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Abstract Purpose Respiratory infections are the most common reason for admission to paediatric intensive care units (PICU). Most patients with lower respiratory tract infection (LRTI) receive broad-spectrum antimicrobials, despite low rates of bacterial culture confirmation. Here, we evaluated a molecular diagnostic test for LRTI to inform the better use of antimicrobials. Methods The Rapid Assay for Sick Children with Acute Lung infection Study was a single-centre, prospective, observational cohort study of mechanically ventilated children (> 37/40 weeks corrected gestation to 18 years) with suspected community acquired or ventilator-associated LRTI. We evaluated the use of a 52-pathogen custom TaqMan Array Card (TAC) to identify pathogens in non-bronchoscopic bronchoalveolar lavage (mini-BAL) samples. TAC results were compared to routine microbiology testing. Primary study outcomes were sensitivity and specificity of TAC, and time to result. Results We enrolled 100 patients, all of whom were tested with TAC and 91 of whom had matching culture samples. TAC had a sensitivity of 89.5% (95% confidence interval (CI95) 66.9–98.7) and specificity of 97.9% (CI95 97.2–98.5) compared to routine bacterial and fungal culture. TAC took a median 25.8 h (IQR 9.1–29.8 h) from sample collection to result. Culture was significantly slower: median 110.4 h (IQR 85.2–141.6 h) for a positive result and median 69.4 h (IQR 52.8–78.6) for a negative result. Conclusions TAC is a reliable and rapid adjunct diagnostic approach for LRTI in critically ill children, with the potential to aid early rationalisation of antimicrobial therapy.

Neisseria meningitidis, the causative agent of meningococcal disease (MD), evades complement-mediated clearance upon infection by ‘hijacking’ the human complement regulator factor H (FH). The FH protein family also comprises the homologous FH-related (FHR) proteins, hypothesized to act as antagonists of FH, and FHR-3 has recently been implicated to play a major role in MD susceptibility. Here, we show that the circulating levels of all FH family proteins, not only FH and FHR-3, are equally decreased during the acute illness. We did neither observe specific consumption of FH or FHR-3 by N. meningitidis, nor of any of the other FH family proteins, suggesting that the globally reduced levels are due to systemic processes including dilution by fluid administration upon admission and vascular leakage. MD severity associated predominantly with a loss of FH rather than FHRs. Additionally, low FH levels associated with renal failure, suggesting insufficient protection of host tissue by the active protection by the FH protein family, which is reminiscent of reduced FH activity in hemolytic uremic syndrome. Retaining higher levels of FH may thus limit tissue injury during MD.

Background: Broad-spectrum antimicrobial therapy is a key driver of antimicrobial resistance. Here, we aimed to review indications for antimicrobial therapy, determine the proportion of suspected bacterial infections that are confirmed by culture, and assess the time taken for microbiology test results to become available in the paediatric intensive care unit (PICU). Methods: A single-centre prospective observational cohort study of 100 consecutive general PICU admissions from 30 October 2019 to 19 February 2020. Data were collected from the hospital medical record and entered into a study database prior to statistical analysis using standard methods. Results: Of all episodes of suspected infection, 22% of lower respiratory tract infection, 43% of bloodstream and 0% of central nervous system infection were associated with growth on microbiology culture. 90% of children received antimicrobial therapy. Hospital-acquired infection occurred less commonly than primary infection, but an organism was grown in a greater proportion (64%) of cultures. Final laboratory reports for negative cultures were issued at a median of 120.3 hours for blood cultures and 55.5 hours for endotracheal tube aspirate cultures. Conclusions: Despite most critically children receiving antimicrobial therapy, infection was often not microbiologically confirmed. Novel molecular diagnostics may improve rationalisation of treatment in this population.

IMPORTANCE:. A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 is hypothesized to play a role in the pathogenesis of invasive infection, but studies in sepsis are lacking. OBJECTIVES:. To study A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 protein level in pediatric sepsis and to study the association with outcome. DESIGN:. Data from two prospective cohort studies. SETTING AND PARTICIPANTS:. Cohort 1 is from a single-center study involving children admitted to PICU with meningococcal sepsis (samples obtained at three time points). Cohort 2 includes patients from a multicenter study involving children admitted to the hospital with invasive bacterial infections of differing etiologies (samples obtained within 48 hr after hospital admission). MAIN OUTCOMES AND MEASURES:. Primary outcome measure was mortality. Secondary outcome measures were PICU-free days at day 28 and hospital length of stay. RESULTS:. In cohort 1 (n = 59), nonsurvivors more frequently had A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels above the detection limit than survivors at admission to PICU (8/11 [73%] and 6/23 [26%], respectively; p = 0.02) and at t = 24 hours (2/3 [67%] and 3/37 [8%], respectively; p = 0.04). In cohort 2 (n = 240), A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels in patients within 48 hours after hospital admission were more frequently above the detection limit than in healthy controls (110/240 [46%] and 14/64 [22%], respectively; p = 0.001). Nonsurvivors more often had detectable A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels than survivors (16/21 [76%] and 94/219 [43%], respectively; p = 0.003), which was mostly attributable to patients with Neisseria meningitidis. CONCLUSIONS AND RELEVANCE:. In children with bacterial infection, detection of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 within 48 hours after hospital admission is associated with death, particularly in meningococcal sepsis. Future studies should confirm the prognostic value of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 and should study pathophysiologic mechanisms.

Introduction Lower respiratory tract infection (LRTI) is the most commonly treated infection in critically ill children. Pathogens are infrequently identified on routine respiratory culture, and this is a time-consuming process. A syndromic approach to rapid molecular testing that includes a wide range of bacterial and fungal targets has the potential to aid clinical decision making and reduce unnecessary broad spectrum antimicrobial prescribing. Here, we describe a single-centre prospective cohort study investigating the use of a 52-pathogen TaqMan array card (TAC) for LRTI in the paediatric intensive care unit (PICU).Methods and analysis Critically ill children with suspected LRTI will be enrolled to this 100 patient single-centre prospective observational study in a PICU in the East of England. Samples will be obtained via routine non-bronchoscopic bronchoalveolar lavage which will be sent for standard microbiology culture in addition to TAC. A blood draw will be obtained via any existing vascular access device. The primary outcomes of the study will be (1) concordance of TAC result with routine culture and 16S rRNA gene sequencing and (2) time of diagnostic result from TAC versus routine culture. Secondary outcomes will include impact of the test on total antimicrobial prescriptions, a description of the inflammatory profile of the lung and blood in response to pneumonia and a description of the clinical experience of medical and nursing staff using TAC.Ethics and dissemination This study has been approved by the Yorkshire and the Humber-Bradford Leeds Research Ethics Committee (REC reference 20/YH/0089). Informed consent will be obtained from all participants. Results will be published in peer-reviewed publications and international conferences.Trial registration number NCT04233268.

Introduction Currently, we are unable to accurately predict mortality or neurological morbidity following resuscitation after paediatric out of hospital (OHCA) or in-hospital (IHCA) cardiac arrest. A clinical prediction model may improve communication with parents and families and risk stratification of patients for appropriate postcardiac arrest care. This study aims to the derive and validate a clinical prediction model to predict, within 1 hour of admission to the paediatric intensive care unit (PICU), neurodevelopmental outcome at 3 months after paediatric cardiac arrest.Methods and analysis A prospective study of children (age: >24 hours and

Objectives:. Sepsis is responsible for a substantial proportion of global childhood morbidity and mortality. However, evidence demonstrates major inaccuracies in the use of the term “sepsis” in clinical practice, coding, and research. Current and previous definitions of sepsis have been developed using expert consensus but the specific criteria used to identify children with sepsis have not been rigorously evaluated. Therefore, as part of the Society of Critical Care Medicine’s Pediatric Sepsis Definition Taskforce, we will conduct a systematic review to synthesize evidence on individual factors, clinical criteria, or illness severity scores that may be used to identify children with infection who have or are at high risk of developing sepsis-associated organ dysfunction and separately those factors, criteria, and scores that may be used to identify children with sepsis who are at high risk of progressing to multiple organ dysfunction or death. Data Sources:. We will identify eligible studies by searching the following databases: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. Study Selection:. We will include all randomized trials and cohort studies published between January 1, 2004, and March 16, 2020. Data Extraction:. Data extraction will include information related to study characteristics, population characteristics, clinical criteria, and outcomes. Data Synthesis:. We will calculate sensitivity and specificity of each criterion for predicting sepsis and conduct a meta-analysis if the data allow. We will also provide pooled estimates of overall hospital mortality. Conclusions:. The potential risk factors, clinical criteria, and illness severity scores from this review which identify patients with infection who are at high risk of developing sepsis-associated organ dysfunction and/or progressing to multiple organ dysfunction or death will be used to inform the next steps of the Pediatric Sepsis Definition Taskforce.

Abstract Background Early recognition and timely intervention are critical steps for the successful management of shock. The objective of this study was to develop a model to predict requirement for hemodynamic intervention in the pediatric intensive care unit (PICU); thus, clinicians can direct their care to patients likely to benefit from interventions to prevent further deterioration. Methods The model proposed in this study was trained on a retrospective cohort of all patients admitted to a tertiary PICU at a single center in the United States, and validated on another retrospective cohort of all patients admitted to the PICU at a single center in the United Kingdom. The PICU clinical information system database (Intellivue Clinical Information Portfolio, Philips, UK) was interrogated to collect physiological and laboratory data. The model was trained using a variant of AdaBoost, which learned a set of low-dimensional classifiers, each of which was age adjusted. Results A total of 7052 patients admitted to the US PICU was used for training the model, and a total of 970 patients admitted to the UK PICU was used for validation. On the training/validation datasets, the model showed better prediction of hemodynamic intervention (area under the receiver operating characteristic (AUROC) = 0.81/0.81) than systolic blood pressure-based (AUCROC = 0.58/0.67) or shock index-based (AUCROC = 0.63/0.65) models. Both of these models were age adjusted using the same classifier. Conclusions The proposed model reliably predicted the need for hemodynamic intervention in PICU patients and provides better classification performance when compared to systolic blood pressure-based or shock index-based models alone. This model could readily be built into a clinical information system to identify patients at risk of hemodynamic instability.

Background: There has been no randomised controlled trial (RCT) of fluid bolus therapy in paediatric sepsis in the developed world despite evidence that excess fluid may be associated with harm. Objectives: To determine the feasibility of the Fluids in Shock (FiSh) trial – a RCT comparing restricted fluid bolus (10 ml/kg) with current practice (20 ml/kg) in children with septic shock in the UK. Design: (1) Qualitative feasibility study exploring parents’ views about the pilot RCT. (2) Pilot RCT over a 9-month period, including integrated parental and staff perspectives study. Setting: (1) Recruitment took place across four NHS hospitals in England and on social media. (2) Recruitment took place across 13 NHS hospitals in England. Participants: (1) Parents of children admitted to a UK hospital with presumed septic shock in the previous 3 years. (2) Children presenting to an emergency department with clinical suspicion of infection and shock after 20 ml/kg of fluid. Exclusion criteria were receipt of > 20 ml/kg of fluid, conditions requiring fluid restriction and the patient not for full active treatment (i.e. palliative care plan in place). Site staff and parents of children in the pilot were recruited to the perspectives study. Interventions: (1) None. (2) Children were randomly allocated (1 : 1) to 10- or 20-ml/kg fluid boluses every 15 minutes for 4 hours if in shock. Main outcome measures: (1) Acceptability of FiSh trial, proposed consent model and potential outcome measures. (2) Outcomes were based on progression criteria, including recruitment and retention rates, protocol adherence and separation between the groups, and collection and distribution of potential outcome measures. Results: (1) Twenty-one parents were interviewed. All would have consented for the pilot study. (2) Seventy-five children were randomised, 40 to the 10-ml/kg fluid bolus group and 35 to the 20-ml/kg fluid bolus group. Two children were withdrawn. Although the anticipated recruitment rate was achieved, there was variability across the sites. Fifty-nine per cent of children in the 10-ml/kg fluid bolus group and 74% in the 20-ml/kg fluid bolus group required only a single trial bolus before shock resolved. The volume of fluid (in ml/kg) was 35% lower in the first hour and 44% lower over the 4-hour period in the 10-ml/kg fluid bolus group. Fluid boluses were delivered per protocol (volume and timing) for 79% of participants in the 10-ml/kg fluid bolus group and for 55% in the 20-ml/kg fluid bolus group, mainly as a result of delivery not being completed within 15 minutes. There were no deaths. Length of hospital stay, paediatric intensive care unit (PICU) transfers, and days alive and PICU free did not differ significantly between the groups. Two adverse events were reported in each group. A questionnaire was completed by 45 parents, 20 families and seven staff were interviewed and 20 staff participated in focus groups. Although a minority of site staff lacked equipoise in favour of more restricted boluses, all supported the trial. Conclusions: Even though a successful feasibility and pilot RCT were conducted, participants were not as unwell as expected. A larger trial is not feasible in its current design in the UK. Future work: Further observational work is required to determine the epidemiology of severe childhood infection in the UK in the postvaccine era. Trial registration: Current Controlled Trials ISRCTN15244462. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 51. See the NIHR Journals Library website for further project information.

Background: Early research in adults admitted to intensive care suggested that tight control of blood glucose during acute illness can be associated with reductions in mortality, length of hospital stay and complications such as infection and renal failure. Prior to our study, it was unclear whether or not children could also benefit from tight control of blood glucose during critical illness. Objectives: This study aimed to determine if controlling blood glucose using insulin in paediatric intensive care units (PICUs) reduces mortality and morbidity and is cost-effective, whether or not admission follows cardiac surgery. Design: Randomised open two-arm parallel group superiority design with central randomisation with minimisation. Analysis was on an intention-to-treat basis. Following random allocation, care givers and outcome assessors were no longer blind to allocation. Setting: The setting was 13 English PICUs. Participants: Patients who met the following criteria were eligible for inclusion: ≥ 36 weeks corrected gestational age; ≤ 16 years; in the PICU following injury, following major surgery or with critical illness; anticipated treatment > 12 hours; arterial line; mechanical ventilation; and vasoactive drugs. Exclusion criteria were as follows: diabetes mellitus; inborn error of metabolism; treatment withdrawal considered; in the PICU > 5 consecutive days; and already in CHiP (Control of Hyperglycaemia in Paediatric intensive care). Intervention: The intervention was tight glycaemic control (TGC): insulin by intravenous infusion titrated to maintain blood glucose between 4.0 and 7.0 mmol/l. Conventional management (CM): This consisted of insulin by intravenous infusion only if blood glucose exceeded 12.0 mmol/l on two samples at least 30 minutes apart; insulin was stopped when blood glucose fell below 10.0 mmol/l. Main outcome measures: The primary outcome was the number of days alive and free from mechanical ventilation within 30 days of trial entry (VFD-30). The secondary outcomes comprised clinical and economic outcomes at 30 days and 12 months and lifetime cost-effectiveness, which included costs per quality-adjusted life-year. Results: CHiP recruited from May 2008 to September 2011. In total, 19,924 children were screened and 1369 eligible patients were randomised (TGC, 694; CM, 675), 60% of whom were in the cardiac surgery stratum. The randomised groups were comparable at trial entry. More children in the TGC than in the CM arm received insulin (66% vs. 16%). The mean VFD-30 was 23 [mean difference 0.36; 95% confidence interval (CI) –0.42 to 1.14]. The effect did not differ among prespecified subgroups. Hypoglycaemia occurred significantly more often in the TGC than in the CM arm (moderate, 12.5% vs. 3.1%; severe, 7.3% vs. 1.5%). Mean 30-day costs were similar between arms, but mean 12-month costs were lower in the TGC than in CM arm (incremental costs –£3620, 95% CI –£7743 to £502). For the non-cardiac surgery stratum, mean costs were lower in the TGC than in the CM arm (incremental cost –£9865, 95% CI –£18,558 to –£1172), but, in the cardiac surgery stratum, the costs were similar between the arms (incremental cost £133, 95% CI –£3568 to £3833). Lifetime incremental net benefits were positive overall (£3346, 95% CI –£11,203 to £17,894), but close to zero for the cardiac surgery stratum (–£919, 95% CI –£16,661 to £14,823). For the non-cardiac surgery stratum, the incremental net benefits were high (£11,322, 95% CI –£15,791 to £38,615). The probability that TGC is cost-effective is relatively high for the non-cardiac surgery stratum, but, for the cardiac surgery subgroup, the probability that TGC is cost-effective is around 0.5. Sensitivity analyses showed that the results were robust to a range of alternative assumptions. Conclusions: CHiP found no differences in the clinical or cost-effectiveness of TGC compared with CM overall, or for prespecified subgroups. A higher proportion of the TGC arm had hypoglycaemia. This study did not provide any evidence to suggest that PICUs should stop providing CM for children admitted to PICUs following cardiac surgery. For the subgroup not admitted for cardiac surgery, TGC reduced average costs at 12 months and is likely to be cost-effective. Further research is required to refine the TGC protocol to minimise the risk of hypoglycaemic episodes and assess the long-term health benefits of TGC. Trial registration: Current Controlled Trials ISRCTN61735247. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 26. See the NIHR Journals Library website for further project information.