Respiratory entrainment related reverse triggering in mechanically ventilated children.

BACKGROUND: The underlying pathophysiological pathways how reverse triggering is being caused are not fully understood. Respiratory entrainment may be one of these mechanisms, but both terms are used interchangeably. We sought to characterize reverse triggering and the relationship with respiratory entrainment among mechanically ventilated children with and without acute lung injury. METHODS: We performed a secondary phyiology analysis of two previously published data sets of invasively mechanically ventilated children < 18 years with and without lung injury mechanically ventilated in a continuous or intermittent mandatory ventilation mode. Ventilator waveforms, electrical activity of the diaphragm measured with surface electromyography and oesophageal tracings were analyzed for entrained and non-entrained reverse triggered breaths. RESULTS: In total 102 measurements (3110 min) from 67 patients (median age 4.9 [1.8 ; 19,1] months) were analyzed. Entrained RT was identified in 12 (12%) and non-entrained RT in 39 (38%) recordings. Breathing variability for entrained RT breaths was lower compared to non-entrained RT breaths. We did not observe breath stacking during entrained RT. Double triggering often occurred during non-entrained RT and led to an increased tidal volume. Patients with respiratory entrainment related RT had a shorter duration of MV and length of PICU stay. CONCLUSIONS: Reverse triggering is not one entity but a clinical spectrum with different mechanisms and consequences. TRIAL REGISTRATION: Not applicable.

Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial.

BACKGROUND: To determine whether intermittent intravenous (IV) paracetamol as primary analgesic would significantly reduce morphine consumption in children aged 0-3 years after cardiac surgery with cardiopulmonary bypass. METHODS: Multi-center, randomized, double-blinded, controlled trial in four level-3 Pediatric Intensive Care Units (PICU) in the Netherlands and Belgium. Inclusion period; March 2016-July 2020. Children aged 0-3 years, undergoing cardiac surgery with cardiopulmonary bypass were eligible. Patients were randomized to continuous morphine or intermittent IV paracetamol as primary analgesic after a loading dose of 100 mcg/kg morphine was administered at the end of surgery. Rescue morphine was given if numeric rating scale (NRS) pain scores exceeded predetermined cutoff values. Primary outcome was median weight-adjusted cumulative morphine dose in mcg/kg in the first 48 h postoperative. For the comparison of the primary outcome between groups, the nonparametric Van Elteren test with stratification by center was used. For comparison of the proportion of patients with one or more NRS pain scores of 4 and higher between the two groups, a non-inferiority analysis was performed using a non-inferiority margin of 20%. RESULTS: In total, 828 were screened and finally 208 patients were included; parents of 315 patients did not give consent and 305 were excluded for various reasons. Fourteen of the enrolled 208 children were withdrawn from the study before start of study medication leaving 194 patients for final analysis. One hundred and two patients received intermittent IV paracetamol, 106 received continuous morphine. The median weight-adjusted cumulative morphine consumption in the first 48 h postoperative in the IV paracetamol group was 5 times lower (79%) than that in the morphine group (median, 145.0 (IQR, 115.0-432.5) mcg/kg vs 692.6 (IQR, 532.7-856.1) mcg/kg; P < 0.001). The rescue morphine consumption was similar between the groups (p = 0.38). Non-inferiority of IV paracetamol administration in terms of NRS pain scores was proven; difference in proportion - 3.1% (95% CI - 16.6-10.3%). CONCLUSIONS: In children aged 0-3 years undergoing cardiac surgery, use of intermittent IV paracetamol reduces the median weight-adjusted cumulative morphine consumption in the first 48 h after surgery by 79% with equal pain relief showing equipoise for IV paracetamol as primary analgesic. Trial Registration Clinicaltrials.gov, Identifier: NCT05853263; EudraCT Number: 2015-001835-20.

Positive end-expiratory pressure in the pediatric intensive care unit.

Application of positive end-expiratory pressure (PEEP) targeted towards improving oxygenation is one of the components of the ventilatory management of pediatric acute respiratory distress syndrome (PARDS). Low end-expiratory airway pressures cause repetitive opening and closure of unstable alveoli, leading to surfactant dysfunction and parenchymal shear injury. Consequently, there is less lung volume available for tidal ventilation when there are atelectatic lung regions. This will increase lung strain in aerated lung areas to which the tidal volume is preferentially distributed. Pediatric critical care practitioners tend to use low levels of PEEP and inherently accept higher FiO2, but these practices may negatively affect patient outcome. The Pediatric Acute Lung Injury Consensus Conference (PALICC) suggests that PEEP should be titrated to oxygenation/oxygen delivery, hemodynamics, and compliance measured under static conditions as compared to other clinical parameters or any of these parameters in isolation in patients with PARDS, while limiting plateau pressure and/or driving pressure limits.

Protocol for the Prone and Oscillation Pediatric Clinical Trial (PROSpect).

OBJECTIVES: Respiratory management for pediatric acute respiratory distress syndrome (PARDS) remains largely supportive without data to support one approach over another, including supine versus prone positioning (PP) and conventional mechanical ventilation (CMV) versus high-frequency oscillatory ventilation (HFOV). DESIGN: We present the research methodology of a global, multicenter, two-by-two factorial, response-adaptive, randomized controlled trial of supine versus PP and CMV versus HFOV in high moderate-severe PARDS, the Prone and Oscillation Pediatric Clinical Trial (PROSpect, www.ClinicalTrials.gov, NCT03896763). SETTING: Approximately 60 PICUs with on-site extracorporeal membrane oxygenation support in North and South America, Europe, Asia, and Oceania with experience using PP and HFOV in the care of patients with PARDS. PATIENTS: Eligible pediatric patients (2 wk old or older and younger than 21 yr) are randomized within 48 h of meeting eligibility criteria occurring within 96 h of endotracheal intubation. INTERVENTIONS: One of four arms, including supine/CMV, prone/CMV, supine/HFOV, or prone/HFOV. We hypothesize that children with high moderate-severe PARDS treated with PP or HFOV will demonstrate greater than or equal to 2 additional ventilator-free days (VFD). MEASUREMENTS AND MAIN RESULTS: The primary outcome is VFD through day 28; nonsurvivors receive zero VFD. Secondary and exploratory outcomes include nonpulmonary organ failure-free days, interaction effects of PP with HFOV on VFD, 90-day in-hospital mortality, and among survivors, duration of mechanical ventilation, PICU and hospital length of stay, and post-PICU functional status and health-related quality of life. Up to 600 patients will be randomized, stratified by age group and direct/indirect lung injury. Adaptive randomization will first occur 28 days after 300 patients are randomized and every 100 patients thereafter. At these randomization updates, new allocation probabilities will be computed based on intention-to-treat trial results, increasing allocation to well-performing arms and decreasing allocation to poorly performing arms. Data will be analyzed per intention-to-treat for the primary analyses and per-protocol for primary, secondary, and exploratory analyses. CONCLUSIONS: PROSpect will provide clinicians with data to inform the practice of PP and HFOV in PARDS.

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.

Fresh Frozen Plasma Versus Solvent Detergent Plasma for Cardiopulmonary Bypass Priming in Neonates and Infants Undergoing Cardiac Surgery: A Retrospective Cohort Study.

OBJECTIVE: Compared with fresh frozen plasma (FFP), Omniplasma has been attributed to an increased coagulation potential and an increased fibrinolytic potential. This study aimed to compare Omniplasma and FFP used for cardiopulmonary bypass (CPB) priming regarding the incidence of postoperative thrombotic or hemorrhagic complications and outcomes in pediatric patients undergoing cardiac surgery. DESIGN: A retrospective observational cohort study SETTING: This single-center study was performed at the University Medical Center Groningen. PARTICIPANT: All pediatric patients up to 10 kg undergoing cardiac surgery with CPB. INTERVENTIONS: Procedures in which FFP was used for CPB priming were compared with those in which Omniplasma was used. MEASUREMENTS AND MAIN RESULTS: The primary outcome parameter was a composite endpoint consisting of the following: (1) pediatric intensive care unit (PICU) mortality, (2) thromboembolic complications, and (3) hemorrhagic complications during PICU stay. The authors included 143 procedures in the analyses, 90 (63%) in the FFP group and 53 (37%) in the Omniplasma group. The occurrence of the combined primary endpoint (FFP 20% v Omniplasma 11%, p = 0.18) and its components did not differ between the used CPB priming agent). Omniplasma for CPB priming was associated with decreased unfractionated heparin administration per kg bodyweight (585 IU v 510 IU, p = 0.03), higher preoperative and postoperative activated clotting times (ACT) discrepancy (90% v 94%, p = 0.03), a lower postoperative ACT value (125 v 118 seconds, p = 0.01), and less red blood cell transfusion per kilogram bodyweight (78 v 55 mL, p = 0.02). However, none of the variables differed statistically significantly in the multivariate logistic regression analyses. CONCLUSIONS: The authors did not find an association between the plasma used for CPB priming and thromboembolic and hemorrhagic complications and death in neonates and infants undergoing cardiac surgery. Omniplasma seems to be safe to use in this population.

Surface electromyography to quantify neuro-respiratory drive and neuro-mechanical coupling in mechanically ventilated children.

BACKGROUND: The patient's neuro-respiratory drive, measured as electrical activity of the diaphragm (EAdi), quantifies the mechanical load on the respiratory muscles. It correlates with respiratory effort but requires a dedicated esophageal catheter. Transcutaneous (surface) monitoring of respiratory muscle electromyographic (sEMG) signals may be considered a suitable alternative to EAdi because of its non-invasive character, with the additional benefit that it allows for simultaneously monitoring of other respiratory muscles. We therefore sought to study the neuro-respiratory drive and timing of inspiratory muscles using sEMG in a cohort of children enrolled in a pediatric ventilation liberation trial. The neuro-mechanical coupling, relating the pressure generated by the inspiratory muscles to the sEMG signals of these muscles, was also calculated. METHODS: This is a secondary analysis of data from a randomized cross-over trial in ventilated patients aged < 5 years. sEMG recordings of the diaphragm and parasternal intercostal muscles (ICM), esophageal pressure tracings and ventilator scalars were simultaneously recorded during continuous spontaneous ventilation and pressure controlled-intermittent mandatory ventilation, and at three levels of pressure support. Neuro-respiratory drive, timing of diaphragm and ICM relative to the mechanical ventilator's inspiration and neuro-mechanical coupling were quantified. RESULTS: Twenty-nine patients were included (median age: 5.9 months). In response to decreasing pressure support, both amplitude of sEMG (diaphragm: p = 0.001 and ICM: p = 0.002) and neuro-mechanical efficiency indices increased (diaphragm: p = 0.05 and ICM: p < 0.001). Poor correlations between neuro-respiratory drive and respiratory effort were found, with R2: 0.088 [0.021-0.152]. CONCLUSIONS: sEMG allows for the quantification of the electrical activity of the diaphragm and ICM in mechanically ventilated children. Both neuro-respiratory drive and neuro-mechanical efficiency increased in response to lower inspiratory assistance. There was poor correlation between neuro-respiratory drive and respiratory effort. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05254691. Registered 24 February 2022, registered retrospectively.

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.

Mechanical ventilation during pediatric extracorporeal life support.

PURPOSE OF REVIEW: To discuss the role of ventilator induced lung injury (VILI) and patient self-inflicted lung injury in ventilated children supported on extracorporeal membrane oxygenation (ECMO). RECENT FINDINGS: While extracorporeal life support is used routinely used every day around the globe to support neonatal, pediatric, and adult patients with refractory cardiac and/or respiratory failure, the optimal approach to mechanical ventilation, especially for those with acute respiratory distress syndrome (ARDS), remains unknown and controversial. Given the lack of definitive data in this population, one must rely on available evidence in those with ARDS not supported with ECMO and extrapolate adult observations. Ventilatory management should include, as a minimum standard, limiting inspiratory and driving pressures, providing a sufficient level of positive end-expiratory pressure, and setting a low rate to reduce mechanical power. Allowing for spontaneous breathing and use of pulmonary specific ancillary treatment modalities must be individualized, while balancing the risk and benefits. Future studies delineating the best strategies for optimizing MV during pediatric extracorporeal life support are much needed. SUMMARY: Future investigations will hopefully provide the needed evidence and better understanding of the overall goal of reducing mechanical ventilation intensity to decrease risk for VILI and promote lung recovery for those supported with ECMO.

Hemodynamic Effects of a High-Frequency Oscillatory Ventilation Open-Lung Strategy in Critically Ill Children With Acquired or Congenital Cardiac Disease.

OBJECTIVES: To study the hemodynamic consequences of an open-lung high-frequency oscillatory ventilation (HFOV) strategy in patients with an underlying cardiac anomaly with or without intracardiac shunt or primary pulmonary hypertension with severe lung injury. DESIGN: Secondary analysis of prospectively collected data. SETTING: Medical-surgical PICU. PATIENTS: Children less than 18 years old with cardiac anomalies (± intracardiac shunt) or primary pulmonary hypertension. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data from 52 subjects were analyzed, of whom 39 of 52 with cardiac anomaly (23/39 with intracardiac shunt) and 13 of 52 with primary pulmonary hypertension. Fourteen patients were admitted postoperatively, and 26 patients were admitted with acute respiratory failure. Five subjects (9.6%) were canulated for ECMO (of whom four for worsening respiratory status). Ten patients (19.2%) died during PICU stay. Median conventional mechanical ventilation settings prior to HFOV were peak inspiratory pressure 30 cm H 2 O (27-33 cm H 2 O), positive end-expiratory pressure 8 cm H 2 O (6-10 cm H 2 O), and F io2 0.72 (0.56-0.94). After transitioning to HFOV, there was no negative effect on mean arterial blood pressure, central venous pressure, or arterial lactate. Heart rate decreased significantly over time ( p < 0.0001), without group differences. The percentage of subjects receiving a fluid bolus decreased over time ( p = 0.003), especially in those with primary pulmonary hypertension ( p = 0.0155) and without intracardiac shunt ( p = 0.0328). There were no significant differences in the cumulative number of daily boluses over time. Vasoactive Infusion Score did not increase over time. Pa co2 decreased ( p < 0.0002) and arterial pH significantly improved ( p < 0.0001) over time in the whole cohort. Neuromuscular blocking agents were used in all subjects switched to HFOV. Daily cumulative sedative doses were unchanged, and no clinically apparent barotrauma was found. CONCLUSIONS: No negative hemodynamic consequences occurred with an individualized, physiology-based open-lung HFOV approach in patients with cardiac anomalies or primary pulmonary hypertension suffering from severe lung injury.

Pulmonary Specific Ancillary Treatment for Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference.

OBJECTIVES: We conducted an updated review of the literature on pulmonary-specific ancillary therapies for pediatric acute respiratory distress syndrome (PARDS) to provide an update to the Pediatric Acute Lung Injury Consensus Conference recommendations and statements about clinical practice and research. DATA SOURCES: MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost). STUDY SELECTION: Searches were limited to children, PARDS or hypoxic respiratory failure and overlap with pulmonary-specific ancillary therapies. DATA EXTRACTION: Title/abstract review, full-text review, and data extraction using a standardized data collection form. DATA SYNTHESIS: The Grading of Recommendations Assessment, Development, and Evaluation approach was used to identify and summarize evidence and develop recommendations. Twenty-six studies were identified for full-text extraction. Four clinical recommendations were generated, related to use of inhaled nitric oxide, surfactant, prone positioning, and corticosteroids. Two good practice statements were generated on the use of routine endotracheal suctioning and installation of isotonic saline prior to endotracheal suctioning. Three research statements were generated related to: the use of open versus closed suctioning, specific methods of airway clearance, and various other ancillary therapies. CONCLUSIONS: The evidence to support or refute any of the specific ancillary therapies in children with PARDS remains low. Further investigation, including a focus on specific subpopulations, is needed to better understand the role, if any, of these various ancillary therapies in PARDS.

Neurocognitive, Psychosocial, and Quality of Life Outcomes After Multisystem Inflammatory Syndrome in Children Admitted to the PICU.

OBJECTIVES: To investigate neurocognitive, psychosocial, and quality of life (QoL) outcomes in children with Multisystem Inflammatory Syndrome in Children (MIS-C) seen 3-6 months after PICU admission. DESIGN: National prospective cohort study March 2020 to November 2021. SETTING: Seven PICUs in the Netherlands. PATIENTS: Children with MIS-C (0-17 yr) admitted to a PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children and/or parents were seen median (interquartile range [IQR] 4 mo [3-5 mo]) after PICU admission. Testing included assessment of neurocognitive, psychosocial, and QoL outcomes with reference to Dutch pre-COVID-19 general population norms. Effect sizes (Hedges' g ) were used to indicate the strengths and clinical relevance of differences: 0.2 small, 0.5 medium, and 0.8 and above large. Of 69 children with MIS-C, 49 (median age 11.6 yr [IQR 9.3-15.6 yr]) attended follow-up. General intelligence and verbal memory scores were normal compared with population norms. Twenty-nine of the 49 followed-up (59%) underwent extensive testing with worse function in domains such as visual memory, g = 1.0 (95% CI, 0.6-1.4), sustained attention, g = 2.0 (95% CI 1.4-2.4), and planning, g = 0.5 (95% CI, 0.1-0.9). The children also had more emotional and behavioral problems, g = 0.4 (95% CI 0.1-0.7), and had lower QoL scores in domains such as physical functioning g = 1.3 (95% CI 0.9-1.6), school functioning g = 1.1 (95% CI 0.7-1.4), and increased fatigue g = 0.5 (95% CI 0.1-0.9) compared with population norms. Elevated risk for posttraumatic stress disorder (PTSD) was seen in 10 of 30 children (33%) with MIS-C. Last, in the 32 parents, no elevated risk for PTSD was found. CONCLUSIONS: Children with MIS-C requiring PICU admission had normal overall intelligence 4 months after PICU discharge. Nevertheless, these children reported more emotional and behavioral problems, more PTSD, and worse QoL compared with general population norms. In a subset undergoing more extensive testing, we also identified irregularities in neurocognitive functions. Whether these impairments are caused by the viral or inflammatory response, the PICU admission, or COVID-19 restrictions remains to be investigated.

Executive Summary of the Second International Guidelines for the Diagnosis and Management of Pediatric Acute Respiratory Distress Syndrome (PALICC-2).

OBJECTIVES: We sought to update our 2015 work in the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS), considering new evidence and topic areas that were not previously addressed. DESIGN: International consensus conference series involving 52 multidisciplinary international content experts in PARDS and four methodology experts from 15 countries, using consensus conference methodology, and implementation science. SETTING: Not applicable. PATIENTS: Patients with or at risk for PARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eleven subgroups conducted systematic or scoping reviews addressing 11 topic areas: 1) definition, incidence, and epidemiology; 2) pathobiology, severity, and risk stratification; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive respiratory support; 8) extracorporeal support; 9) morbidity and long-term outcomes; 10) clinical informatics and data science; and 11) resource-limited settings. The search included MEDLINE, EMBASE, and CINAHL Complete (EBSCOhost) and was updated in March 2022. Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to summarize evidence and develop the recommendations, which were discussed and voted on by all PALICC-2 experts. There were 146 recommendations and statements, including: 34 recommendations for clinical practice; 112 consensus-based statements with 18 on PARDS definition, 55 on good practice, seven on policy, and 32 on research. All recommendations and statements had agreement greater than 80%. CONCLUSIONS: PALICC-2 recommendations and consensus-based statements should facilitate the implementation and adherence to the best clinical practice in patients with PARDS. These results will also inform the development of future programs of research that are crucially needed to provide stronger evidence to guide the pediatric critical care teams managing these patients.

Early Neuromuscular Blockade in Moderate-to-Severe Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: The use of neuromuscular blocking agents (NMBAs) in pediatric acute respiratory distress syndrome (PARDS) is common but unsupported by efficacy data. We sought to compare the outcomes between patients with moderate-to-severe PARDS receiving continuous NMBA during the first 48 hours of endotracheal intubation (early NMBA) and those without. DESIGN: Secondary analysis of data from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial, a pediatric multicenter cluster randomized trial of sedation. SETTING: Thirty-one PICUs in the United States. PATIENTS: Children 2 weeks to 17 years receiving invasive mechanical ventilation (MV) for moderate-to-severe PARDS (i.e., oxygenation index ≥ 8 and bilateral infiltrates on chest radiograph on days 0-1 of endotracheal intubation). INTERVENTIONS: NMBA for the entire duration of days 1 and 2 after intubation. MEASUREMENTS AND MAIN RESULTS: Among 1,182 RESTORE patients with moderate-to-severe PARDS, 196 (17%) received early NMBA for a median of 50.0% ventilator days (interquartile range, 33.3-60.7%). The propensity score model predicting the probability of receiving early NMBA included high-frequency oscillatory ventilation on days 0-2 (odds ratio [OR], 7.61; 95% CI, 4.75-12.21) and severe PARDS on days 0-1 (OR, 2.16; 95% CI, 1.50-3.12). After adjusting for risk category, early use of NMBA was associated with a longer duration of MV (hazard ratio, 0.57; 95% CI, 0.48-0.68; p < 0.0001), but not with mortality (OR, 1.62; 95% CI, 0.92-2.85; p = 0.096) compared with no early use of NMBA. Other outcomes including cognitive, functional, and physical impairment at 6 months post-PICU discharge were similar. Outcomes did not differ when comparing high versus low NMBA usage sites or when patients were stratified by baseline Pao2/Fio2 less than 150. CONCLUSIONS: Early NMBA use was associated with a longer duration of MV. This propensity score analysis underscores the need for a randomized controlled trial in pediatrics.

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.

Effect of pediatric ventilation weaning technique on work of breathing.

BACKGROUND: Ventilator liberation is one of the most challenging aspects in patients with respiratory failure. Most patients are weaned through a transition from full to partial respiratory support, whereas some advocate using a continuous spontaneous ventilation (CSV). However, there is little scientific evidence supporting the practice of pediatric ventilator liberation, including the timing of onset of and the approach to weaning mode. We sought to explore differences in patient effort between a pressure controlled continuous mode of ventilation (PC-CMV) [in this cohort PC assist/control (PC-A/C)] with a reduced ventilator rate and CSV, and to study changes in patient effort with decreasing PS. METHODS: In this prospective physiology cross-over study, we randomized children < 5 years to first PC-A/C with a 25% reduction in ventilator rate, or CSV (continuous positive airway pressure [CPAP] + PS). Patients were then crossed over to the other arm. Patient effort was measured by calculating inspiratory work of breathing (WOB) using the Campbell diagram (WOBCampbell), and by pressure-rate-product (PRP) and pressure-time-product (PTP). Respiratory inductance plethysmography (RIP) was used to calculate the phase angle. Measurements were obtained at baseline, during PC-A/C and CPAP + PS, and during decreasing set PS (maximum -6 cmH2O). RESULTS: Thirty-six subjects with a median age of 4.4 (IQR 1.5-11.9) months and median ventilation time of 4.9 (IQR 3.4-7.0) days were included. Nearly all patients (94.4%) were admitted with primary respiratory failure. WOBCampbell during baseline [0.67 (IQR 0.38-1.07) Joules/L] did not differ between CSV [0.49 (IQR 0.17-0.83) Joules/L] or PC-A/C [0.47 (IQR 0.17-1.15) Joules/L]. Neither PRP, PTP, ∆Pes nor phase angle was different between the two ventilator modes. Reducing pressure support resulted in a statistically significant increase in patient effort, albeit that these differences were clinically negligible. CONCLUSIONS: Patient effort during pediatric ventilation liberation was not increased when patients were in a CSV mode of ventilation compared to a ventilator mode with a ventilator back-up rate. Reducing the level of PS did not lead to clinically relevant increases in patient effort. These data may aid in a better approach to pediatric ventilation liberation. Trial registration clinicaltrials.gov NCT05254691. Registered 24 February 2022.

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.

Efficacy of a loading dose of IV salbutamol in children with severe acute asthma admitted to a PICU: a randomized controlled trial.

The optimal dose regimen for intravenous (IV) treatment in children with severe acute asthma (SAA) is still a matter of debate. We assessed the efficacy of adding a salbutamol loading dose to continuous infusion with salbutamol in children admitted to a pediatric intensive care unit (PICU) with SAA. This multicentre, placebo-controlled randomized trial in the PICUs of four tertiary care children's hospitals included children (2-18 years) with SAA admitted between 2017 and 2019. Children were randomized to receive either a loading dose IV salbutamol (15 mcg/kg, max. 750 mcg) or normal saline while on continuous salbutamol infusion. The primary outcome was the asthma score (Qureshi) 1 h after the intervention. Analysis of covariance models was used to evaluate sensitivity to change in asthma scores. Serum concentrations of salbutamol were obtained. Fifty-eight children were included (29 in the intervention group). Median baseline asthma score was 12 (IQR 10-13) in the intervention group and 11 (9-12) in the control group (p = 0.032). The asthma score 1 h after the intervention did not differ significantly between the groups (p = 0.508, ß-coefficient = 0.283). The median increase in salbutamol plasma levels 10 min after the intervention was 13 µg/L (IQR 5-24) in the intervention group and 4 µg/L (IQR 0-7) in the control group (p = 0.001). Side effects were comparable between both groups. CONCLUSION: We found no clinical benefit of adding a loading dose IV salbutamol to continuous infusion of salbutamol, in children admitted to the PICU with SAA. Clinically significant side effects from the loading dose were not encountered. WHAT IS KNOWN: • Pediatric asthma guidelines struggle with an evidence-based approach for the treatment of SAA beyond the initial steps of oxygen suppletion, repetitive administration of inhaled ß2-agonists, and systemic steroids. • During an SAA episode, effective delivery of inhaled drugs is unpredictable due to severe airway obstruction. WHAT IS NEW: • This study found no beneficial effect of an additional loading dose IV salbutamol in children admitted to the PICU. • This study found no clinically significant side effects from the loading dose.

Commentary on High-Flow Nasal Cannula and Continuous Positive Airway Pressure Practices After the First-Line Support for Assistance in Breathing in Children Trials.

Continuous positive airway pressure (CPAP) and heated humidified high-flow nasal cannula (HFNC) are commonly used to treat children admitted to the PICU who require more respiratory support than simple oxygen therapy. Much has been published on these two treatment modalities over the past decade, both in Pediatric Critical Care Medicine (PCCM ) and elsewhere. The majority of these studies are observational analyses of clinical, administrative, or quality improvement datasets and, therefore, are only able to establish associations between exposure to treatment and outcomes, not causation. None of the initial randomized clinical trials comparing HFNC and CPAP were definitive due to their relatively small sample sizes with insufficient power for meaningful clinical outcomes (e.g., escalation to bilevel noninvasive ventilation or intubation, duration of PICU-level respiratory support, mortality) and often yielded ambiguous findings or conflicting results. The recent publication of the First-Line Support for Assistance in Breathing in Children (FIRST-ABC) trials represented a major step toward understanding the role of CPAP and HFNC use in critically ill children. These large, pragmatic, randomized clinical trials examined the efficacy of CPAP and HFNC either for "step up" (i.e., escalation in respiratory support) during acute respiratory deterioration or for "step down" (i.e., postextubation need for respiratory support) management. This narrative review examines the body of evidence on HFNC published in PCCM , contextualizes the findings of randomized clinical trials of CPAP and HFNC up to and including the FIRST-ABC trials, provides guidance to PICU clinicians on how to implement the literature in current practice, and discusses remaining knowledge gaps and future research priorities.

Driving Pressure Is Associated With Outcome in Pediatric Acute Respiratory Failure.

OBJECTIVES: Driving pressure (ratio of tidal volume over respiratory system compliance) is associated with mortality in acute respiratory distress syndrome. We sought to evaluate if such association could be identified in critically ill children. DESIGN: We studied the association between driving pressure on day 1 of mechanical ventilation and ventilator-free days at day 28 through secondary analyses of prospectively collected physiology data. SETTING: Medical-surgical university hospital PICU. PATIENTS: Children younger than 18 years (stratified by Pediatric Mechanical Ventilation Consensus Conference clinical phenotype definitions) without evidence of spontaneous respiration. INTERVENTIONS: Inspiratory hold maneuvers. MEASUREMENTS AND MAIN RESULTS: Data of 222 patients with median age 11 months (2-51 mo) were analyzed. Sixty-five patients (29.3%) met Pediatric Mechanical Ventilation Consensus Conference criteria for restrictive and 78 patients (35.1%) for mixed lung disease, and 10.4% of all patients had acute respiratory distress syndrome. Driving pressure calculated by the ratio of tidal volume over respiratory system compliance for the whole cohort was 16 cm H2O (12-21 cm H2O) and correlated with the static airway pressure gradient (plateau pressure minus positive end-expiratory pressure) (Spearman correlation coefficient = 0.797; p < 0.001). Bland-Altman analysis showed that the dynamic pressure gradient (peak inspiratory pressure minus positive end-expiratory pressure) overestimated driving pressure (levels of agreement -2.295 to 7.268). Rematching the cohort through a double stratification procedure (obtaining subgroups of patients with matched mean levels for one variable but different mean levels for another ranking variable) showed a reduction in ventilator-free days at day 28 with increasing driving pressure in patients ventilated for a direct pulmonary indication. Competing risk regression analysis showed that increasing driving pressure remained independently associated with increased time to extubation (p < 0.001) after adjusting for Pediatric Risk of Mortality III 24-hour score, presence of direct pulmonary indication jury, and oxygenation index. CONCLUSIONS: Higher driving pressure was independently associated with increased time to extubation in mechanically ventilated children. Dynamic assessments of driving pressure should be cautiously interpreted.