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Executive summary: surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children

Introduction

In 2001, the Surviving Sepsis Campaign (SSC) began to develop evidence-based guidelines and recommendations for the resuscitation and management of patients with sepsis. With the 2016 edition, the Society of Critical Care Medicine and European Society of Intensive Care Medicine recommended a separate task force be dedicated to guideline formulation for children.

The objective of the “Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-associated Organ Dysfunction in Children” is to provide guidance for the care of infants, children, and adolescents with septic shock and other sepsis-associated organ dysfunction. Recommendations are intended to guide “best practice” rather than to establish a treatment algorithm or to define standard of care and cannot replace the clinician’s decision-making capability when presented with a patient’s unique set of clinical variables.

Methods

This executive summary briefly reviews the methodology, with additional details provided in the complete guidelines document published in Pediatric Critical Care Medicine and Intensive Care Medicine.

Definitions

For these guidelines, we defined “septic shock” in children as severe infection leading to cardiovascular dysfunction (including hypotension, need for treatment with a vasoactive medication, or impaired perfusion) and “sepsis-associated organ dysfunction” in children as severe infection leading to cardiovascular and/or noncardiovascular organ dysfunction. These definitions include the criteria set forth by the 2005 International Pediatric Sepsis Consensus Conference [1], as the majority of studies used to establish evidence for these guidelines referred to this nomenclature. However, studies that defined sepsis in children as severe infection leading to life-threatening organ dysfunction were included even if criteria used to define sepsis deviated from the 2005 consensus definitions. Because several methods to identify acute organ dysfunction in children are currently available, we did not to require a specific definition or scheme for this purpose.

Scope of patients

The panel intended these guidelines to apply to all patients from greater than or equal to 37 weeks gestation at birth to 18 years with septic shock or other sepsis-associated acute organ dysfunction. Practically, all infants, children, and adolescents with septic shock or other sepsis-associated organ dysfunction are included in this scope. For simplicity, we used the term “children” to refer to infants, school-aged children, and adolescents in these guidelines.

All recommendations apply to children with septic shock and other sepsis-associated acute organ dysfunction unless specific qualifications, such as the subset with immune compromise, are included in the recommendation. Even though these guidelines are not intended to address the management of infection with or without systemic inflammatory response syndrome when there is not associated acute organ dysfunction, we recognize that sepsis exists as a spectrum and some children without known acute organ dysfunction may still benefit from similar therapies as those with known organ dysfunction. Finally, acknowledging that neonatal sepsis, especially in premature babies, may have distinct pathology, biology, and therapeutic considerations, newborns less than 37 weeks gestation are excluded from the scope of these guidelines. The panel sought to include term neonates (0–28 days) born at greater than or equal to 37 weeks gestation within the scope of these guidelines because these infants may be recognized and resuscitated outside of a newborn nursery or neonatal ICU. However, because the panel did not specifically address studies of neonates with perinatal infection or all conditions that can be associated with neonatal sepsis (e.g., persistent pulmonary hypertension of the newborn), these guidelines do not address all management considerations for neonatal sepsis.

Application of guidelines by local resource availability

The intended users of these guidelines are health professionals caring for children in a hospital, emergency, or other acute care setting. However, many of the recommendations are likely to apply to the care of children in other settings and will need to be adapted to specific environments and resource availability. In addition, these guidelines were largely developed without consideration of the availability of healthcare services, although we realize that medical care is necessarily carried out within the confines of locally available resources. The panel supports that these guidelines should constitute a general scheme of “best practice,” but that translation of these guidelines to treatment algorithms or bundles and standards of care will need to account for variation in the availability of local healthcare resources, particularly in resource-limited settings.

Selection and organization of panel members

The selection of panel members was based on their expertise in specific aspects of pediatric sepsis, with broad international and multi-professional representation from diverse geographic settings and healthcare systems. Three members from the lay public were also included.

Panelists were divided into the following subgroups: (1) recognition and management of infection, (2) hemodynamics and resuscitation, (3) ventilation, (4) endocrine and metabolic therapies, and (5) adjunctive therapies. A sixth subgroup reviewed research priorities. Each subgroup was supported by a trained methodologist.

Question development and outcome prioritization

The panel selected topics addressed in the 2016 adult SSC guidelines that were relevant to children, as well as other key topics important to children with sepsis. The PICO format, which describes the population (P), intervention (I), control (C), and outcomes (O), was used for all guideline questions. For practical reasons, we excluded several issues pertaining to general acute or critical illness that were not specific for sepsis (e.g., head-of-bed positioning during invasive mechanical ventilation) and have been addressed in other guidelines (e.g., Pediatric Acute Lung Injury Consensus Conference) [2]. However, topics with particular relevance to children with septic shock or other sepsis-associated acute organ dysfunction were included in this guideline, even if there was evaluation of similar or overlapping topics in previous publications. The final list of PICO questions is provided as Supplemental Table 1 (Supplemental Digital Content 1, http://links.lww.com/PCC/B139) in the complete guidelines.

Search strategy and evidence summation

Professional medical librarians assisted with the literature searches and utilized a combination of controlled vocabulary (e.g., “sepsis,” “bacterial infections,” “critical illness,” “intensive care units,” “pediatrics,” “NICU,” “PICU,” “emergency service”), key words (e.g., “toxic shock,” “blood poisoning,” “acute infection,” “child”), and qualifiers specific to each PICO question. Only English language studies were included. As this was the inaugural version of these guidelines for children, all publications through May 1, 2017, were considered. Key studies published after the conclusion of the initial literature search were incorporated into the evidence synthesis if identified by panel members as important and relevant even if they were not part of the initial literature review.

Formulation of recommendations

The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) principles guided the assessment of quality of evidence from high to very low and were used to determine the strength of recommendations. The GRADE approach to assess the quality of evidence is based on the evaluation of six domains: (1) risk of bias, (2) inconsistency, (3) indirectness, (4) imprecision, (5) publication bias, and (6) assessment of the balance between benefit and harm, patients’ values and preferences, cost and resources, and feasibility and acceptability of the intervention [3].

The panel initially considered research focused on pediatric patients using the following hierarchy of evidence: systematic reviews, randomized controlled trials, prospective observational studies, retrospective observational studies, case–control studies, and large case series. Research focusing on children with septic shock and other sepsis-associated organ dysfunction was prioritized, although studies inclusive of more general pediatric populations (e.g., all PICU patients) were considered for some questions on a case-by-case basis. If there were insufficient data in children with sepsis or general pediatric illness, data from adult studies were considered using a pre-specified framework to guide appropriateness of indirect evidence.

Each of the subgroups used the Evidence-to-Decision (EtD) framework to facilitate transition from evidence to recommendations. The EtD framework ensured that panel members took into consideration not only the quality of evidence and magnitude of effect, but also balance between benefits and harms, patients’ values and preferences, resources, cost, acceptability, and feasibility [4].

We classified recommendations as strong or weak using the language “We recommend…” or “We suggest…,” respectively. We judged a strong recommendation in favor of an intervention to have desirable effects of adherence that will clearly outweigh the undesirable effects. The implications of calling a recommendation strong are that most patients would accept that intervention and that most clinicians should use it in most situations. However, a strong recommendation does not imply a standard of care, and circumstances may exist in which a strong recommendation cannot or should not be followed for an individual patient. We judged a weak recommendation in favor of an intervention to have desirable consequences of adherence that will probably outweigh the undesirable consequences, but confidence is diminished either because the quality of evidence was low or the benefits and risks were closely balanced. We anticipate that a weak recommendation, while still relevant for most patients in most settings, will be more heavily influenced by clinical circumstances and patients’ values than a strong recommendation. We permitted strong recommendations “for” an intervention based on low or very low quality of evidence when the intervention had the potential to improve survival and there was low risk for immediate harm. We permitted strong recommendations “against” an intervention based on low or very low quality of evidence when there was uncertain benefit but very likely or certain harm, including high costs [5].

Best practice statements (BPSs) were offered when the evidence could not be summarized using GRADE methodology but the benefit or harm was deemed unequivocal. In addition, when evidence was insufficient to make a recommendation, but the panel felt that some guidance may be appropriate, we issued an “in our practice” statement. The “in our practice” statements were developed through a survey of panelists to ascertain their state of current practice in an attempt to describe current variation in care. “In our practice” statements, therefore, should not be construed as recommendations.

Voting process

Panel members convened to review evidence and discuss recommendations in-person and through web conferences. Panelists then indicated agreement or disagreement (or abstention if conflict of interest present) with each recommendation. Up to three rounds of voting were conducted in an attempt to achieve consensus. Acceptance of a statement required votes from 75% of panel members with an 80% agreement threshold.

Conflict of interest policy

Conflict-of-interest disclosures were sought from all panelists prior to commencing activities, with updates annually and as needed. There was no industry input into or support of the guideline development process. Only librarians and a supporting project manager received compensation for their work.

Recommendations

The consensus recommendations of the “Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-associated Organ Dysfunction in Children” are summarized in Table 1 of this executive summary. The rationale and evidence profiles supporting each recommendations are presented in the complete guidelines [6]. The panel issued 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction, including six strong recommendations, 49 weak recommendations, and nine BPSs. For 13 questions, no recommendations could be made, but, for 10 of these, “in our practice” statements were provided. In addition, 52 knowledge gaps and research opportunities were identified (see complete guidelines).

Table 1 Executive summary of guidelines

Conclusions

Although most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations, these guidelines regarding the management of children with septic shock and other sepsis-associated organ dysfunction should provide a foundation for consistent care to improve outcomes and inform future research.

References

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    Pediatric Acute Lung Injury Consensus Conference Group (2015) Pediatric acute respiratory distress syndrome: consensus recommendations from the pediatric acute lung injury consensus conference. Pediatr Crit Care Med 16:428–439

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    Guyatt GH, Oxman AD, Vist GE, GRADE Working Group et al (2008) GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 336:924–926

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    Neumann I, Brignardello-Petersen R, Wiercioch W et al (2016) The GRADE evidence-to-decision framework: a report of its testing and application in 15 international guideline panels. Implement Sci 11:93

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    Alexander PE, Gionfriddo MR, Li SA et al (2016) A number of factors explain why WHO guideline developers make strong recommendations inconsistent with GRADE guidance. J Clin Epidemiol 70:111–122

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    Weiss SL, Peters MJ, Alhazzani W et al (2020) Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med 21

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Correspondence to Scott L. Weiss.

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Conflicts of interest

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, Pediatric Academic Societies, 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 (Steering committee member for various studies being implemented through the Network from intramural funding, governmental, or grant funding from Gerber Foundation). Dr. Nadel (past president) received funding from La Jolla Pharmaceutical (consulting), and he participates in the European Society of Pediatric and Neonatal Intensive Care Medicine (ESPNIC) (Medical President). Dr. Brierley (past president) participates in the ESPNIC. Dr. Carrol participates in 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 provided testimony for legal cases involving 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 Intravenous Immunoglobulins in toxic shock syndrome in children). Dr. Karam participates in BloodNet, PALISI, ISBT, AABB, and CCCTG. Dr. Kneyber participates in the ESPNIC. 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 (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 reports service on committees and board seats for the SCCM’s American College of Critical Care Medicine (Regent), Society of Critical Care Anesthesiologists (director), the 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 and Co, Astellas, and Cempra Pharmaceuticals, and he received other support from Karius, Empatica, and Bluespark Technologies. Dr. Zimmerman received funding from Immunexpress, Seattle and is Past President of SCCM (sepsis biomarker research), and he participates in the AAP and Pediatric Academic Society. 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.

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The following sponsoring organizations with formal liaison appointees endorse this guideline: American Academy of Pediatrics; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; American Thoracic Society; Australian and New Zealand Intensive Care Society; Canadian Critical Care Society; European Society of Neonatal and Pediatric Intensive Care; Pediatric Infectious Diseases Society; Scandinavian Society of Anaesthesiology and Intensive Care Medicine; Society of Infectious Diseases Pharmacists; UK Sepsis Trust; World Federation of Pediatric Intensive and Critical Care Societies.

The Society of Critical Care Medicine guidelines are intended for general information only, are not medical advice, and do not replace professional advice, which should be sought for any medical condition. The full disclaimer for guidelines can be accessed at https://www.sccm.org/Research/Guidelines/Guidelines.

This article is being simultaneously published in the journals Pediatric Critical Care Medicine (https://doi.org/10.1097/PCC.0000000000002197) and Intensive Care Medicine (https://doi.org/10.1007/s00134-019-05877-7).

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Weiss, S.L., Peters, M.J., Alhazzani, W. et al. Executive summary: surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Intensive Care Med 46, 1–9 (2020). https://doi.org/10.1007/s00134-019-05877-7

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