Protocol for a Randomized Multiple Center Trial of Conservative Versus Liberal Oxygenation Targets in Critically Ill Children (Oxy-PICU): Oxygen in Paediatric Intensive Care

OBJECTIVES: Oxygen administration is a fundamental part of pediatric critical care, with supplemental oxygen offered to nearly every acutely unwell child. However, optimal targets for systemic oxygenation are unknown. Oxy-PICU aims to evaluate the clinical effectiveness and cost-effectiveness of a conservative peripheral oxygen saturation (Spo2) target of 88-92% compared with a liberal target of more than 94%. DESIGN: Pragmatic, open, multiple-center, parallel group randomized control trial with integrated economic evaluation. SETTING: Fifteen PICUs across England, Wales, and Scotland. PATIENTS: Infants and children age more than 38 week-corrected gestational age to 16 years who are accepted to a participating PICU as an unplanned admission and receiving invasive mechanical ventilation with supplemental oxygen for abnormal gas exchange. INTERVENTION: Adjustment of ventilation and inspired oxygen settings to achieve an Spo2 target of 88-92% during invasive mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Randomization is 1:1 to a liberal Spo2 target of more than 94% or a conservative Spo2 target of 88-92% (inclusive), using minimization with a random component. Minimization will be performed on: age, site, primary reason for admission, and severity of abnormality of gas exchange. Due to the emergency nature of the treatment, approaching patients for written informed consent will be deferred to after randomization. The primary clinical outcome is a composite of death and days of organ support at 30 days. Baseline demographics and clinical status will be recorded as well as daily measures of oxygenation and organ support, and discharge outcomes. This trial received Health Research Authority approval on December 23, 2019 (reference: 272768), including a favorable ethical opinion from the East of England-Cambridge South Research Ethics Committee (reference number: 19/EE/0362). Trial findings will be disseminated in national and international conferences and peer-reviewed journals

Mechanical power in pediatric acute respiratory distress syndrome:a PARDIE study

BACKGROUND: Mechanical power is a composite variable for energy transmitted to the respiratory system over time that may better capture risk for ventilator-induced lung injury than individual ventilator management components. We sought to evaluate if mechanical ventilation management with a high mechanical power is associated with fewer ventilator-free days (VFD) in children with pediatric acute respiratory distress syndrome (PARDS). METHODS: Retrospective analysis of a prospective observational international cohort study. RESULTS: There were 306 children from 55 pediatric intensive care units included. High mechanical power was associated with younger age, higher oxygenation index, a comorbid condition of bronchopulmonary dysplasia, higher tidal volume, higher delta pressure (peak inspiratory pressure—positive end-expiratory pressure), and higher respiratory rate. Higher mechanical power was associated with fewer 28-day VFD after controlling for confounding variables (per 0.1 J·min(−1)·Kg(−1) Subdistribution Hazard Ratio (SHR) 0.93 (0.87, 0.98), p = 0.013). Higher mechanical power was not associated with higher intensive care unit mortality in multivariable analysis in the entire cohort (per 0.1 J·min(−1)·Kg(−1) OR 1.12 [0.94, 1.32], p = 0.20). But was associated with higher mortality when excluding children who died due to neurologic reasons (per 0.1 J·min(−1)·Kg(−1) OR 1.22 [1.01, 1.46], p = 0.036). In subgroup analyses by age, the association between higher mechanical power and fewer 28-day VFD remained only in children < 2-years-old (per 0.1 J·min(−1)·Kg(−1) SHR 0.89 (0.82, 0.96), p = 0.005). Younger children were managed with lower tidal volume, higher delta pressure, higher respiratory rate, lower positive end-expiratory pressure, and higher PCO(2) than older children. No individual ventilator management component mediated the effect of mechanical power on 28-day VFD. CONCLUSIONS: Higher mechanical power is associated with fewer 28-day VFDs in children with PARDS. This association is strongest in children < 2-years-old in whom there are notable differences in mechanical ventilation management. While further validation is needed, these data highlight that ventilator management is associated with outcome in children with PARDS, and there may be subgroups of children with higher potential benefit from strategies to improve lung-protective ventilation. Take Home Message: Higher mechanical power is associated with fewer 28-day ventilator-free days in children with pediatric acute respiratory distress syndrome. This association is strongest in children <2-years-old in whom there are notable differences in mechanical ventilation management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13054-021-03853-6

Organizational characteristics of European pediatric onco-critical care: An international cross-sectional survey

BACKGROUND Intensified treatment protocols have improved survival of pediatric oncology patients. However, these treatment protocols are associated with increased treatment-related morbidity requiring admission to pediatric intensive care unit (PICU). We aimed to describe the organizational characteristics and processes of care for this patient group across PICUs in Europe. METHODS A web-based survey was sent to PICU directors or representative physicians between February and June 2021. RESULTS Responses were obtained from 77 PICUs of 12 European countries. Organizational characteristics were similar across the different countries of Europe. The median number of PICU beds was 12 (IQR 8-16). The majority of the PICUs was staffed by pediatric intensivists and had a 24/7 intensivist coverage. Most PICUs had a nurse-to-patient ratio of 1:1 or 1:2. The median numbers of yearly planned and unplanned PICU admissions of pediatric cancer patients were 20 (IQR 10-45) and 10 (IQR 10-30, respectively. Oncology specific practices within PICU were less common in participating centres. This included implementation of oncology protocols in PICU (30%), daily rounds of PICU physicians on the wards (13%), joint mortality and morbidity meetings or complex patients' discussions (30% and 40%, respectively) and participation of parents during clinical rounds (40%). CONCLUSION Our survey provides an overview on the delivery of critical care for oncology patients in PICU across European countries. Multidisciplinary care for these vulnerable and challenging patients remains complex and challenging. Future studies need to determine the effects of differences in PICU organization and processes of care on patients' outcome

A clinical and economic evaluation of Control of Hyperglycaemia in Paediatric intensive care (CHiP): a randomised controlled trial.

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

Exercise Induced Systemic Venous Hypertension in the Fontan Circulation

Increasingly end-organ injury is being demonstrated late after institution of the Fontan circulation, particularly liver fibrosis and cirrhosis. The exact mechanisms for these late phenomena remain largely elusive. Hypothesizing that exercise induces precipitous systemic venous hypertension and insufficient cardiac output for the exercise demand, i.e. a possible mechanism for end-organ injury, we sought to demonstrate the dynamic exercise responses in systemic venous (SVP) and concurrent end organ perfusion. Ten stable Fontan patients and 9 control subjects underwent incremental cycle ergometry based cardiopulmonary exercise testing. SVP was monitored in the right upper limb and regional tissue oxygen saturation was monitored in the brain and kidney using Near Infrared Spectroscopy. SVP rose profoundly in concert with workload in the Fontan group, described by the regression equation 15.97+0.073 Watts per mm Hg. In contrast SVP did not change in healthy controls. Regional renal (p<0.01) and cerebral tissue saturations (p<0.001) were significantly lower and fell more rapidly in Fontan patients. We conclude that in a stable group of adult patients with Fontan circulation high intensity exercise was associated with systemic venous hypertension and reduced systemic oxygen delivery. This physiologic substrate has the potential to contribute to endorgan injury

Distinct clinical phenotypes in paediatric cancer patients with sepsis are associated with different outcomes—an international multicentre retrospective study

Background Identifying phenotypes in sepsis patients may enable precision medicine approaches. However, the generalisability of these phenotypes to specific patient populations is unclear. Given that paediatric cancer patients with sepsis have different host response and pathogen profiles and higher mortality rates when compared to noncancer patients, we determined whether unique, reproducible, and clinically-relevant sepsis phenotypes exist in this specific patient population

Use of selective gut decontamination in critically ill children: protocol for the Paediatric Intensive Care and Infection Control (PICnIC) pilot study.

INTRODUCTION: Healthcare-associated infections (HCAIs) are a major cause of morbidity and mortality in critically ill children. In critically ill adults, there are data that suggest the use of Selective Decontamination of the Digestive tract (SDD), alongside standard infection control measures reduce mortality and the incidence of HCAIs. SDD-enhanced infection control has not been compared directly with standard infection prevention strategies in the Paediatric Intensive Care Unit (PICU) population. The aim of this pilot study is to determine the feasibility of conducting a multicentre cluster randomised controlled trial (cRCT) in critically ill children comparing SDD with standard infection control. METHODS AND ANALYSIS: Paediatric Intensive Care and Infection Control is a parallel group pilot cRCT, with integrated mixed-methods study, comparing incorporation of SDD into infection control procedures to standard care. After a 1-week pretrial ecology surveillance period, recruitment to the cRCT will run for a period of 18 weeks, comprising: (1) baseline control period (2) pre, mid and post-trial ecology surveillance periods and (3) intervention period. Six PICUs (in England, UK) will begin with usual care in period 1, then will be randomised 1:1 by the trial statistician using computer-based randomisation, to either continue to deliver usual care or commence delivery of the intervention (SDD) in period 2. Outcomes measures include parent and healthcare professionals' views on trial feasibility, adherence to the SDD intervention, estimation of recruitment rate and understanding of potential patient-centred primary and secondary outcome measures for the definitive trial. The planned recruitment for the cRCT is 324 participants. ETHICS AND DISSEMINATION: The trial received favourable ethical opinion from West Midlands-Black Country Research Ethics Committee (reference: 20/WM/0061) and approval from the Health Research Authority (IRAS number: 239324). Informed consent is not required for SDD intervention or anonymised data collection but is sought for investigations as part of the study, any identifiable data collected and monitoring of medical records. Results will be disseminated via publications in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: ISRCTN40310490

Selective digestive tract decontamination to prevent healthcare associated infections in critically ill children: the PICNIC multicentre randomised pilot clinical trial.

Healthcare-associated infections (HCAIs) are a major cause of morbidity and mortality in critically ill children. Data from adult studies suggest Selective Decontamination of the Digestive tract (SDD) may reduce the incidence of HCAIs and improve survival. There are no data from randomised clinical trials in the paediatric setting. An open label, parallel group pilot cRCT and mixed-methods perspectives study was conducted in six paediatric intensive care units (PICUs) in England. Participants were children (> 37 weeks corrected gestational age, up to 16 years) requiring mechanical ventilation expected to last for at least 48 h. Sites undertook standard care for a period of 9 weeks and were randomised into 3 sites which continued standard care and 3 where SDD was incorporated into infection control practice for eligible children. Interviews and focus groups were conducted for parents and staff working in PICU. 434 children fulfilled eligibility criteria, of whom 368 (85%) were enrolled. This included 207 in the baseline phase (Period One) and 161 in the intervention period (Period Two). In sites delivering SDD, the majority (98%) of children received at least one dose of SDD and of these, 68% commenced within the first 6 h. Whilst admission swabs were collected in 91% of enrolled children, consent for the collection of additional swabs was low (44%). Recruited children were representative of the wider PICU population. Overall, 3.6 children/site/week were recruited compared with the potential recruitment rate for a definitive cRCT of 3 children/site/week, based on data from all UK PICUs. Parents (n = 65) and staff (n = 44) were supportive of the aims of the study, suggesting adaptations for a larger definitive trial including formulation and administration of SDD paste, approaches to consent and ecology monitoring. Stakeholders identified preferred clinical outcomes, focusing on complications of critical illness and quality-of-life. A definitive cRCT in SDD to prevent HCAIs in critically ill children is feasible but should include adaptations to ecology monitoring along with the dosing schedule and packaging into a paediatric specific format. A definitive study is supported by the findings with adaptations to ecology monitoring and SDD administration.Trial Registration: ISRCTN40310490 Registered 30/10/2020

NEUROlogical Prognosis After Cardiac Arrest in Kids (NEUROPACK) study: protocol for a prospective multicentre clinical prediction model derivation and validation study in children after cardiac arrest

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 <16 years), admitted to 1 of the 24 participating PICUs in the UK and Ireland, following an OHCA or IHCA. Patients are included if requiring more than 1 min of cardiopulmonary resuscitation and mechanical ventilation at PICU admission Children who had cardiac arrests in PICU or neonatal intensive care unit will be excluded. Candidate variables will be identified from data submitted to the Paediatric Intensive Care Audit Network registry. Primary outcome is neurodevelopmental status, assessed at 3 months by telephone interview using the Vineland Adaptive Behavioural Score II questionnaire. A clinical prediction model will be derived using logistic regression with model performance and accuracy assessment. External validation will be performed using the Therapeutic Hypothermia After Paediatric Cardiac Arrest trial dataset. We aim to identify 370 patients, with successful consent and follow-up of 150 patients. Patient inclusion started 1 January 2018 and inclusion will continue over 18 months. Ethics and dissemination Ethical review of this protocol was completed by 27 September 2017 at the Wales Research Ethics Committee 5, 17/WA/0306. The results of this study will be published in peer-reviewed journals and presented in conferences. Trial registration number NCT03574025