Lung-Protective Mechanical Ventilation Strategies in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: Reduced morbidity and mortality associated with lung-protective mechanical ventilation is not proven in pediatric acute respiratory distress syndrome. This study aims to determine if a lung-protective mechanical ventilation protocol in pediatric acute respiratory distress syndrome is associated with improved clinical outcomes. DESIGN: This pilot study over April 2016 to September 2019 adopts a before-and-after comparison design of a lung-protective mechanical ventilation protocol. All admissions to the PICU were screened daily for fulfillment of the Pediatric Acute Lung Injury Consensus Conference criteria and included. SETTING: Multidisciplinary PICU. PATIENTS: Patients with pediatric acute respiratory distress syndrome. INTERVENTIONS: Lung-protective mechanical ventilation protocol with elements on peak pressures, tidal volumes, end-expiratory pressure to FIO2 combinations, permissive hypercapnia, and permissive hypoxemia. MEASUREMENTS AND MAIN RESULTS: Ventilator and blood gas data were collected for the first 7 days of pediatric acute respiratory distress syndrome and compared between the protocol (n = 63) and nonprotocol groups (n = 69). After implementation of the protocol, median tidal volume (6.4 mL/kg [5.4-7.8 mL/kg] vs 6.0 mL/kg [4.8-7.3 mL/kg]; p = 0.005), PaO2 (78.1 mm Hg [67.0-94.6 mm Hg] vs 74.5 mm Hg [59.2-91.1 mm Hg]; p = 0.001), and oxygen saturation (97% [95-99%] vs 96% [94-98%]; p = 0.007) were lower, and end-expiratory pressure (8 cm H2O [7-9 cm H2O] vs 8 cm H2O [8-10 cm H2O]; p = 0.002] and PaCO2 (44.9 mm Hg [38.8-53.1 mm Hg] vs 46.4 mm Hg [39.4-56.7 mm Hg]; p = 0.033) were higher, in keeping with lung protective measures. There was no difference in mortality (10/63 [15.9%] vs 18/69 [26.1%]; p = 0.152), ventilator-free days (16.0 [2.0-23.0] vs 19.0 [0.0-23.0]; p = 0.697), and PICU-free days (13.0 [0.0-21.0] vs 16.0 [0.0-22.0]; p = 0.233) between the protocol and nonprotocol groups. After adjusting for severity of illness, organ dysfunction and oxygenation index, the lung-protective mechanical ventilation protocol was associated with decreased mortality (adjusted hazard ratio, 0.37; 95% CI, 0.16-0.88). CONCLUSIONS: In pediatric acute respiratory distress syndrome, a lung-protective mechanical ventilation protocol improved adherence to lung-protective mechanical ventilation strategies and potentially mortality.

High-Risk ERT for Children With Cardiac Critical Illness.

BACKGROUND: A protocolized extubation readiness test (ERT), including a spontaneous breathing trial (SBT), is recommended for patients who are intubated. This quality-improvement project aimed to improve peri-extubation outcomes by using a high-risk ERT protocol in intubated cardiac patients in addition to a standard-risk protocol. METHODS: After baseline data collection, we implemented a standard-risk ERT protocol (pressure support plus PEEP), followed by a high-risk ERT protocol (PEEP alone) in cardiac subjects who were intubated. The primary outcome, a composite of extubation failure and rescue noninvasive respiratory support, was compared between phases. Ventilator duration and use of postextubation respiratory support were balancing measures. RESULTS: A total of 213 cardiac subjects who were intubated were studied, with extubation failure and rescue noninvasive respiratory support occurring in 10 of 213 (4.7%) and 8 of 213 (3.8%), respectively. We observed a reduction in the composite outcome among the 3 consecutive phases (5/29 [17.2%], 10/110 [9.1%] vs 3/74 [4.1%]; P = .10), but this did not reach statistical significance. In the logistic regression model when adjusting for admission type, the high-risk ERT protocol was associated with a significant reduction of the composite outcome (adjusted odds ratio 0.20, 95% CI 0.04-0.091; P = .037), whereas the standard-risk ERT protocol was not (adjusted odds ratio 0.48, 95% CI 0.15-1.53; P = .21). This was not accompanied by a longer ventilator duration (2.0 [1.0, 3.0], 2.0 [1.0, 4.0] vs 2.0 [1.0, 6.0] days; P = .99). CONCLUSIONS: In this quality-improvement project, a high-risk ERT protocol was implemented with improvement in peri-extubation outcomes among cardiac subjects.

Respiratory Support After Extubation in Children With Pediatric ARDS.

BACKGROUND: Postextubation respiratory support in pediatric ARDS may be used to support the recovering respiratory system and promote timely, successful liberation from mechanical ventilation. This study's aims were to (1) describe the use of postextubation respiratory support in pediatric ARDS from the time of extubation to hospital discharge, (2) identify potential risk factors for postextubation respiratory support, and (3) provide preliminary data for future larger studies. METHODS: This pilot single-center prospective cohort study recruited subjects with pediatric ARDS. Subjects' respiratory status up to hospital discharge, the use of postextubation respiratory support, and how it changed over time were recorded. Analysis was performed comparing subjects who received postextubation respiratory support versus those who did not and compared its use among pediatric ARDS severity categories. Multivariable logistic regression was used to determine variables associated with the use of postextubation respiratory support and included oxygenation index (OI), ventilator duration, and weight. RESULTS: Seventy-three subjects with pediatric ARDS, with median age and OI of 4 (0.6-10.5) y and 7.3 (4.9-12.7), respectively, were analyzed. Postextubation respiratory support was provided to 54/73 (74%) subjects: 28/45 (62.2%), 19/21 (90.5%), and 7/7 (100%) for mild, moderate, and severe pediatric ARDS, respectively, (P = .01). OI and mechanical ventilation duration were higher in subjects who received postextubation respiratory support (8.7 [5.4-14] vs 4.6 [3.7-7], P < .001 and 10 [7-17] d vs 4 [2-7] d, P < .001) compared to those who did not. At hospital discharge, 12/67 (18.2%) survivors received home respiratory support (6 subjects died prior to hospital discharge). In the multivariable model, ventilator duration (adjusted odds ratio 1.3 [95% CI 1.0-1.7], P = .050) and weight (adjusted odds ratio 0.95 [95% CI 0.91-0.99], P = .02) were associated with the use of postextubation respiratory support. CONCLUSIONS: The majority of intubated subjects with pediatric ARDS received respiratory support postextubation, and a substantial proportion continued to require it up to hospital discharge.

Tests and Indices Predicting Extubation Failure in Children: A Systematic Review and Meta-analysis.

INTRODUCTION: There is lack of consensus on what constitutes best practice when assessing extubation readiness in children. This systematic review aims to synthesize data from existing literature on pre-extubation assessments and evaluate their diagnostic accuracies in predicting extubation failure (EF) in children. METHODS: A systematic search in PubMed, EMBASE, Web of Science, CINAHL, and Cochrane was performed from inception of each database to 15 July 2021. Randomized controlled trials or observational studies that studied the association between pre-extubation assessments and extubation outcome in the pediatric intensive care unit population were included. Meta-analysis was performed for studies that report diagnostic tests results of a combination of parameters. RESULTS: In total, 41 of 11,663 publications screened were included (total patients, n = 8111). Definition of EF across studies was heterogeneous. Fifty-five unique pre-extubation assessments were identified. Parameters most studied were: respiratory rate (RR) (13/41, n = 1945), partial pressure of arterial carbon dioxide (10/41, n = 1379), tidal volume (13/41, n = 1945), rapid shallow breathing index (RBSI) (9/41, n = 1400), and spontaneous breathing trials (SBT) (13/41, n = 5652). Meta-analysis shows that RSBI, compliance rate oxygenation pressure (CROP) index, and SBT had sensitivities ranging from 0.14 to 0.57. CROP index had the highest sensitivity [0.57, 95% confidence interval (CI) 0.4-0.73] and area under curve (AUC, 0.98). SBT had the highest specificity (0.93, 95% CI 0.92-0.94). CONCLUSIONS: Pre-extubation assessments studied thus far remain poor predictors of EF. CROP index, having the highest AUC, should be further explored as a predictor of EF. Standardizing the EF definition will allow better comparison of pre-extubation assessments.

The Physiological Basis of High-Frequency Oscillatory Ventilation and Current Evidence in Adults and Children: A Narrative Review.

High-frequency oscillatory ventilation (HFOV) is a type of invasive mechanical ventilation that employs supra-physiologic respiratory rates and low tidal volumes (VT) that approximate the anatomic deadspace. During HFOV, mean airway pressure is set and gas is then displaced towards and away from the patient through a piston. Carbon dioxide (CO2) is cleared based on the power (amplitude) setting and frequency, with lower frequencies resulting in higher VT and CO2 clearance. Airway pressure amplitude is significantly attenuated throughout the respiratory system and mechanical strain and stress on the alveoli are theoretically minimized. HFOV has been purported as a form of lung protective ventilation that minimizes volutrauma, atelectrauma, and biotrauma. Following two large randomized controlled trials showing no benefit and harm, respectively, HFOV has largely been abandoned in adults with ARDS. A multi-center clinical trial in children is ongoing. This article aims to review the physiologic rationale for the use of HFOV in patients with acute respiratory failure, summarize relevant bench and animal models, and discuss the potential use of HFOV as a primary and rescue mode in adults and children with severe respiratory failure.

The Association Between Alveolar Dead Space Fraction and Mortality in Pediatric Acute Respiratory Distress Syndrome: A Prospective Cohort Study.

Background: Alveolar dead-space fraction (AVDSF), the volume of alveolar gas that does not participate in gas exchange, has been reported to predict mortality and morbidity in adults with acute respiratory distress syndrome (ARDS). This study aims to characterize AVDSF in patients with pediatric ARDS (PARDS), to determine its association with clinical outcomes and examine the validity of a previously studied cutoff (AVDSF > 0.25). Methods: This was a prospective cohort study performed in the setting of a lung protective mechanical ventilation protocol. AVDSF was calculated by the equation: AVDSF = [partial pressure of arterial carbon dioxide (PaCO2) - end tidal carbon dioxide (etCO2)]/PaCO2. Receiver operating curve and Youden index were used to identify an AVDSF cutoff associated with mortality, which characterized "high or low AVDSF" groups. Correlation between AVDSF and clinical indices of severity were determined [including daily oxygenation index (OI), admission Pediatric Index of Mortality 2 (PIM 2) and Pediatric Logistic Organ Dysfunction (PELOD) scores]. The primary outcome, mortality in PARDS patients, was compared between the high and low AVDSF groups and analyzed in a multivariable logistic regression adjusting for inotrope use and PIM 2 score. Secondary outcomes included 28-day ventilator-free (VFD) and intensive care unit-free (IFD) days. Results: Sixty-nine PARDS patients with a median (interquartile range) age of 4.5 (0.8, 10.6) years were included in this analysis. Daily AVDSF correlated with daily OI (R 2 = 0.10; p < 0.001). Mean AVDSF over the first 7 days of PARDS correlated with PIM 2 (R 2 = 0.10; p = 0.010) and PELOD (R 2 = 0.12; p = 0.004) scores. The greatest area under the curve identified an AVDSF cutoff of 0.22, which was close to the previously suggested 0.25. The high AVDSF group had higher mortality [7/19 (36.8%) vs. 5/50 (10.0%); p = 0.009] and lower VFD [2 (0, 18) vs. 21 (15, 24); p = 0.007] and IFD [0 (0, 16) vs. 16 (5, 21); p = 0.013]. In the multivariable model, being in the high AVDSF group [adjusted odds ratio 4.67 (95% CI: 1.12, 19.39)] was significantly associated with mortality. Conclusions: High AVDSF was independently associated with increased mortality and decreased VFD and IFD. AVDSF may be complementary to oxygenation indices in risk stratifying PARDS and warrant further study.

Respiratory Therapist-Driven Extubation Readiness Testing in a Single Pediatric ICU.

BACKGROUND: There is currently no standardized way to determine suitability for extubation of pediatric ICU (PICU) patients, potentially resulting in prolonged duration of mechanical ventilation. We aimed to design and implement a protocol for screening all intubated PICU patients for extubation readiness. METHODS: We adopted the quality improvement (QI) Model for Improvement with Plan-Do-Study-Act (PDSA) cycles to achieve this aim. This QI project was conducted over 11 months in a multidisciplinary PICU. Outcome measures included the (1) development of a standardized extubation readiness test (ERT) that was acceptable and safe; (2) performance of ERT on > 80% of all mechanically ventilated subjects; and (3) maintenance or reduction in mechanical ventilation duration, extubation failure (non-elective re-intubation within 48 h of extubation), and need for rescue noninvasive ventilation (NIV). Balancing measures were to ensure (1) no compromise of the subject's clinical status; and (2) acceptability of the ERT workflow by medical, nursing, and respiratory therapist (RT) teams. RESULTS: Four PDSA cycles were necessary to achieve the aims of this study. During the QI period, 438 subjects were admitted to the PICU. The ERT was championed by the RTs who conducted the test during office hours. ERT performance increased from 0% (baseline) to 90% (fourth PDSA cycle). Extubation failure rate after implementing ERT was reduced compared to baseline (4/31 [12.9%] vs 3/127 [2.4%], P = .01), whereas need for rescue NIV (3/31 [9.7%] vs 10/127 [7.9%], P = .74) and duration of mechanical ventilation (2 [1-7] d vs 1 [1-3] d, P = .09) were unchanged. PICU length of stay was reduced after implementing ERT (5 [3-10] d vs 3 [1-6] d, P = .01). No subject was destabilized as a result of ERT, and PICU staff found the workflow acceptable. CONCLUSIONS: An acceptable and safe ERT protocol was implemented and found to improve outcomes in PICU subjects on mechanical ventilation.

The longitudinal course of pediatric acute respiratory distress syndrome and its time to resolution: A prospective observational study.

Background: The longitudinal course of patients with pediatric acute respiratory distress syndrome (PARDS) is not well described. In this study, we describe the oxygenation index (OI) and oxygen saturation index (OSI) in mild, moderate, and severe PARDS over 28 days and provide pilot data for the time to resolution of PARDS (T res), as a short-term respiratory-specific outcome, hypothesizing that it is associated with the severity of PARDS and clinical outcomes. Methods: This prospective observational study recruited consecutive patients with PARDS. OI and OSI were trended daily over 28 days. T res (defined as OI < 4 or OSI < 5.3 on 2 consecutive days) were described based on PARDS severity and analyzed with Poisson and logistic regression to determine its association with conventional outcomes [mechanical ventilation (MV) duration, intensive care unit (ICU) and hospital length of stay, 28-day ventilator-free days (VFD), and 28-day ICU-free days (IFD)]. Results: There were 121 children included in this study, 33/121(27.3%), 44/121(36.4%), and 44/121(36.4%) in the mild, moderate, and severe groups of PARDS, respectively. OI and OSI clearly differentiated mild, moderate, and severe groups in the first 7days of PARDS; however, this differentiation was no longer present after 7days. Median T res was 4 (interquartile range: 3, 6), 5 (4, 7), and 7.5 (7, 11.5) days; p < 0.001 for the mild, moderate, and severe groups of PARDS, respectively. T res was associated with increased MV duration, ICU and hospital length of stay, and decreased VFD and IFD. Conclusion: The oxygenation defect in PARDS took progressively longer to resolve across the mild, moderate, and severe groups. T res is a potential short-term respiratory-specific outcome, which may be useful in addition to conventional clinical outcomes but needs further validation in external cohorts.

Large scale cytokine profiling uncovers elevated IL12-p70 and IL-17A in severe pediatric acute respiratory distress syndrome.

The specific cytokines that regulate pediatric acute respiratory distress syndrome (PARDS) pathophysiology remains unclear. Here, we evaluated the respiratory cytokine profile in PARDS to identify the molecular signatures associated with severe disease. A multiplex suspension immunoassay was used to profile 45 cytokines, chemokines and growth factors. Cytokine concentrations were compared between severe and non-severe PARDS, and correlated with oxygenation index (OI). Partial least squares regression modelling and regression coefficient plots were used to identify a composite of key mediators that differentially segregated severe from non-severe disease. The mean (standard deviation) age and OI of this cohort was 5.2 (4.9) years and 17.8 (11.3), respectively. Early PARDS patients with severe disease exhibited a cytokine signature that was up-regulated for IL-12p70, IL-17A, MCP-1, IL-4, IL-1ß, IL-6, MIP-1ß, SCF, EGF and HGF. In particular, pro-inflammatory cytokines (IL-6, MCP-1, IP-10, IL-17A, IL-12p70) positively correlated with OI early in the disease. Whereas late PARDS was characterized by a differential lung cytokine signature consisting of both up-regulated (IL-8, IL-12p70, VEGF-D, IL-4, GM-CSF) and down-regulated (IL-1ß, EGF, Eotaxin, IL-1RA, and PDGF-BB) profiles segregating non-severe and severe groups. This cytokine signature was associated with increased transcription, T cell activation and proliferation as well as activation of mitogen-activated protein kinase pathway that underpin PARDS severity.

Characteristics and trajectory of patients with pediatric acute respiratory distress syndrome.

OBJECTIVE: This study delineates the disease trajectory of patients with pediatric acute respiratory distress syndrome (PARDS) defined by the Pediatric Acute Lung Injury Consensus Conference (PALICC) definition, and evaluates the impact of comorbidities on outcomes. METHODS: This prospective study over November 2017-October 2019 was conducted in a single-center multidisciplinary pediatric intensive care unit (PICU) and included patients <21years of age with PARDS. Clinical history of those requiring mechanical ventilation for <3 days was interrogated and cases in which the diagnosis of PARDS were unlikely, identified. The impact of chronic comorbidities on clinical outcomes, in particular, pulmonary disease and immunosuppression, were analyzed. RESULTS: Eighty-five of 1272 PICU admissions (6.7%) met the criteria for PARDS and were included. Median age and oxygenation indexes were 2.8 (0.6, 8.3) years and 10.6 (7.6, 15.4), respectively. Overall mortality was 12 out of 85 (14.1%). Despite fulfilling criteria in 6/85 (7.1%), hypoxemia contributed by bronchospasm, mucus plugging, fluid overload, and atelectasis was quickly reversible and PARDS was unlikely in these patients. Comorbidities (57/85 [67.1%]) were not associated with worsened outcomes. However, pre-existing pulmonary disease and immunosuppression were associated with severe PARDS (12/20 [60.0%] vs 19/65 [29.2%]; P = .017), extracorporeal membrane oxygenation use (5/20 [25.0%] vs 3/65 [4.6%]; P = .016) and reduced ventilator free days (VFD) (15 [0, 19] vs 21 [6, 23]; P = .039), compared with those without them. CONCLUSION: A small percentage of children fulfilling the PALICC definition had quickly reversible hypoxemia with likely alternate pathophysiology to PARDS. Patients with pulmonary comorbidities and immunosuppression had a more severe course of PARDS compared with others.

Critically Ill Patients with COVID-19: A Narrative Review on Prone Position.

INTRODUCTION: Prone position is known to improve mortality in patients with acute respiratory distress syndrome (ARDS). The impact of prone position in critically ill patients with coronavirus disease of 2019 (COVID-19) remains to be determined. In this review, we describe the mechanisms of action of prone position, systematically appraise the current experience of prone position in COVID-19 patients, and highlight unique considerations for prone position practices during this pandemic. METHODS: For our systematic review, we searched PubMed, Scopus and EMBASE from January 1, 2020, to April 16, 2020. After completion of our search, we became aware of four relevant publications during article preparation that were published in May and June 2020, and these studies were reviewed for eligibility and inclusion. We included all studies reporting clinical characteristics of patients admitted to the hospital with COVID-19 disease who received respiratory support with high-flow nasal cannula, or noninvasive or mechanical ventilation and reported the use of prone position. The full text of eligible articles was reviewed, and data regarding study design, patient characteristics, interventions and outcomes were extracted. RESULTS: We found seven studies (total 1899 patients) describing prone position in COVID-19. Prone position has been increasingly used in non-intubated patients with COVID-19; studies show high tolerance and improvement in oxygenation and lung recruitment. Published studies lacked a description of important clinical outcomes (e.g., mortality, duration of mechanical ventilation). CONCLUSIONS: Based on the findings of our review, we recommend prone position in patients with moderate to severe COVID-19 ARDS as per existing guidelines. A trial of prone position should be considered for non-intubated COVID-19 patients with hypoxemic respiratory failure, as long as this does not result in a delay in intubation.