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.

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.

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.

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.

High Breath-by-Breath Variability Is Associated With Extubation Failure in Children.

OBJECTIVES: Extubation failure is multifactorial, and most tools to assess extubation readiness only evaluate snapshots of patient physiology. Understanding variability in respiratory variables may provide additional information to inform extubation readiness assessments. DESIGN: Secondary analysis of prospectively collected physiologic data of children just prior to extubation during a spontaneous breathing trial. Physiologic data were cleaned to provide 40 consecutive breaths and calculate variability terms, coefficient of variation and autocorrelation, in commonly used respiratory variables (i.e., tidal volume, minute ventilation, and respiratory rate). Other clinical variables included diagnostic and demographic data, median values of respiratory variables during spontaneous breathing trials, and the change in airway pressure during an occlusion maneuver to measure respiratory muscle strength (maximal change in airway pressure generated during airway occlusion [PiMax]). Multivariable models evaluated independent associations with reintubation and prolonged use of noninvasive respiratory support after extubation. SETTING: Acute care, children's hospital. PATIENTS: Children were included from the pediatric and cardiothoracic ICUs who were greater than 37 weeks gestational age up to and including 18 years who were intubated greater than or equal to 12 hours with planned extubation. We excluded children who had a contraindication to an esophageal catheter or respiratory inductance plethysmography bands. INTERVENTIONS: Noninterventional study. MEASUREMENTS AND MAIN RESULTS: A total of 371 children were included, 32 of them were reintubated. Many variability terms were associated with reintubation, including coefficient of variation and autocorrelation of the respiratory rate. After controlling for confounding variables such as age and neurologic diagnosis, both coefficient of variation of respiratory rate(p < 0.001) and low PiMax (p = 0.002) retained an independent association with reintubation. Children with either low PiMax or high coefficient of variation of respiratory rate had a nearly three-fold higher risk of extubation failure, and when these children developed postextubation upper airway obstruction, reintubation rates were greater than 30%. CONCLUSIONS: High respiratory variability during spontaneous breathing trials is independently associated with extubation failure in children, with very high rates of extubation failure when these children develop postextubation upper airway obstruction.

The role of computer-based clinical decision support systems to deliver protective mechanical ventilation.

PURPOSE OF REVIEW: Mechanical ventilation of adults and children with acute respiratory failure necessitates balancing lung and diaphragm protective ventilation. Computerized decision support (CDS) offers advantages in circumstances where complex decisions need to be made to weigh potentially competing risks, depending on the physiologic state of the patient. RECENT FINDINGS: Significant variability in how ventilator protocols are applied still exists and clinical data show that there continues to be wide variability in ventilator management. We have developed a CDS, which we are currently testing in a Phase II randomized controlled trial. The CDS is called Real-time Effort Driven ventilator management (REDvent). We will describe the rationale and methods for development of CDS for lung and diaphragm protective ventilation, using the REDvent CDS as an exemplar. SUMMARY: Goals for achieving compliance and physiologic objectives can be met when CDS instructions are simple and explicit, provide the clinician with the underlying rule set, permit acceptable reasons for declining and allow for iterative adjustments.

Real-Time Effort Driven Ventilator Management: A Pilot Study.

OBJECTIVES: Mechanical ventilation of patients with acute respiratory distress syndrome should balance lung and diaphragm protective principles, which may be difficult to achieve in routine clinical practice. Through a Phase I clinical trial, we sought to determine whether a computerized decision support-based protocol (real-time effort-driven ventilator management) is feasible to implement, results in improved acceptance for lung and diaphragm protective ventilation, and improves clinical outcomes over historical controls. DESIGN: Interventional nonblinded pilot study. SETTING: PICU. PATIENTS: Mechanically ventilated children with acute respiratory distress syndrome. INTERVENTIONS: A computerized decision support tool was tested which prioritized lung-protective management of peak inspiratory pressure-positive end-expiratory pressure, positive end-expiratory pressure/FIO2, and ventilatory rate. Esophageal manometry was used to maintain patient effort in a physiologic range. Protocol acceptance was reported, and enrolled patients were matched 4:1 with respect to age, initial oxygenation index, and percentage of immune compromise to historical control patients for outcome analysis. MEASUREMENTS AND MAIN RESULTS: Thirty-two patients were included. Acceptance of protocol recommendations was over 75%. One-hundred twenty-eight matched historical controls were used for analysis. Compared with historical controls, patients treated with real-time effort-driven ventilator management received lower peak inspiratory pressure-positive end-expiratory pressure and tidal volume, and higher positive end-expiratory pressure when FIO2 was greater than 0.60. Real-time effort-driven ventilator management was associated with 6 more ventilator-free days, shorter duration until the first spontaneous breathing trial and 3 fewer days on mechanical ventilation among survivors (all p ≤ 0.05) in comparison with historical controls, while maintaining no difference in the rate of reintubation. CONCLUSIONS: A computerized decision support-based protocol prioritizing lung-protective ventilation balanced with reduction of controlled ventilation to maintain physiologic levels of patient effort can be implemented and may be associated with shorter duration of ventilation.

Neurally adjusted ventilatory assist mitigates ventilator-induced diaphragm injury in rabbits.

BACKGROUND: Ventilator-induced diaphragmatic dysfunction is a serious complication associated with higher ICU mortality, prolonged mechanical ventilation, and unsuccessful withdrawal from mechanical ventilation. Although neurally adjusted ventilatory assist (NAVA) could be associated with lower patient-ventilator asynchrony compared with conventional ventilation, its effects on diaphragmatic dysfunction have not yet been well elucidated. METHODS: Twenty Japanese white rabbits were randomly divided into four groups, (1) no ventilation, (2) controlled mechanical ventilation (CMV) with continuous neuromuscular blockade, (3) NAVA, and (4) pressure support ventilation (PSV). Ventilated rabbits had lung injury induced, and mechanical ventilation was continued for 12 h. Respiratory waveforms were continuously recorded, and the asynchronous events measured. Subsequently, the animals were euthanized, and diaphragm and lung tissue were removed, and stained with Hematoxylin-Eosin to evaluate the extent of lung injury. The myofiber cross-sectional area of the diaphragm was evaluated under the adenosine triphosphatase staining, sarcomere disruptions by electron microscopy, apoptotic cell numbers by the TUNEL method, and quantitative analysis of Caspase-3 mRNA expression by real-time polymerase chain reaction. RESULTS: Physiological index, respiratory parameters, and histologic lung injury were not significantly different among the CMV, NAVA, and PSV. NAVA had lower asynchronous events than PSV (median [interquartile range], NAVA, 1.1 [0-2.2], PSV, 6.8 [3.8-10.0], p = 0.023). No differences were seen in the cross-sectional areas of myofibers between NAVA and PSV, but those of Type 1, 2A, and 2B fibers were lower in CMV compared with NAVA. The area fraction of sarcomere disruptions was lower in NAVA than PSV (NAVA vs PSV; 1.6 [1.5-2.8] vs 3.6 [2.7-4.3], p < 0.001). The proportion of apoptotic cells was lower in NAVA group than in PSV (NAVA vs PSV; 3.5 [2.5-6.4] vs 12.1 [8.9-18.1], p < 0.001). There was a tendency in the decreased expression levels of Caspase-3 mRNA in NAVA groups. Asynchrony Index was a mediator in the relationship between NAVA and sarcomere disruptions. CONCLUSIONS: Preservation of spontaneous breathing using either PSV or NAVA can preserve the cross sectional area of the diaphragm to prevent atrophy. However, NAVA may be superior to PSV in preventing sarcomere injury and apoptosis of myofibrotic cells of the diaphragm, and this effect may be mediated by patient-ventilator asynchrony.

Derivation and Validation of an Objective Effort of Breathing Score in Critically Ill Children.

OBJECTIVES: To derive and validate a score that correlates with an objective measurement of a child's effort of breathing. DESIGN: Secondary analysis of a previously conducted observational study. SETTING: The pediatric and cardiothoracic ICUs of a quaternary-care children's hospital. PATIENTS: Patients more than 37 weeks gestational age to age 18 years who were undergoing extubation. INTERVENTIONS: Effort of breathing was measured in patients following extubation using esophageal manometry to calculate pressure rate product. Simultaneously, members of a multidisciplinary team (nurse, physician, and respiratory therapist) assessed respiratory function using a previously validated tool. Elements of the tool that were significantly associated with pressure rate product in univariate analysis were identified and included in a multivariate model. An Effort of Breathing score was derived from the results of the model using data from half of the subjects (derivation cohort) and then validated using data from the remaining subjects (validation cohort) by calculating the area under the receiver operator characteristic curve for pressure rate product greater than 90th percentile and for the need for reintubation. MEASUREMENTS AND MAIN RESULTS: Among 409 subjects, the median age was 5 months, and nearly half were cardiac surgery patients (49.1%). Retractions, stridor, and pulsus paradoxus were included in the Simple Score. Area under the receiver operator characteristic curve for pressure rate product greater than 90th percentile was 0.8359 (95% CI, 0.7996-0.8722) in the derivation cohort and 0.7930 (0.7524-0.8337) in the validation cohort. Area under the receiver operator characteristic curve for reintubation was 0.7280 (0.6807-0.7752) when all scores were analyzed individually and was 0.7548 (0.6644-0.8452) if scores from three clinicians from different disciplines were summated. Results were similar regardless of provider discipline or training. CONCLUSIONS: A scoring system was derived and validated, performed acceptably to predict increased effort of breathing or need for advanced respiratory support and may function best when used by a team.

Evaluating the Practice of Repositioning Endotracheal Tubes in Neonates and Children Based on Radiographic Location.

OBJECTIVES: Chest radiographs are commonly performed in the ICU setting to confirm the position of the endotracheal tube. The purpose of this study was to evaluate the practice and accuracy of repositioning endotracheal tubes in the pediatric population based on chest radiograph. DESIGN: Retrospective review of patient's medical record and chest radiograph. SETTING: Single-institution, academic children's hospital. PATIENTS: PICU and cardiothoracic ICU patients who had repositioning of their endotracheal tube from September 1, 2016, to September 1, 2017. MEASUREMENTS AND MAIN RESULTS: Chest radiograph before and after endotracheal tube repositioning were examined measuring the distance from the endotracheal tube tip to carina. A total of 183 endotracheal tube repositionings were assessed. Twenty-nine percent of endotracheal tube repositionings resulted in a persistently malpositioned endotracheal tube, requiring another intervention. For intended endotracheal tube repositioning of ± 2.0 cm, the actual change measured compared to intended adjustment was a median of 0.7 cm (interquartile range, 0.35-1.1 cm). For intended ± 1.5 cm, the median difference was 0.4 cm (interquartile range, 0.16-0.90 cm). For intended ± 1.0 cm, the median difference was 0.5 cm (interquartile range, 0.20-0.90 cm). For intended ± 0.5 cm, the median difference was 0.3 cm (interquartile range, 0.2-0.88 cm). When the head was malpositioned the difference from intended endotracheal tube repositioning to actual was median 0.70 cm (interquartile range, 0.40-1.1 cm), this was significantly higher than when the head was in a good position CONCLUSIONS:: When repositioning endotracheal tubes based on chest radiograph, there is a significant difference between intended and actual adjustment with great variability. Avoiding very small repositionings (± 0.5 cm) and standardizing head position prior to daily chest radiograph may reduce these errors.

A pilot study to assess short-term physiologic outcomes of transitioning infants with severe bronchopulmonary dysplasia from ICU to two subacute ventilators.

INTRODUCTION: This study was designed to evaluate short-term physiologic outcomes of transitioning neonates with bronchopulmonary dysplasia (BPD) from intensive care unit (ICU) ventilators to both the Trilogy 202 (Philips Healthcare, Andover, MA) and LTV 1200 (CareFusion, Yorba Linda, CA) subacute ventilators. METHODS: Six infants with BPD requiring tracheostomies for support with a neonatal-specific ICU ventilator underwent placement of esophageal balloon catheters, airway pressure transducers, flow sensors, oxygen saturation (SpO2), and end tidal carbon dioxide (PETCO2) monitors. Noninvasive gas exchange, airflow, and airway and esophageal pressures (PES) were recorded following 20 min on the ICU ventilator. The infants were placed on the Trilogy 202 and LTV 1200 ventilators in random order at identical settings as the ICU ventilator. We measured noninvasive gas exchange, pressure-rate product (respiratory rate × ΔPES), ventilator response times, and the percentage of spontaneous breaths that triggered the ventilator at 20 min in each subject while being supported with each of the different subacute ventilators. RESULTS: The mean (SD) weight of the six infants was 4.983 (0.56) kg. There were no differences in heart rate (p = 0.51) or SpO2 (p = 0.97) but lower PETCO2, ΔPES, respiratory rate, pressure rate-product, response times, and greater percentage of subject initiated breaths that triggered the ventilator (p < 0.05) was observed with the Trilogy 202 than the LTV 1200. All six infants transitioned successfully from the ICU ventilator to the Trilogy 202 ventilator. CONCLUSION: In this small group of infants with BPD, the Trilogy 202 ventilator performed better than the LTV 1200. The improved subject efforts, per cent subject triggering, and response times observed with the Trilogy are likely related to differences in triggering algorithms, location of triggering mechanisms, and gas delivery system performance within the ventilators. These pilot data may be useful for informing future clinical study design and understanding differences in the level of support provided by different subacute ventilators in infants with BPD.

Risk Factors for Pediatric Extubation Failure: The Importance of Respiratory Muscle Strength.

OBJECTIVE: Respiratory muscle weakness frequently develops during mechanical ventilation, although in children there are limited data about its prevalence and whether it is associated with extubation outcomes. We sought to identify risk factors for pediatric extubation failure, with specific attention to respiratory muscle strength. DESIGN: Secondary analysis of prospectively collected data. SETTING: Tertiary care PICU. PATIENTS: Four hundred nine mechanically ventilated children. INTERVENTIONS: Respiratory measurements using esophageal manometry and respiratory inductance plethysmography were made preextubation during airway occlusion and on continuous positive airway pressure of 5 and pressure support of 10 above positive end-expiratory pressure 5 cm H2O, as well as 5 and 60 minutes postextubation. MEASUREMENTS AND MAIN RESULTS: Thirty-four patients (8.3%) were reintubated within 48 hours of extubation. Reintubation risk factors included lower maximum airway pressure during airway occlusion (aPiMax) preextubation, longer length of ventilation, postextubation upper airway obstruction, high respiratory effort postextubation (pressure rate product, pressure time product, tension time index), and high postextubation phase angle. Nearly 35% of children had diminished respiratory muscle strength (aPiMax ≤ 30 cm H2O) at the time of extubation, and were nearly three times more likely to be reintubated than those with preserved strength (aPiMax > 30 cm H2O; 14% vs 5.5%; p = 0.006). Reintubation rates exceeded 20% when children with low aPiMax had moderately elevated effort after extubation (pressure rate product > 500), whereas children with preserved aPiMax had reintubation rates greater than 20% only when postextubation effort was very high (pressure rate product > 1,000). When children developed postextubation upper airway obstruction, reintubation rates were 47.4% for those with low aPiMax compared to 15.4% for those with preserved aPiMax (p = 0.02). Multivariable risk factors for reintubation included acute neurologic disease, lower aPiMax, postextubation upper airway obstruction, higher preextubation positive end-expiratory pressure, higher postextubation pressure rate product, and lower height. CONCLUSIONS: Neuromuscular weakness at the time of extubation was common in children and was independently associated with reintubation, particularly when postextubation effort was high.

Comparison of Effort of Breathing for Infants on Nasal Modes of Respiratory Support.

OBJECTIVE: To directly compare effort of breathing between high flow nasal cannula (HFNC), nasal intermittent mechanical ventilation (NIMV), and nasal continuous positive airway pressure (NCPAP). STUDY DESIGN: This was a single center prospective cross-over study for patients <6 months in the cardiothoracic or pediatric intensive care unit receiving nasal noninvasive respiratory support after extubation. We measured effort of breathing using esophageal manometry with pressure-rate product (PRP) on all 3 modes. NIMV synchrony was determined by comparing patient efforts (esophageal manometry) with mechanically delivered breaths (spirometry in ventilator circuit). On NIMV, PRP and synchrony was also measured after adding a nasal clip on 26 patients. RESULTS: Forty-two children were included. Median (IQR) age was 2 (0.5, 4) months. There was no difference in median PRP between HFNC 6 liters per minute, 355 (270,550), NIMV 12/5 cm H2O, 341 (235, 472), and NCPAP 5 cm H2O, 340 (245,506) (P?=?.33). Results were similar regardless of HFNC flow rate or NIMV inspiratory pressure. Median PRP on CPAP of 5 cm H2O prior to extubation 255 (176, 375) was significantly lower than all postextubation values (P??.07)). However, as NIMV synchrony improved (>60%), PRP on NIMV was lower than on HFNC. CONCLUSIONS: For infants, effort of breathing is similar on HFNC, NIMV, and NCPAP after extubation, regardless of flow rate or inspiratory pressure. We speculate that bi-level NIMV may be superior if high levels of synchrony can be achieved.

The Relationship between High Flow Nasal Cannula Flow Rate and Effort of Breathing in Children.

OBJECTIVE: To use an objective metric of effort of breathing to determine optimal high flow nasal cannula (HFNC) flow rates in children <3 years of age. STUDY DESIGN: Single-center prospective trial in a 24-bed pediatric intensive care unit of children <3 years of age on HFNC. We measured the percent change in pressure∙rate product (PRP) (an objective measure of effort of breathing) as a function of weight-indexed flow rates of 0.5, 1.0, 1.5, and 2.0 L/kg/minute. For a subgroup of patients, 2 different HFNC delivery systems (Fisher & Paykel [Auckland, New Zealand] and Vapotherm [Exeter, New Hampshire]) were compared. RESULTS: Twenty-one patients (49 titration episodes) were studied. The most common diagnoses were bronchiolitis and pneumonia. Overall, there was a significant difference in the percent change in PRP from baseline (of 0.5 L/kg/minute) with increasing flow rates for the entire cohort (P < .001) with largest change at 2.0 L/kg/min (-21%). Subgroup analyses showed no significant difference in percent change in PRP from baseline when comparing the 2 different HFNC delivery systems (P = .12). Patients ≤8 kg experienced a larger percent change in PRP as HFNC flow rates were increased (P = .001) than patients >8 kg. CONCLUSIONS: The optimal HFNC flow rate to reduce effort of breathing in infants and young children is approximately 1.5-2.0 L/kg/minute with more benefit seen in children ≤8 kg.

Volume and Pressure Delivery During Pediatric High-Frequency Oscillatory Ventilation.

OBJECTIVE: Identify variables independently associated with delivered tidal volume (VT) and measured mean airway pressure during high-frequency oscillatory ventilation across the range of pediatric endotracheal tube sizes. DESIGN: In vitro study. SETTING: Research laboratory. INTERVENTIONS: An in vitro bench model of the intubated pediatric respiratory system during high-frequency oscillatory ventilation was used to obtain delivered VT and mean airway pressure (in the distal lung) for various endotracheal tube sizes. Measurements were taken at different combinations of ventilator set mean airway pressure (Paw), amplitude (ΔP), frequency, and test lung compliance. Multiple regression analysis was used to construct multivariable models predicting delivered VT and mean airway pressure. MEASUREMENTS AND MAIN RESULTS: Variables independently associated with higher delivered VT for all endotracheal tube sizes include higher ΔP (p < 0.001), lower frequency (p < 0.001), and higher test lung compliance (p < 0.001). A multiplicative interaction between frequency and ΔP magnifies the delivered VT when ΔP is high and frequency is low (p < 0.001). Delivered mean airway pressure becomes lower than set Paw as ΔP increases (p < 0.001) and frequency increases (p < 0.05). Ventilator set Paw is the largest determinant of delivered mean airway pressure; however, increasing ΔP resulted in a lower delivered mean airway pressure. For example, in a 4.0 mm ID endotracheal tube, increasing ΔP by 10 cm H2O resulted in an average decrease of delivered mean airway pressure by 4.5%. CONCLUSIONS: This is the first study to quantify the interaction between ΔP and frequency in delivered VT and the effect of ΔP and frequency on delivered mean airway pressure. These results demonstrate the need to measure or estimate VT and delivered pressures during high-frequency oscillatory ventilation and may be useful in determining optimal strategies for lung protective ventilation during high-frequency oscillatory ventilation.

Inhaled Treprostinil Drug Delivery During Mechanical Ventilation and Spontaneous Breathing Using Two Different Nebulizers.

OBJECTIVES: To determine the feasibility of delivering inhaled treprostinil during mechanical ventilation and spontaneous unassisted ventilation using the Tyvaso Inhalation System and the vibrating mesh nebulizer. We sought to compare differences in fine particle fraction, and absolute inhaled treprostinil mass delivered to neonatal, pediatric, and adult models affixed with a face mask, conventional, and high-frequency ventilation between Tyvaso Inhalation System and with different nebulizer locations between Tyvaso Inhalation System and vibrating mesh nebulizer. DESIGN: Fine particle fraction was first determined via impaction with both the Tyvaso Inhalation System and vibrating mesh nebulizer. Next, a test lung configured with neonatal, pediatric, and adult mechanics and a filter to capture medication was attached to a realistic face model during spontaneous breathing or an endotracheal tube during conventional ventilation and high-frequency oscillator ventilator. Inhaled treprostinil was then nebulized with both the Tyvaso Inhalation System and vibrating mesh nebulizer, and the filter was analyzed via high-performance liquid chromatography. Testing was done in triplicate. Independent two-sample t tests were used to compare mean fine particle fraction and inhaled mass between devices. Analysis of variance with Tukey post hoc tests were used to compare within device differences. SETTING: Academic children's hospital aerosol research laboratory. MEASUREMENTS AND MAIN RESULTS: Fine particle fraction was not different between the Tyvaso Inhalation System and vibrating mesh nebulizer (0.78 ± 0.04 vs 0.77 ± 0.08, respectively; p = 0.79). The vibrating mesh nebulizer delivered the same or greater inhaled treprostinil than the Tyvaso Inhalation System in every simulated model and condition. When using the vibrating mesh nebulizer, delivery was highest when using high-frequency oscillator ventilator in the neonatal and pediatric models, and with the nebulizer in the distal position in the adult model. CONCLUSIONS: The vibrating mesh nebulizer is a suitable alternative to the Tyvaso Inhalation System for inhaled treprostinil delivery. Fine particle fraction is similar between devices, and vibrating mesh nebulizer delivery meets or exceeds delivery of the Tyvaso Inhalation System. Delivery for infants and children during high-frequency oscillator ventilator with the vibrating mesh nebulizer may result in higher than expected dosages.

Change in Oxygen Consumption Following Inhalation of Albuterol in Comparison with Levalbuterol in Healthy Adult Volunteers.

BACKGROUND: Albuterol is the most commonly used ß agonist to treat reversible lower airway obstruction. Albuterol contains a racemic mixture of two enantiomers. Levalbuterol contains the single R form enantiomer. Levalbuterol is frequently prescribed to limit cardiovascular toxicity. OBJECTIVE: We examined changes in oxygen consumption (V'O2) and heart rate (HR) following administration of albuterol and levalbuterol. METHODS: This is a prospective, randomized, single-blinded, controlled study of healthy adult volunteers. Subjects separately received albuterol (5 mg) and levalbuterol (2.5 mg) aerosolized over 15 min. V'O2 and vital signs were measured before the medications and 5, 10, 20, 40, and 60 min after. RESULTS: We enrolled 24 volunteers with a median age of 32 years. Compared to baseline, there was a significant maximum increase in V'O2 following administration of both albuterol (median 17% (1, 3 IQR 9, 43%) p < 0.001) and levalbuterol (median 23% (1, 3 IQR 10, 32%) p < 0.001). There was no significant difference between the maximum increase in V'O2 following administration of albuterol compared to levalbuterol (p = 0.57). Compared to baseline, there was a significant maximal increase in HR with both albuterol (median 30% (1, 3 IQR 19, 43%) p < 0.001) and levalbuterol (median 23% (1, 3 IQR 19, 31%) p < 0.001). There was a statistically significant greater increase in maximal HR following administration of albuterol as compared to levalbuterol (p = 0.009). CONCLUSION: Albuterol and levalbuterol both cause a significant increase in V'O2 and HR. There was no significant difference between albuterol and levalbuterol regarding the maximum increase in V'O2. There was a statistically significant but likely clinically insignificant difference in maximum increase in HR in patients with adequate oxygen delivery when comparing albuterol to levalbuterol.

Evaluating Risk Factors for Pediatric Post-extubation Upper Airway Obstruction Using a Physiology-based Tool.

RATIONALE: Subglottic edema is the most common cause of pediatric extubation failure, but few studies have confirmed risk factors or prevention strategies. This may be due to subjective assessment of stridor or inability to differentiate supraglottic from subglottic disease. OBJECTIVES: Objective 1 was to assess the utility of calibrated respiratory inductance plethysmography (RIP) and esophageal manometry to identify clinically significant post-extubation upper airway obstruction (UAO) and differentiate subglottic from supraglottic UAO. Objective 2 was to identify risk factors for subglottic UAO, stratified by cuffed versus uncuffed endotracheal tubes (ETTs). METHODS: We conducted a single-center prospective study of children receiving mechanical ventilation. UAO was defined by inspiratory flow limitation (measured by RIP and esophageal manometry) and classified as subglottic or supraglottic based on airway maneuver response. Clinicians performed simultaneous blinded clinical UAO assessment at the bedside. MEASUREMENTS AND MAIN RESULTS: A total of 409 children were included, 98 of whom had post-extubation UAO and 49 (12%) of whom were subglottic. The reintubation rate was 34 (8.3%) of 409, with 14 (41%) of these 34 attributable to subglottic UAO. Five minutes after extubation, RIP and esophageal manometry better identified patients who subsequently received UAO treatment than clinical UAO assessment (P < 0.006). Risk factors independently associated with subglottic UAO included low cuff leak volume or high preextubation leak pressure, poor sedation, and preexisting UAO (P < 0.04) for cuffed ETTs; and age (range, 1 mo to 5 yr) for uncuffed ETTs (P < 0.04). For uncuffed ETTs, the presence or absence of preextubation leak was not associated with subglottic UAO. CONCLUSIONS: RIP and esophageal manometry can objectively identify subglottic UAO after extubation. Using this technique, preextubation leak pressures or cuff leak volumes predict subglottic UAO in children, but only if the ETT is cuffed.