Oxygen supplementation is a recommended treatment for children with severe pneumonia or hypoxaemia. The open, fractional-factorial Children's Oxygen Administration Strategies Trial (COAST) recruited Kenyan and Ugandan children with severe pneumonia and hypoxaemia. Participants in the severe hypoxaemia stratum (SpO2 < 80%) were randomised to high-flow nasal therapy (HFNT) or low-flow oxygen (LFO), and in the hypoxaemia stratum (SpO2 80-91%) to HFNT, LFO or permissive hypoxaemia (ratio 1:1:2). The trial stopped early and there is ongoing uncertainty about the clinical benefits of the alternative strategies. There is a lack of evidence about the relative costs, of alternative oxygen delivery for critically-ill children in low- and middle- income countries. We used data from COAST to conduct a cost-consequence analysis of the treatment strategies. We measured resource use for 28 days post-randomisation (n = 1,842). Resources included oxygen delivery, medications, blood and fluid products, diagnostic tests, point of care tests, hospital admission and length of stay. We calculated the total costs and reported the incremental costs as the difference in the mean total costs between groups, adjusting for baseline differences. In the severe hypoxaemia stratum, the mean total cost was $393.04 for HFNT and $218.73 for LFO. In the hypoxemia stratum, the mean total costs were $391.95 (HFNT), $198.26 (LFO) and $167.80 (permissive). The adjusted cost difference between HFNT versus LFO and liberal versus permissive was $184.43 (95% CI l: $127.90, $240.95), and $124.01 (95% CI: $99.53, $148.49), respectively. The differences of HFNT and LFO versus permissive were $216.22 (95% CI: $160.77, $271.68) and $31.80 (95% CI: $11.49, $52.11), respectively. For children with severe hypoxaemia, HFNT is more costly than LFO. For children with hypoxaemia, either of HFNT or LFO were more costly than permissive hypoxaemia. The main driver of costs for HFNT is the high cost of equipment and consumables; other costs were similar across treatment groups in both strata, as were health outcomes.

OBJECTIVE:To describe the prespecified analysis plan for Protocolized Evaluation of Permissive Blood Pressure Targets vs. Usual Care (PRESSURE), a trial comparing a permissive mean arterial pressure (MAP) target above the age-specific fifth centile with usual care in critically ill children.DESIGN:Pragmatic, open, multicenter, parallel group randomized controlled trial with integrated economic evaluation.SETTING:Twenty-one PICUs in the United Kingdom.PATIENTS:Infants and children older than 38 weeks corrected gestational age to 16 years, accepted to a participating PICU, on invasive mechanical ventilation (IMV) and receiving vasoactive drugs for hypotension.INTERVENTION:Adjustment of hemodynamic support to achieve a permissive MAP target greater than the fifth centile for age during IMV.MEASUREMENTS AND MAIN RESULTS:The primary outcome is a composite 30-day mortality and duration of IMV, and it will be analyzed with a two-sample rank-sum test. Components will also be analyzed separately. Sensitivity analyses will adjust for adherence, and subgroup analyses will test interactions with baseline covariates. Secondary analyses will compare mortality at various time-points, duration of survival, time to liberation from IMV, functional status changes, receipt of renal replacement therapy and length of stay. The health economic analysis will follow the intention-to-treat principle and report the mean (95% CI) incremental costs, quality-adjusted life years and cost-effectiveness up to 12 months.CONCLUSIONS:Results will be reported following this plan through peer-reviewed publications and conference presentations.

Importance:Routine assessment of gastric residual volume (GRV) to guide enteral feeding in critically ill children is widespread but not based on evidence. Perceived high gastric volumes often lead to withholding feeds, impairing nutritional delivery. Objective:To evaluate the effect of not routinely assessing GRV compared with assessments at least every 6 hours in children undergoing mechanical ventilation on the duration of mechanical ventilation and survival and achievement of nutritional targets. Design, Setting, and Participants:A pragmatic, multicenter, randomized, noninferiority trial in 23 pediatric intensive care units (PICUs) in the UK and 1 in Switzerland. A total of 4700 children aged 0 to 16 years who were receiving invasive ventilation and starting enteral feeds were recruited between June 29, 2023, and December 7, 2025, with 30-day follow-up completed on January 6, 2026. Interventions:Children were randomized (1:1) to receive usual care (GRV assessment every 6 hours) or no routine GRV assessment to guide enteral feeding. In the no routine GRV assessment group, feed tolerance was assessed using only clinical signs. All other enteral feeding practices followed local protocols. Main Outcomes and Measures:The clinical co-primary outcome (noninferiority) was a composite of survival and days free from mechanical ventilation at 30 days. The nutritional co-primary outcome (superiority) was the percentage of children meeting energy requirements by 72 hours. Results:Of the 4700 children randomized (2352 to the no routine GRV assessment group and 2348 to the usual care group), 4460 were included in the intention-to-treat analysis (median [IQR] age, 8 [1-44] months; 1925 [42.6%] females). No routine GRV assessment was noninferior to regular 6-hourly assessments for survival and days free from mechanical ventilation at 30 days (median [IQR], 25 [21-27] days in both groups; adjusted odds ratio [OR], 0.95 [95% CI, 0.86-1.05]). Results of the per-protocol analysis were consistent with the intention-to-treat analysis (adjusted OR, 1.01 [95% CI, 0.90-1.13]). The mean percentage of energy requirements achieved by 72 hours was 80.3% in the no routine GRV assessment group and 76.8% in the usual care group (adjusted mean difference, 3.2 [95% CI, 1.3-5.2] percentage points; P < .001). Conclusions and Relevance:Among critically ill children being enterally fed, not assessing GRV routinely was noninferior to regular assessments every 6 hours and significantly increased nutritional achievement at 72 hours. Trial Registration:isrctn.org Identifier: ISRCTN79668198.

OBJECTIVES:To assess the impact of skin tone on the measurement and diagnostic accuracy of five fingertip pulse oximeters used by patients in the NHS (National Health Service) England COVID Oximetry @home scheme. DESIGN:Measurement and diagnostic accuracy study (exploring pulse oximeter accuracy across skin tones-EXAKT). SETTING:Twenty four intensive care units in England between June 2022 and August 2024. PARTICIPANTS:903 critically ill adults admitted to intensive care units screened for or enrolled into a trial evaluating different approaches to oxygen therapy. INTERVENTIONS:Pulse oximetry derived peripheral oxygen saturation (SpO2) measurements were compared with paired arterial oxygen saturation (SaO2) measurements from arterial blood analysed by co-oximetry (gold standard). Skin tone (individual typology angle) was objectively measured using a handheld spectrophotometer. MAIN OUTCOME MEASURES:Pulse oximeter measurement accuracy was assessed for bias, precision, and overall accuracy. Diagnostic accuracy for identifying SaO2 ≤92% was assessed by false negative and false positive rates for SpO2 using thresholds of ≤92% and ≤94%, and the area under the receiver operating characteristic curve, and by the presence of occult hypoxaemia (SaO2 <88% with SpO2 >92%). RESULTS:11 018 paired SpO2-SaO2 measurements were analysed. All tested pulse oximeters overestimated at lower values and underestimated at higher values of SaO2. On average, SpO2 readings were 0.6-1.5 percentage points higher for patients with darker skin tone (individual typology angle -44°) than for those with lighter skin tone (46°). At both SpO2 thresholds assessed, false negative rates increased with darker skin tones; the proportion of SpO2 measurements >94% despite a paired SaO2 ≤92% ranged from 5.3 to 35.3 percentage points higher for patients with darker skin tones than for those with lighter skin tones (7.6-62.2% v 1.2-26.9%, rate ratio 2.3-7.1). By contrast, false positive rates decreased with darker skin tones. CONCLUSIONS:Five pulse oximeters provided by the NHS England COVID Oximetry @home scheme yielded higher SpO2 measurements for patients with darker skin tones compared with those with lighter skin tones, which could translate into potentially clinically important differences in false negative and false positive rates for detecting hypoxaemia. TRIAL REGISTRATION:ClinicalTrials.gov NCT05481515.

OBJECTIVES:To describe the prespecified statistical analysis plan for the GASTRIC-PICU, a trial to evaluate the clinical and cost-effectiveness of no routine gastric residual volume (GRV) measurement to guide enteral feeding in mechanically ventilated children admitted to a pediatric intensive care. DESIGN:Multicenter, randomised, noninferiority, open-label trial with embedded economic evaluation. SETTING:Twenty-three PICUs across England, Scotland, Northern Ireland, and Switzerland. PATIENTS:Infants and children older than 38 weeks corrected gestational age to 16 years, accepted to a participating PICU, on mechanical ventilation and being fed enterally by the gastric route. INTERVENTIONS:Standard PICU feeding protocols, but without regular GRV measurement to guide feeding. MEASUREMENTS AND MAIN RESULTS:The primary clinical outcome is an ordinal composite of survival and days free from mechanical ventilation at 30 days (noninferiority). The primary effect estimate will be the adjusted odds ratio from a proportional odds logistic regression model with two-sided 95% CI. If the lower limit is not less than 1/1.2, we will declare noninferiority. The coprimary nutritional outcome is the percentage of the child's estimated energy requirements achieved by 72 hours, which will be tested for superiority. CONCLUSIONS:The GASTRIC-PICU trial will assess the noninferiority of no routine GRV measurements compared with standard at least 6-hourly GRV measurements. Prespecified statistical and health economic analysis plans for the GASTRIC-PICU study have been developed before trial completion to minimize analytical bias.

Adults who survive intensive care unit (ICU) admission with sepsis (sepsis survivors) have immune impairments involving concurrent inflammation and immunosuppression that increase their long-term risk of reinfections and mortality. Vaccine immunogenicity could therefore be abnormal in sepsis survivors but has never been examined. Here, in a 1:1 randomized, placebo-controlled trial, we tested the efficacy and immunogenicity of a single intramuscular dose of 13-valent pneumococcal conjugate vaccine (PCV13) in 214 sepsis survivors at ICU discharge. The PCV13 group (n = 104) experienced 43 primary outcome events (time to first infection-related rehospitalization or death during 365 days of follow-up) among 72.5 person-years of follow-up compared with 38 events among 76.5 person-years of follow-up in the placebo group (n = 110) [hazard ratio, 1.23 (95% CI, 0.80 to 1.91)]. The PCV13 group experienced higher rates of reinfections and received earlier antibiotic prescriptions in primary care. There were no vaccine-related serious adverse events. PCV13 immunogenicity assessments included serotype-specific immunoglobulin G (IgG), immunophenotyping, and pan-leukocyte RNA sequencing measured at baseline and 10 and 30 days postrandomization. PCV13-induced serotype-specific IgG responses varied across serotypes and participants, without excessive cytokine responses. PCV-induced blood transcriptional module responses in antigen-presenting cells and helper T cells were also variable. Variations in PCV13 immunogenicity were associated with age in men, body mass index in women, and cytotoxicity-associated gene modules regardless of sex. This trial showed that PCV13 administered at ICU discharge did not benefit this sepsis survivor population and underscores the need for further research to delineate treatable molecular mechanisms of postsepsis immune dysfunction (ClinicalTrials.gov identifier NCT03565159).

BACKGROUND:The optimal thromboprophylaxis among critically ill adults with COVID-19 is uncertain. OBJECTIVES:To determine the effectiveness and safety of intermediate-dose heparin compared with standard low-dose thromboprophylaxis. METHODS:In an ongoing adaptive platform trial (randomized embedded multifactorial adaptive platform for community-acquired pneumonia), critically ill patients with COVID-19 were randomized to intermediate-dose heparin or standard low-dose thromboprophylaxis. Interventions were continued in hospital for up to 14 days. The primary endpoint was organ support-free days (OSFDs), an ordinal outcome combining in-hospital survival and the number of days free of intensive care unit-based respiratory or cardiovascular organ support through 21 days. The primary analysis was an adjusted Bayesian hierarchical cumulative logistic model. An odds ratio (OR) > 1.0 represents an improved outcome with intermediate-dose heparin. RESULTS:Between April 27, 2021 and November 25, 2023, 1255 critically ill adults with COVID-19 were enrolled from 78 sites in 15 countries, of whom 1254 completed follow-up (n = 572 intermediate-dose, n = 682 low-dose). Enrollment was terminated prior to reaching a prespecified statistical trigger due to declining case numbers and slow recruitment. Median age was 59 years, and 36.7% were female (n = 461/1255). The probability that intermediate-dose heparin improved OSFDs was 73.5% (OR, 1.06; 95% credible interval, 0.87, 1.30), which did not meet the prespecified superiority threshold of 99%. Hospital survival was 77.1% (441/572) and 76.7% (523/682) in the intermediate- and low-dose heparin groups, respectively (median adjusted OR, 1.14; 95% credible interval, 0.86, 1.52). Major bleeding occurred in 10 of 572 (1.7%) and 14 of 682 (2.1%) patients receiving intermediate and standard low doses, respectively. CONCLUSION:Intermediate-dose heparin did not improve OSFDs or survival compared with standard thromboprophylaxis in critically ill patients with COVID-19. (ClinicalTrials.gov number: CT02735707).

Importance Routine assessment of gastric residual volume (GRV) to guide enteral feeding in critically ill children is widespread but not based on evidence. Perceived high gastric volumes often lead to withholding feeds, impairing nutritional delivery. Objective To evaluate the effect of not routinely assessing GRV compared with assessments at least every 6 hours in children undergoing mechanical ventilation on the duration of mechanical ventilation and survival and achievement of nutritional targets. Design, Setting, and Participants A pragmatic, multicenter, randomized, noninferiority trial in 23 pediatric intensive care units (PICUs) in the UK and 1 in Switzerland. A total of 4700 children aged 0 to 16 years who were receiving invasive ventilation and starting enteral feeds were recruited between June 29, 2023, and December 7, 2025, with 30-day follow-up completed on January 6, 2026. Interventions Children were randomized (1:1) to receive usual care (GRV assessment every 6 hours) or no routine GRV assessment to guide enteral feeding. In the no routine GRV assessment group, feed tolerance was assessed using only clinical signs. All other enteral feeding practices followed local protocols. Main Outcomes and Measures The clinical co–primary outcome (noninferiority) was a composite of survival and days free from mechanical ventilation at 30 days. The nutritional co–primary outcome (superiority) was the percentage of children meeting energy requirements by 72 hours. Results Of the 4700 children randomized (2352 to the no routine GRV assessment group and 2348 to the usual care group), 4460 were included in the intention-to-treat analysis (median [IQR] age, 8 [1-44] months; 1925 [42.6%] females). No routine GRV assessment was noninferior to regular 6-hourly assessments for survival and days free from mechanical ventilation at 30 days (median [IQR], 25 [21-27] days in both groups; adjusted odds ratio [OR], 0.95 [95% CI, 0.86-1.05]). Results of the per-protocol analysis were consistent with the intention-to-treat analysis (adjusted OR, 1.01 [95% CI, 0.90-1.13]). The mean percentage of energy requirements achieved by 72 hours was 80.3% in the no routine GRV assessment group and 76.8% in the usual care group (adjusted mean difference, 3.2 [95% CI, 1.3-5.2] percentage points; P < .001). Conclusions and Relevance Among critically ill children being enterally fed, not assessing GRV routinely was noninferior to regular assessments every 6 hours and significantly increased nutritional achievement at 72 hours. Trial Registration isrctn.org Identifier: ISRCTN79668198

OBJECTIVES:A conservative oxygenation strategy is recommended in adult and pediatric guidelines for the management of acute respiratory distress syndrome to reduce iatrogenic lung damage. In the recently reported Oxy-PICU trial, targeting peripheral oxygen saturations (Spo2) between 88% and 92% was associated with a shorter duration of organ support and greater survival, compared with Spo2 greater than 94%, in mechanically ventilated children following unplanned admission to PICU. We investigated whether this benefit was greater in those who had severely impaired oxygenation at randomization.DESIGN:Post hoc analysis of a pragmatic, open-label, multicenter randomized controlled trial.SETTING:Fifteen PICUs across England and Scotland.PATIENTS:Children between 38 weeks old corrected gestational age and 15 years accepted to a participating PICU as an unplanned admission and receiving invasive mechanical ventilation with supplemental oxygen for abnormal gas exchange.INTERVENTIONS:A mixed-effects ordinal regression model was used to explore the effect of severity of lung injury, dichotomized to an oxygen saturation index (OSI) less than 12 or greater than or equal to 12 at randomization, the trial group allocation, age, and Pediatric Index of Mortality-3 on the composite ordinal outcome measure of duration of organ support at day 30 and mortality, with death being the worst outcome. An interaction term was included to specifically understand the effect of trial arm allocation on those with and OSI less than 12 and OSI greater than or equal to 12.MEASUREMENTS AND MAIN RESULTS:Data were available for 1775 of 1986 eligible children. Two hundred twelve of 1775 children had an OSI greater than or equal to 12 at randomization. The trial primary outcome did not vary significantly according to OSI category. Both children with OSI less than 12 (odds ratio [OR], 0.85; 95% CI, 0.71-1.01) and OSI greater than or equal to 12 (OR, 0.95; 95% CI, 0.49-1.84) benefited from conservative arm allocation, with relative benefit greater for those with an OSI less than 12.CONCLUSIONS:These data do not provide evidence that a conservative oxygenation strategy should be limited to mechanically ventilated children with severely impaired oxygenation.

BackgroundWe sought to estimate whether a lower mean arterial blood pressure target, compared with a higher mean arterial blood pressure target, reduced 90-day all-cause mortality among critically ill adult patients with vasodilatory shock.MethodsWe conducted an individual patient data meta-analysis of randomized controlled trials that evaluated the effect of distinct thresholds of mean arterial blood pressure to guide vasopressor support among critically ill adults identified in a systematic literature search. The main exposure was a lower mean arterial pressure target compared with a higher mean arterial pressure target (including usual care). The primary outcome was 90-day all-cause mortality. We used a Bayesian random effects log-binomial model to estimate risk ratios with 95% credible intervals (CrIs).ResultsBetween 2010 and 2019, 3352 patients were randomly assigned in three trials (SEPSISPAM, OVATION pilot trial, and 65-Trial) across 103 hospitals from the United Kingdom, France, and Canada. When compared with a higher mean arterial blood pressure target or usual care, the risk ratio for 90-day all-cause mortality associated with a lower blood pressure target was 0.93 (95% CrI, 0.76 to 1.07; low certainty, posterior probability of benefit 87%). Results were consistent across multiple secondary and sensitivity analyses, including adjustment for prognostically important baseline covariates and alternative modeling techniques. Multiple approaches to evaluate the heterogeneity of treatment effect did not identify any subgroups that may potentially benefit from higher mean arterial blood pressure targets.ConclusionsTargeting a lower mean arterial blood pressure for vasopressor therapy in critically ill patients with vasodilatory shock possibly reduced 90-day all-cause mortality. However, the certainty of evidence is low, and this analysis does not exclude the possibility that lower targets may cause harm overall. Vasopressors are widely used among critically ill adults. However, there is a lack of clarity on the appropriate blood pressure target. An individual patient data meta-analysis compared higher versus lower mean arterial blood pressure targets for patients with vasodilatory shock.

OBJECTIVES:Sepsis trials likely include patients who vary in response to therapeutic interventions. The optimal approach to identify such differences in treatment response remains unclear. Estimating individualized absolute risk differences (iARDs) to model treatment response at an individual patient level using supervised effect models applied to randomized trial data may be informative. We explored the relationship between two subgrouping approaches and a recently published iARD model for the effect of early goal-directed therapy (EGDT) resuscitation in sepsis. DESIGN:Secondary analysis of the Protocolized Care for Early Septic Shock (ProCESS) and Australasian Resuscitation in Sepsis Evaluation (ARISE) trials. We applied clinical subtypes (α, β, γ, δ) to 829 ProCESS and 1588 ARISE patients and biologic "hyperinflammatory" and "nonhyperinflammatory" subphenotypes to 363 ProCESS patients with biomarker data using established methods. We predicted iARDs with supervised learning using clinical variables as predictors and 90-day mortality as the primary outcome. We evaluated iARD variability within subgroups. SETTING:Eighty-one sites worldwide. PATIENTS/SUBJECTS:Adults with septic shock. INTERVENTIONS:EGDT or usual care. MEASUREMENTS AND MAIN RESULTS:The average treatment effect of EGDT appeared to vary within both clinical and biologic subphenotypes. EGDT appeared potentially beneficial in the β and nonhyperinflammatory subphenotypes but harmful in the γ and hyperinflammatory subphenotypes. However, the predicted iARDs within each subgroup ranged from considerable harm to considerable benefit. For example, for the β-subtype, the average mortality reduction from EGDT was 8.5% (95% CI, -0.4 to 17.5), but the iARDs ranged from a 29% increase to a 16% reduction in mortality, with 39% of patients predicted to be harmed. CONCLUSIONS:Although both clinical and biologic phenotyping may identify subgroups whose average treatment effect is beneficial or harmful, individual risks and benefits within subgroups still vary dramatically, raising concern that phenotyping may not reliably or safely personalize sepsis care.

Background Recent epidemiological studies reported conflicting results regarding mortality trends for traumatic brain injury (TBI) patients. Mortality trends for the critically ill TBI population, and their drivers of changes, remains understudied. Particularly, withdrawal of life-sustaining therapy (WLST) decisions were rarely evaluated concurrently. In this study, we aimed to describe hospital mortality and WLST trends over the past 15 years in England, Wales and Northern Ireland for TBI patients admitted to an intensive care unit (ICU). Methods Observational cohort study, involving 235 adult ICUs participating in the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme (CMP). From April 1, 2009 to March 31, 2024, all TBI patients were included. Comparator cohorts consisted of patients with trauma, sepsis, and vascular brain injury recorded in the CMP. The primary outcome was hospital mortality. The secondary outcome was the incidence of WLST decisions. We also examined the proportion of patients experiencing predefined early secondary brain insults. Findings Of the 2,324,961 ICU admissions, we identified 45,684 unique TBI patients. Over the study period, hospital mortality for TBI patients increased from 25.6% (1021/3988) to 35.0% (1306/3727). The proportion of WLST decisions rose from 7.5% (301/4024) to 19.7% (759/3850). After adjustment for main confounders, multivariable analyses confirmed these trends. No similar trends were observed among the comparator cohorts. TBI patients were exposed to hypotension, hypocapnia, hypercapnia and hyperglycaemia in 49.8% (22,559/45,298), 29.9% (12,356/41,262), 33.6% (13,869/41,262) and 29.2% (12,127/41,505) of cases, respectively. Half of patients (50.3%, 20,747/41,265) were exposed to hypoxaemia, and this proportion increased markedly from 36.9% (1359/3684) to 61.2% (2186/3572) over time. Interpretation For critically ill TBI patients, hospital mortality and WLST decisions rates increased over time. These findings raise important questions regarding the processes and ethical frameworks underpinning WLST decisions. Funding UKRI, NIHR, UK Ministry of Defence, Alzheimer’s Research UK, French Society of Anaesthesiology and Critical Care, Gueules Cassées Foundation, INNOVEO donation fund.

Background Peripheral oxygen saturation (SpO(2)) above 94% is typical in children in paediatric intensive critical care units (PICUs) who are receiving invasive ventilation and supplemental oxygen. In a previous report from the Oxy-PICU trial, we showed that lower (conservative) oxygenation targets (SpO(2) 88-92%) are beneficial, showing small but statistically significant differences in duration of organ support and large but non-significant cost reductions at 30 days. In this pre-specified analysis of the Oxy-PICU trial, we compare longer-term outcomes and cost-effectiveness of conservative versus liberal (SpO(2) >94%) oxygenation targets in children with emergency PICU admission. Methods Oxy-PICU was a pragmatic, multicentre, open-label, randomised controlled trial in England and Scotland. Eligible children were older than 38 weeks and younger than 16 years and had been admitted for emergency care in one of 15 participating PICUs, where they received invasive respiratory support for abnormal gas exchange. Participants were randomly assigned (1:1) to either a conservative oxygenation target (SpO(2) 88-92%) or liberal oxygenation target (SpO(2) >94%). Survival status was assessed at 90 days and 1 year, and health-related quality of life (HRQoL), quality-adjusted life-years (QALYs), health-care costs, and incremental net monetary benefit were assessed at 1 year after the index hospital admission and randomisation. HRQoL was measured with age-appropriate Paediatric Quality of Life Generic Core Scales and mapped onto the Child Health Utility 9D index score. HRQoL and survival data were combined to construct QALYs. Costs at 1 year were derived from use of hospital, outpatient, and community health services. The trial was registered in the ISRCTN registry (ISRCTN92103439). Findings 2040 children were enrolled between Sept 1, 2020 and May 15, 2022. 1868 (916%) children were included in the 90-day survival analysis; of these 930 (498%) had been assigned liberal oxygen and 938 (502%) conservative oxygen. 1867 (915%) children were included in the 1-year survival analysis; 930 (498%) had been assigned liberal oxygenation and 937 (502%) conservative oxygen. At 90 days, 35 (37%) patients in the conservative oxygenation group and 45 (48%) patients in the liberal oxygenation group had died (adjusted hazard ratio [aHR] 075 [95% CI 048 to 117]). By 1 year, 52 (55%) patients in the conservative oxygenation group and 66 (71%) patients in the liberal oxygenation group had died (aHR 077 [95%CI 053 to 110]). Overall, mean HRQoL, life-years, and QALYs at 1 year were similar in the two groups. The adjusted incremental effect on cost of conservative oxygenation versus liberal oxygenation was -879 pound (95% CI -9036 to 7278), whereas the incremental difference in QALYs was estimated at 0001 (-0010 to 0011), leading to an incremental net monetary benefit of 894 pound (-7290 to 9078) associated with conservative oxygenation relative to liberal oxygenation. These results did not vary by age (<12 months vs >= 12 months), comorbidity at baseline, age-adjusted heart rate, or haemoglobin level at admission and were robust to alternative assumptions. Interpretation Compared with usual care (SpO(2) >94%) for invasively ventilated children who are admitted as an emergency to a PICU, conservative oxygenation (SpO(2) 88-92%) was not associated with differences in longer-term survival, costs, or cost-effectiveness. Taken together with previous findings of Oxy-PICU that conservative oxygenation compared with liberal oxygenation leads to better patient-centred and parent-centred outcomes at 30 days, these findings support the use of conservative oxygenation targets for this population.

BACKGROUND:In Africa, severe pneumonia remains the major cause of paediatric hospitalisation, resulting in high requirements for oxygen therapy. Adequate supplies of oxygen are key challenges for many low-resource hospitals. The World Health Organization manual for oxygen therapy advises 2-3 days of oxygen therapy for pneumonia and recommends against early weaning, even in the absence of hypoxaemia. Few data support this recommendation. We describe the oxygen use and timing of weaning in the COAST trial of oxygen therapy (ISRCTN15622505). METHODS:Children aged 28 days to 12 years presenting to 6 hospitals in Uganda and Kenya with severe pneumonia and hypoxaemia (saturations < 92% on pulse oximetry (SpO2) were eligible for the trial. Children in two strata (a) severe hypoxaemia (SpO2 < 80%) and (b) moderate hypoxaemia (SpO2 80-91%) were allocated to receive high flow nasal therapy (HFNT), low flow oxygen delivery (LFO) or control (no immediate oxygen (moderate hypoxaemia stratum only)). Children were closely monitored over 48 h by pulse oximetry and weaned off oxygen once SpO2 > 92%. We describe the oxygen use and proportion requiring respiratory support over time by intervention strategy. RESULTS:Of the 1842 children enroled the majority, 1454 (79%) had moderate hypoxaemia. In this stratum, by 2 and 8 h, 148 (41%) and 200/360 (55.6%) in the LFO arm had been weaned; in the HFNT arm, 213/362 (59%) were receiving respiratory support at 2 h in room alone, and by 8 h, 164/362 (45%) had been weaned. At 48 h, in the respective strata, 77-80% and 53-63% still had respiratory distress but without hypoxaemia and were thus not receiving oxygen. Median oxygen use at 48 h in the moderate hypoxaemia group was highest in LFO am 480L (IQR 236.2, 2132.2) compared to 113.4 L (IQR 0.0, 1453.9) in the HFNT and 0 L (IQR 0.0) in the control arms. Children requiring oxygen beyond 48 h, 17/33 (51.1%) and 9/46 (19.5%) in the respective strata, had additional cardiac conditions. CONCLUSIONS:Closely monitoring SpO2 resulted in early weaning and reduced the use of and exposure to oxygen. Where oxygen supplies are at a premium, this approach may improve equitable access for children with severe pneumonia.

Importance Supplemental oxygen is frequently given to patients in intensive care units (ICUs); however, there is insufficient evidence to guide its therapeutic use and to minimize the potential harm caused by administering too little or too much. Objective To determine whether reducing exposure to supplemental oxygen through a strategy of conservative oxygen therapy by using a peripheral oxygen saturation (Spo2) target of 90% (range, 88%-92%) reduces mortality at 90 days in mechanically ventilated adult patients receiving supplemental oxygen in the ICU. Design, Setting, and Participants Multicenter, pragmatic, randomized clinical trial conducted in 97 ICUs in the UK including 16 500 mechanically ventilated patients receiving supplemental oxygen. Participants were enrolled between May 2021 and November 2024. Follow-up was completed in February 2025. Interventions Participants randomized to conservative oxygen therapy (n = 8258) received the lowest fraction of inspired oxygen possible to maintain their Spo(2) at 90%. Participants randomized to usual oxygen therapy (n = 8242) received oxygen therapy at the discretion of the treating clinician. Main Outcomes and Measures The primary outcome was all-cause mortality at 90 days. Secondary outcomes included duration of ICU and acute hospital stay among survivors, days alive and free from organ support at 30 days, and mortality at other time points. Results Of 16 500 randomized patients, primary outcome data were available for 16 394 (8211 in the conservative and 8183 in the usual oxygen therapy group). Randomized groups were similar (median age, 60 [IQR, 48-71] years and 38.2% females in both groups [n = 5652]). Exposure to supplemental oxygen was 29% lower for participants in the conservative oxygen therapy group compared with the usual oxygen therapy group. By 90 days, 2908 participants (35.4%) in the conservative oxygen therapy group had died compared with 2858 (34.9%) in the usual oxygen therapy group. After adjustment for prespecified baseline variables, the risk difference was 0.7 percentage points (95% CI, -0.7 to 2.0; P = .28). There were no significant differences in durations in ICU or hospital stay, days alive and free from organ support at 30 days, or mortality at other time points. Conclusions and Relevance In adult patients receiving mechanical ventilation and supplemental oxygen in the ICU, minimizing oxygen exposure through conservative oxygen therapy did not significantly reduce all-cause mortality at 90 days.

Introduction The development of the target trial emulation (TTE) methodology has enhanced the conduct of non-randomised studies. By leveraging readily available routinely collected data, TTEs offer opportunities for complementing randomised controlled trials (RCTs), providing more precise estimates and improving the external validity of RCTs. To explore this potential, we selected a successfully completed RCT as a case study. In the FIRST-line support for Assistance in Breathing in Children (FIRST-ABC) step-up RCT, high flow nasal cannula (HFNC) was found to be non-inferior to continuous positive airway pressure (CPAP) in terms of time to liberation from respiratory support in the paediatric critical care setting. We will emulate the FIRST-ABC step-up trial using routinely collected data from the Paediatric Intensive Care Audit Network (PICANet) database.Methods and analysis This is a protocol for a TTE that will use longitudinally collected data from the PICANet database. The study aims to emulate the FIRST-ABC step-up RCT using an observational study design in a frequentist framework. We will benchmark the results against the published trial. The study will apply a new-user design by selecting children admitted to paediatric intensive care units that started HFNC or non-invasive ventilatory support (as a surrogate for CPAP). The eligibility criteria and selected outcomes will reflect those of FIRST-ABC within the constraints of the available routinely collected data. We will use advanced quantitative doubly robust methods to minimise the impact of confounding by indication and allow for heterogeneity according to child characteristics. The analysis will be repeated using a Bayesian approach for follow-up research.Ethics and dissemination The research received ethics approval from the London School of Hygiene & Tropical Medicine Research Ethics Committee. This study will expand the findings from the FIRST-ABC step-up RCT, providing additional insight from a large representative sample using real-world data. The frequentist and Bayesian approaches will enable a discussion about the advantages and drawbacks of the two strategies. The results will be disseminated to the research and clinical community and made accessible to the public. In addition, the study results will be used in future research, which aims to supplement RCTs with additional evidence from a TTE.

Background: In the United Kingdom, around 184,000 adults are admitted to an intensive care unit (ICU) each year with over 30% receiving mechanical ventilation. Oxygen is the commonest therapeutic intervention provided to these patients but it is unclear how much oxygen should be administered for the best clinical outcomes. Methods: The UK-ROX trial will evaluate the clinical and cost-effectiveness of conservative oxygen therapy (the minimum oxygen concentration required to maintain an oxygen saturation of 90% ± 2%) versus usual oxygen therapy in critically ill adults receiving supplemental oxygen when invasively mechanically ventilated in ICUs in England, Wales and Northern Ireland. The trial will recruit 16,500 patients from approximately 100 UK adult ICUs. Using a deferred consent model, enrolled participants will be randomly allocated (1:1) to conservative or usual oxygen therapy until ICU discharge or 90 days after randomisation. Objectives: The primary clinical outcome is all cause mortality at 90 days following randomisation. Discussion: The UK-ROX trial has received ethical approval from the South Central – Oxford C Research Ethics Committee (Reference: 20/SC/0423) and the Confidentiality Advisory Group (Reference: 22/CAG/0154). The trial commenced in May 2021 and, at the time of publication, 95 sites had opened to recruitment.

Background Severe pneumonia in African children results in poor long-term outcomes (deaths/readmissions) with undernutrition as a key risk factor. We hypothesised additional energy/protein-rich Ready-to-Use Therapeutic Foods (RUTF) would meet additional nutritional requirements and improve outcomes. Methods COAST-Nutrition was an open-label Phase 2 randomised controlled trial in children (aged 6 months-12 years) hospitalised with severe pneumonia (and hypoxaemia, SpO(2) <92%) in Mbale, Soroti, Jinja, Masaka Regional Referral Hospitals, Uganda and Kilifi County Hospital, Kenya (ISRCTN10829073 (registered 6th June 2018) PACTR202106635355751 (registered 2nd June 2021)). Children were randomised (ratio 1:1) to enhanced nutritional supplementation with RUTF (plus usual diet) for 56 days vs usual diet (control). The primary outcome was change in mid-upper arm circumference (MUAC) at 90 days as a composite with mortality. Secondary outcomes include anthropometric status, mortality, and readmissions at Days 28, 90 and 180. Findings Between 12 August 2018 and 22 April 2022, 846 eligible children were randomised, 424 to RUTF and 422 to usual diet, and followed for 180-days [12 (1%) lost-to-follow-up]. RUTF supplement was initiated in 417/419 (>99%). By Day 90, there was no significant difference in the composite endpoint (probabilistic index 0.49, 95% CI 0.45-0.53, p = 0.74). Respective 90-day mortality (13/420 3.1% vs 14/421 3.3%) and MUAC increment (0.54 (SD 0.85) vs 0.55 (SD 0.81)) were similar between arms. There was no difference in any anthropometric secondary endpoints to Day 28, 90 or 180 except skinfold thickness at Day 28 and Day 90 was greater in the RUTF arm. Serious adverse events were higher in the RUTF arm (n = 164 vs 108), mainly due to hospital readmission for acute illness (54/387 (14%) vs 37/375 (10%). Interpretation Our study suggested that nutritional supplementation with RUTF did not improve outcomes to 180 days in children with severe pneumonia. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Rationale: Sepsis is a frequent cause of ICU admission and mortality. Objectives: To evaluate temporal trends in the presentation and outcomes of patients admitted to the ICU with sepsis and to assess the contribution of changing case mix to outcomes. Methods: We conducted a retrospective cohort study of patients admitted to 261 ICUs in the United Kingdom during 1988-1990 and 1996-2019 with nonsurgical sepsis. Measurements and Main Results: A total of 426,812 patients met study inclusion criteria. The patients had a median (interquartile range) age of 66 (53-75) years, and 55.6% were male. The most common sites of infection were respiratory (60.9%), genitourinary (11.5%), and gastrointestinal (10.3%). Compared with patients in 1988-1990, patients in 2017-2019 were older (median age, 66 vs. 63 yr), were less acutely ill (median Acute Physiology and Chronic Health Evaluation II acute physiology score, 14 vs. 20), andmore often had genitourinary sepsis (13.4% vs. 2.0%). Hospitalmortality decreased from54.6% (95% confidence interval [CI], 51.0-58.1%) in 1988-1990 to 32.4% (95% CI, 32.1-32.7%) in 2017-2019, with an adjusted odds ratio of 0.64 (95% CI, 0.54-0.75). The adjusted absolute hospitalmortality reduction from 1988-1990 to 2017-2019 was 8.8% (95% CI, 5.6-12.1). Thus, of the observed 22.2-percentage point reduction in hospitalmortality, 13.4 percentage points (60% of total reduction) were explained by case mix changes, whereas 8.8 percentage points (40% of total reduction) were not explained bymeasured factors andmay be a result of improvements in ICUmanagement. Conclusions: Over a 30-year period, mortality for ICU admissions with sepsis decreased substantially. Although changes in case mix accounted for the majority of observed mortality reduction, there was an 8.8-percentage point reduction in mortality not explained by case mix.