Clinical Effects of Nitric Oxide Added to the Oxygenator of Children on Extracorporeal Membrane Oxygenation: Pre-Post Cohort Study.

Nitric oxide (NO) can be safely delivered through the sweep gas to the oxygenator of an extracorporeal membrane oxygenation (ECMO) circuit. It has theoretical benefits such as preventing platelet adhesion to surfaces, mitigating inflammatory response and protection against ischemia-reperfusion injury. In this uncontrolled before-after study of children on ECMO, the outcomes of those who received NO were compared with those who did not. Among 393 ECMO runs (from 337 patients), 192 of 393 (49%) received NO and 201 of 393 (51%) did not. The use of NO was associated with a 37% reduction in circuit change (adjusted risk ratio [aRR]: 0.63, 95% confidence interval [CI]: 0.42-0.93). The aRR (95% CI) for risk of neurologic injury was 0.72 (0.47-1.11). We observed potential heterogeneity of treatment effect for the risk of neurologic injury in children who had cardiac surgery: the risk with NO was lower in those who had cardiac surgery (aRR: 0.50, 95% CI: 0.26-0.96). There was no difference in survival between the study groups. In children managed with NO delivered through the ECMO circuit, we report a reduction in observed rate of circuit change and lower risk of neurologic injury in children who underwent cardiac surgery. Nitric oxide therapy on ECMO warrants prospective evaluation in children.

High risk of necrotising enterocolitis in term-born neonates with CHD delivered by caesarean section: a case-control study.

OBJECTIVE: Necrotising enterocolitis is linked with altered intestinal microbiota, and caesarean birth is associated with imbalance of newborn intestinal microbiome. We aimed to investigate the role of delivery mode (vaginal or caesarean) and gestational age in the development of necrotising enterocolitis among term-born neonates (≥ 37 weeks) with CHD. METHODS: Case-control study. We studied all newborns with CHD who underwent cardiac surgery during the neonatal (≤ 28 days of age) period, between 2007 and 2017. Totally, 60 cases of necrotising enterocolitis were matched (by year of birth and type of congenital heart lesion) with 180 controls (1:3 ratio). Multivariable conditional logistic regression was used to assess the study question. RESULTS: The overall prevalence of necrotising enterocolitis was 6.3% in term-born newborns with CHD. Neonates with a left-ventricular outflow tract lesion or single ventricle lesion accounted for 55% (n = 33) of cases. 62% (n = 37) cases were in the modified Bell's stage 2 or more for necrotising enterocolitis classification. In multivariable modelling, gestational age at birth was not associated with the development of necrotising enterocolitis [adjusted odds ratio per week increase, 95% confidence interval: 1.20 (0.90-1.60)]. Birth by caesarean delivery (compared to vaginal) was strongly associated with development of necrotising enterocolitis [adjusted odds ratio (95% confidence interval): 2.64 (1.31-5.29)]. We failed to identify an association between preoperative enteral nutrition and necrotising enterocolitis. CONCLUSION: This study showed a high risk of necrotising enterocolitis in newborns with critical CHD born via caesarean. This information is important given the high prevalence of planned birth by caesarean in newborns with CHD.

Multi-modal MRI of hippocampal morphometry and connectivity after pediatric severe TBI.

This investigation explores memory performance using the California Verbal Learning Test in relation to morphometric and connectivity measures of the memory network in severe traumatic brain injury. Twenty-two adolescents with severe traumatic brain injury were recruited for multimodal MRI scanning 1-2 years post-injury at 13 participating sites. Analyses included hippocampal volume derived from anatomical T1-weighted imaging, fornix white matter microstructure from diffusion tensor imaging, and hippocampal resting-state functional magnetic resonance imaging connectivity as well as diffusion-based structural connectivity. A typically developing control cohort of forty-nine age-matched children also underwent scanning and neurocognitive assessment. Results showed hippocampus volume was decreased in traumatic brain injury with respect to controls. Further, hippocampal volume loss was associated with worse performance on memory and learning in traumatic brain injury subjects. Similarly, hippocampal fornix fractional anisotropy was reduced in traumatic brain injury with respect to controls, while decreased fractional anisotropy in the hippocampal fornix also was associated with worse performance on memory and learning in traumatic brain injury subjects. Additionally, reduced structural connectivity of left hippocampus to thalamus and calcarine sulcus was associated with memory and learning in traumatic brain injury subjects. Functional connectivity in the left hippocampal network was also associated with memory and learning in traumatic brain injury subjects. These regional findings from a multi-modal neuroimaging approach should not only be useful for gaining valuable insight into traumatic brain injury induced memory and learning disfunction, but may also be informative for monitoring injury progression, recovery, and for developing rehabilitation as well as therapy strategies.

Potential benefits of prenatal diagnosis of TGA in Australia may be outweighed by the adverse effects of earlier delivery: likely causation and potential solutions.

OBJECTIVE: Prenatal diagnosis of transposition of great arteries (TGA) is expected to improve postoperative outcomes after neonatal arterial switch operation (ASO); however, published reports give conflicting results. We aimed to determine the association between prenatal diagnosis and early postoperative outcomes after neonatal ASO. METHODS: Cohort study involving 243 newborns who underwent ASO (70% prenatally diagnosed) between 2010 and 2019. Multivariable regression was used to determine the association between prenatal diagnosis and (a) birth characteristics and (b) postoperative outcomes. RESULTS: Gestational age and birthweight centile were lower and small-for-gestational-age more common (11.8% vs 1.4%) in those diagnosed prenatally. Among births which followed labour induction or prelabour caesarean, prenatal diagnosis was associated with earlier gestation at birth (mean (SD), 38.5 (1.6) vs 39.2 (1.4), p=0.01). Among births which followed spontaneous labour, prenatal diagnosis was associated with earlier gestation at labour onset (38.2 (1.8) vs 39.2 (1.4), p=0.01). Prenatal diagnosis was associated with longer postoperative mechanical ventilation (incidence rate ratio 1.74, 95% CI 1.37 to 2.21), intensive care (1.70, 1.31 to 2.21) and hospital length of stay (1.37, 1.14 to 1.66) after ASO. Gestational age mediated up to 60% of the effect of prenatal diagnosis on postoperative outcomes. CONCLUSION: Among newborns undergoing ASO for TGA, prenatal diagnosis is associated with poorer early postoperative outcomes. In addition to minimising iatrogenic factors (such as planned births) resulting in earlier births, evaluation of other dynamics following a prenatal diagnosis which may result in poor fetal growth and earlier onset of spontaneous labour is important.

Safety and feasibility of adjunct autologous cord blood stem cell therapy during the Norwood heart operation.

BACKGROUND: We conducted this phase I, open-label safety and feasibility trial of autologous cord blood (CB) stem cell (CBSC) therapy via a novel blood cardioplegia-based intracoronary infusion technique during the Norwood procedure in neonates with an antenatal diagnosis of hypoplastic left heart syndrome (HLHS). CBSC therapy may support early cardiac remodeling with enhancement of right ventricle (RV) function during the critical interstage period. METHODS: Clinical grade CB mononucleated cells (CBMNCs) were processed to NetCord-FACT International Standards. To maximize yield, CBSCs were not isolated from CBMNCs. CBMNCs were stored at 4 °C (no cryopreservation) for use within 3 days and delivered after each cardioplegia dose (4 × 15 mL). RESULTS: Of 16 patients with antenatal diagnosis, 13 were recruited; of these 13 patients, 3 were not treated due to placental abruption (n = 1) or conditions delaying the Norwood for >4 days (n = 2) and 10 received 644.9 ± 134 × 106 CBMNCs, representing 1.5 ± 1.1 × 106 (CD34+) CBSCs. Interstage mortality was 30% (n = 3; on days 7, 25, and 62). None of the 36 serious adverse events (53% linked to 3 deaths) were related to CBMNC therapy. Cardiac magnetic resonance imaging before stage 2 (n = 5) found an RV mass index comparable to that in an exact-matched historical cohort (n = 22), with a mean RV ejection fraction of 66.2 ± 4.5% and mean indexed stroke volume of 47.4 ± 6.2 mL/m2 versus 53.5 ± 11.6% and 37.2 ± 10.3 mL/m2, respectively. All 7 survivors completed stage 2 and are alive with normal RV function (6 with ≤mild and 1 with moderate tricuspid regurgitation). CONCLUSIONS: This trial demonstrated that autologous CBMNCs delivered in large numbers without prior cryopreservation via a novel intracoronary infusion technique at cardioplegic arrest during Norwood palliation on days 2 to 3 of life is feasible and safe.

A Clinical Score for Quantifying Edema in Mechanically Ventilated Children With Congenital Heart Disease in Intensive Care.

Standardized clinical measurements of edema do not exist. OBJECTIVES: To describe a 19-point clinical edema score (CES), investigate its interobserver agreement, and compare changes between such CES and body weight. DESIGN SETTING AND PARTICIPANTS: Prospective observational study in a tertiary PICU of mechanically ventilated children with congenital heart disease. MAIN OUTCOMES AND MEASURES: Differences in the median CES between observer groups. RESULTS: We studied 61 children, with a median age of 8.0 days (interquartile range, 1.0-14.0 d). A total of 539 CES were performed by three observer groups (medical 1 [reference], medical 2, and bedside nurse) at 0, 24, and 48 hours from enrollment. Overall, there was close agreement between observer groups in mean, median, and upper quartile of CES scores, with least agreement observed in the lower quartile of scores. Across all quartiles of CES, after adjusting for baseline weight, cardiac surgical risk, duration of cardiopulmonary bypass, or peritoneal dialysis during the study, observer groups returned similar mean scores (medical 2: 25th centile +0.1 [95% CI, -0.2 to 0.5], median +0.6 [95% CI, -0.4 to 1.5], 75th centile +0.1 [95% CI, -1.1 to 1.4] and nurse: 25th centile +0.5 [95% CI, 0.0-0.9], median +0.7 [95% CI, 0.0-1.5], 75th centile -0.2 [95% CI, -1.3 to 1.0]) Within a multivariable mixed-effects linear regression model, including adjustment for baseline CES, each 1 point increase in CES was associated with a 12.1 grams (95% CI, 3.2-21 grams) increase in body weight. CONCLUSIONS AND RELEVANCE: In mechanically ventilated children with congenital heart disease, three groups of observers tended to agree when assessing overall edema using an ordinal clinical score assessed in six body regions, with agreement least at low edema scores. An increase in CES was associated with an increase in body weight, suggesting some validity for quantifying edema. Further exploration of the CES as a rapid clinical tool is indicated.

Longitudinal cohort study investigating neurodevelopmental and socioemotional outcomes in school-entry aged children after open heart surgery in Australia and New Zealand: the NITRIC follow-up study protocol.

INTRODUCTION: Despite growing awareness of neurodevelopmental impairments in children with congenital heart disease (CHD), there is a lack of large, longitudinal, population-based cohorts. Little is known about the contemporary neurodevelopmental profile and the emergence of specific impairments in children with CHD entering school. The performance of standardised screening tools to predict neurodevelopmental outcomes at school age in this high-risk population remains poorly understood. The NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial randomised 1371 children <2 years of age, investigating the effect of gaseous nitric oxide applied into the cardiopulmonary bypass oxygenator during heart surgery. The NITRIC follow-up study will follow this cohort annually until 5 years of age to assess outcomes related to cognition and socioemotional behaviour at school entry, identify risk factors for adverse outcomes and evaluate the performance of screening tools. METHODS AND ANALYSIS: Approximately 1150 children from the NITRIC trial across five sites in Australia and New Zealand will be eligible. Follow-up assessments will occur in two stages: (1) annual online screening of global neurodevelopment, socioemotional and executive functioning, health-related quality of life and parenting stress at ages 2-5 years; and (2) face-to-face assessment at age 5 years assessing intellectual ability, attention, memory and processing speed; fine motor skills; language and communication; and socioemotional outcomes. Cognitive and socioemotional outcomes and trajectories of neurodevelopment will be described and demographic, clinical, genetic and environmental predictors of these outcomes will be explored. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Children's Health Queensland (HREC/20/QCHQ/70626) and New Zealand Health and Disability (21/NTA/83) Research Ethics Committees. The findings will inform the development of clinical decision tools and improve preventative and intervention strategies in children with CHD. Dissemination of the outcomes of the study is expected via publications in peer-reviewed journals, presentation at conferences, via social media, podcast presentations and medical education resources, and through CHD family partners. TRIAL REGISTRATION NUMBER: The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry as 'Gene Expression to Predict Long-Term Neurodevelopmental Outcome in Infants from the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) Study - A Multicentre Prospective Trial'. TRIAL REGISTRATION: ACTRN12621000904875.

A qualitative investigation of paediatric intensive care staff attitudes towards the diagnosis of lower respiratory tract infection in the molecular diagnostics era.

Background: In the past decade, molecular diagnostic syndromic arrays incorporating a range of bacterial and viral pathogens have been described. It is unclear how paediatric intensive care unit (PICU) staff diagnose lower respiratory tract infection (LRTI) and integrate diagnostic array results into antimicrobial decision-making. Methods: An online survey with eleven questions was distributed throughout paediatric intensive care societies in the UK, continental Europe and Australasia with a total of 755 members. Participants were asked to rate the clinical factors and investigations they used when prescribing for LRTI. Semi-structured interviews were undertaken with staff who participated in a single-centre observational study of a 52-pathogen diagnostic array. Results: Seventy-two survey responses were received; most responses were from senior doctors. Whilst diagnostic arrays were used less frequently than routine investigations (i.e. microbiological culture), they were of comparable perceived utility when making antimicrobial decisions. Prescribers reported that for arrays to be clinically impactful, they would need to deliver results within 6 h for stable patients and within 1 h for unstable patients to inform their immediate decision to prescribe antimicrobials. From 16 staff interviews, we identified that arrays were helpful for the diagnosis and screening of bacterial LRTI. Staff reported it could be challenging to interpret results in some cases due to the high sensitivity of the test. Therefore, results were considered within the context of the patient and discussed within the multidisciplinary team. Conclusions: Diagnostic arrays were considered of comparable value to microbiological investigations by PICU prescribers. Our findings support the need for further clinical and economic evaluation of diagnostic arrays in a randomised control trial. Trial registration: Clinicaltrials.gov, NCT04233268. Registered on 18 January 2020. Supplementary Information: The online version contains supplementary material available at 10.1007/s44253-023-00008-z.

Agreement Between Measured Weight and Fluid Balance in Mechanically Ventilated Children in Intensive Care.

OBJECTIVES: To investigate the agreement between change in body weight (BW) and fluid balance (FB), and the precision and safety of BW measurement in mechanically ventilated infants in intensive care. DESIGN: Prospective observational study. SETTING: Tertiary PICU. PATIENTS: Infants following cardiac surgery, at baseline, 24 hours, and 48 hours. INTERVENTIONS: BW and FB measurement at three time points. MEASUREMENTS AND MAIN RESULTS: Between May 2021 and September 2022, we studied 61 children. The median age was 8 days (interquartile range [IQR], 1.0-14.0 d). The median BW at baseline was 3,518 g (IQR, 3,134-3,928 g). Change in BW was -36 g (IQR, -145 to 105 g) and -97 g (IQR, -240 to -28 g) between baseline and 24 hours, and between 24 and 48 hours, respectively. Change in FB was -82 mL (IQR, -173 to 12 mL) and -107 mL (IQR, -226 to 103) between baseline and 24 hours, and between 24 and 48 hours, respectively. In Bland-Altman analyses, the mean bias between BW and FB at 24 and 48 hours was 54 g (95% CI, 12-97) and -43 g (95% CI, -108 to 23), respectively. This exceeded 1% of the median BW, and limits of agreement ranged from 7.6% to 15% of baseline BW. The precision of paired weight measurements, performed sequentially at each time interval, was high (median difference of ≤1% of BW at each time point). The median weight of connected devices ranged from 2.7% to 3% of BW. There were no episodes of tube or device dislodgments and no change in vasoactive therapies during weight measurements. CONCLUSIONS: There is moderate agreement between the changes in FB and BW, albeit greater than 1% of baseline BW, and the limits of this agreement are wide. Weighing mechanically ventilated infants in intensive care is a relatively safe and precise method for estimating change in fluid status. Device weight represents a relatively large proportion of BW.

Leadership during airway management in the intensive care unit: A video-reflexive ethnography study.

Effective leadership is crucial to team performance within the intensive care unit. This novel study aimed to explore how staff members from an intensive care unit conceptualize leadership and what facilitators and barriers to leadership exist within a simulated workplace. It also aimed to identify factors that intersect with their perceptions of leadership. This study was underpinned by interpretivism, and video-reflexive ethnography was chosen as the methodology for the study. The use of both video recording (to capture the complex interactions occurring in the ICU) and team reflexivity allowed repeated analysis of those interactions by the research team. Purposive sampling was used to recruit participants from an ICU in a large tertiary and private hospital in Australia. Simulation groups were designed to replicate the typical clinical teams involved in airway management within the intensive care unit. Twenty staff participated in the four simulation activities (five staff per simulation group). Each group simulated the intubations of three patients with hypoxia and respiratory distress due to severe COVID-19. All 20 participants who completed the study simulations were invited to attend video-reflexivity sessions with their respective group. Twelve of the 20 participants (60%) from the simulations took part in the reflexive sessions. Video-reflexivity sessions (142 min) were transcribed verbatim. Transcripts were then imported into NVivo software for analysis. The five stages of framework analysis were used to conduct thematic analysis of the video-reflexivity focus group sessions, including the development of a coding framework. All transcripts were coded in NVivo. NVivo queries were conducted to explore patterns in the coding. The following key themes regarding participants' conceptualizations of leadership within the intensive care were identified: (1) leadership is both a group/shared process and individualistic/hierarchical; (2) leadership is communication; and (3) gender is a key leadership dimension. Key facilitators identified were: (1) role allocation; (2) trust, respect and staff familiarity; and (3) the use of checklists. Key barriers identified were: (1) noise and (2) personal protective equipment. The impact of socio-materiality on leadership within the intensive care unit is also identified.

Changes in von Willebrand Factor Multimers, Concentration, and Function During Pediatric Extracorporeal Membrane Oxygenation.

OBJECTIVES: To investigate changes in von Willebrand factor (VWF) concentration, function, and multimers during pediatric extracorporeal membrane oxygenation (ECMO) and determine whether routine monitoring of VWF during ECMO would be useful in predicting bleeding. DESIGN: Prospective observational study of pediatric ECMO patients from April 2017 to May 2019. SETTING: The PICU in a large, tertiary referral pediatric ECMO center. PATIENTS: Twenty-five neonates and children (< 18 yr) supported by venoarterial ECMO. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arterial blood samples were collected within 24 hours pre-ECMO, daily for the first 5 days of ECMO, every second day until decannulation, and 24 hours post-ECMO. The STA R Max analyzer was used to measure VWF antigen (VWF:Ag) and ristocetin cofactor (VWF:RCo) activity. VWF collagen binding (VWF:CB) was measured using an enzyme-linked immunosorbent assay. VWF multimers were measured using the semi-automated Hydragel 11 VWF Multimer assay. Corresponding clinical data for each patient was also recorded. A total of 25 venoarterial ECMO patients were recruited (median age, 73 d; interquartile range [IQR], 3 d to 1 yr). The median ECMO duration was 4 days (IQR, 3-8 d) and 15 patients had at least one major bleed during ECMO. The percentage of high molecular weight multimers (HMWM) decreased and intermediate molecular weight multimers increased while patients were on ECMO, irrespective of a bleeding status. VWF:Ag increased and the VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios decreased while patients were on ECMO compared with the baseline pre-ECMO samples and healthy children. CONCLUSIONS: Neonates and children on ECMO exhibited a loss of HMWM and lower VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag ratios compared with healthy children, irrespective of major bleeding occurring. Therefore, monitoring VWF during ECMO would not be useful in predicting bleeding in these patients and changes to other hemostatic factors should be investigated to further understand bleeding during ECMO.

Opinion: on the importance of maintaining the functional form of explanatory variables.

In medical research, continuous variables are often categorised into two or more groups before being included in the analysis; this practice often comes with a cost, such as loss of power in analysis, less reliable estimates, and can often leave residual confounding in the results. In this research report, we show this by way of estimates from a regression analysis looking at the association between acute kidney injury and post-operative mortality in a sample of 194 neonates who underwent the Norwood operation. Two models were developed, one using a continuous measure of renal function as the main explanatory variable and second using a categorised version of the same variable. A continuous measure of renal function is more likely to yield reliable estimates and also maintains more statistical power in the analysis to detect a relation between the exposure and outcome. It also reveals the true biological relationship between the exposure and outcome. Categorising a continuous variable may not only miss an important message, it can also get it wrong. Additionally, given a non-linear relationship is commonly encountered between the exposure and outcome variable, investigators are advised to retain a predictor with a linear term only when supported by data. All of this is particularly important in small data sets which account for the majority of clinical research studies.

Factors XI and XII in extracorporeal membrane oxygenation: longitudinal profile in children.

Background: Extracorporeal membrane oxygenation (ECMO) is used in children with cardiopulmonary failure. While the majority of ECMO centers use unfractionated heparin, other anticoagulants, including factor XI and factor XII inhibitors are emerging, which may prove suitable for ECMO patients. However, before these anticoagulants can be applied in these patients, baseline data of FXI and FXII changes need to be acquired. Objectives: This study aimed to describe the longitudinal profile of FXI and FXII antigenic levels and function before, during, and after ECMO in children. Methods: This is a prospective observational study in neonatal and pediatric patients with ECMO (<18 years). All patients with venoarterial ECMO and with sufficient plasma volume collected before ECMO, on day 1 and day 3, and 24 hours postdecannulation were included. Antigenic levels and functional activity of FXI and FXII were determined in these samples. Longitudinal profiles of these values were created using a linear mixed model. Results: Sixteen patients were included in this study. Mean FXI and FXII antigenic levels (U/mL) changed from 7.9 and 53.2 before ECMO to 6.0 and 34.5 on day 3 and they recovered to 8.8 and 39.4, respectively, after stopping ECMO. Function (%) of FXI and FXII decreased from 59.1 and 59.0 to 49.0 and 50.7 on day 3 and recovered to 66.0 and 54.4, respectively. Conclusion: This study provides the first insights into changes of the contact pathway in children undergoing ECMO. FXI and FXII antigen and function change during ECMO. Results from this study can be used as starting point for future contact pathway anticoagulant studies in pediatric patients with ECMO.

Fluid Accumulation in Mechanically Ventilated, Critically Ill Children: Retrospective Cohort Study of Prevalence and Outcome.

OBJECTIVES: To describe the prevalence, patterns, explanatory variables, and outcomes associated with fluid accumulation (FA) in mechanically ventilated children. DESIGN: Retrospective cohort study. SETTING: Tertiary PICU. PATIENTS: Children mechanically ventilated for greater than or equal to 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between July 2016 and July 2021, 1,636 children met eligibility criteria. Median age was 5.5 months (interquartile range [IQR], 0.7-46.5 mo), and congenital heart disease was the most common diagnosis. Overall, by day 7 of admission, the median maximum cumulative FA, as a percentage of estimated admission weight, was 7.5% (IQR, 3.3-15.1) occurring at a median of 4 days after admission. Overall, higher FA was associated with greater duration of mechanical ventilation (MV) (mean difference, 1.17 [95% CI, 1.13-1.22]; p < 0.001]), longer intensive care length of stay (LOS) (mean difference, 1.16 [95% CI, 1.12-1.21]; p < 0.001]), longer hospital LOS (mean difference, 1.19 [95% CI, 1.13-1.26]; p < 0.001]), and increased mortality (odds ratio, 1.31 [95% CI, 1.08-1.59]; p = 0.005). However, these associations depended on the effects of children with extreme values, and there was no increase in risk up to 20% FA, overall, in children following cardiopulmonary bypass and in children in the general ICU. When excluding children with maximum FA of >10%, there was no association with duration of MV (mean difference, 0.99 [95% CI, 0.94-1.04]; p = 0.64) and intensive care or hospital LOS (mean difference, 1.01 [95% CI, 0.96-1.06]; p = 0.70 and 1.01 [95% CI, 0.95-1.08]; 0.79, respectively) but an association with reduced mortality 0.71 (95% CI, 0.53-0.97; p = 0.03). CONCLUSIONS: In mechanically ventilated critically ill children, greater maximum FA was associated with longer duration of MV, intensive care LOS, hospital LOS, and mortality. However, these findings were driven by extreme values of FA of greater than 20%, and up to 10%, there was reduced mortality and no signal of harm.