Outcomes of interventions in neonatal sepsis: A systematic review of qualitative research.

BACKGROUND: While a systematic review exists detailing neonatal sepsis outcomes from clinical trials, there remains an absence of a qualitative systematic review capturing the perspectives of key stakeholders. OBJECTIVES: Our aim is to identify outcomes from qualitative research on any intervention to prevent or improve the outcomes of neonatal sepsis that are important to parents, other family members, healthcare providers, policymakers, and researchers as a part of the development of a core outcome set (COS) for neonatal sepsis. SEARCH STRATEGY: A literature search was carried out using MEDLINE, EMBASE, CINAHL, and PsycInfo databases. SELECTION CRITERIA: Publications describing qualitative data relating to neonatal sepsis outcomes were included. DATA COLLECTION AND ANALYSIS: Drawing on the concepts of thematic synthesis, texts related to outcomes were coded and grouped. These outcomes were then mapped to the domain headings of an existing model. MAIN RESULTS: Out of 6777 records screened, six studies were included. Overall, 19 outcomes were extracted from the included studies. The most frequently reported outcomes were those in the domains related to parents, healthcare workers and individual organ systemas such as gastrointestinal system. The remaining outcomes were classified under the headings of general outcomes, miscellaneous outcomes, survival, and infection. CONCLUSIONS: The outcomes identified in this review are different from those reported in neonatal sepsis clinical trials, thus highlighting the importance of incorporating qualitative studies into COS development to encapsulate all relevant stakeholders' perspectives.

Critical Organ Dysfunction and Preoperative Mortality in Newborns with Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is fatal without surgical intervention. An important subset of HLHS patients die prior to surgical intervention, but this population is underevaluated. The neonatal sequential organ failure assessment score (nSOFA) is an operational definition of organ dysfunction that can identify those with a high risk of mortality among neonatal intensive care unit (NICU) patients. The utility of the nSOFA to predict preoperative mortality in the unique HLHS population is unknown and could inform care, particularly care provided by neonatology staff. We performed a multicenter retrospective cohort study of HLHS cases across three level IV NICUs from January 1, 2009 to December 3, 2023. Patients were classified as either survived or died prior to surgical intervention. Demographic variables were curated from medical records including the maximum nSOFA (nSOFAmax) before surgical intervention or death. We identified 265 patients with HLHS over the study period. The nSOFAmax was greater in patients who died preoperatively (14/265; 5%) compared with survivors to surgical intervention (median 8 [interquartile range, 6, 12] vs. 2 [0, 4]; p < 0.001). The area under receiver operating characteristics curve for the nSOFAmax to discriminate for mortality was 0.93 (95% confidence interval, 0.88-0.98; p < 0.001). Compared with an nSOFAmax of 0, the likelihood ratio for preoperative death doubled at 2, tripled at 4, and was 10-fold at 9. This is the first demonstration of nSOFA utility in specific to congenital heart disease and HLHS. The nSOFAmax represents a novel, electronic health record-compatible, and generalizable method to identify patient-level organ dysfunction and risk for preoperative mortality in HLHS patients. KEY POINTS: · An important subset of HLHS patients die preoperatively.. · nSOFA can be used to measure preoperative HLHS severity.. · nSOFA predicts preoperative mortality risk in HLHS patients..

The frequency and timing of sepsis-associated coagulopathy in the neonatal intensive care unit.

Introduction: Sepsis is a common cause of morbidity and mortality in the neonatal intensive care unit (NICU). The frequency and severity of sepsis-associated coagulopathy as well as its relationship to illness severity are unclear. Methods: We performed a single-center, retrospective, observational cohort study of all infants admitted to the University of Florida Health (UF Health), level IV NICU between January 1st 2012 to March 1st 2020 to measure the frequency of sepsis-associated coagulopathy as well as its temporal relationship to critical illness in the NICU population. All clinical data in the electronic health record were extracted and deposited into an integrated data repository that was used for this work. Results: We identified 225 new sepsis episodes in 216 patients. An evaluation for sepsis-associated coagulopathy was performed in 96 (43%) episodes. Gram-negative pathogen, nSOFA score at evaluation, and mortality were greater among episodes that included a coagulopathy evaluation compared with those that did not. Abnormal coagulation results were common (271/339 evaluations; 80%) and were predominantly prothrombin times. Intervention (plasma or cryoprecipitate) followed a minority (84/271; 31%) of abnormal results, occurred in 40/96 (42%) episodes that were often associated with >1 intervention (29/40; 73%), and coincided with thrombocytopenia in 37/40 (93%) and platelet transfusion in 27/40 (68%). Shapley Additive Explanations modeling demonstrated strong predictive performance for the composite outcome of death and/or treatment for coagulopathy in neonates (f1 score 0.8, area under receiver operating characteristic curve 0.83 for those with abnormal coagulation values). The three most important features influencing the composite outcome of death or treatment for coagulopathy included administration of vasoactive medications, hematologic dysfunction assessed by the maximum nSOFA platelet score, and early sepsis (≤72 h after birth). Conclusions: A coagulopathy evaluation was performed in a minority of NICU patients with sepsis and was associated with greater illness severity and mortality. Abnormal results were common but infrequently associated with intervention, and intervention was contemporaneous with thrombocytopenia. The most important feature that influenced the composite outcome of death or treatment for coagulopathy was the administration of vasoactive-inotropic medications. These data help to identify NICU patients at risk of sepsis-associated coagulopathy.

International Consensus Criteria for Pediatric Sepsis and Septic Shock.

Importance: Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children. Objective: To update and evaluate criteria for sepsis and septic shock in children. Evidence Review: The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria. Findings: Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively. Conclusions and Relevance: The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock.

Importance: The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach. Objective: To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings. Design, Setting, and Participants: Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set. Exposure: Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock. Main Outcomes and Measures: The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity. Results: Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings. Conclusions and Relevance: The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

NRBC concentrations over time in neonates with moderate to severe neonatal encephalopathy with and without sentinel events.

OBJECTIVE: To study the serum concentrations of nucleated red blood cells (NRBC) over time in neonates with moderate to severe neonatal encephalopathy (NE). STUDY DESIGN: A retrospective cohort study with subjects subdivided into three groups: definite sentinel events (n = 52), probable sentinel events (n = 20) and no history of sentinel events (n = 63). Peak absolute NRBC and NRBC/100 WBC were compared between groups and with MRI Injury score, cord and admission pH/base deficit. RESULTS: Absolute NRBC peaked at 24.05 h after birth (CI: 15.30-32.79), 17.56 h after birth (CI: 7.35-27.77), and 39.81 h after birth (CI: 28.73-50.89) in each respective group. The peak in absolute NRBC correlated with the severity of injury in the grey matter in group 2 and white matter in groups 1 and 2. Higher peak absolute NRBC value correlated to a lower admission ABG pH. CONCLUSION: NRBC peak at 24 h after birth in neonates with sentinel events.

Protocol for the development of a core outcome set for neonatal sepsis (NESCOS).

Neonatal sepsis is a serious public health problem; however, there is substantial heterogeneity in the outcomes measured and reported in research evaluating the effectiveness of the treatments. Therefore, we aim to develop a Core Outcome Set (COS) for studies evaluating the effectiveness of treatments for neonatal sepsis. Since a systematic review of key outcomes from randomised trials of therapeutic interventions in neonatal sepsis was published recently, we will complement this with a qualitative systematic review of the key outcomes of neonatal sepsis identified by parents, other family members, parent representatives, healthcare providers, policymakers, and researchers. We will interpret the outcomes of both studies using a previously established framework. Stakeholders across three different groups i.e., (1) researchers, (2) healthcare providers, and (3) patients' parents/family members and parent representatives will rate the importance of the outcomes in an online Real-Time Delphi Survey. Afterwards, consensus meetings will be held to agree on the final COS through online discussions with key stakeholders. This COS is expected to minimize outcome heterogeneity in measurements and publications, improve comparability and synthesis, and decrease research waste.

Evaluation of the Neonatal Sequential Organ Failure Assessment and Mortality Risk in Neonates with Early-Onset Infection.

BACKGROUND: The discriminative utility of the neonatal sequential organ failure assessment (nSOFA) for early-onset sepsis (EOS) mortality in the neonatal intensive care unit (NICU) is unknown. OBJECTIVES: The objective of the study was to determine the utility of nSOFA for EOS mortality. METHODS: Multicenter, retrospective cohort study of NICU patients with EOS between 2012 and 2023. nSOFA scores of survivors and non-survivors were compared, and area under the receiver operating characteristics curve (AUROC) for mortality was calculated. RESULTS: 104 subjects were identified (88 lived, 16 died). AUROC at blood culture collection (T0), 6 h after collection (T6), and the maximum nSOFA at T0 or T6 (T0-6max) were 0.76 (95% CI: 0.62, 0.91), 0.89 (0.80, 0.99), and 0.87 (0.77, 0.97), respectively. Analyses restricted to birthweight (<1.5, <1 kg) or gestational age (<32, <29 week) cutoffs revealed AUROC ranges of 0.86-0.92 for T6 and 0.82-0.84 for T0-6max. CONCLUSIONS: The nSOFA showed good-to-excellent discrimination of mortality among infants with EOS in the NICU.

Reporting of Social Determinants of Health in Pediatric Sepsis Studies.

OBJECTIVE: Standardized, consistent reporting of social determinants of health (SDOH) in studies on children with sepsis would allow for: 1) understanding the association of SDOH with illness severity and outcomes, 2) comparing populations and extrapolating study results, and 3) identification of potentially modifiable socioeconomic factors for policy makers. We, therefore, sought to determine how frequently data on SDOH were reported, which factors were collected and how these factors were defined in studies of sepsis in children. DATA SOURCES AND SELECTION: We reviewed 106 articles (published between 2005 and 2020) utilized in a recent systematic review on physiologic criteria for pediatric sepsis. DATA EXTRACTION: Data were extracted by two reviewers on variables that fell within the World Health Organization's SDOH categories. DATA SYNTHESIS: SDOH were not the primary outcome in any of the included studies. Seventeen percent of articles (18/106) did not report on any SDOH, and a further 36.8% (39/106) only reported on gender/sex. Of the remaining 46.2% of articles, the most reported SDOH categories were preadmission nutritional status (35.8%, 38/106) and race/ethnicity (18.9%, 20/106). However, no two studies used the same definition of the variables reported within each of these categories. Six studies reported on socioeconomic status (3.8%, 6/106), including two from upper-middle-income and four from lower middle-income countries. Only three studies reported on parental education levels (2.8%, 3/106). No study reported on parental job security or structural conflict. CONCLUSIONS: We found overall low reporting of SDOH and marked variability in categorizations and definitions of SDOH variables. Consistent and standardized reporting of SDOH in pediatric sepsis studies is needed to understand the role these factors play in the development and severity of sepsis, to compare and extrapolate study results between settings and to implement policies aimed at improving socioeconomic conditions related to sepsis.

Sepsis and Mortality Prediction in Very Low Birth Weight Infants: Analysis of HeRO and nSOFA.

OBJECTIVE: Scores to predict sepsis or define sepsis severity could improve care for very low birth weight (VLBW) infants. The heart rate characteristics (HRC) index (HeRO score) was developed as an early warning system for late-onset sepsis (LOS), and also rises before necrotizing enterocolitis (NEC). The neonatal sequential organ failure assessment (nSOFA) was developed to predict sepsis-associated mortality using respiratory, hemodynamic, and hematologic data. The aim of this study was to analyze the HRC index and nSOFA near blood cultures in VLBW infants relative to diagnosis and sepsis-associated mortality. STUDY DESIGN: Retrospective, single-center study of VLBW infants from 2011 to 2019. We analyzed HRC index and nSOFA around blood cultures diagnosed as LOS/NEC. In a subgroup of the cohort, we analyzed HRC and nSOFA near the first sepsis-like illness (SLI) or sepsis ruled-out (SRO) compared with LOS/NEC. We compared scores by diagnosis and mortality during treatment. RESULTS: We analyzed 179 LOS/NEC, 93 SLI, and 96 SRO blood culture events. In LOS/NEC, the HRC index increased before the blood culture, while nSOFA increased at the time of culture. Both scores were higher in nonsurvivors compared with survivors and in LOS/NEC compared with SRO. The nSOFA 12 hours after the time of blood culture predicted mortality during treatment better than any other time point analyzed (area under the curve 0.91). CONCLUSION: The HRC index provides earlier warning of imminent sepsis, whereas nSOFA after blood culture provides better prediction of mortality. KEY POINTS: · The HRC index and nSOFA provide complementary information on sepsis risk and sepsis-related mortality risk.. · This study adds to existing literature evaluating these risk scores independently by analyzing them together and in cases of not only proven but also suspected infections.. · The impact of combining risk models could be improved outcomes for premature infants..

Neonatal sepsis definitions from randomised clinical trials.

INTRODUCTION: Neonatal sepsis is a leading cause of infant mortality worldwide with non-specific and varied presentation. We aimed to catalogue the current definitions of neonatal sepsis in published randomised controlled trials (RCTs). METHOD: A systematic search of the Embase and Cochrane databases was performed for RCTs which explicitly stated a definition for neonatal sepsis. Definitions were sub-divided into five primary criteria for infection (culture, laboratory findings, clinical signs, radiological evidence and risk factors) and stratified by qualifiers (early/late-onset and likelihood of sepsis). RESULTS: Of 668 papers screened, 80 RCTs were included and 128 individual definitions identified. The single most common definition was neonatal sepsis defined by blood culture alone (n = 35), followed by culture and clinical signs (n = 29), and then laboratory tests/clinical signs (n = 25). Blood culture featured in 83 definitions, laboratory testing featured in 48 definitions while clinical signs and radiology featured in 80 and 8 definitions, respectively. DISCUSSION: A diverse range of definitions of neonatal sepsis are used and based on microbiological culture, laboratory tests and clinical signs in contrast to adult and paediatric sepsis which use organ dysfunction. An international consensus-based definition of neonatal sepsis could allow meta-analysis and translate results to improve outcomes.

Frequency of Acute Kidney Injury and Association With Mortality Among Extremely Preterm Infants.

Importance: Neonatal acute kidney injury (AKI) is common and associated with morbidity and mortality. The temporal relationship between AKI and critical illness, as well as the frequency of AKI definition components (urine output and serum creatinine [sCr] concentration change), are unknown in extremely low-birth-weight (ELBW) (<1000 g), extremely preterm (<29 weeks' completed gestational age [GA]) infants. Objective: To measure the frequency of AKI from birth to death or discharge with attention to the definition components as well as the temporal relationship of AKI to critical illness and death. Design, Setting, and Participants: A single-center, multiyear, retrospective cohort study was conducted at an academic level IV neonatal intensive care unit between January 1, 2012, and January 1, 2020. Participants included inborn ELBW and infants at 22 to 28 weeks' completed GA with confirmed congenital anomalies who survived 12 hours or more. Exposures: Extremely preterm birth and ELBW. Main Outcomes and Measures: The primary outcome was AKI frequency. The timing, severity, and criteria for AKI were measured. The temporal relationship between AKI, organ dysfunction, and outcomes were quantified using odds ratios (ORs), logistic regression, and Shapley Additive Explanations. Acute kidney injury recognition, imaging, pediatric nephrology consultation, and follow-up were determined. Results: A total of 436 infants (52% male; 44% Black) met the inclusion criteria (median BW, 725 g; median GA, 25.7 wk). Acute kidney injury was common in the first week of life (44%), primarily based on the change in the sCr concentration criterion (88%), and negatively associated with GA (OR, 0.69; 95% CI, 0.60-0.78), but positively associated with antecedent critical illness (OR, 1.17; 95% CI, 1.12-1.23), severe intraventricular hemorrhage (OR, 1.86; 95% CI, 1.12-3.08), late-onset sepsis (OR, 1.03; 95% CI, 1.02-1.03), and mortality (OR, 2.77; 95% CI, 1.63-4.72). Acute kidney injury had negligible clinical contribution to death within the model (Shapley Additive Explanation, <0.5% change to outcome) relative to antecedent patient-concentration organ dysfunction (6%-15% change). Among infants with severe AKI, recognition (32%), nephrology inpatient consultation (16%), and outpatient follow-up (9%) were not common. Conclusions and Relevance: In this cohort study of ELBW infants, AKI was common in the first week of life, inversely associated with GA, and followed organ (primarily cardiovascular) dysfunction. Acute kidney injury considered as the primary pathway to mortality was rare, and amelioration of AKI to modify death was not well supported.

The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota.

Although modern clinical practices such as cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how the gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system, as assessed by single-cell proteomic and transcriptomic analyses. Early-life antibiotic exposure rendered newborn macaques more susceptible to bacterial pneumonia, concurrent with increases in neutrophil senescence and hyperinflammation, broad inflammatory cytokine signaling, and macrophage dysfunction. This pathogenic reprogramming of pulmonary immunity was further reflected by a hyperinflammatory signature in all pulmonary immune cell subsets coupled with a global loss of tissue-protective, homeostatic pathways in the lungs of dysbiotic newborns. Fecal microbiota transfer was associated with partial correction of the broad immune maladaptations and protection against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity and support the idea that gut microbiota promote the balance between pathways driving tissue repair and inflammatory responses associated with clinical recovery from infection in infants. Our results highlight a potential role for microbial transfer for immune support in these at-risk infants.

Evaluation of the Neonatal Sequential Organ Failure Assessment and Mortality Risk in Preterm Infants with Necrotizing Enterocolitis.

INTRODUCTION: The neonatal sequential organ failure assessment (nSOFA) score is a tool for calculating mortality risk of infants in the neonatal intensive care unit. The utility of the nSOFA in determining the risk of mortality or the association with surgical intervention among infants with necrotizing enterocolitis (NEC) has not been investigated. METHODS: We performed a retrospective, cohort study of preterm (<37 weeks) infants with NEC Bell's stage ≥ IIA at six hospitals from 2008 to 2020. An nSOFA score (range 0-15) was assigned to each patient at nine time points from 48 h before or after clinical illness was suspected. RESULTS: Of the 259 infants, nSOFA scores for infants who died (n = 39) or had the composite outcome of surgery or death (n = 114) were significantly higher (p < 0.05) early in the NEC course compared to nSOFA scores for infants who survived medical NEC. Twelve hours after evaluation, the area under the receiver operating characteristic curve was 0.87 (95% confidence interval [CI], 0.80-0.93) to discriminate for mortality and 0.84 (95% CI, 0.79-0.90) for surgery or death (p < 0.001). A maximum nSOFA score of ≥4 at -6, 0, 6, or 12 h following evaluation was associated with a 20-fold increase in mortality and 19-fold increase in surgery or death compared with a score of <4 (p < 0.001). CONCLUSION: In this multicenter cohort, the nSOFA score was able to discriminate well for death as well as surgery or death among infants with NEC. The nSOFA is a clinical research tool that may be used in infants with NEC to improve classification by objective quantification of organ dysfunction.

Neonatal sepsis: a systematic review of core outcomes from randomised clinical trials.

BACKGROUND: The lack of a consensus definition of neonatal sepsis and a core outcome set (COS) proves a substantial impediment to research that influences policy and practice relevant to key stakeholders, patients and parents. METHODS: A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In the included studies, the described outcomes were extracted in accordance with the provisions of the Core Outcome Measures in Effectiveness Trials (COMET) handbook and registered. RESULTS: Among 884 abstracts identified, 90 randomised controlled trials (RCTs) were included in this review. Only 30 manuscripts explicitly stated the primary and/or secondary outcomes. A total of 88 distinct outcomes were recorded across all 90 studies included. These were then assigned to seven different domains in line with the taxonomy for classification proposed by the COMET initiative. The most frequently reported outcome was survival with 74% (n = 67) of the studies reporting an outcome within this domain. CONCLUSIONS: This systematic review constitutes one of the initial phases in the protocol for developing a COS in neonatal sepsis. The paucity of standardised outcome reporting in neonatal sepsis hinders comparison and synthesis of data. The final phase will involve a Delphi Survey to generate a COS in neonatal sepsis by consensus recommendation. IMPACT: This systematic review identified a wide variation of outcomes reported among published RCTs on the management of neonatal sepsis. The paucity of standardised outcome reporting hinders comparison and synthesis of data and future meta-analyses with conclusive recommendations on the management of neonatal sepsis are unlikely. The final phase will involve a Delphi Survey to determine a COS by consensus recommendation with input from all relevant stakeholders.

Hourly Kinetics of Critical Organ Dysfunction in Extremely Preterm Infants.

Rationale: Use of severity of illness scores to classify patients for clinical care and research is common outside of the neonatal ICU. Extremely premature (<29 weeks' gestation) infants with extremely low birth weight (<1,000 g) experience significant mortality and develop severe pathology during the protracted birth hospitalization. Objectives: To measure at high resolution the changes in organ dysfunction that occur from birth to death or discharge home by gestational age and time, and among extremely preterm infants with and without clinically meaningful outcomes using the neonatal sequential organ failure assessment score. Methods: A single-center, retrospective, observational cohort study of inborn, extremely preterm infants with extremely low birth weight admitted between January 2012 and January 2020. Neonatal sequential organ failure assessment scores were calculated every hour for every patient from admission until death or discharge. Measurements and Main Results: Longitudinal, granular scores from 436 infants demonstrated early and sustained discrimination of those who died versus those who survived to discharge. The discrimination for mortality by the maximum score was excellent (area under curve, 0.91; 95% confidence intervals, 0.88-0.94). Among survivors with and without adverse outcomes, most score variation occurred at the patient level. The weekly average score over the first 28 days was associated with the sum of adverse outcomes at discharge. Conclusions: The neonatal sequential organ failure assessment score discriminates between survival and nonsurvival on the first day of life. The major contributor to score variation occurred at the patient level. There was a direct association between scores and major adverse outcomes, including death.

Criteria for Pediatric Sepsis-A Systematic Review and Meta-Analysis by the Pediatric Sepsis Definition Taskforce.

OBJECTIVE: To determine the associations of demographic, clinical, laboratory, organ dysfunction, and illness severity variable values with: 1) sepsis, severe sepsis, or septic shock in children with infection and 2) multiple organ dysfunction or death in children with sepsis, severe sepsis, or septic shock. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from January 1, 2004, and November 16, 2020. STUDY SELECTION: Case-control studies, cohort studies, and randomized controlled trials in children greater than or equal to 37-week-old postconception to 18 years with suspected or confirmed infection, which included the terms "sepsis," "septicemia," or "septic shock" in the title or abstract. DATA EXTRACTION: Study characteristics, patient demographics, clinical signs or interventions, laboratory values, organ dysfunction measures, and illness severity scores were extracted from eligible articles. Random-effects meta-analysis was performed. DATA SYNTHESIS: One hundred and six studies met eligibility criteria of which 81 were included in the meta-analysis. Sixteen studies (9,629 patients) provided data for the sepsis, severe sepsis, or septic shock outcome and 71 studies (154,674 patients) for the mortality outcome. In children with infection, decreased level of consciousness and higher Pediatric Risk of Mortality scores were associated with sepsis/severe sepsis. In children with sepsis/severe sepsis/septic shock, chronic conditions, oncologic diagnosis, use of vasoactive/inotropic agents, mechanical ventilation, serum lactate, platelet count, fibrinogen, procalcitonin, multi-organ dysfunction syndrome, Pediatric Logistic Organ Dysfunction score, Pediatric Index of Mortality-3, and Pediatric Risk of Mortality score each demonstrated significant and consistent associations with mortality. Pooled mortality rates varied among high-, upper middle-, and lower middle-income countries for patients with sepsis, severe sepsis, and septic shock (p < 0.0001). CONCLUSIONS: Strong associations of several markers of organ dysfunction with the outcomes of interest among infected and septic children support their inclusion in the data validation phase of the Pediatric Sepsis Definition Taskforce.

Refining the Pediatric Multiple Organ Dysfunction Syndrome.

Since its introduction into the medical literature in the 1970s, the term multiple organ dysfunction syndrome (or some variant) has been applied broadly to any patient with >1 concurrent organ dysfunction. However, the epidemiology, mechanisms, time course, and outcomes among children with multiple organ dysfunction vary substantially. We posit that the term pediatric multiple organ dysfunction syndrome (or MODS) should be reserved for patients with a systemic pathologic state resulting from a common mechanism (or mechanisms) that affects numerous organ systems simultaneously. In contrast, children in whom organ injuries are attributable to distinct mechanisms should be considered to have additive organ system dysfunctions but not the syndrome of MODS. Although such differentiation may not always be possible with current scientific knowledge, we make the case for how attempts to differentiate multiple organ dysfunction from other states of additive organ dysfunctions can help to evolve clinical and research priorities in diagnosis, monitoring, and therapy from largely organ-specific to more holistic strategies.