Advertisement

Challenges in the recognition and management of paediatric sepsis — The journey

  • Amanda Harley
    Correspondence
    Corresponding author at: Queensland Children’s Hospital, Brisbane 4101, QLD, Australia.
    Affiliations
    School of Nursing, Midwifery and Social Work, The University of Queensland, Brisbane, QLD, Australia

    Child Health Research Centre, The University of Queensland, and Paediatric Intensive Care Unit, Queensland Children’s Hospital, Brisbane, QLD, Australia

    Department of Emergency Medicine, Gold Coast University Hospital, Gold Coast, QLD, Australia
    Search for articles by this author
  • Luregn J. Schlapbach
    Affiliations
    Child Health Research Centre, The University of Queensland, and Paediatric Intensive Care Unit, Queensland Children’s Hospital, Brisbane, QLD, Australia

    Department of Intensive Care Medicine and Neonatology, and Children’s Research Center, University Children’s Hospital Zurich, Switzerland
    Search for articles by this author
  • Amy N.B. Johnston
    Affiliations
    School of Nursing, Midwifery and Social Work, The University of Queensland, Brisbane, QLD, Australia

    Department of Emergency Medicine, Princess Alexandra Hospital, Brisbane, QLD, Australia
    Search for articles by this author
  • Debbie Massey
    Affiliations
    School of Nursing and Midwifery, Southern Cross University, Coolangatta, QLD, Australia
    Search for articles by this author
Open AccessPublished:April 15, 2021DOI:https://doi.org/10.1016/j.auec.2021.03.006

      Abstract

      Paediatric sepsis remains a leading cause of childhood death. Morbidity is high, with up to one third of children affected developing ongoing, sometimes lifelong sequelae. To address the major burden of sepsis on child health, there is need for a unified approach to care, as outlined in the Australian National Action Plan for sepsis. While the Surviving Sepsis Campaign 2020 guidelines provided evidence-based recommendations for sepsis management in hospital, additional emphasis on families, pre-hospital recognition and post-sepsis care incorporating the multidisciplinary team is paramount to achieve quality patient outcomes. The role of families, paramedics and nurses in recognising and managing paediatric sepsis remains an under-represented area in current literature. The aim of this paper is to critically discuss key challenges surrounding the journey of paediatric sepsis, drawing on contemporary literature to highlight key areas pertinent to recognition and management of sepsis in children. Application of a holistic, patient-centred focus will provide an overview of paediatric sepsis, aiming to inform future development for enhanced healthcare delivery and identify critical areas for further research.

      Keywords

      What is already known about the topic?
      • Paediatric sepsis is a leading cause of childhood death globally; deemed an international health priority by the World Health Organisation.
      • Research findings over the past decade have enabled a better understanding of sepsis, prompting policy change.
      • Early recognition and management are paramount to reducing morbidity and mortality, with focus primarily on the critical care phase.
      What this paper adds
      • This piece contributes a unique overview and critical discussion of literature around paediatric sepsis, extending beyond critical care to include community, pre-hospital, and post-sepsis care.
      • It provides initiative for translation of the National and Global Action Plan for paediatric sepsis to guide the patient journey, aiming to enhance healthcare delivery.
      • It highlights requirements for future nursing and pre-hospital role development and contribution to care to enable provision of a comprehensive, multifaceted approach.

      1. Introduction

      Paediatric sepsis is a major cause of preventable mortality in children globally [
      • Fleischmann-Struzek C.
      • Goldfarb D.M.
      • Schlattmann P.
      • Schlapbach L.J.
      • Reinhart K.
      • Kissoon N.
      The global burden of paediatric and neonatal sepsis: a systematic review.
      ]. Morbidity and mortality rates in some settings are comparable to those seen in critically unwell adult populations [
      • Weiss S.L.
      • Fitzgerald J.C.
      • Pappachan J.
      • Wheeler D.
      • Jaramillo-Bustamante J.C.
      • Salloo A.
      • et al.
      Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study.
      ]. Over half of the global reported incidence of sepsis relates to the neonatal and paediatric population [
      • Rudd K.E.
      • Johnson S.C.
      • Agesa K.M.
      • Shackelford K.A.
      • Tsoi D.
      • Kievlan D.R.
      • et al.
      Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study.
      ]. While the majority of the approximatively three million paediatric infection-related deaths occur in low and middle income countries, the burden of disease is high even in well-resourced settings [
      • Liu L.
      • Oza S.
      • Hogan D.
      • Perin J.
      • Rudan I.
      • Lawn J.E.
      • et al.
      Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis.
      ]. In Australia, an estimated 55,000 patients across all age groups experience sepsis each year, and in 2017 an estimated 8700 deaths were recorded as being sepsis related [
      • Rudd K.E.
      • Johnson S.C.
      • Agesa K.M.
      • Shackelford K.A.
      • Tsoi D.
      • Kievlan D.R.
      • et al.
      Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study.
      ]. Approximately 25% of paediatric intensive care unit (PICU) deaths in Australia and New Zealand were related to severe infections [
      • Schlapbach L.J.
      • Straney L.
      • Alexander J.
      • Maclaren G.
      • Festa M.
      • Schibler A.
      • et al.
      Mortality related to invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand, 2002–13: a multicentre retrospective cohort study.
      ]. In addition, a rapidly growing body of evidence demonstrates the long-lasting impact of sepsis on patients and families [
      • Zimmerman J.J.
      • Banks A.R.
      • Berg J.R.
      • Zuppa M.A.
      • Newth L.C.
      • Wessel W.D.
      • et al.
      Trajectory of mortality and health-related quality of life morbidity following community-acquired pediatric septic shock.
      ,
      • Schlapbach J.L.
      Paediatric sepsis.
      ]. It is estimated that up to one third of children who survive sepsis are left with significant morbidity including amputations, cognitive impairment and other, sometimes life-long conditions which will affect their Quality of Life (QoL) [
      • Weiss S.L.
      • Fitzgerald J.C.
      • Pappachan J.
      • Wheeler D.
      • Jaramillo-Bustamante J.C.
      • Salloo A.
      • et al.
      Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study.
      ].
      In 2017, the World Health Organisation (WHO) launched a resolution highlighting the need for a coordinated international approach to improve prevention, recognition, and management of sepsis in both adult and paediatric populations [
      • Reinhart K.
      • Daniels R.
      • Kissoon N.
      • Machado F.R.
      • Schachter R.D.
      • Finfer S.
      Recognizing Sepsis as a global health priority — a WHO resolution.
      ]. The George Institute for Global Health responded by producing a National Action Plan for sepsis, outlining key recommendations to reduce the impact of sepsis in Australia [
      • Australia Sepsis Network
      Stopping sepsis: a national action plan.
      ]. To date, there is no reliable early diagnostic test to identify sepsis and no standardised assessment or management of sepsis across Australian or international health facilities [
      • Romero B.
      • Fry M.
      • Roche M.
      The impact of evidence-based sepsis guidelines on emergency department clinical practice: a pre-post medical record audit.
      ,
      • Davis L.A.
      • Carcillo A.J.
      • Aneja K.R.
      • Deymann J.A.
      • Lin C.J.
      • Nguyen C.T.
      • et al.
      American college of critical care medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock.
      ].
      Standardisation to improve recognition, escalation of care and management of sepsis has been the focus of a number of quality improvement campaigns on sepsis. The Surviving Sepsis Campaign (SSC) highlighted the importance of timely recognition of paediatric sepsis, using this as a trigger to launch a sepsis treatment bundle [
      • Weiss S.L.
      • Peters M.J.
      • Alhazzani W.
      • Agus M.S.D.
      • Flori H.R.
      • Inwald D.P.
      • et al.
      Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
      ]. The role that parents, the community, and healthcare staff, including nurses, play in timely recognition of sepsis is increasingly recognised and acknowledged in care pathways [
      • Harley A.
      • Latour J.M.
      • Schlapbach L.J.
      The role of parental concerns in the recognition of Sepsis in children: a literature review.
      ,
      • Harley A.
      • Johnston A.N.B.
      • Denny K.J.
      • Keijzers G.
      • Crilly J.
      • Massey D.
      Emergency nurses’ knowledge and understanding of their role in recognising and responding to patients with sepsis: a qualitative study.
      ].
      A comprehensive approach to paediatric sepsis needs to integrate every phase of the patient’s journey inclusive of pre-hospital, Emergency Department (ED), PICU, and post-sepsis care. We aim to critically discuss key challenges around the recognition and management of paediatric sepsis, incorporating different, yet complimentary perspectives that contribute to the paediatric patient journey. This critical discussion sheds light on current challenges and opportunities that healthcare workers and policy makers should consider when developing, implementing and evaluating interventions to improve the recognition and management of paediatric sepsis. The paper will follow the patient journey starting with the systematic recognition of sepsis, recognition by parents, pre-hospital and ED clinicians, followed by treatment and post sepsis care. Key contemporary literature is used to inform the discussion, including international studies to ensure the best available evidence has been included.
      An overview of the complex journey for paediatric patients diagnosed with sepsis, including articulation of the key elements in this journey is provided schematically in Fig. 1.
      Fig. 1
      Fig. 1The paediatric sepsis journey.
      Abbreviation: Post Traumatic Stress Disorder (PTSD).

      2. Recognition

      2.1 Systematic approaches to sepsis recognition

      Febrile conditions account for up to one in five paediatric presentations to the ED [
      • Alqudah M.
      • Qudah B.
      • Cowin L.
      • George A.
      • Johnson M.
      Understanding presentations of children with fever to a Sydney emergency department.
      ] with viral illnesses ranking as the most common diagnosis, often presenting with similar signs and symptoms as children who subsequently develop fulminant sepsis [
      • Buntsma D.
      Patterns of paediatric emergency presentations to a tertiary referral centre in the Northern territory.
      ]. Clinicians face unique challenges in discriminating between a child with a self-limiting viral illness or critical illness such as sepsis where symptoms can be hard to recognise in early stages [
      • Schlapbach J.L.
      Paediatric sepsis.
      ,
      • Harley A.
      • Latour J.M.
      • Schlapbach L.J.
      The role of parental concerns in the recognition of Sepsis in children: a literature review.
      ,
      • Biban P.
      Pediatric septic shock in the Emergency Department: can we set the alarm clock a little forward?.
      ,
      • Schlapbach L.J.
      • Weiss S.L.
      • Wolf J.
      Reducing collateral damage from mandates for time to antibiotics in pediatric sepsis-primum non nocere.
      ]. A sentinel case review conducted in Queensland, Australia, from 2012 to 2014 identified 25% of events in paediatric cases were attributed to sepsis, with key contributory themes identified as delayed or missed diagnoses of sepsis and lack of a sepsis pathway [
      • Queensland Paediatric Quality Council
      Multi-incident analysis of SAC 1 paediatric clinical incidents 2012-2014.
      ]. Launey et al. explored 23 fatal cases of serious paediatric bacterial infection in France and reported suboptimal care in 76% of cases [
      • Launay E.
      • Gras-Le Guen C.
      • Martinot A.
      • Assathiany R.
      • Blanchais T.
      • Mourdi N.
      • et al.
      Suboptimal care in the initial management of children who died from severe bacterial infection: a population-based confidential inquiry.
      ]. Of importance, the authors made reference to the SSC recommendations, suggesting implementation of a sepsis protocol to improve care [
      • Launay E.
      • Gras-Le Guen C.
      • Martinot A.
      • Assathiany R.
      • Blanchais T.
      • Mourdi N.
      • et al.
      Suboptimal care in the initial management of children who died from severe bacterial infection: a population-based confidential inquiry.
      ] Several observational studies from high income settings have identified earlier recognition and improved outcomes following implementation of tools such as sepsis pathways [
      • Paul R.
      • Melendez E.
      • Stack A.
      • Capraro A.
      • Monuteaux M.
      • Neuman M.I.
      Improving adherence to PALS septic shock guidelines.
      ,
      • Paul R.
      • Neuman M.I.
      • Monuteaux M.C.
      • Melendez E.
      Adherence to PALS sepsis guidelines and hospital length of stay.
      ,
      • Cruz A.T.
      • Perry A.M.
      • Williams E.A.
      • Graf J.M.
      • Wuestner E.R.
      • Patel B.
      Implementation of goal-directed therapy for children with suspected sepsis in the emergency department.
      ,
      • Balamuth L.F.
      • Weiss C.S.
      • Fitzgerald W.J.
      • Hayes R.K.
      • Centkowski R.S.
      • Chilutti R.M.
      • et al.
      Protocolized treatment is associated with decreased organ dysfunction in pediatric severe Sepsis.
      ,
      • Lane R.D.
      • Funai T.
      • Reeder R.
      • Larsen G.Y.
      High reliability pediatric septic shock quality improvement initiative and decreasing mortality (Report).
      ]. Accordingly, the latest iteration of the paediatric SSC guidelines acknowledges the difficulties with paediatric sepsis recognition, recommending institutions adopt a systematic screening approach to assist with early recognition [
      • Weiss S.L.
      • Peters M.J.
      • Alhazzani W.
      • Agus M.S.D.
      • Flori H.R.
      • Inwald D.P.
      • et al.
      Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
      ]. The development of reliable screening tools for sepsis is hampered by insufficient specificity and sensitivity [
      • Todi S.
      Sepsis: new horizons.
      ] attributed to the myriad of signs and symptoms that patients with sepsis develop and the complexity of the condition. In addition, implementation of systematic screening approaches must ensure adaptation and calibration to the respective epidemiology and setting of participating institutions [
      • Paul R.
      • Melendez E.
      • Stack A.
      • Capraro A.
      • Monuteaux M.
      • Neuman M.I.
      Improving adherence to PALS septic shock guidelines.
      ,
      • Cruz A.T.
      • Perry A.M.
      • Williams E.A.
      • Graf J.M.
      • Wuestner E.R.
      • Patel B.
      Implementation of goal-directed therapy for children with suspected sepsis in the emergency department.
      ,
      • Larsen G.
      • Mecham N.
      • Greenberg R.
      An emergency department septic shock protocol and care guideline for children initiated at triage.
      ].
      Sepsis pathways are designed with the aim of guiding clinicians in recognising and managing sepsis, providing standardisation of approaches, cognitive aids, and assisting in data collection for benchmarking and evaluation. Pathways typically consist of screening and treatment components aimed at increasing the reliability of recognition and empowering clinicians to escalate care quickly [
      • Weiss S.L.
      • Peters M.J.
      • Alhazzani W.
      • Agus M.S.D.
      • Flori H.R.
      • Inwald D.P.
      • et al.
      Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
      ]. Traditionally, recognition and treatment of sepsis has been in EDs or the hospital setting. However, with the increasing awareness that early recognition and prompt treatment modalities improve outcomes in paediatric sepsis, the importance of parental contribution to patient diagnosis has been established.

      2.2 Recognition of sepsis by parents

      Sepsis is predominantly acquired in the community, yet the role parents play as the expert of their child in recognising sepsis, remains poorly explored [
      • Harley A.
      • Latour J.M.
      • Schlapbach L.J.
      The role of parental concerns in the recognition of Sepsis in children: a literature review.
      ]. Sepsis is defined as infection with a dysregulated host response leading to life-threatening organ dysfunction, concepts which are challenging for the wider public to understand, which may be an obstacle to prompt presentations to a health service [
      • Singer M.
      • Deutschman C.S.
      • Seymour C.W.
      • Shankar-Hari M.
      • Annane D.
      • Bauer M.
      • et al.
      The third international consensus definitions for sepsis and septic shock (Sepsis-3).
      ,
      • Weiss S.L.
      • Pomerantz W.S.
      Septic shock in children: rapid recognition and initial resuscitation (first hour).
      ]. Indeed, a recent survey in Australia showed only 14% of Australians could identify a sign of sepsis [
      • Australia Sepsis Network
      Stopping sepsis: a national action plan.
      ] despite the increase in morbidity and mortality associated with delayed hospital presentation [
      • Weiss S.L.
      • Pomerantz W.S.
      Septic shock in children: rapid recognition and initial resuscitation (first hour).
      ]. While parents may not be trained to recognise organ dysfunction, they often state “this illness was different” or “I sensed something was wrong” in relation to the deterioration of their child in the course of sepsis [
      • Harley A.
      • Latour J.M.
      • Schlapbach L.J.
      The role of parental concerns in the recognition of Sepsis in children: a literature review.
      ,
      • Gill F.J.
      • Leslie G.D.
      • Marshall A.P.
      Barriers and facilitators to implementing a process to enable parent escalation of care for the deteriorating child in hospital.
      ], concepts that have received little exploration in the literature. For example, parents may assist in clinician assessment of a child’s mental status based on their expertise on normal behaviour of their child. At present, “parental concern” is used as a trigger in several institutional sepsis recognition tools [,
      • Clinical Excellence Commission
      ]. However, a recent systematic review on parental concern as a recognition tool for sepsis identified only one original study reporting on diagnostic accuracy [
      • Harley A.
      • Latour J.M.
      • Schlapbach L.J.
      The role of parental concerns in the recognition of Sepsis in children: a literature review.
      ]. In this study, covering 3981 children presenting to primary care centres with an acute infection, parental concern coupled with clinician’s gut feeling that something was wrong, provided superior identification compared to routine physiological-based criteria [
      • Van Den Bruel A.
      • Aertgeerts B.
      • Bruyninckx R.
      • Aerts M.
      • Buntinx F.
      Signs and symptoms for diagnosis of serious infections in children: a prospective study in primary care.
      ]. These data, while limited in generalisability, support the design of future sepsis awareness campaigns and triage clinician education. Future research should further ascertain the role parents can play in the early recognition of sepsis.
      Parental education about the key features of sepsis has substantial potential to result in earlier recognition of sepsis. Not uncommonly, children with sepsis have been discharged home following clinical review in the ED with common diagnoses such as “flu-like symptoms”, “bronchiolitis”, or “gastroenteritis”, because the clinical features of sepsis were not yet evident. Re-presentation to health services represents a reoccurring pattern observed in many root cause analyses on fatal paediatric sepsis [
      • Queensland Paediatric Quality Council
      Multi-incident analysis of SAC 1 paediatric clinical incidents 2012-2014.
      ]. In adults, up to 45% of patients hospitalised with sepsis presented to a health service within one week prior to hospitalisation [
      • Liu V.X.
      • Escobar G.J.
      • Chaudhary R.C.
      • Prescott H.C.
      Healthcare utilization and infection in the week prior to sepsis hospitalization.
      ], identifying an important gap in pre-sepsis encounters that could inform early recognition. Development of future models to improve community awareness including risk-stratification post discharge should expand to the paediatric population. Accordingly, efforts to improve community, including parental awareness of sepsis is a key recommendation from the National Action Plan on sepsis in Australia [
      • Australia Sepsis Network
      Stopping sepsis: a national action plan.
      ]. Despite such recommendations, previous literature has reported barriers for health professionals to embrace and empower parents to escalate concern [
      • Gill F.J.
      • Leslie G.D.
      • Marshall A.P.
      Parent escalation of care for the deteriorating child in hospital: a health-care improvement study.
      ,
      • Dwyer Ta
      • Flenady T.
      • Kahl J.
      • Quinney L.
      Evaluation of a patient and family activated escalation system: Ryan’s rule.
      ], leaving an area warranting further investigation and evaluation. As many children with sepsis deteriorate in the community Emergency Medical Services (EMS) are often their first contact with health care. Thus, there is an urgent need to explore, assess and evaluate EMS ability to recognise sepsis in children.

      2.3 Recognition of sepsis in the pre-hospital environment

      The majority of sepsis studies focus on recognition and initiation of treatment at hospital presentation [
      • Liu V.X.
      • Escobar G.J.
      • Chaudhary R.C.
      • Prescott H.C.
      Healthcare utilization and infection in the week prior to sepsis hospitalization.
      ,
      • Jeffery A.D.
      • Mutsch K.S.
      • Knapp L.
      Knowledge and recognition of SIRS and sepsis among pediatric nurses.
      ]. Importantly, over 50% of community-acquired paediatric sepsis fatalities occur within the first two days of hospital admission [
      • Schlapbach L.
      • MacLaren G.
      • Festa M.
      • Alexander J.
      • Erickson S.
      • Beca J.
      • et al.
      Prediction of pediatric sepsis mortality within 1 h of intensive care admission.
      ], highlighting the importance of early recognition and presentation to healthcare facilities to commence treatment. Recognition by EMS in the pre-hospital phase may contribute to improved outcomes [
      • Van Der Wekken L.C.W.
      • Alam N.
      • Holleman F.
      • van Exter P.
      • Kramer M.H.H.
      • Nanayakkara P.W.B.
      Epidemiology of sepsis and its recognition by emergency medical services personnel in the Netherlands.
      ,
      • Green R.S.
      • Travers A.H.
      • Cain E.
      • Campbell S.G.
      • Jensen J.L.
      • Petrie D.A.
      • et al.
      Paramedic recognition of sepsis in the prehospital setting: a prospective observational study.
      ,
      • Groenewoudt A.M.
      • Roest M.M.A.
      • Leijten M.F.
      • Stassen M.P.
      Septic patients arriving with emergency medical services: a seriously ill population.
      ]. Recognition of paediatric sepsis by EMS carries additional challenges as the physiological parameters indicating illness severity are different to those in adult populations. For example, unlike in adults with sepsis, hypotension is a late sign of sepsis in the paediatric population and initiation of treatment should not depend on presence of hypotension [
      • Schlapbach L.
      • MacLaren G.
      • Festa M.
      • Alexander J.
      • Erickson S.
      • Beca J.
      • et al.
      Prediction of pediatric sepsis mortality within 1 h of intensive care admission.
      ]. To date, there is no literature on EMS and paediatric sepsis recognition [
      • Van Der Wekken L.C.W.
      • Alam N.
      • Holleman F.
      • van Exter P.
      • Kramer M.H.H.
      • Nanayakkara P.W.B.
      Epidemiology of sepsis and its recognition by emergency medical services personnel in the Netherlands.
      ,
      • Groenewoudt A.M.
      • Roest M.M.A.
      • Leijten M.F.
      • Stassen M.P.
      Septic patients arriving with emergency medical services: a seriously ill population.
      ,
      • Smyth M.A.
      • Brace-McDonnell S.J.
      • Perkins G.D.
      Identification of adults with sepsis in the prehospital environment: a systematic review.
      ]. An EMS study focusing on adult patients indicated accurate recognition of sepsis in only 10.8% of cases highlighting a need for sepsis-specific training for EMS personnel. This important finding indicates that there is significant opportunity to improve recognition of sepsis and improve outcomes [
      • Groenewoudt A.M.
      • Roest M.M.A.
      • Leijten M.F.
      • Stassen M.P.
      Septic patients arriving with emergency medical services: a seriously ill population.
      ], which should extend to include the paediatric population. A recent randomised controlled study (RCT) was conducted on adults with sepsis to receive early, pre-hospital antibiotics. Although the trial did not report a mortality benefit, secondary analyses revealed that targeted education substantially improved recognition of sepsis by EMS personnel [
      • Alam N.
      • Oskam E.
      • Stassen P.M.
      • Exter P.V.
      • Van de Ven P.M.
      • Haak H.R.
      • et al.
      Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial.
      ], recognition is key to improving outcomes [
      • Rhodes A.
      • Evans L.E.
      • Alhazzani W.
      • Levy M.M.
      • Antonelli M.
      • Ferrer R.
      • et al.
      Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016.
      ], extending beyond mortality measures [
      • Weiss S.L.
      • Peters M.J.
      • Alhazzani W.
      • Agus M.S.D.
      • Flori H.R.
      • Inwald D.P.
      • et al.
      Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
      ,
      • Zimmerman J.J.
      • Banks A.R.
      • Berg J.R.
      • Zuppa M.A.
      • Newth L.C.
      • Wessel W.D.
      • et al.
      Critical illness factors associated with long-term mortality and health-related quality of life morbidity following community-acquired pediatric septic shock.
      ]. Further support for this finding stems from a study assessing the impact of a pre-hospital sepsis screening tool coupled with education that reported a recognition accuracy of 78.2% in a study of 629 adults [
      • Green R.S.
      • Travers A.H.
      • Cain E.
      • Campbell S.G.
      • Jensen J.L.
      • Petrie D.A.
      • et al.
      Paramedic recognition of sepsis in the prehospital setting: a prospective observational study.
      ]. Additional research and associated education is therefore needed to explore pre-hospital interventions in children with sepsis, targeting early recognition. The experience acquired with the implementation of sepsis recognition tools in the hospital setting should inform design of pre-hospital quality improvement initiatives in conjunction with targeted education.

      2.4 Recognition of sepsis in Emergency Departments — the role of nurses

      Acknowledgement of the fundamental role that nurses play in early recognition is evident through the development of nursing-specific actions formulated from SSC guidelines [
      • Harley A.
      • Johnston A.N.B.
      • Denny K.J.
      • Keijzers G.
      • Crilly J.
      • Massey D.
      Emergency nurses’ knowledge and understanding of their role in recognising and responding to patients with sepsis: a qualitative study.
      ,
      • Kleinpell R.
      • Aitken L.
      • Schorr C.A.
      Implications of the new international sepsis guidelines for nursing care.
      ,
      • Kleinpell R.
      • Blot S.
      • Boulanger C.
      • Fulbrook P.
      • Blackwood B.
      International critical care nursing considerations and quality indicators for the 2017 surviving sepsis campaign guidelines.
      ], however their role in paediatric sepsis recognition has received limited exploration. Nurses in EDs are typically the first point of patient contact and responsible for initial patient assessment, including recognition and escalation of patient deterioration [
      • Jeffery A.D.
      • Mutsch K.S.
      • Knapp L.
      Knowledge and recognition of SIRS and sepsis among pediatric nurses.
      ,
      • Delaney M.M.
      • Friedman M.I.
      • Dolansky M.A.
      • Fitzpatrick J.J.
      Impact of a sepsis educational program on nurse competence.
      ]. The integral function of nurses in initiating sepsis identification and management was highlighted in a 2019 qualitative study exploring nurses’ role in recognising and responding to sepsis [
      • Harley A.
      • Johnston A.N.B.
      • Denny K.J.
      • Keijzers G.
      • Crilly J.
      • Massey D.
      Emergency nurses’ knowledge and understanding of their role in recognising and responding to patients with sepsis: a qualitative study.
      ]. Observed organisational and nurse’s knowledge deficits indicated a need for improved and contextually appropriate education. They also indicate the need for utilisation of a specific sepsis pathway to overcome perceived barriers such as roles and responsibilities in recognition and escalation of care [
      • Harley A.
      • Johnston A.N.B.
      • Denny K.J.
      • Keijzers G.
      • Crilly J.
      • Massey D.
      Emergency nurses’ knowledge and understanding of their role in recognising and responding to patients with sepsis: a qualitative study.
      ]. Nurse-led pathways, or protocols for sepsis management advocate for nurse-led multidisciplinary teams to speed recognition, initiate treatment, and facilitate appropriate escalation [
      • Kleinpell R.
      • Blot S.
      • Boulanger C.
      • Fulbrook P.
      • Blackwood B.
      International critical care nursing considerations and quality indicators for the 2017 surviving sepsis campaign guidelines.
      ,
      • Maclay T.
      • Rephann A.
      The impact of early identification and a critical care-based sepsis response team on sepsis outcomes.
      ]. The lack of standardisation of nursing education and variable empowerment of nurses across institutions may contribute to variability of care in sepsis recognition and management and negatively effect paediatric outcomes [
      • Harley A.
      • Johnston A.N.B.
      • Denny K.J.
      • Keijzers G.
      • Crilly J.
      • Massey D.
      Emergency nurses’ knowledge and understanding of their role in recognising and responding to patients with sepsis: a qualitative study.
      ,
      • Jeffery A.D.
      • Mutsch K.S.
      • Knapp L.
      Knowledge and recognition of SIRS and sepsis among pediatric nurses.
      ]. Structured education across health care services and disciplines is likely to improve reliability of sepsis recognition and treatment [
      • Delaney M.M.
      • Friedman M.I.
      • Dolansky M.A.
      • Fitzpatrick J.J.
      Impact of a sepsis educational program on nurse competence.
      ,
      • Goulart L.d.S.
      • Ferreira Júnior M.A.
      • Sarti E.C.F.B.
      • Sousa Á.F.L.d.
      • Ferreira A.M.
      • Frota O.P.
      Are nurses updated on the proper management of patients with sepsis?.
      ].
      Studies exploring nurse’s knowledge of sepsis highlight limitations in current education curricula [
      • Harley A.
      • Johnston A.N.B.
      • Denny K.J.
      • Keijzers G.
      • Crilly J.
      • Massey D.
      Emergency nurses’ knowledge and understanding of their role in recognising and responding to patients with sepsis: a qualitative study.
      ,
      • Jeffery A.D.
      • Mutsch K.S.
      • Knapp L.
      Knowledge and recognition of SIRS and sepsis among pediatric nurses.
      ], although little is known about the translation of knowledge to practice in the field of sepsis. A Canadian study surveying 312 ED nurses identified knowledge of sepsis was in general low, despite receiving education on sepsis in multiple forums [
      • Storozuk S.A.
      • MacLeod M.L.P.
      • Freeman S.
      • Banner D.
      A survey of sepsis knowledge among Canadian emergency department registered nurses.
      ]. Further exploration on knowledge translation and contextual knowledge to understand these shortcomings is required [
      • Storozuk S.A.
      • MacLeod M.L.P.
      • Freeman S.
      • Banner D.
      A survey of sepsis knowledge among Canadian emergency department registered nurses.
      ]. Curriculum expansion to include specific education on topics such as recognising and responding to patient deterioration has been recommended for nursing education and should be extended to include paediatric sepsis [
      • Currey J.
      • Massey D.
      • Allen J.
      • Jones D.
      What nurses involved in a Medical Emergency Teams consider the most vital areas of knowledge and skill when delivering care to the deteriorating ward patient. A nurse-oriented curriculum development project.
      ,
      • Harley A.
      • Massey D.
      • Ullman A.J.
      • Reid-Searl K.
      • Schlapbach L.J.
      • Takashima M.
      • et al.
      Final year nursing student’s exposure to education and knowledge about sepsis: a multi-university study.
      ], future efforts will require education and knowledge translation methodologies to operate in parallel.
      Nurses play a central role promoting and enhancing patient safety by identifying critical status changes during patient deterioration [
      • Nelson P.D.
      • Lemaster H.T.
      • Plost N.G.
      • Zahner L.M.
      Recognizing sepsis in the adult patient.
      ] and activating protocols. Studies indicating low compliance with sepsis protocols and guidelines are of concern. For example, a 2009 audit revealed poor adherence with the American College of Critical Care Medicine-Paediatric Advanced Life Support guideline for children with sepsis [
      • Inwald D.P.
      • Tasker R.C.
      • Peters M.J.
      • Nadel S.
      Emergency management of children with severe sepsis in the United Kingdom: the results of the Paediatric Intensive Care Society sepsis audit.
      ]. The low compliance with the guideline is not an isolated result, variability in guideline application exists globally and nationally [
      • Evans I.V.R.
      • Phillips G.S.
      • Alpern E.R.
      • Angus D.C.
      • Friedrich M.E.
      • Kissoon N.
      • et al.
      Association between the New York sepsis care mandate and in-hospital mortality for pediatric sepsis.
      ,
      • Burrell A.R.
      • McLaws M.L.
      • Fullick M.
      • Sullivan R.B.
      • Sindhusake D.
      SEPSIS KILLS: early intervention saves lives.
      ]. These findings highlight the need for comprehensive multidisciplinary approaches including nurses to enable improved implementation and maintenance of sepsis guidelines to ensure positive patient outcomes [
      • Robson W.
      • Beavis S.
      • Spittle N.
      An audit of ward nurses’ knowledge of sepsis.
      ].

      3. Treatment

      3.1 Management of paediatric sepsis

      Early treatment of paediatric sepsis can substantially decrease mortality rates based on observational data [
      • Evans I.V.R.
      • Phillips G.S.
      • Alpern E.R.
      • Angus D.C.
      • Friedrich M.E.
      • Kissoon N.
      • et al.
      Association between the New York sepsis care mandate and in-hospital mortality for pediatric sepsis.
      ,
      • Cruz A.T.
      • Lane R.D.
      • Balamuth F.
      • Aronson P.L.
      • Ashby D.W.
      • Neuman M.I.
      • et al.
      Updates on pediatric sepsis.
      ], however robust, high-quality evidence for current treatment regimes specifically for children, remains limited. Further complexity arises from the variable application of sepsis criteria in past studies, compounded by the lack of specificity in the 2005 criteria for ‘Systematic Inflammatory Response Syndrome’ (SIRS) criteria [
      • Goldstein B.
      • Giroir B.
      • Randolph A.
      International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics.
      ] and subsequent definition of sepsis. SIRS criteria is the nonspecific inflammatory process that occurs for many pathophysiological conditions, not isolated to sepsis. This current definition categorises children with an infection and SIRS criteria as sepsis [
      • Goldstein B.
      • Giroir B.
      • Randolph A.
      International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics.
      ]. Consequently, variable study results have been produced with varying illness severity amongst populations. The latest iteration of the Paediatric SSC uses the term “sepsis-associated organ dysfunction” [
      • Weiss S.L.
      • Peters M.J.
      • Alhazzani W.
      • Agus M.S.D.
      • Flori H.R.
      • Inwald D.P.
      • et al.
      Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
      ]. A paediatric sepsis definition taskforce has been formed and revised criteria for an updated definition is eagerly awaited [
      • Schlapbach L.J.
      • Kissoon N.
      Defining pediatric sepsis.
      ].
      The concept that a combination of interventions, designated a care bundle, is more likely to result in improved outcomes has become widely adopted [
      • Balamuth L.F.
      • Weiss C.S.
      • Fitzgerald W.J.
      • Hayes R.K.
      • Centkowski R.S.
      • Chilutti R.M.
      • et al.
      Protocolized treatment is associated with decreased organ dysfunction in pediatric severe Sepsis.
      ,
      • Lane R.D.
      • Funai T.
      • Reeder R.
      • Larsen G.Y.
      High reliability pediatric septic shock quality improvement initiative and decreasing mortality (Report).
      ,
      • Evans I.V.R.
      • Phillips G.S.
      • Alpern E.R.
      • Angus D.C.
      • Friedrich M.E.
      • Kissoon N.
      • et al.
      Association between the New York sepsis care mandate and in-hospital mortality for pediatric sepsis.
      ]. A ‘sepsis care bundle’ includes initial resuscitation and treatment actions such as blood culture collection, commencement of antibiotics and administration of fluid bolus(es) [
      • Weiss S.L.
      • Peters M.J.
      • Alhazzani W.
      • Agus M.S.D.
      • Flori H.R.
      • Inwald D.P.
      • et al.
      Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
      ] within 180 min for children with sepsis-associated organ dysfunction and within 60 min for those with septic shock [
      • Weiss S.L.
      • Peters M.J.
      • Alhazzani W.
      • Agus M.S.D.
      • Flori H.R.
      • Inwald D.P.
      • et al.
      Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
      ]. In a large cohort of children managed under the New York state mandate for sepsis care, lower mortality was observed in children with sepsis where treatment with a sepsis ‘bundle’ was administered within one hour of recognition [
      • Evans I.V.R.
      • Phillips G.S.
      • Alpern E.R.
      • Angus D.C.
      • Friedrich M.E.
      • Kissoon N.
      • et al.
      Association between the New York sepsis care mandate and in-hospital mortality for pediatric sepsis.
      ]. In a single centre study in children, rapid delivery of antibiotics in children with septic shock correlated with lower mortality [
      • Weiss S.L.
      • Fitzgerald J.C.
      • Balamuth F.
      • Alpern E.R.
      • Lavelle J.
      • Chilutti M.
      • et al.
      Delayed antimicrobial therapy increases mortality and organ dysfunction duration in pediatric sepsis.
      ]. Additional paediatric studies are required to develop robust evidence focusing on other individual bundle elements to ascertain their impact on paediatric outcomes, and their relative contribution to the paediatric sepsis care bundle [
      • Evans I.V.R.
      • Phillips G.S.
      • Alpern E.R.
      • Angus D.C.
      • Friedrich M.E.
      • Kissoon N.
      • et al.
      Association between the New York sepsis care mandate and in-hospital mortality for pediatric sepsis.
      ].
      Based on evidence and biological rationale, blood culture collection and administration of antibiotics represent widely accepted bundle components [
      • Weiss S.L.
      • Peters M.J.
      • Alhazzani W.
      • Agus M.S.D.
      • Flori H.R.
      • Inwald D.P.
      • et al.
      Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
      ,
      • Rhodes A.
      • Evans L.E.
      • Alhazzani W.
      • Levy M.M.
      • Antonelli M.
      • Ferrer R.
      • et al.
      Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016.
      ]. The liberal use of fluids has however, recently come under scrutiny [
      • Macdonald S.
      • Keijzers G.
      • Taylor D.
      • Kinnear F.
      • Arendts G.
      • Fatovich D.
      • et al.
      Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial.
      ,
      • Maitland K.
      • Kiguli S.
      • Opoka R.
      • Engoru C.
      • Olupot-Olupot P.
      • Akech S.
      • et al.
      Mortality after fluid bolus in African children with severe infection.
      ,
      • Gelbart B.
      Fluid bolus therapy in pediatric sepsis: current knowledge and future direction. (Report).
      ,
      • Keijzers G.
      • Macdonald S.P.J.
      • Udy A.A.
      • Arendts G.
      • Bailey M.
      • Bellomo R.
      • et al.
      The Australasian Resuscitation In Sepsis Evaluation: fluids or vasopressors in emergency department sepsis (ARISE FLUIDS), a multi-centre observational study describing current practice in Australia and New Zealand.
      ,
      • Maitland K.
      • George E.C.
      • Evans J.A.
      • Kiguli S.
      • Olupot-Olupot P.
      • Akech S.O.
      • et al.
      Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial. (Report).
      ]. Historically, rapid high volume fluid administration in suspected sepsis has been a cornerstone of treatment [
      • Carcillo A.J.
      • Fields I.A.
      Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock.
      ]. More recently, observational studies indicate potential for harm associated with high volume fluid administration in sepsis in both adult and paediatric populations [
      • Macdonald S.
      • Keijzers G.
      • Taylor D.
      • Kinnear F.
      • Arendts G.
      • Fatovich D.
      • et al.
      Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial.
      ,
      • Maitland K.
      • Kiguli S.
      • Opoka R.
      • Engoru C.
      • Olupot-Olupot P.
      • Akech S.
      • et al.
      Mortality after fluid bolus in African children with severe infection.
      ,
      • Gelbart B.
      Fluid bolus therapy in pediatric sepsis: current knowledge and future direction. (Report).
      ,
      • Maitland K.
      • George E.C.
      • Evans J.A.
      • Kiguli S.
      • Olupot-Olupot P.
      • Akech S.O.
      • et al.
      Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial. (Report).
      ]. A large paediatric multicentre trial (FEAST) [
      • Maitland K.
      • Kiguli S.
      • Opoka R.
      • Engoru C.
      • Olupot-Olupot P.
      • Akech S.
      • et al.
      Mortality after fluid bolus in African children with severe infection.
      ], performed in a low resource setting where intensive care was not available, demonstrated higher mortality in children receiving larger volumes of fluid. FEAST has served as the foundation for recent studies to assess fluid-restrictive strategies aimed at improving patient outcomes [
      • Macdonald S.
      • Keijzers G.
      • Taylor D.
      • Kinnear F.
      • Arendts G.
      • Fatovich D.
      • et al.
      Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial.
      ,
      • Inwald D.
      • Canter R.
      • Woolfall K.
      • O’Hara C.
      • Mouncey P.
      • Zenasni Z.
      • et al.
      Restricted fluid bolus versus current practice in children with septic shock: the FiSh feasibility study and pilot RCT.
      ,
      • Parker M.J.
      • Thabane L.
      • Fox-Robichaud A.
      • Liaw P.
      • Choong K.
      A trial to determine whether septic shock-reversal is quicker in pediatric patients randomized to an early goal-directed fluid-sparing strategy versus usual care (SQUEEZE): study protocol for a pilot randomized controlled trial.
      ,
      • Corl K.A.
      • Prodromou M.
      • Merchant R.C.
      • Gareen I.
      • Marks S.
      • Banerjee D.
      • et al.
      The restrictive IV fluid trial in severe sepsis and septic shock (RIFTS): a randomized pilot study.
      ,
      • Self W.H.
      • Semler M.W.
      • Bellomo R.
      • Brown S.M.
      • Deboisblanc B.P.
      • Exline M.C.
      • et al.
      Liberal versus restrictive intravenous fluid therapy for early septic shock: rationale for a randomized trial.
      ,
      • Meyhoff T.S.
      • Hjortrup P.B.
      • Møller M.H.
      • Wetterslev J.
      • Lange T.
      • Kjær M.B.N.
      • et al.
      Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial—protocol and statistical analysis plan.
      ]. This indicates a need to test fluid-restrictive resuscitation algorithms [
      • Macdonald S.
      • Keijzers G.
      • Taylor D.
      • Kinnear F.
      • Arendts G.
      • Fatovich D.
      • et al.
      Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial.
      ,
      • Corl K.A.
      • Prodromou M.
      • Merchant R.C.
      • Gareen I.
      • Marks S.
      • Banerjee D.
      • et al.
      The restrictive IV fluid trial in severe sepsis and septic shock (RIFTS): a randomized pilot study.
      ,
      • Keijzers G.
      • Macdonald S.P.J.
      • Udy A.A.
      • Arendts G.
      • Bailey M.
      • Bellomo R.
      • et al.
      The Australasian Resuscitation In Sepsis evaluation: FLUid or vasopressors in Emergency Department Sepsis, a multicentre observational study (ARISE FLUIDS observational study): rationale, methods and analysis plan.
      ,
      • Brierley A.J.
      • Carcillo Y.J.
      • Choong Y.K.
      • Cornell Y.T.
      • Decaen Y.A.
      • Deymann Y.A.
      • et al.
      Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine.
      ] in paediatric populations, which can be achieved by earlier initiation of peripheral inotropes in lieu of additional fluid administration.
      At present, various strategies exist to treat refractory septic shock, such as Hydrocortisone and immunomodulation, and extracorporeal therapies. A novel and highly controversial approach includes administration of Hydrocortisone, Thiamine and Vitamin C (HAT) [
      • Donnino M.W.
      • Andersen L.W.
      • Chase M.
      Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study.
      ], showing some promise for decreased mortality in a United States RCT (p < .001) [
      • Marik E.P.
      • Khangoora V.
      • Rivera R.
      • Hooper M.H.
      • Catravas J.
      Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study.
      ]. A systematic review of metabolic resuscitation in septic shock revealed nine registered RCTs [
      • Moskowitz A.
      • Andersen W.L.
      • Huang T.D.
      • Berg M.K.
      • Grossestreuer V.A.
      • Marik E.P.
      • et al.
      Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation.
      ]. Recently, two such studies presented conflicting results based on a primary outcome reflecting resolution of septic shock [
      • Fujii T.
      • Luethi N.
      • Young P.J.
      • Frei D.R.
      • Eastwood G.M.
      • French C.J.
      • et al.
      Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial.
      ,
      • Iglesias J.
      • Vassallo A.V.
      • Patel V.V.
      • Sullivan J.B.
      • Cavanaugh J.
      • Elbaga Y.
      Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: The ORANGES Trial.
      ]. Both studies were conducted in adult populations with small sample sizes, and similar metabolic studies on the management of paediatric septic shock are pending. Future studies for paediatrics should extend beyond shock resolution as a primary outcome to include focus on improvements (patient benefits) from reduction in measures of morbidity, such as long-term outcomes.

      3.2 Management of care post-sepsis

      The importance of long-term outcomes post-sepsis are increasingly recognised [
      • Zimmerman J.J.
      • Banks A.R.
      • Berg J.R.
      • Zuppa M.A.
      • Newth L.C.
      • Wessel W.D.
      • et al.
      Trajectory of mortality and health-related quality of life morbidity following community-acquired pediatric septic shock.
      ,
      • Killien E.
      • Farris R.
      • Watson R.
      • Flanagin M.
      • Zimmerman J.
      Deterioration in health-related quality of life is common among children surviving sepsis.
      ,
      • Simon W.D.
      • Clark B.R.S.
      • Watson S.R.R.
      No pain, no gain in pediatric sepsis?.
      ,
      • Aspesberro F.
      • Mangione-Smith R.
      • Zimmerman J.
      Health-related quality of life following pediatric critical illness.
      ,
      • Syngal P.
      • Giuliano J.
      Health-related quality of life after pediatric severe sepsis.
      ]. Research focus is shifting from predominately mortality outcomes [
      • Aspesberro F.
      • Mangione-Smith R.
      • Zimmerman J.
      Health-related quality of life following pediatric critical illness.
      ], to include QoL and functional outcomes [
      • Zimmerman J.J.
      • Banks A.R.
      • Berg J.R.
      • Zuppa M.A.
      • Newth L.C.
      • Wessel W.D.
      • et al.
      Trajectory of mortality and health-related quality of life morbidity following community-acquired pediatric septic shock.
      ,
      • Syngal P.
      • Giuliano J.
      Health-related quality of life after pediatric severe sepsis.
      ]. Such shifts are critical given the burden of sepsis sequelae on a child’s life can include physical, psychological and developmental compromise [
      • Zimmerman J.J.
      • Banks A.R.
      • Berg J.R.
      • Zuppa M.A.
      • Newth L.C.
      • Wessel W.D.
      • et al.
      Critical illness factors associated with long-term mortality and health-related quality of life morbidity following community-acquired pediatric septic shock.
      ,
      • Killien E.
      • Farris R.
      • Watson R.
      • Flanagin M.
      • Zimmerman J.
      Deterioration in health-related quality of life is common among children surviving sepsis.
      ,
      • Schlapbach L.J.
      • Aebischer M.
      • Adams M.
      • Natalucci G.
      • Bonhoeffer J.
      • Latzin P.
      • et al.
      Impact of sepsis on neurodevelopmental outcome in a Swiss national cohort of extremely premature infants. (Report).
      ]. Recent guidelines highlight the need for research to identify and test predictors of long-term morbidity [
      • Coopersmith M.C.
      • De Backer S.D.
      • Deutschman R.C.
      • Ferrer S.R.
      • Lat E.I.
      • Machado E.F.
      • et al.
      Surviving sepsis campaign: research priorities for sepsis and septic shock.
      ]. Given the high morbidity and life-long impacts of sepsis, it is important to look beyond the traditional acute phase of ‘avoid and treat organ dysfunction’ [
      • Zimmerman J.J.
      • Banks A.R.
      • Berg J.R.
      • Zuppa M.A.
      • Newth L.C.
      • Wessel W.D.
      • et al.
      Critical illness factors associated with long-term mortality and health-related quality of life morbidity following community-acquired pediatric septic shock.
      ] and begin to recognise the role and value of patient-centred care for sepsis survivors and families [
      • Aspesberro F.
      • Mangione-Smith R.
      • Zimmerman J.
      Health-related quality of life following pediatric critical illness.
      ,
      • Gill F.J.
      • Pascoe E.
      • Monterosso L.
      • Young J.
      • Burr C.
      • Tanner A.
      • et al.
      Parent and staff perceptions of family-centered care in two Australian children’s hospitals.
      ], inclusive of those who have lost a child. Secondary to survival, clinicians and families of children admitted to PICU chose QoL as the preferred outcome measure for their child [
      • Merritt D.C.
      • Menon S.K.
      • Agus R.M.S.
      • Choong J.K.
      • McNally J.D.
      • O’hearn J.K.
      • et al.
      Beyond survival: pediatric critical care interventional trial outcome measure preferences of families and healthcare professionals.
      ]. Families are at risk of isolation given the lack of formal support systems after sepsis. There is a lack of information on consumer perspectives and patient-focussed outcomes which may assist in reviewing the impact of sepsis on QoL. As we explore the ways to recognise and manage sepsis it is important to investigate the support structures and processes required by families and review the implications of sepsis recovery for survivors and the healthcare system on an ongoing basis, encompassing holistic patient care.

      4. Concluding statement — the need for a national approach

      This critical discussion of the key challenges around the recognition and management of paediatric sepsis highlights that, despite substantial progress in quality improvement initiatives and research, gaps in practice, research and education remain. In Australia, the National Action Plan for sepsis outlines how the WHO recommendations could be implemented locally [
      • Reinhart K.
      • Daniels R.
      • Kissoon N.
      • Machado F.R.
      • Schachter R.D.
      • Finfer S.
      Recognizing Sepsis as a global health priority — a WHO resolution.
      ,
      • Australia Sepsis Network
      Stopping sepsis: a national action plan.
      ]. Although currently, Australian states and territories do not have a standardised, nor mandated approach to sepsis care [
      • Weiss S.L.
      • Peters M.J.
      • Alhazzani W.
      • Agus M.S.D.
      • Flori H.R.
      • Inwald D.P.
      • et al.
      Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
      ,
      • Rhodes A.
      • Evans L.E.
      • Alhazzani W.
      • Levy M.M.
      • Antonelli M.
      • Ferrer R.
      • et al.
      Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016.
      ,
      • Dellinger R.
      • Levy M.
      • Rhodes A.
      • Annane D.
      • Gerlach H.
      • Opal S.
      • et al.
      Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012.
      ,
      • Dellinger R.
      • Levy M.
      • Carlet J.
      • Bion J.
      • Parker M.
      • Jaeschke R.
      • et al.
      Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008.
      ]. A streamlined, unified approach will enable standardised education, co-ordination, aligned care, and benchmarking, ensuring synergy between states and individual facilities. This is more likely to succeed by encompassing each of the different, yet complimentary perspectives and key components of sepsis recognition and management that contribute to the patient journey (Fig. 1). Specifically, Australia should leverage off the international experience in the field and adapt existing programs, such as the hospital training programs targeting sepsis recognition and management in the UK [
      • Robson W.P.
      • Daniels R.
      The sepsis six: helping patients to survive sepsis.
      ], alongside development of a national trust. New York State described improved outcomes stemming from implementation of mandated sepsis care [
      • Evans I.V.R.
      • Phillips G.S.
      • Alpern E.R.
      • Angus D.C.
      • Friedrich M.E.
      • Kissoon N.
      • et al.
      Association between the New York sepsis care mandate and in-hospital mortality for pediatric sepsis.
      ]. Each of these programs has expanded to include community awareness initiatives. Interestingly, the state of New York has embedded sepsis education into the school curriculum to improve sepsis awareness [
      • Line H.
      Jeremy Hunt launches nationwide sepsis campaign to help parents spot the signs in children [Media News].
      ,
      • New York State Education Department
      Sepsis.
      ]. In addition, sepsis education in undergraduate nursing and medical sectors is known to vary greatly across institutions [
      • Harley A.
      • Massey D.
      • Ullman A.J.
      • Reid-Searl K.
      • Schlapbach L.J.
      • Takashima M.
      • et al.
      Final year nursing student’s exposure to education and knowledge about sepsis: a multi-university study.
      ]. Nursing education aims to prepare students for entry into the workforce [
      • Schwartz S.
      Educating the nurse of the future: a report of the independent review into nursing education.
      ], and thus should integrate contemporary updates and priorities for change such as sepsis care [
      • Reinhart K.
      • Daniels R.
      • Kissoon N.
      • Machado F.R.
      • Schachter R.D.
      • Finfer S.
      Recognizing Sepsis as a global health priority — a WHO resolution.
      ,
      • Australia Sepsis Network
      Stopping sepsis: a national action plan.
      ]. A national quality and safety standard of care on sepsis may provide further incentive for universities to develop a unified approach to curriculum development around sepsis [
      • Darcy-Mahoney E.A.
      • Hancock E.L.
      • Iorianni-Cimbak A.
      • Curley A.Q.M.
      Using high-fidelity simulation to bridge clinical and classroom learning in undergraduate pediatric nursing.
      ]. In conclusion, integration of the community, healthcare and university sector targeting the recognition and management of children with sepsis is needed to enable a sustainable improvement in paediatric sepsis outcomes. This critical discussion can help direct healthcare workers and policy makers as they develop, implement and evaluate interventions to improve the recognition and management of paediatric sepsis.

      Authorship contribution statement

      AH and LJS were responsible for conceptualisation and design. AH drafted the manuscript and subsequent versions. All authors contributed to manuscript development, critical review, revision and approved the final manuscript.

      Funding sources

      No funding was provided.

      Conflict of interest

      There are no conflicts of interest to declare.

      Acknowledgements

      We would like to thank Queensland Children’s Hospital and Clinical Excellence Queensland for supporting the Paediatric Sepsis Project aiming to improve the care for children with sepsis. Katie East for assisting in graphic design. We also thank the families, clinicians and researchers for sharing insights into the journey of paediatric sepsis.

      References

        • Fleischmann-Struzek C.
        • Goldfarb D.M.
        • Schlattmann P.
        • Schlapbach L.J.
        • Reinhart K.
        • Kissoon N.
        The global burden of paediatric and neonatal sepsis: a systematic review.
        Lancet Respir Med. 2018; 6: 223-230
        • Weiss S.L.
        • Fitzgerald J.C.
        • Pappachan J.
        • Wheeler D.
        • Jaramillo-Bustamante J.C.
        • Salloo A.
        • et al.
        Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study.
        Am J Respir Crit Care Med. 2015; 191: 1147-1157
        • Rudd K.E.
        • Johnson S.C.
        • Agesa K.M.
        • Shackelford K.A.
        • Tsoi D.
        • Kievlan D.R.
        • et al.
        Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study.
        Lancet. 2020; 395: 200-211
        • Liu L.
        • Oza S.
        • Hogan D.
        • Perin J.
        • Rudan I.
        • Lawn J.E.
        • et al.
        Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis.
        Lancet. 2015; 385: 430-440
        • Schlapbach L.J.
        • Straney L.
        • Alexander J.
        • Maclaren G.
        • Festa M.
        • Schibler A.
        • et al.
        Mortality related to invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand, 2002–13: a multicentre retrospective cohort study.
        Lancet Infect Dis. 2015; 15: 46-54
        • Zimmerman J.J.
        • Banks A.R.
        • Berg J.R.
        • Zuppa M.A.
        • Newth L.C.
        • Wessel W.D.
        • et al.
        Trajectory of mortality and health-related quality of life morbidity following community-acquired pediatric septic shock.
        Crit Care Med. 2020; 48: 329-337
        • Schlapbach J.L.
        Paediatric sepsis.
        Curr Opin Infect Dis. 2019; 32: 497-504
        • Reinhart K.
        • Daniels R.
        • Kissoon N.
        • Machado F.R.
        • Schachter R.D.
        • Finfer S.
        Recognizing Sepsis as a global health priority — a WHO resolution.
        N Engl J Med. 2017; 377: 414-417
        • Australia Sepsis Network
        Stopping sepsis: a national action plan.
        The George Institute for Global Health, 2017
        • Romero B.
        • Fry M.
        • Roche M.
        The impact of evidence-based sepsis guidelines on emergency department clinical practice: a pre-post medical record audit.
        J Clin Nurs. 2017; 26: 3588-3596
        • Davis L.A.
        • Carcillo A.J.
        • Aneja K.R.
        • Deymann J.A.
        • Lin C.J.
        • Nguyen C.T.
        • et al.
        American college of critical care medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock.
        Crit Care Med. 2017; 45: 1061-1093
        • Weiss S.L.
        • Peters M.J.
        • Alhazzani W.
        • Agus M.S.D.
        • Flori H.R.
        • Inwald D.P.
        • et al.
        Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
        Intensive Care Med. 2020; 46: 10-67
        • Harley A.
        • Latour J.M.
        • Schlapbach L.J.
        The role of parental concerns in the recognition of Sepsis in children: a literature review.
        Front Pediatr. 2019; 7: 161
        • Harley A.
        • Johnston A.N.B.
        • Denny K.J.
        • Keijzers G.
        • Crilly J.
        • Massey D.
        Emergency nurses’ knowledge and understanding of their role in recognising and responding to patients with sepsis: a qualitative study.
        Int Emerg Nurs. 2019; 43: 106-112
        • Alqudah M.
        • Qudah B.
        • Cowin L.
        • George A.
        • Johnson M.
        Understanding presentations of children with fever to a Sydney emergency department.
        Nurs Res Pract. 2019; 3: 1-4
        • Buntsma D.
        Patterns of paediatric emergency presentations to a tertiary referral centre in the Northern territory.
        J Paediatr Child Health. 2017; 53: 3
        • Biban P.
        Pediatric septic shock in the Emergency Department: can we set the alarm clock a little forward?.
        Pediatr Crit Care Med. 2016; 17: 1011-1012
        • Schlapbach L.J.
        • Weiss S.L.
        • Wolf J.
        Reducing collateral damage from mandates for time to antibiotics in pediatric sepsis-primum non nocere.
        JAMA Pediatr. 2019; 173: 409-410
        • Queensland Paediatric Quality Council
        Multi-incident analysis of SAC 1 paediatric clinical incidents 2012-2014.
        Report. Queensland Health, 2018
        • Launay E.
        • Gras-Le Guen C.
        • Martinot A.
        • Assathiany R.
        • Blanchais T.
        • Mourdi N.
        • et al.
        Suboptimal care in the initial management of children who died from severe bacterial infection: a population-based confidential inquiry.
        Pediatr Crit Care Med. 2010; 11: 469-474
        • Paul R.
        • Melendez E.
        • Stack A.
        • Capraro A.
        • Monuteaux M.
        • Neuman M.I.
        Improving adherence to PALS septic shock guidelines.
        Pediatrics. 2014; 133: e1358
        • Paul R.
        • Neuman M.I.
        • Monuteaux M.C.
        • Melendez E.
        Adherence to PALS sepsis guidelines and hospital length of stay.
        Pediatrics. 2012; 130: e273-e280
        • Cruz A.T.
        • Perry A.M.
        • Williams E.A.
        • Graf J.M.
        • Wuestner E.R.
        • Patel B.
        Implementation of goal-directed therapy for children with suspected sepsis in the emergency department.
        Pediatrics. 2011; 127: e758
        • Balamuth L.F.
        • Weiss C.S.
        • Fitzgerald W.J.
        • Hayes R.K.
        • Centkowski R.S.
        • Chilutti R.M.
        • et al.
        Protocolized treatment is associated with decreased organ dysfunction in pediatric severe Sepsis.
        Pediatr Crit Care Med. 2016; 17: 817-822
        • Lane R.D.
        • Funai T.
        • Reeder R.
        • Larsen G.Y.
        High reliability pediatric septic shock quality improvement initiative and decreasing mortality (Report).
        Pediatrics. 2016; 138
        • Todi S.
        Sepsis: new horizons.
        Indian J Crit Care Med. 2010; 14: 1-2
        • Larsen G.
        • Mecham N.
        • Greenberg R.
        An emergency department septic shock protocol and care guideline for children initiated at triage.
        Pediatrics. 2011; 127: E1585-E1592
        • Singer M.
        • Deutschman C.S.
        • Seymour C.W.
        • Shankar-Hari M.
        • Annane D.
        • Bauer M.
        • et al.
        The third international consensus definitions for sepsis and septic shock (Sepsis-3).
        J Am Med Assoc. 2016; 315: 801-810
        • Weiss S.L.
        • Pomerantz W.S.
        Septic shock in children: rapid recognition and initial resuscitation (first hour).
        2019 ([Available from: https://www.uptodate.com/contents/septic-shock-in-children-rapid-recognition-and-initial-resuscitation-first-hour])
        • Gill F.J.
        • Leslie G.D.
        • Marshall A.P.
        Barriers and facilitators to implementing a process to enable parent escalation of care for the deteriorating child in hospital.
        Health Expect. 2018; 21: 1095-1103
        • National Institute for Health and Care Excellence (NICE)
        Sepsis: risk stratification tools.
        • Clinical Excellence Commission
        Paediatric sepsis pathway.
        • Van Den Bruel A.
        • Aertgeerts B.
        • Bruyninckx R.
        • Aerts M.
        • Buntinx F.
        Signs and symptoms for diagnosis of serious infections in children: a prospective study in primary care.
        Br J Gen Pract. 2007; 57: 538-546
        • Liu V.X.
        • Escobar G.J.
        • Chaudhary R.C.
        • Prescott H.C.
        Healthcare utilization and infection in the week prior to sepsis hospitalization.
        Crit Care Med. 2018; 46: 513-516
        • Gill F.J.
        • Leslie G.D.
        • Marshall A.P.
        Parent escalation of care for the deteriorating child in hospital: a health-care improvement study.
        Health Expect. 2019; 22: 1078-1088
        • Dwyer Ta
        • Flenady T.
        • Kahl J.
        • Quinney L.
        Evaluation of a patient and family activated escalation system: Ryan’s rule.
        Aust Crit Care. 2020; 33: 39-46
        • Jeffery A.D.
        • Mutsch K.S.
        • Knapp L.
        Knowledge and recognition of SIRS and sepsis among pediatric nurses.
        Pediatr Nurs. 2014; 40: 271
        • Schlapbach L.
        • MacLaren G.
        • Festa M.
        • Alexander J.
        • Erickson S.
        • Beca J.
        • et al.
        Prediction of pediatric sepsis mortality within 1 h of intensive care admission.
        Intensive Care Med. 2017; 43: 1085-1096
        • Van Der Wekken L.C.W.
        • Alam N.
        • Holleman F.
        • van Exter P.
        • Kramer M.H.H.
        • Nanayakkara P.W.B.
        Epidemiology of sepsis and its recognition by emergency medical services personnel in the Netherlands.
        Prehosp Emerg Care. 2016; 20: 90-96
        • Green R.S.
        • Travers A.H.
        • Cain E.
        • Campbell S.G.
        • Jensen J.L.
        • Petrie D.A.
        • et al.
        Paramedic recognition of sepsis in the prehospital setting: a prospective observational study.
        Emerg Med Int. 2016; 20166717261
        • Groenewoudt A.M.
        • Roest M.M.A.
        • Leijten M.F.
        • Stassen M.P.
        Septic patients arriving with emergency medical services: a seriously ill population.
        Eur J Emerg Med. 2014; 21: 330-335
        • Smyth M.A.
        • Brace-McDonnell S.J.
        • Perkins G.D.
        Identification of adults with sepsis in the prehospital environment: a systematic review.
        BMJ. 2016; 6e011218
        • Alam N.
        • Oskam E.
        • Stassen P.M.
        • Exter P.V.
        • Van de Ven P.M.
        • Haak H.R.
        • et al.
        Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial.
        Lancet Respir Med. 2018; 6: 40-50
        • Rhodes A.
        • Evans L.E.
        • Alhazzani W.
        • Levy M.M.
        • Antonelli M.
        • Ferrer R.
        • et al.
        Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016.
        Crit Care Med. 2017; 45
        • Zimmerman J.J.
        • Banks A.R.
        • Berg J.R.
        • Zuppa M.A.
        • Newth L.C.
        • Wessel W.D.
        • et al.
        Critical illness factors associated with long-term mortality and health-related quality of life morbidity following community-acquired pediatric septic shock.
        Crit Care Med. 2020; 48: 319-328
        • Kleinpell R.
        • Aitken L.
        • Schorr C.A.
        Implications of the new international sepsis guidelines for nursing care.
        Am J Crit Care. 2013; 22 (1937-710X (Electronic))
        • Kleinpell R.
        • Blot S.
        • Boulanger C.
        • Fulbrook P.
        • Blackwood B.
        International critical care nursing considerations and quality indicators for the 2017 surviving sepsis campaign guidelines.
        Intensive Care Med. 2019; 45: 1663
        • Delaney M.M.
        • Friedman M.I.
        • Dolansky M.A.
        • Fitzpatrick J.J.
        Impact of a sepsis educational program on nurse competence.
        J Contin Educ Nurs. 2015; 46: 179-186
        • Maclay T.
        • Rephann A.
        The impact of early identification and a critical care-based sepsis response team on sepsis outcomes.
        Crit Care Nurse. 2017; 37: 88-91
        • Goulart L.d.S.
        • Ferreira Júnior M.A.
        • Sarti E.C.F.B.
        • Sousa Á.F.L.d.
        • Ferreira A.M.
        • Frota O.P.
        Are nurses updated on the proper management of patients with sepsis?.
        Esc Anna Nery. 2019; : 23
        • Storozuk S.A.
        • MacLeod M.L.P.
        • Freeman S.
        • Banner D.
        A survey of sepsis knowledge among Canadian emergency department registered nurses.
        Australas Emerg Care. 2019; 22: 119-125
        • Currey J.
        • Massey D.
        • Allen J.
        • Jones D.
        What nurses involved in a Medical Emergency Teams consider the most vital areas of knowledge and skill when delivering care to the deteriorating ward patient. A nurse-oriented curriculum development project.
        Nurse Educ Today. 2018; 67: 77-82
        • Harley A.
        • Massey D.
        • Ullman A.J.
        • Reid-Searl K.
        • Schlapbach L.J.
        • Takashima M.
        • et al.
        Final year nursing student’s exposure to education and knowledge about sepsis: a multi-university study.
        Nurse Educ Today. 2021; 97104703
        • Nelson P.D.
        • Lemaster H.T.
        • Plost N.G.
        • Zahner L.M.
        Recognizing sepsis in the adult patient.
        AJN. 2009; 109: 40-45
        • Inwald D.P.
        • Tasker R.C.
        • Peters M.J.
        • Nadel S.
        Emergency management of children with severe sepsis in the United Kingdom: the results of the Paediatric Intensive Care Society sepsis audit.
        Arch Dis Child. 2009; 94: 348
        • Evans I.V.R.
        • Phillips G.S.
        • Alpern E.R.
        • Angus D.C.
        • Friedrich M.E.
        • Kissoon N.
        • et al.
        Association between the New York sepsis care mandate and in-hospital mortality for pediatric sepsis.
        J Am Med Assoc. 2018; 320: 358-367
        • Burrell A.R.
        • McLaws M.L.
        • Fullick M.
        • Sullivan R.B.
        • Sindhusake D.
        SEPSIS KILLS: early intervention saves lives.
        Med J Aust. 2016; 204: 73
        • Robson W.
        • Beavis S.
        • Spittle N.
        An audit of ward nurses’ knowledge of sepsis.
        Nurs Crit Care. 2007; 12: 86-92
        • Cruz A.T.
        • Lane R.D.
        • Balamuth F.
        • Aronson P.L.
        • Ashby D.W.
        • Neuman M.I.
        • et al.
        Updates on pediatric sepsis.
        JACEP Open. 2020; 5: 981-983
        • Goldstein B.
        • Giroir B.
        • Randolph A.
        International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics.
        Pediatr Crit Care Med. 2005; 6: 2-8
        • Schlapbach L.J.
        • Kissoon N.
        Defining pediatric sepsis.
        JAMA Pediatr. 2018; 172: 312-314
        • Weiss S.L.
        • Fitzgerald J.C.
        • Balamuth F.
        • Alpern E.R.
        • Lavelle J.
        • Chilutti M.
        • et al.
        Delayed antimicrobial therapy increases mortality and organ dysfunction duration in pediatric sepsis.
        Crit Care Med. 2014; 42: 2409-2417
        • Macdonald S.
        • Keijzers G.
        • Taylor D.
        • Kinnear F.
        • Arendts G.
        • Fatovich D.
        • et al.
        Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial.
        Intensive Care Med. 2018; 44: 2070-2078
        • Maitland K.
        • Kiguli S.
        • Opoka R.
        • Engoru C.
        • Olupot-Olupot P.
        • Akech S.
        • et al.
        Mortality after fluid bolus in African children with severe infection.
        N Engl J Med. 2011; 364: 2483-2495
        • Gelbart B.
        Fluid bolus therapy in pediatric sepsis: current knowledge and future direction. (Report).
        Front Pediatr. 2018; 6
        • Keijzers G.
        • Macdonald S.P.J.
        • Udy A.A.
        • Arendts G.
        • Bailey M.
        • Bellomo R.
        • et al.
        The Australasian Resuscitation In Sepsis Evaluation: fluids or vasopressors in emergency department sepsis (ARISE FLUIDS), a multi-centre observational study describing current practice in Australia and New Zealand.
        Emerg Med Australas. 2020; 32: 586-598
        • Maitland K.
        • George E.C.
        • Evans J.A.
        • Kiguli S.
        • Olupot-Olupot P.
        • Akech S.O.
        • et al.
        Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial. (Report).
        BMC Med. 2013; 11
        • Carcillo A.J.
        • Fields I.A.
        Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock.
        Crit Care Med. 2002; 30: 1365-1378
        • Inwald D.
        • Canter R.
        • Woolfall K.
        • O’Hara C.
        • Mouncey P.
        • Zenasni Z.
        • et al.
        Restricted fluid bolus versus current practice in children with septic shock: the FiSh feasibility study and pilot RCT.
        Health Technol Assess. 2018; 22
        • Parker M.J.
        • Thabane L.
        • Fox-Robichaud A.
        • Liaw P.
        • Choong K.
        A trial to determine whether septic shock-reversal is quicker in pediatric patients randomized to an early goal-directed fluid-sparing strategy versus usual care (SQUEEZE): study protocol for a pilot randomized controlled trial.
        Trials. 2016; 17: 556
        • Corl K.A.
        • Prodromou M.
        • Merchant R.C.
        • Gareen I.
        • Marks S.
        • Banerjee D.
        • et al.
        The restrictive IV fluid trial in severe sepsis and septic shock (RIFTS): a randomized pilot study.
        Crit Care Med. 2019; 47: 951-959
        • Self W.H.
        • Semler M.W.
        • Bellomo R.
        • Brown S.M.
        • Deboisblanc B.P.
        • Exline M.C.
        • et al.
        Liberal versus restrictive intravenous fluid therapy for early septic shock: rationale for a randomized trial.
        Ann Emerg Med. 2018; 72: 457-466
        • Meyhoff T.S.
        • Hjortrup P.B.
        • Møller M.H.
        • Wetterslev J.
        • Lange T.
        • Kjær M.B.N.
        • et al.
        Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial—protocol and statistical analysis plan.
        Acta Anaesthesiol Scand. 2019; 63: 1262-1271
        • Keijzers G.
        • Macdonald S.P.J.
        • Udy A.A.
        • Arendts G.
        • Bailey M.
        • Bellomo R.
        • et al.
        The Australasian Resuscitation In Sepsis evaluation: FLUid or vasopressors in Emergency Department Sepsis, a multicentre observational study (ARISE FLUIDS observational study): rationale, methods and analysis plan.
        Emerg Med Australas. 2019; 31: 90-96
        • Brierley A.J.
        • Carcillo Y.J.
        • Choong Y.K.
        • Cornell Y.T.
        • Decaen Y.A.
        • Deymann Y.A.
        • et al.
        Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine.
        Crit Care Med. 2009; 37: 666-688
        • Donnino M.W.
        • Andersen L.W.
        • Chase M.
        Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study.
        Crit Care Med. 2016; 44: 360-367
        • Marik E.P.
        • Khangoora V.
        • Rivera R.
        • Hooper M.H.
        • Catravas J.
        Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study.
        Chest. 2017; 151: 1229-1238
        • Moskowitz A.
        • Andersen W.L.
        • Huang T.D.
        • Berg M.K.
        • Grossestreuer V.A.
        • Marik E.P.
        • et al.
        Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation.
        Crit Care. 2018; 22: 283
        • Fujii T.
        • Luethi N.
        • Young P.J.
        • Frei D.R.
        • Eastwood G.M.
        • French C.J.
        • et al.
        Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial.
        J Am Med Assoc. 2020; 323: 423-431
        • Iglesias J.
        • Vassallo A.V.
        • Patel V.V.
        • Sullivan J.B.
        • Cavanaugh J.
        • Elbaga Y.
        Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: The ORANGES Trial.
        Chest. 2020; 158: 164-173
        • Killien E.
        • Farris R.
        • Watson R.
        • Flanagin M.
        • Zimmerman J.
        Deterioration in health-related quality of life is common among children surviving sepsis.
        Crit Care Med. 2016; 44: 407
        • Simon W.D.
        • Clark B.R.S.
        • Watson S.R.R.
        No pain, no gain in pediatric sepsis?.
        Pediatr Crit Care Med. 2014; 15: 264-266
        • Aspesberro F.
        • Mangione-Smith R.
        • Zimmerman J.
        Health-related quality of life following pediatric critical illness.
        Intensive Care Med. 2015; 41: 1235-1246
        • Syngal P.
        • Giuliano J.
        Health-related quality of life after pediatric severe sepsis.
        Healthcare. 2018; 6
        • Schlapbach L.J.
        • Aebischer M.
        • Adams M.
        • Natalucci G.
        • Bonhoeffer J.
        • Latzin P.
        • et al.
        Impact of sepsis on neurodevelopmental outcome in a Swiss national cohort of extremely premature infants. (Report).
        Pediatrics. 2011; 128: e348
        • Coopersmith M.C.
        • De Backer S.D.
        • Deutschman R.C.
        • Ferrer S.R.
        • Lat E.I.
        • Machado E.F.
        • et al.
        Surviving sepsis campaign: research priorities for sepsis and septic shock.
        Crit Care Med. 2018; 46: 1334-1356
        • Gill F.J.
        • Pascoe E.
        • Monterosso L.
        • Young J.
        • Burr C.
        • Tanner A.
        • et al.
        Parent and staff perceptions of family-centered care in two Australian children’s hospitals.
        EJPCH. 2014; 1
        • Merritt D.C.
        • Menon S.K.
        • Agus R.M.S.
        • Choong J.K.
        • McNally J.D.
        • O’hearn J.K.
        • et al.
        Beyond survival: pediatric critical care interventional trial outcome measure preferences of families and healthcare professionals.
        Pediatr Crit Care Med. 2018; 19: e105-e111
        • Dellinger R.
        • Levy M.
        • Rhodes A.
        • Annane D.
        • Gerlach H.
        • Opal S.
        • et al.
        Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012.
        Intensive Care Med. 2013; 39: 165-228
        • Dellinger R.
        • Levy M.
        • Carlet J.
        • Bion J.
        • Parker M.
        • Jaeschke R.
        • et al.
        Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008.
        Intensive Care Med. 2008; 34: 17-60
        • Robson W.P.
        • Daniels R.
        The sepsis six: helping patients to survive sepsis.
        Br J Nurs. 2008; 17: 16-21
        • Line H.
        Jeremy Hunt launches nationwide sepsis campaign to help parents spot the signs in children [Media News].
        2016 ([Available from: https://www.independent.co.uk/life-style/health-and-families/health-news/sepsis-campaign-nhs-jeremy-hunt-children-condition-what-are-symptoms-signs-child-health-a7476426.html])
        • New York State Education Department
        Sepsis.
        2019 ([Available from: http://www.nysed.gov/curriculum-instruction/sepsis])
        • Schwartz S.
        Educating the nurse of the future: a report of the independent review into nursing education.
        • Darcy-Mahoney E.A.
        • Hancock E.L.
        • Iorianni-Cimbak A.
        • Curley A.Q.M.
        Using high-fidelity simulation to bridge clinical and classroom learning in undergraduate pediatric nursing.
        NET. 2013; 33: 648-654