr. Cruz has testified as an expert witness in cases of children with tuberculosis-related meningitis and is an associate editor for Pediatrics. Dr. De Luca serves as Medical President-elect on the Executive Committee of ESPNIC, he served as a consultant and lecturer on the external advisory board and received research and educational grants from Chiesi Farmaceutici S.p.A and AbbVie, and travel grants from AbbVie, he has been a lecturer for Philips, Radiometer, and Waire. Dr. Faust served as chair of the UK NICE Guideline Committee for Sepsis in Children and Adults published in 2016 and for Lyme disease published in 2018, serves as a regional representative to the UK NHS England Clinical Reference Group for commissioning pediatric specialist medicine care (immunology and infection). Dr. Hall receives funding from La Jolla Pharmaceuticals (consultant on the data safety monitoring board for a clinical trial of a sepsis therapeutic), and he participates in the ATS (online journal club editor) and the American Board of Pediatrics (Critical Care Medicine sub-board). Dr. Ishimine participates in SAEM (Consensus Conference Co-Chair), American Board of Pediatrics/American Board of Emergency Medicine (Immediate Past Chair of the Pediatric Emergency Medicine Subboard), and the American College of Emergency Physicians (Pediatric Emergency Medicine Committee member). Dr. Javouhey received funding from CSL Behring (trial on IV Immunoglobulins in toxic shock syndrome in children). Dr. Karam participates in BloodNet, PALISI, ISBT, AABB, and CCCTG. Dr. Kneyber participates in the European Society for Pediatric and Neonatal Intensive Care. Dr. MacLaren participates in Extracorporeal Life Support Organization (Executive Committee). Dr. Mehta participates in the American Society for Parenteral and Enteral Nutrition (president). Dr. Møller participates in the Science Systems and Applications, Inc (board member). Dr. Newth received funding from Philips Research North America (consulting concerning monitoring in PICU), and he participates in the ATS. Dr. Nishisaki’s institutional department receives an unrestricted grant from Nihon Kohden (involves an activity to develop a device to measure capillary refill time), and he participates in the Society for Simulation in Healthcare and International Society for Pediatric Simulation. Dr. Nunnally participates in American College of Critical Care Medicine (Regent), Society of Critical Care Anesthesiologists (director), American Society of Anesthesiologists (committee), International Anesthesia Research Society, and NYSA. Dr. Randolph’s institution received funding from Genentech (influenza biomarker study research support); she has received funding from Bristol Myers Squibb (consultant in 2017) and La Jolla Pharmaceuticals (design of pediatric septic shock trial of angiotensin II); and she participates in the ATS and the International Sepsis Forum. Dr. Ranjit participates as the Chancellor of College of Pediatric Critical Care, India. Dr. Tume participates in ESPNIC (Nursing President) and the UK PICS Scientific and Education Committee. Dr. Verger participates in the American Association of Critical-Care Nurses (Cert. Corp. Governance Committee) and the Academy of Nursing (Acute and Critical Care Special Interest Group). Dr. Williams participates in the Pediatric Cardiac Intensive Care Society. Dr. Wolf received funding support for participation in industry-sponsored research from Merck & Co, Astellas, and Cempra Pharmaceuticals, and he received other support from Karius, Empatica, and Bluespark Technologies. Dr. Zimmerman (Past President of SCCM) received funding from Immunexpress, Seattle (sepsis biomarker research), and he participates in the AAP and PAS. Dr. Tissieres received funding from Baxter acute therapies, Bristol-Myers Squibb Company, Chiesi Farmaceutici S.p.A., Faron Pharmaceuticals (consulting, renal replacement therapy), and Biomerieux, funding from La Jolla Pharmaceuticals, Chiesi Farmaceutici S.p.A., and is President ESPNIC (research grant, biomarkers sepsis), and he participates in the Swiss Intensive Care Society, Swiss Pediatric Society, and the French Society of Intensive Care. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Framework to determine the appropriateness of using indirect evidence from studies of children without sepsis or from adults.

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