Association between Age and Mortality in Pediatric and Adult Acute Respiratory Distress Syndrome.

Rationale: The epidemiology, management, and outcomes of acute respiratory distress syndrome (ARDS) differ between children and adults, with lower mortality rates in children despite comparable severity of hypoxemia. However, the relationship between age and mortality is unclear.Objective: We aimed to define the association between age and mortality in ARDS, hypothesizing that it would be nonlinear.Methods: We performed a retrospective cohort study using data from two pediatric ARDS observational cohorts (n = 1,236), multiple adult ARDS trials (n = 5,547), and an adult observational ARDS cohort (n = 1,079). We aligned all datasets to meet Berlin criteria. We performed unadjusted and adjusted logistic regression using fractional polynomials to assess the potentially nonlinear relationship between age and 90-day mortality, adjusting for sex, PaO2/FiO2, immunosuppressed status, year of study, and observational versus randomized controlled trial, treating each individual study as a fixed effect.Measurements and Main Results: There were 7,862 subjects with median ages of 4 years in the pediatric cohorts, 52 years in the adult trials, and 61 years in the adult observational cohort. Most subjects (43%) had moderate ARDS by Berlin criteria. Ninety-day mortality was 19% in the pediatric cohorts, 33% in the adult trials, and 67% in the adult observational cohort. We found a nonlinear relationship between age and mortality, with mortality risk increasing at an accelerating rate between 11 and 65 years of age, after which mortality risk increased more slowly.Conclusions: There was a nonlinear relationship between age and mortality in pediatric and adult ARDS.

Noninvasive Surrogate for Physiologic Dead Space Using the Carbon Dioxide Ventilatory Equivalent: Testing in a Single-Center Cohort, 2017-2023.

OBJECTIVES: We sought to evaluate the association between the carbon dioxide (co2) ventilatory equivalent (VEqco2 = minute ventilation/volume of co2 produced per min), a marker of dead space that does not require a blood gas measurement, and mortality risk. We compared the strength of this association to that of physiologic dead space fraction (VD/Vt = [Paco2-mixed-expired Pco2]/Paco2) as well as to other commonly used markers of dead space (i.e., the end-tidal alveolar dead space fraction [AVDSf = (Paco2-end-tidal Pco2)/Paco2], and ventilatory ratio [VR = (minute ventilation × Paco2)/(age-adjusted predicted minute ventilation × 37.5)]). DESIGN: Retrospective cohort data, 2017-2023. SETTING: Quaternary PICU. PATIENTS: One hundred thirty-one children with acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All dead space markers were calculated at the same 1-minute timepoint for each patient within the first 72 hours of using invasive mechanical ventilation. The 131 children had a median (interquartile range, IQR) age of 5.8 (IQR 1.4, 12.6) years, oxygenation index (OI) of 7.5 (IQR 4.6, 14.3), VD/Vt of 0.47 (IQR 0.38, 0.61), and mortality was 17.6% (23/131). Higher VEqco2 (p = 0.003), VD/Vt (p = 0.002), and VR (p = 0.013) were all associated with greater odds of mortality in multivariable models adjusting for OI, immunosuppressive comorbidity, and overall severity of illness. We failed to identify an association between AVDSf and mortality in the multivariable modeling. Similarly, we also failed to identify an association between OI and mortality after controlling for any dead space marker in the modeling. For the 28-day ventilator-free days outcome, we failed to identify an association between VD/Vt and the dead space markers in multivariable modeling, although OI was significant. CONCLUSIONS: VEqco2 performs similarly to VD/Vt and other surrogate dead space markers, is independently associated with mortality risk, and may be a reasonable noninvasive surrogate for VD/Vt.

Executive Summary: International Clinical Practice Guidelines for Pediatric Ventilator Liberation, A Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Document.

Rationale: Pediatric-specific ventilator liberation guidelines are lacking despite the many studies exploring elements of extubation readiness testing. The lack of clinical practice guidelines has led to significant and unnecessary variation in methods used to assess pediatric patients' readiness for extubation. Methods: Twenty-six international experts comprised a multiprofessional panel to establish pediatrics-specific ventilator liberation clinical practice guidelines, focusing on acutely hospitalized children receiving invasive mechanical ventilation for more than 24 hours. Eleven key questions were identified and first prioritized using the Modified Convergence of Opinion on Recommendations and Evidence. A systematic review was conducted for questions that did not meet an a priori threshold of ⩾80% agreement, with Grading of Recommendations, Assessment, Development, and Evaluation methodologies applied to develop the guidelines. The panel evaluated the evidence and drafted and voted on the recommendations. Measurements and Main Results: Three questions related to systematic screening using an extubation readiness testing bundle and a spontaneous breathing trial as part of the bundle met Modified Convergence of Opinion on Recommendations criteria of ⩾80% agreement. For the remaining eight questions, five systematic reviews yielded 12 recommendations related to the methods and duration of spontaneous breathing trials, measures of respiratory muscle strength, assessment of risk of postextubation upper airway obstruction and its prevention, use of postextubation noninvasive respiratory support, and sedation. Most recommendations were conditional and based on low to very low certainty of evidence. Conclusions: This clinical practice guideline provides a conceptual framework with evidence-based recommendations for best practices related to pediatric ventilator liberation.

Pleural and transpulmonary pressures to tailor protective ventilation in children.

This review aims to: (1) describe the rationale of pleural (PPL) and transpulmonary (PL) pressure measurements in children during mechanical ventilation (MV); (2) discuss its usefulness and limitations as a guide for protective MV; (3) propose future directions for paediatric research. We conducted a scoping review on PL in critically ill children using PubMed and Embase search engines. We included peer-reviewed studies using oesophageal (PES) and PL measurements in the paediatric intensive care unit (PICU) published until September 2021, and excluded studies in neonates and patients treated with non-invasive ventilation. PL corresponds to the difference between airway pressure and PPL Oesophageal manometry allows measurement of PES, a good surrogate of PPL, to estimate PL directly at the bedside. Lung stress is the PL, while strain corresponds to the lung deformation induced by the changing volume during insufflation. Lung stress and strain are the main determinants of MV-related injuries with PL and PPL being key components. PL-targeted therapies allow tailoring of MV: (1) Positive end-expiratory pressure (PEEP) titration based on end-expiratory PL (direct measurement) may be used to avoid lung collapse in the lung surrounding the oesophagus. The clinical benefit of such strategy has not been demonstrated yet. This approach should consider the degree of recruitable lung, and may be limited to patients in which PEEP is set to achieve an end-expiratory PL value close to zero; (2) Protective ventilation based on end-inspiratory PL (derived from the ratio of lung and respiratory system elastances), might be used to limit overdistention and volutrauma by targeting lung stress values < 20-25 cmH2O; (3) PPL may be set to target a physiological respiratory effort in order to avoid both self-induced lung injury and ventilator-induced diaphragm dysfunction; (4) PPL or PL measurements may contribute to a better understanding of cardiopulmonary interactions. The growing cardiorespiratory system makes children theoretically more susceptible to atelectrauma, myotrauma and right ventricle failure. In children with acute respiratory distress, PPL and PL measurements may help to characterise how changes in PEEP affect PPL and potentially haemodynamics. In the PICU, PPL measurement to estimate respiratory effort is useful during weaning and ventilator liberation. Finally, the use of PPL tracings may improve the detection of patient ventilator asynchronies, which are frequent in children. Despite these numerous theoritcal benefits in children, PES measurement is rarely performed in routine paediatric practice. While the lack of robust clincal data partially explains this observation, important limitations of the existing methods to estimate PPL in children, such as their invasiveness and technical limitations, associated with the lack of reference values for lung and chest wall elastances may also play a role. PPL and PL monitoring have numerous potential clinical applications in the PICU to tailor protective MV, but its usefulness is counterbalanced by technical limitations. Paediatric evidence seems currently too weak to consider oesophageal manometry as a routine respiratory monitoring. The development and validation of a noninvasive estimation of PL and multimodal respiratory monitoring may be worth to be evaluated in the future.

Effort and work-of-breathing parameters strongly correlate with increased resistance in an animal model.

BACKGROUND: Effort of Breathing (EOB) calculations may be a reliable alternative to Work of Breathing (WOB) calculations in which Respiratory Inductance Plethysmography (RIP) replaces spirometry. We sought to compare EOB and WOB measurements in a nonhuman primate model of increasing extrathoracic inspiratory resistance simulating upper airway obstruction (UAO). METHODS: RIP, spirometry, and esophageal manometry were measured in spontaneously breathing, intubated Rhesus monkeys utilizing 11 calibrated resistors randomly applied for 2-min. EOB was calculated breath-by-breath as Pressure Rate Product (PRP) and Pressure Time Product (PTP). WOB was calculated from the Pressure-Volume curve based on spirometry (WOBSPIR) or RIP flow (WOBRIP). RESULTS: WOB, PRP and PTP showed similar linear increases when exposed to higher levels of resistive loads. When comparing WOBSPIR to WOBRIP, a similar strong correlation was seen for both signals as resistance increased and there were no statistically significant differences. CONCLUSION: EOB and WOB parameters utilizing esophageal manometry and RIP, independent of spirometry, showed a strong correlation as a function of increasing inspiratory resistance in nonhuman primates. This allows several potential monitoring possibilities for non-invasively ventilated patients or situations where spirometry is not available. IMPACT: EOB and WOB parameters showed a strong correlation as a function of increasing inspiratory resistance in nonhuman primates. There was a strong correlation between spirometry-based WOB versus RIP-based WOB. To date, it has remained untested as to whether EOB is a reliable alternative for WOB and if RIP can replace spirometry in these measurements. Our results enable additional potential monitoring possibilities for non-invasively ventilated patients or situations where spirometry is not available. Where spirometry is not available, there is no need to apply a facemask post extubation to a spontaneously breathing, non-intubated infant to make objective EOB measurements.

The end-tidal alveolar dead space fraction for risk stratification during the first week of invasive mechanical ventilation: an observational cohort study.

BACKGROUND: The end-tidal alveolar dead space fraction (AVDSf = [PaCO2-PETCO2]/PaCO2) is a metric used to estimate alveolar dead space. Higher AVDSf on the first day of mechanical ventilation is associated with mortality and fewer ventilator-free days. It is not clear if AVDSf is associated with length of ventilation in survivors, how AVDSf performs for risk stratification beyond the first day of ventilation, or whether AVDSf adds predictive value to oxygenation (oxygenation index [OI]) or severity of illness (Pediatric Risk of Mortality [PRISM III]) markers. METHODS: Retrospective single-center observational cohort study of children and young adults receiving invasive mechanical ventilation. In those with arterial or capillary blood gases, AVDSf was calculated at the time of every blood gas for the first week of mechanical ventilation. RESULTS: There were 2335 children and young adults (median age 5.8 years [IQR 1.2, 13.2]) enrolled with 8004 analyzed AVDSf values. Higher AVDSf was associated with mortality and longer length of ventilation in survivors throughout the first week of ventilation after controlling for OI and PRISM III. Higher OI was not associated with increased mortality until ≥ 48 h of ventilation after controlling for AVDSf and PRISM III. When using standardized variables, AVDSf effect estimates were generally higher than OI for mortality, whereas OI effect estimates were generally higher than AVDSf for the length of ventilation in survivors. An AVDSf > 0.3 was associated with a higher mortality than an AVDSf < 0.2 within each pediatric acute respiratory distress syndrome severity category. The maximum AVDSf within 12 h of intensive care unit admission demonstrated good risk stratification for mortality (AUC 0.768 [95% CI 0.732, 0.803]). AVDSf did not improve mortality risk stratification when added to PRISM III but did improve mortality risk stratification when added to the gas exchange components of PRISM III (minimum 12-h PaO2 and maximum 12-h PCO2) (p < 0.00001). CONCLUSIONS: AVDSf is associated with mortality and length of ventilation in survivors throughout the first week of invasive mechanical ventilation. Some analyses suggest AVDSf may better stratify mortality risk than OI, whereas OI may better stratify risk for prolonged ventilation in survivors than AVDSf.

Estimation of inspiratory effort using airway occlusion maneuvers in ventilated children: a secondary analysis of an ongoing randomized trial testing a lung and diaphragm protective ventilation strategy.

BACKGROUND: Monitoring respiratory effort in ventilated patients is important to balance lung and diaphragm protection. Esophageal manometry remains the gold standard for monitoring respiratory effort but is invasive and requires expertise for its measurement and interpretation. Airway pressures during occlusion maneuvers may provide an alternative, although pediatric data are limited. We sought to determine the correlation between change in esophageal pressure during tidal breathing (∆Pes) and airway pressure measured during three airway occlusion maneuvers: (1) expiratory occlusion pressure (Pocc), (2) airway occlusion pressure (P0.1), and (3) respiratory muscle pressure index (PMI) in children. We also sought to explore pediatric threshold values for these pressures to detect excessive or insufficient respiratory effort. METHODS: Secondary analysis of physiologic data from children between 1 month and 18 years of age with acute respiratory distress syndrome enrolled in an ongoing randomized clinical trial testing a lung and diaphragm protective ventilation strategy (REDvent, R01HL124666). ∆Pes, Pocc, P0.1, and PMI were measured. Repeated measure correlations were used to investigate correlation coefficients between ∆Pes and the three measures, and linear regression equations were generated to identify potential therapeutic thresholds. RESULTS: There were 653 inspiratory and 713 expiratory holds from 97 patients. Pocc had the strongest correlation with ∆Pes (r = 0.68), followed by PMI (r = 0.60) and P0.1 (r = 0.42). ∆Pes could be reliably estimated using the regression equation ∆Pes = 0.66 [Formula: see text] Pocc (R2 = 0.82), with Pocc cut-points having high specificity and moderate sensitivity to detect respective ∆Pes thresholds for high and low respiratory effort. There were minimal differences in the relationship between Pocc and ∆Pes based on age (infant, child, adolescent) or mode of ventilation (SIMV versus Pressure Support), although these differences were more apparent with P0.1 and PMI. CONCLUSIONS: Airway occlusion maneuvers may be appropriate alternatives to esophageal pressure measurement to estimate the inspiratory effort in children, and Pocc represents the most promising target. TRIAL REGISTRATION: NCT03266016; August 23, 2017.

Methodology of the Second Pediatric Acute Lung Injury Consensus Conference.

OBJECTIVES: This article describes the methodology used for The Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2). The PALLIC-2 sought to develop evidence-based clinical recommendations and when evidence was lacking, expert-based consensus statements and research priorities for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS). DATA SOURCES: Electronic searches were conducted using PubMed, Embase, and Cochrane Library (CENTRAL) databases from 2012 to March 2022. STUDY SELECTION: Content was divided into 11 sections related to PARDS, with abstract and full text screening followed by data extraction for studies which met inclusion with no exclusion criteria. DATA EXTRACTION: We used a standardized data extraction form to construct evidence tables, grade the evidence, and formulate recommendations or statements using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. DATA SYNTHESIS: This consensus conference was comprised of a multidisciplinary group of international experts in pediatric critical care, pulmonology, respiratory care, and implementation science which followed standards set by the Institute of Medicine, using the GRADE system and Research And Development/University of California, Los Angeles appropriateness method, modeled after PALICC 2015. The panel of 52 content and four methodology experts had several web-based meetings over the course of 2 years. We conducted seven systematic reviews and four scoping reviews to cover the 11 topic areas. Dissemination was via primary publication listing all statements and separate supplemental publications for each subtopic that include supporting arguments for each recommendation and statement. CONCLUSIONS: A consensus conference of experts from around the world developed recommendations and consensus statements for the definition and management of PARDS and identified evidence gaps which need further research.

Association of Interventions With Outcomes in Children At-Risk for Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

OBJECTIVES: Describe the frequency with which transfusion and medications that modulate lung injury are administered to children meeting at-risk for pediatric acute respiratory distress syndrome (ARF-PARDS) criteria and evaluate for associations of transfusion, fluid balance, nutrition, and medications with unfavorable clinical outcomes. DESIGN: Secondary analysis of the Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study, a prospective point prevalence study. All enrolled ARF-PARDS patients were included unless they developed subsequent pediatric acute respiratory distress syndrome (PARDS) within 24 hours of PICU admission or PICU length of stay was less than 24 hours. Univariate and multivariable analyses were used to identify associations between therapies given during the first 2 calendar days after ARF-PARDS diagnosis and subsequent PARDS diagnosis (primary outcome), 28-day PICU-free days (PFDs), and 28-day ventilator-free days (VFDs). SETTING: Thirty-seven international PICUs. PATIENTS: Two hundred sixty-seven children meeting Pediatric Acute Lung Injury Consensus Conference ARF-PARDS criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the first 2 days after meeting ARF-PARDS criteria, 55% of subjects received beta-agonists, 42% received corticosteroids, 28% received diuretics, and 9% were transfused. Subsequent PARDS (15%) was associated with platelet transfusion (n = 11; adjusted odds ratio: 4.75 [95% CI 1.03-21.92]) and diuretics (n = 74; 2.55 [1.19-5.46]) in multivariable analyses that adjusted for comorbidities, PARDS risk factor, initial oxygen saturation by pulse oximetry:Fio2 ratio, and initial type of ventilation. Beta-agonists were associated with lower adjusted odds of subsequent PARDS (0.43 [0.19-0.98]). Platelets and diuretics were also associated with fewer PFDs and fewer VFDs in the multivariable models, and TPN was associated with fewer PFDs. Corticosteroids, net fluid balance, and volume of enteral feeding were not associated with the primary or secondary outcomes. CONCLUSIONS: There is an independent association between platelet transfusion, diuretic administration, and unfavorable outcomes in children at risk for PARDS, although this may be related to treatment bias and unmeasured confounders. Nevertheless, prospective evaluation of the role of these management strategies on outcomes in children with ARF-PARDS is needed.

Noninvasive Ventilation for Pediatric Acute Respiratory Distress Syndrome: Experience From the 2016/2017 Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Prospective Cohort Study.

OBJECTIVES: The worldwide practice and impact of noninvasive ventilation (NIV) in pediatric acute respiratory distress syndrome (PARDS) is unknown. We sought to describe NIV use and associated clinical outcomes in PARDS. DESIGN: Planned ancillary study to the 2016/2017 prospective Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study. SETTING: One hundred five international PICUs. PATIENTS: Patients with newly diagnosed PARDS admitted during 10 study weeks. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children were categorized by their respiratory support at PARDS diagnosis into NIV or invasive mechanical ventilation (IMV) groups. Of 708 subjects with PARDS, 160 patients (23%) received NIV at PARDS diagnosis (NIV group). NIV failure rate (defined as tracheal intubation or death) was 84 of 160 patients (53%). Higher nonrespiratory pediatric logistic organ dysfunction (PELOD-2) score, Pa o2 /F io2 was less than 100 at PARDS diagnosis, immunosuppression, and male sex were independently associated with NIV failure. NIV failure was 100% among patients with nonrespiratory PELOD-2 score greater than 2, Pa o2 /F io2 less than 100, and immunosuppression all present. Among patients with Pa o2 /F io2 greater than 100, children in the NIV group had shorter total duration of NIV and IMV, than the IMV at initial diagnosis group. We failed to identify associations between NIV use and PICU survival in a multivariable Cox regression analysis (hazard ratio 1.04 [95% CI, 0.61-1.80]) or mortality in a propensity score matched analysis ( p = 0.369). CONCLUSIONS: Use of NIV at PARDS diagnosis was associated with shorter exposure to IMV in children with mild to moderate hypoxemia. Even though risk of NIV failure was high in some children, we failed to identify greater hazard of mortality in these patients.

Derivation, Validation, and Clinical Relevance of a Pediatric Sepsis Phenotype With Persistent Hypoxemia, Encephalopathy, and Shock.

OBJECTIVES: Untangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of targeted therapies. Our aim was to analyze the organ dysfunction trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify reproducible and clinically relevant sepsis phenotypes and determine if they are associated with heterogeneity of treatment effect (HTE) to common therapies. DESIGN: Multicenter observational cohort study. SETTING: Thirteen PICUs in the United States. PATIENTS: Patients admitted with suspected infections to the PICU between 2012 and 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used subgraph-augmented nonnegative matrix factorization to identify candidate trajectory-based phenotypes based on the type, severity, and progression of organ dysfunction in the first 72 hours. We analyzed the candidate phenotypes to determine reproducibility as well as prognostic, therapeutic, and biological relevance. Overall, 38,732 children had suspected infection, of which 15,246 (39.4%) had sepsis-associated MODS with an in-hospital mortality of 10.1%. We identified an organ dysfunction trajectory-based phenotype (which we termed persistent hypoxemia, encephalopathy, and shock) that was highly reproducible, had features of systemic inflammation and coagulopathy, and was independently associated with higher mortality. In a propensity score-matched analysis, patients with persistent hypoxemia, encephalopathy, and shock phenotype appeared to have HTE and benefit from adjuvant therapy with hydrocortisone and albumin. When compared with other high-risk clinical syndromes, the persistent hypoxemia, encephalopathy, and shock phenotype only overlapped with 50%-60% of patients with septic shock, moderate-to-severe pediatric acute respiratory distress syndrome, or those in the top tier of organ dysfunction burden, suggesting that it represents a nonsynonymous clinical phenotype of sepsis-associated MODS. CONCLUSIONS: We derived and validated the persistent hypoxemia, encephalopathy, and shock phenotype, which is highly reproducible, clinically relevant, and associated with HTE to common adjuvant therapies in children with sepsis.

The Modified Clinical Progression Scale for Pediatric Patients: Evaluation as a Severity Metric and Outcome Measure in Severe Acute Viral Respiratory Illness.

OBJECTIVES: To develop, evaluate, and explore the use of a pediatric ordinal score as a potential clinical trial outcome metric in children hospitalized with acute hypoxic respiratory failure caused by viral respiratory infections. DESIGN: We modified the World Health Organization Clinical Progression Scale for pediatric patients (CPS-Ped) and assigned CPS-Ped at admission, days 2-4, 7, and 14. We identified predictors of clinical improvement (day 14 CPS-Ped ≤ 2 or a three-point decrease) using competing risks regression and compared clinical improvement to hospital length of stay (LOS) and ventilator-free days. We estimated sample sizes (80% power) to detect a 15% clinical improvement. SETTING: North American pediatric hospitals. PATIENTS: Three cohorts of pediatric patients with acute hypoxic respiratory failure receiving intensive care: two influenza (pediatric intensive care influenza [PICFLU], n = 263, 31 sites; PICFLU vaccine effectiveness [PICFLU-VE], n = 143, 17 sites) and one COVID-19 ( n = 237, 47 sites). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Invasive mechanical ventilation rates were 71.4%, 32.9%, and 37.1% for PICFLU, PICFLU-VE, and COVID-19 with less than 5% mortality for all three cohorts. Maximum CPS-Ped (0 = home at respiratory baseline to 8 = death) was positively associated with hospital LOS ( p < 0.001, all cohorts). Across the three cohorts, many patients' CPS-Ped worsened after admission (39%, 18%, and 49%), with some patients progressing to invasive mechanical ventilation or death (19%, 11%, and 17%). Despite this, greater than 76% of patients across cohorts clinically improved by day 14. Estimated sample sizes per group using CPS-Ped to detect a percentage increase in clinical improvement were feasible (influenza 15%, n = 142; 10%, n = 225; COVID-19, 15% n = 208) compared with mortality ( n > 21,000, all), and ventilator-free days (influenza 15%, n = 167). CONCLUSIONS: The CPS-Ped can be used to describe the time course of illness and threshold for clinical improvement in hospitalized children and adolescents with acute respiratory failure from viral infections. This outcome measure could feasibly be used in clinical trials to evaluate in-hospital recovery.

Critical Emergency Department Interventions and Clinical Deterioration in Children With Nonsevere Traumatic Intracranial Hemorrhage.

OBJECTIVE: Substantial practice variation exists in the management of children with nonsevere traumatic intracranial hemorrhage (tICH). A comprehensive understanding of rates and timing of clinically important tICH, including critical interventions and deterioration, along with associated clinical and neuroradiographic characteristics, will inform accurate risk stratification. METHODS: We conducted a single-center retrospective cohort study of children aged younger than 18 years evaluated in the emergency department (ED) from May 1, 2014 to February 28, 2020 with tICH and initial Glasgow Coma Scale (GCS) score of higher than 8. We determined rates of clinically important tICH after injury and within 96 hours of ED arrival, defined as immediate ED interventions (intubation, hyperosmotic agents, or neurosurgery within 4 hours of arrival) or clinically important deterioration (signs/symptoms with change in management). Associations between outcome and clinical and neuroradiographic characteristics were calculated using individual logistic regression models. RESULTS: Our sample included 135 children. Clinically important tICH was observed in 13.3% (n = 18); 9 (6.7%) underwent immediate ED interventions and 9 (6.7%) developed deterioration. Most (93.3%, n = 127) presented with an initial GCS ≥ 14, including all children who later deteriorated. Initial GCS (P = 0.001) and nonaccidental trauma (P = 0.024) mechanism were associated with the outcome. None of the 71 (52.6%) children with initial GCS ≥ 14, isolated, nonepidural hemorrhage after accidental injury developed clinically important tICH. CONCLUSIONS: Clinically important tICH occurred in 13% of children with nonsevere tICH, and 7% of children who did not undergo immediate ED interventions later deteriorated, all of whom had an initial GCS ≥ 14. However, a subgroup of children was identified as low risk based on clinical and neuroradiographic characteristics.

Epidemiology and Outcomes of Critically Ill Children at Risk for Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

OBJECTIVES: Interventional trials aimed at pediatric acute respiratory distress syndrome prevention require accurate identification of high-risk patients. In this study, we aimed to characterize the frequency and outcomes of children meeting "at risk for pediatric acute respiratory distress syndrome" criteria as defined by the Pediatric Acute Lung Injury Consensus Conference. DESIGN: Planned substudy of the prospective multicenter, international Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study conducted during 10 nonconsecutive weeks (May 2016-June 2017). SETTING: Thirty-seven international PICUs. PATIENTS: Three-hundred ten critically ill children meeting Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated the frequency of children at risk for pediatric acute respiratory distress syndrome and rate of subsequent pediatric acute respiratory distress syndrome diagnosis and used multivariable logistic regression to identify factors associated with subsequent pediatric acute respiratory distress syndrome. Frequency of at risk for pediatric acute respiratory distress syndrome was 3.8% (95% CI, 3.4-5.2%) among the 8,122 critically ill children who were screened and 5.8% (95% CI, 5.2-6.4%) among the 5,334 screened children on positive pressure ventilation or high-flow oxygen. Among the 310 at-risk children, median age was 2.1 years (interquartile range, 0.5-7.3 yr). Sixty-six children (21.3%) were subsequently diagnosed with pediatric acute respiratory distress syndrome, a median of 22.6 hours (interquartile range, 9.8-41.0 hr) later. Subsequent pediatric acute respiratory distress syndrome was associated with increased mortality (21.2% vs 3.3%; p < 0.001) and longer durations of invasive ventilation and PICU care. Subsequent pediatric acute respiratory distress syndrome rate did not differ by respiratory support modality at the time of meeting at risk criteria but was independently associated with lower initial saturation:Fio2 ratio, progressive tachycardia, and early diuretic administration. CONCLUSIONS: The Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria identify critically ill children at high risk of pediatric acute respiratory distress syndrome and poor outcomes. Interventional trials aimed at pediatric acute respiratory distress syndrome prevention should target patients early in their illness course and include patients on high-flow oxygen and positive pressure ventilation.

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 PCO2 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.

Clinical Challenges in Pediatric Ventilation Liberation: A Meta-Narrative Review.

OBJECTIVES: To map the evidence for ventilation liberation practices in pediatric respiratory failure using the Realist And MEta-narrative Evidence Syntheses: Evolving Standards publication standards. DATA SOURCES: CINAHL, MEDLINE, COCHRANE, and EMBASE. Trial registers included the following: ClinicalTrials.gov, European Union clinical trials register, International Standardized Randomized Controlled Trial Number register. STUDY SELECTION: Abstracts were screened followed by review of full text. Articles published in English language incorporating a heterogeneous population of both infants and older children were assessed. DATA EXTRACTION: None. DATA SYNTHESIS: Weaning can be considered as the process by which positive pressure is decreased and the patient becomes increasingly responsible for generating the energy necessary for effective gas exchange. With the growing use of noninvasive respiratory support, extubation can lie in the middle of the weaning process if some additional positive pressure is used after extubation, while for some extubation may constitute the end of weaning. Testing for extubation readiness is a key component of the weaning process as it allows the critical care practitioner to assess the capability and endurance of the patient's respiratory system to resume unassisted ventilation. Spontaneous breathing trials (SBTs) are often seen as extubation readiness testing (ERT), but the SBT is used to determine if the patient can maintain adequate spontaneous ventilation with minimal ventilatory support, whereas ERT implies the patient is ready for extubation. CONCLUSIONS: Current literature suggests using a structured approach that includes a daily assessment of patient's readiness to extubate may reduce total ventilation time. Increasing evidence indicates that such daily assessments needs to include SBTs without added pressure support. Measures of elevated load as well as measures of impaired respiratory muscle capacity are independently associated with extubation failure in children, indicating that these should also be assessed as part of ERT.

Pediatric Acute Lung Injury and Sepsis Investigators (PALISI): Evolution of an Investigator-Initiated Research Network.

The Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network originated over 20 years ago to foster research to optimize the care of critically ill infants and children. Over this period, PALISI has seen two major evolutions: formalization of our network infrastructure and a broadening of our clinical research focus. First, the network is unique in that its activities and meetings are funded by subscriptions from members who now comprise a multidisciplinary group of investigators from over 90 PICUs all over the United States (US) and Canada, with collaborations across the globe. In 2020, the network converted into a standalone, nonprofit organizational structure (501c3), making the PALISI Network formally independent of academic and clinical institutions or professional societies. Such an approach allows us to invest in infrastructure and future initiatives with broader opportunities for fund raising. Second, our research investigations have expanded beyond the original focus on sepsis and acute lung injury, to incorporate the whole field of pediatric critical care, for example, efficient liberation from mechanical ventilator support, prudent use of blood products, improved safety of intubation practices, optimal sedation practices and glucose control, and pandemic research on influenza and COVID-19. Our network approach in each field follows, where necessary, the full spectrum of clinical and translational research, including: immunobiology studies for understanding basic pathologic mechanisms; surveys to explore contemporary clinical practice; consensus conferences to establish agreement about literature evidence; observational prevalence and incidence studies to measure scale of a clinical issue or question; case control studies as preliminary best evidence for design of definitive prospective studies; and, randomized controlled trials for informing clinical care. As a research network, PALISI and its related subgroups have published over 350 peer-reviewed publications from 2002 through September 2022.

Direction and Magnitude of Change in Plateau From Peak Pressure During Inspiratory Holds Can Identify the Degree of Spontaneous Effort and Elastic Workload in Ventilated Patients.

OBJECTIVES: Inspiratory holds with measures of airway pressure to estimate driving pressure (elastic work) are often limited to patients without respiratory effort. We sought to evaluate if measures of airway pressure during inspiratory holds could be used for patients with spontaneous respiratory effort during mechanical ventilation to estimate the degree of spontaneous effort and elastic work. DESIGN: We compared the direction and degree of change in airway pressure during inspiratory holds versus esophageal pressure through secondary analysis of physiologic data. SETTING: ICUs at Children's Hospital Los Angeles. PATIENTS: Children with pediatric acute respiratory distress syndrome with evidence of spontaneous respiration while on pressure control or pressure support ventilation. INTERVENTIONS: Inspiratory hold maneuvers. MEASUREMENTS AND MAIN RESULTS: From airway pressure, we defined "plateau - peak pressure" as Pmusc, index, which was divided into three categories for analysis (< -1 ["negative"], between -1 and 1 ["neutral"], and > 1 cm H2O ["positive"]). A total of 30 children (age 36.8 mo [16.1-70.3 mo]) from 65 study days, comprising 118 inspiratory holds were included. Pmusc, index was "negative" in 29 cases, was "neutral" in 17 cases, and was "positive" in 72 cases. As Pmusc, index went from negative to neutral to positive, there was larger negative deflection in esophageal pressure -5.0 (-8.2 to 1.9), -5.9 (-7.6 to 4.3), and -10.7 (-18.1 to 7.9) cm H2O (p < 0.0001), respectively. There was a correlation between max negative esophageal pressure and Pmusc, index (r = -0.52), and when Pmusc, index was greater than or equal to 7 cm H2O, the max negative esophageal pressure was greater than 10 cm H2O. There was a stronger correlation between Pmusc, index and markers of elastic work from esophageal pressure (r = 0.84). CONCLUSIONS: The magnitude of plateau minus peak pressure during an inspiratory hold is correlated with the degree of inspiratory effort, particularly for those with high elastic work. It may be useful to identify patients with excessively high effort or high driving pressure.

Adherence to Lung-Protective Ventilation Principles in Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

OBJECTIVES: To describe mechanical ventilation management and factors associated with nonadherence to lung-protective ventilation principles in pediatric acute respiratory distress syndrome. DESIGN: A planned ancillary study to a prospective international observational study. Mechanical ventilation management (every 6 hr measurements) during pediatric acute respiratory distress syndrome days 0-3 was described and compared with Pediatric Acute Lung Injury Consensus Conference tidal volume recommendations (< 7 mL/kg in children with impaired respiratory system compliance, < 9 mL/kg in all other children) and the Acute Respiratory Distress Syndrome Network lower positive end-expiratory pressure/higher Fio2 grid recommendations. SETTING: Seventy-one international PICUs. PATIENTS: Children with pediatric acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Analyses included 422 children. On pediatric acute respiratory distress syndrome day 0, median tidal volume was 7.6 mL/kg (interquartile range, 6.3-8.9 mL/kg) and did not differ by pediatric acute respiratory distress syndrome severity. Plateau pressure was not recorded in 97% of measurements. Using delta pressure (peak inspiratory pressure - positive end-expiratory pressure), median tidal volume increased over quartiles of median delta pressure (p = 0.007). Median delta pressure was greater than or equal to 18 cm H2O for all pediatric acute respiratory distress syndrome severity levels. In severe pediatric acute respiratory distress syndrome, tidal volume was greater than or equal to 7 mL/kg 62% of the time, and positive end-expiratory pressure was lower than recommended by the positive end-expiratory pressure/Fio2 grid 70% of the time. In multivariable analysis, tidal volume nonadherence was more common with severe pediatric acute respiratory distress syndrome, fewer PICU admissions/yr, non-European PICUs, higher delta pressure, corticosteroid use, and pressure control mode. Adherence was associated with underweight stature and cuffed endotracheal tubes. In multivariable analysis, positive end-expiratory pressure/Fio2 grid nonadherence was more common with higher pediatric acute respiratory distress syndrome severity, ventilator decisions made primarily by the attending physician, pre-ICU cardiopulmonary resuscitation, underweight stature, and age less than 2 years. Adherence was associated with respiratory therapist involvement in ventilator management and longer time from pediatric acute respiratory distress syndrome diagnosis. Higher nonadherence to tidal volume and positive end-expiratory pressure recommendations were independently associated with higher mortality and longer duration of ventilation after adjustment for confounding variables. In stratified analyses, these associations were primarily influenced by children with severe pediatric acute respiratory distress syndrome. CONCLUSIONS: Nonadherence to lung-protective ventilation principles is common in pediatric acute respiratory distress syndrome and may impact outcome. Modifiable factors exist that may improve adherence.

Subglottic Post-Extubation Upper Airway Obstruction Is Associated With Long-Term Airway Morbidity in Children.

OBJECTIVES: Post-extubation upper airway obstruction is the most common cause of extubation failure in children, but there are few data regarding long-term morbidity. We aim to describe the frequency of long-term airway sequelae in intubated children and determine the association with post-extubation upper airway obstruction. DESIGN: Retrospective, post hoc analysis of previously identified prospective cohort of children in the pediatric/cardiothoracic ICU at Children's Hospital Los Angeles from July 2012 to April 2015. A single provider blinded to the upper airway obstruction classification reviewed the electronic medical records of all patients in the parent study, before and after the index extubation (extubation during parent study), to identify pre-index and post-index upper airway disease. Primary outcomes were prevalence of newly diagnosed airway anomalies following index extubation. SETTING: Single center, tertiary, 391-bed children's hospital. PATIENTS: From the parent study, 327 children younger than 18 years (intubated for at least 12 hr) were included if they received subsequent care (regardless of specialty) after the index extubation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: New airway anomalies were identified in 40 of 327 children (12.2%). Patients labeled with subglottic upper airway obstruction at the index extubation were more likely to be diagnosed with new airway anomalies on subsequent follow-up, receive long-term Otolaryngology follow-up, or receive airway surgery (all p ≤ 0.006). In multivariable modeling, upper airway obstruction as the primary reason for initial intubation (odds ratio, 3.71; CI, 1.50-9.19), reintubation during the index ICU admission (odds ratio, 4.44; CI, 1.67-11.80), pre-index airway anomaly (odds ratio, 3.31; CI, 1.36-8.01), and post-extubation subglottic upper airway obstruction (odds ratio, 3.50; CI, 1.46-8.34) remained independently associated with the diagnosis of new airway anomalies. CONCLUSIONS: Post-extubation subglottic upper airway obstruction is associated with a three-fold greater odds of long-term airway morbidity. These patients may represent an at-risk population that should be monitored closely after leaving the ICU.