Digital Twins of Acute Hypoxemic Respiratory Failure Patients Suggest a Mechanistic Basis for Success and Failure of Noninvasive Ventilation.

OBJECTIVES: To clarify the mechanistic basis for the success or failure of noninvasive ventilation (NIV) in acute hypoxemic respiratory failure (AHRF). DESIGN: We created digital twins based on mechanistic computational models of individual patients with AHRF. SETTING: Interdisciplinary Collaboration in Systems Medicine Research Network. SUBJECTS: We used individual patient data from 30 moderate-to-severe AHRF patients who had failed high-flow nasal cannula (HFNC) therapy and subsequently underwent a trial of NIV. INTERVENTIONS: Using the digital twins, we evaluated lung mechanics, quantified the separate contributions of external support and patient respiratory effort to lung injury indices, and investigated their relative impact on NIV success or failure. MEASUREMENTS AND MAIN RESULTS: In digital twins of patients who successfully completed/failed NIV, after 2 hours of the trial the mean (sd) of the change in total lung stress was -10.9 (6.2)/-0.35 (3.38) cm H2O, mechanical power -13.4 (12.2)/-1.0 (5.4) J/min, and total lung strain 0.02 (0.24)/0.16 (0.30). In the digital twins, positive end-expiratory pressure (PEEP) produced by HFNC was similar to that set during NIV. In digital twins of patients who failed NIV vs. those who succeeded, intrinsic PEEP was 3.5 (0.6) vs. 2.3 (0.8) cm H2O, inspiratory pressure support was 8.3 (5.9) vs. 22.3 (7.2) cm H2O, and tidal volume was 10.9 (1.2) vs. 9.4 (1.8) mL/kg. In digital twins, successful NIV increased respiratory system compliance +25.0 (16.4) mL/cm H2O, lowered inspiratory muscle pressure -9.7 (9.6) cm H2O, and reduced the contribution of patient spontaneous breathing to total driving pressure by 57.0%. CONCLUSIONS: In digital twins of AHRF patients, successful NIV improved lung mechanics, lowering respiratory effort and indices associated with lung injury. NIV failed in patients for whom only low levels of positive inspiratory pressure support could be applied without risking patient self-inflicted lung injury due to excessive tidal volumes.

Mechanical chest compressions as a last-ditch attempt to salvage a profoundly hypoxic but normotensive patient with a massive pulmonary embolism.

Massive pulmonary embolism is a common cause of morbidity and mortality. For patients presenting with massive pulmonary embolism, severe hypoxia is usually associated with severe hypotension. These patients should be considered for thrombectomy should thrombolysis and respiratory support fail to improve their condition. Should thrombectomy not be available or suitable, consideration should be given to offering mechanical chest compressions to 'break up the clot'. We describe a case in which this seemingly led to survival and full recovery.

Effect of noninvasive ventilation on mortality and clinical outcomes among patients with severe hypoxemic COVID-19 pneumonia after high-flow nasal oxygen failure: a multicenter retrospective French cohort with propensity score analysis.

BACKGROUND: We assessed the effect of noninvasive ventilation (NIV) on mortality and length of stay after high flow nasal oxygenation (HFNO) failure among patients with severe hypoxemic COVID-19 pneumonia. METHODS: In this multicenter, retrospective study, we enrolled COVID-19 patients admitted in intensive care unit (ICU) for severe COVID-19 pneumonia with a HFNO failure from December 2020 to January 2022. The primary outcome was to compare the 90-day mortality between patients who required a straight intubation after HFNO failure and patients who received NIV after HFNO failure. Secondary outcomes included ICU and hospital length of stay. A propensity score analysis was performed to control for confounding factors between groups. Exploratory outcomes included a subgroup analysis for 90-day mortality. RESULTS: We included 461 patients with HFNO failure in the analysis, 233 patients in the straight intubation group and 228 in the NIV group. The 90-day mortality did not significantly differ between groups, 58/228 (25.4%) int the NIV group compared with 59/233 (25.3%) in the straight intubation group, with an adjusted hazard ratio (HR) after propensity score weighting of 0.82 [95%CI, 0.50-1.35] (p = 0.434). ICU length of stay was significantly shorter in the NIV group compared to the straight intubation group, 10.0 days [IQR, 7.0-19.8] versus 18.0 days [IQR,11.0-31.0] with a propensity score weighted HR of 1.77 [95%CI, 1.29-2.43] (p < 0.001). A subgroup analysis showed a significant increase in mortality rate for intubated patients in the NIV group with 56/122 (45.9%), compared to 59/233 (25.3%) for patients in the straight intubation group (p < 0.001). CONCLUSIONS: In severely hypoxemic COVID-19 patients, no significant differences were observed on 90-day mortality between patients receiving straight intubation and those receiving NIV after HFNO failure. NIV strategy was associated with a significant reduction in ICU length of stay, despite an increase in mortality in the subgroup of patients finally intubated.

Respiratory support with standard low-flow oxygen therapy, high-flow oxygen therapy or continuous positive airway pressure in adults with acute hypoxaemic respiratory failure in a resource-limited setting: protocol for a randomised, open-label, clinical trial - the Acute Respiratory Intervention StudiEs in Africa (ARISE-AFRICA) study.

RATIONALE: Acute hypoxaemic respiratory failure (AHRF) is associated with high mortality in sub-Saharan Africa. This is at least in part due to critical care-related resource constraints including limited access to invasive mechanical ventilation and/or highly skilled acute care workers. Continuous positive airway pressure (CPAP) and high-flow oxygen by nasal cannula (HFNC) may prove useful to reduce intubation, and therefore, improve survival outcomes among critically ill patients, particularly in resource-limited settings, but data in such settings are lacking. The aim of this study is to determine whether CPAP or HFNC as compared with standard oxygen therapy, could reduce mortality among adults presenting with AHRF in a resource-limited setting. METHODS: This is a prospective, multicentre, randomised, controlled, stepped wedge trial, in which patients presenting with AHRF in Uganda will be randomly assigned to standard oxygen therapy delivered through a face mask, HFNC oxygen or CPAP. The primary outcome is all-cause mortality at 28 days. Secondary outcomes include the number of patients with criteria for intubation at day 7, the number of patients intubated at day 28, ventilator-free days at day 28 and tolerance of each respiratory support. ETHICS AND DISSEMINATION: The study has obtained ethical approval from the Research and Ethics Committee, School of Biomedical Sciences, College of Health Sciences, Makerere University as well as the Uganda National Council for Science and Technology. Patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04693403. PROTOCOL VERSION: 8 September 2023; version 5.

Noninvasive ventilation on reintubation in patients with obesity and hypoxemic respiratory failure following abdominal surgery: a post hoc analysis of a randomized clinical trial.

PURPOSE: Although noninvasive ventilation (NIV) may reduce reintubation in patients with acute hypoxemic respiratory failure following abdominal surgery, this strategy has not been specifically assessed in patients with obesity. METHODS: We conducted a post hoc analysis of a multicenter randomized controlled trial comparing NIV delivered via facial mask to standard oxygen therapy among patients with obesity and acute hypoxemic respiratory failure within 7 days after abdominal surgery. The primary outcome was reintubation within 7 days. Secondary outcomes were invasive ventilation-free days at day 30, intensive care unit (ICU)-acquired pneumonia and 30-day survival. RESULTS: Among 293 patients with hypoxemic respiratory failure following abdominal surgery, 76 (26%) patients had obesity and were included in the intention-to-treat analysis. Reintubation rate was significantly lower with NIV (13/42, 31%) than with standard oxygen therapy (19/34, 56%) within 7 days (absolute difference: - 25%, 95% confidence interval (CI) - 49 to - 1%, p = 0.03). NIV was associated with significantly more invasive ventilation-free days compared with standard oxygen therapy (27.1 ± 8.6 vs 22.7 ± 11.1 days; p = 0.02), while fewer patients developed ICU-acquired pneumonia (1/42, 2% vs 6/34, 18%; p = 0.04). The 30-day survival was 98% in the NIV group (41/42) versus 85% in the standard oxygen therapy (p = 0.08). In patients with body mass index (BMI) < 30 kg/m2, no significant difference was observed between NIV (36/105, 34%) and standard oxygen therapy (47/109, 43%, p = 0.03). An interaction test showed no statistically significant difference between the two subsets (BMI ≥ 30 kg/m2 and BMI < 30 kg/m2). CONCLUSIONS: Among patients with obesity and hypoxemic respiratory failure following abdominal surgery, use of NIV compared with standard oxygen therapy reduced the risk of reintubation within 7 days, contrary to patients without obesity. However, no interaction was found according to the presence of obesity or not, suggesting either a lack of power to conclude in the non-obese subgroup despite existing differences, or that the statistical difference found in the overall sample was driven by a large effect in the obese subsets.

Thoracic Society of Australia and New Zealand clinical practice guideline on adult home oxygen therapy.

This Thoracic Society of Australia and New Zealand Guideline on the provision of home oxygen therapy in adults updates a previous Guideline from 2015. The Guideline is based upon a systematic review and meta-analysis of literature to September 2022 and the strength of recommendations is based on GRADE methodology. Long-term oxygen therapy (LTOT) is recommended for its mortality benefit for patients with COPD and other chronic respiratory diseases who have consistent evidence of significant hypoxaemia at rest (PaO2 ≤ 55 mm Hg or PaO2 ≤59 mm Hg in the presence of hypoxaemic sequalae) while in a stable state. Evidence does not support the use of LTOT for patients with COPD who have moderate hypoxaemia or isolated nocturnal hypoxaemia. In the absence of hypoxaemia, there is no evidence that oxygen provides greater palliation of breathlessness than air. Evidence does not support the use of supplemental oxygen therapy during pulmonary rehabilitation in those with COPD and exertional desaturation but normal resting arterial blood gases. Both positive and negative effects of LTOT have been described, including on quality of life. Education about how and when to use oxygen therapy in order to maximize its benefits, including the use of different delivery devices, expectations and limitations of therapy and information about hazards and risks associated with its use are key when embarking upon this treatment.

Addition of Mask to High-flow Nasal Oxygen: A Strategy to Improve Oxygenation in Hypoxemic Respiratory Failure Secondary to COVID-19.

PURPOSE: High-flow nasal cannula (HFNO) reduces the need for invasive mechanical ventilation in COVID-19 patients with hypoxemic-respiratory failure. During HFNO entrainment of room air dilutes the delivered fractional inspiratory oxygen (FiO2), thereby preventing improvement in oxygenation. The placement of a mask over HFNO to improve oxygenation has provided conflicting results. We aimed to determine and compare the effect of placing various mask types over HFNO on oxygen saturation (SPO2). MATERIALS AND METHODS: In this prospective physiological study 40 patients with COVID-19-associated hypoxemic respiratory failure on HFNO with O2 concentration <92% were included. The effect of placing different masks over HFNO on oxygenation, respiratory rate, heart rate, blood pressure, patient comfort, and partial pressure of carbon dioxide level (pCO2) was recorded after a prespecified time interval. RESULTS: We observed a significantly higher mean SPO2 and lower mean respiratory rate on using various study masks over HFNO compared to HFNO alone. On comparing various mask types, the use of N95 masks and nonrebreather (NRB) masks with O2 showed a significant increase in O2 concentration and reduction in respiratory rate compared to surgical mask (SM) and NRB without O2. The proportion of patients who achieved SPO2 of >92% was higher with the use of N95 masks (47.5%) or NRB with O2 (45%) over HFNO compared to SM (35%) and NRB without O2 (35%). No significant change was observed in heart rate, blood pressure, and CO2 level with the use of any mask over HFNO. CONCLUSION: This study demonstrates improvement in oxygenation and reduction in respiratory rate with the use of various masks over HFNO in patients of COVID-19-related hypoxemic-respiratory-failure. Significantly greater benefit was achieved with the use of N95 or NRB with O2 compared to SM or NRB without O2.

Chronic Obstructive Pulmonary Disease and Oxygen Therapy: A Double-edged Sword.

Oxygen, like all medicines, is a drug which needs moderation. Hypoxia, as well as excess oxygen supplementation, can be harmful in a patient with chronic obstructive pulmonary disease (COPD). Both the European and the British guidelines recommend a target oxygen saturation of 88-92% in patients with COPD. Hypoxia can result in symptoms, such as restlessness, anxiety, agitation, and headache, while excess oxygen can lead to altered sensorium due to the retention of carbon dioxide (CO2) in patients with COPD. We often come across patients who come with breathlessness and have hypoxia, and the knee-jerk reaction is to start the patient on oxygen support to maintain an oxygen saturation of >95%, and this may result in hypercapnia and type II respiratory failure. Here, we present a descriptive review of the proper application of oxygen therapy in a patient presenting with acute exacerbation of COPD, the rationale behind the target oxygen saturations, and the mechanisms of type II respiratory failure due to hyperoxygenation.

Combination of acute intermittent hypoxia and intermittent transcutaneous electrical stimulation in obstructive sleep apnea: a randomized controlled crossover trial.

Intermittent hypoxia (IH) and intermittent transcutaneous electrical stimulation (ITES) might benefit patients with obstructive sleep apnea (OSA). However, the therapeutic value of combined IH and ITES in OSA is unknown. In this prospective, randomized, controlled crossover study, normoxia (air exposure for 50 min before sleep and sham stimulation for 6 h during sleep), IH (5 repeats of 5 min 10-12 % O2 alternating with 5 min air for 50 min, and sham stimulation for 6 h), ITES (air exposure for 50 min and 6 repeats of 30 min transcutaneous electrical stimulation alternating with 30 min of sham stimulation for 6 h), and IH&ITES (10-12 % O2 alternating with air for 50 min and transcutaneous electrical stimulation alternating with sham stimulation for 6 h) were administered to patients with OSA over four single-night sessions. The primary endpoint was difference in OSA severity between the interventions according to apnea-hypopnea index (AHI) and oxygen desaturation index (ODI). The efficacy was response to IH, ITES, IH&ITES defined as a ≥50 % reduction in AHI compared with normoxia. Twenty participants (17 male, 3 female) completed the trial. The median (IQR) AHI decreased from 14.5 (10.8, 17.5) events/h with normoxia to 6.9 (3.9, 14.8) events/h with IH (p=0.020), 5.7 (3.4, 9.1) events/h with ITES (p=0.001), and 3.5 (1.8, 6.4) events/h with IH&ITES (p=0.001). AHI was significantly different between IH and IH&ITES (p=0.042) but not between ITES and IH&ITES (p=0.850). For mild-moderate OSA (n=17), IH, ITES, and IH&ITES had a significant effect on AHI (p=0.013, p=0.001, p=0.001, respectively) compared with normoxia, but there were no differences in post hoc pairwise comparisons between intervention groups. No serious adverse events were observed. In conclusion, IH, ITES, and IH&ITES significantly reduced OSA severity. IH&ITES showed better efficacy in mild-moderate OSA than IH and was comparable to ITES. Our data do not support recommending IH&ITES over ITES for OSA.

Characterizing the Racial Discrepancy in Hypoxemia Detection in Venovenous Extracorporeal Membrane Oxygenation: An Extracorporeal Life Support Organization Registry Analysis.

PURPOSE: Skin pigmentation influences peripheral oxygen saturation (SpO2) compared to arterial saturation of oxygen (SaO2). Occult hypoxemia (SaO2 ≤ 88% with SpO2 ≥ 92%) is associated with increased in-hospital mortality in venovenous-extracorporeal membrane oxygenation (VV-ECMO) patients. We hypothesized VV-ECMO cannulation, in addition to race/ethnicity, accentuates the SpO2-SaO2 discrepancy due to significant hemolysis. METHODS: Adults (≥ 18 years) supported with VV-ECMO with concurrently measured SpO2 and SaO2 measurements from over 500 centers in the Extracorporeal Life Support Organization Registry (1/2018-5/2023) were included. Multivariable logistic regressions were performed to examine whether race/ethnicity was associated with occult hypoxemia in pre-ECMO and on-ECMO SpO2-SaO2 calculations. RESULTS: Of 13,171 VV-ECMO patients, there were 7772 (59%) White, 2114 (16%) Hispanic, 1777 (14%) Black, and 1508 (11%) Asian patients. The frequency of on-ECMO occult hypoxemia was 2.0% (N = 233). Occult hypoxemia was more common in Black and Hispanic patients versus White patients (3.1% versus 1.7%, P < 0.001 and 2.5% versus 1.7%, P = 0.025, respectively). In multivariable logistic regression, Black patients were at higher risk of pre-ECMO occult hypoxemia versus White patients (adjusted odds ratio [aOR] = 1.55, 95% confidence interval [CI] = 1.18-2.02, P = 0.001). For on-ECMO occult hypoxemia, Black patients (aOR = 1.79, 95% CI = 1.16-2.75, P = 0.008) and Hispanic patients (aOR = 1.71, 95% CI = 1.15-2.55, P = 0.008) had higher risk versus White patients. Higher pump flow rates (aOR = 1.29, 95% CI = 1.08-1.55, P = 0.005) and on-ECMO 24-h lactate (aOR = 1.06, 95% CI = 1.03-1.10, P < 0.001) significantly increased the risk of on-ECMO occult hypoxemia. CONCLUSION: SaO2 should be carefully monitored if using SpO2 during ECMO support for Black and Hispanic patients especially for those with high pump flow and lactate values at risk for occult hypoxemia.

Mesenchymal stem cell-derived exosomes ameliorate hypoxic pulmonary hypertension by inhibiting the Hsp90aa1/ERK/pERK pathway.

Hypoxic pulmonary hypertension (HPH) is a serious and life-threatening chronic cardiopulmonary disease characterized by progressive elevation of pulmonary artery pressure and pulmonary vascular remodeling. Mesenchymal stem cell- derived exosomes (MSC-Exos) can relieve HPH by reversing pulmonary vascular remodeling. The HPH model was established in healthy male Sprague-Dawley (SD) rats aged 6 to 8 weeks. The rats were placed in a room with oxygen concentration of (10 ± 1) % for 8 hours a day over 28 days, were then injected intravenously with MSC-Exos (100 ug protein/kg) or equal-volume phosphate buffer saline (PBS) once a day over 1 week. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI) and pulmonary vascular remodeling were observed after anesthesia. In addition, platelet-derived growth factor BB (PDGF-BB) was used to stimulate rat pulmonary artery smooth muscle cells (PASMCs) to construct HPH pathological cell models. The results showed that MSC-Exos could not only reduce the elevation of RVSP, right ventricular hypertrophy and the degree of pulmonary vascular remodeling in HPH rats, but also reduce the proliferation, migration and apoptosis resistance of PASMCs. Finally, GSE53408 and GSE113439 datasets were analyzed and showed that the expression of Hsp90aa1 and pERK/ERK were significantly increased in HPH, also could be inhibited by MSC-Exos. Meanwhile, inhibition of Hsp90aa1 also reduced PASMCs migration and pERK/ERK protein level. In conclusion, MSC-Exos alleviated HPH by suppressing PASMCs proliferation, migration and apoptosis resistance through inhibiting the Hsp90aa1/ERK/pERK pathway.

Automated oxygen titration with non-invasive ventilation in hypoxaemic adults with cardiorespiratory disease: a randomised cross-over trial.

BACKGROUND: Closed-loop oxygen control systems automatically adjust the fraction of inspired oxygen (FiO2) to maintain oxygen saturation (SpO2) within a predetermined target range. Their performance with low and high-flow oxygen therapies, but not with non-invasive ventilation, has been established. We compared the effect of automated oxygen on achieving and maintaining a target SpO2 range with nasal high flow (NHF), bilevel positive airway pressure (bilevel) and continuous positive airway pressure (CPAP), in stable hypoxaemic patients with chronic cardiorespiratory disease. METHODS: In this open-label, three-way cross-over trial, participants with resting hypoxaemia (n=12) received each of NHF, bilevel and CPAP treatments, in random order, with automated oxygen titrated for 10 min, followed by 36 min of standardised manual oxygen adjustments. The primary outcome was the time taken to reach target SpO2 range (92%-96%). Secondary outcomes included time spent within target range and physiological responses to automated and manual oxygen adjustments. RESULTS: Two participants were randomised to each of six possible treatment orders. During automated oxygen control (n=12), the mean (±SD) time to reach target range was 114.8 (±87.9), 56.6 (±47.7) and 67.3 (±61) seconds for NHF, bilevel and CPAP, respectively, mean difference 58.3 (95% CI 25.0 to 91.5; p=0.002) and 47.5 (95% CI 14.3 to 80.7; p=0.007) seconds for bilevel and CPAP versus NHF, respectively. Proportions of time spent within target range were 68.5% (±16.3), 65.6% (±28.7) and 74.7% (±22.6) for NHF, bilevel and CPAP, respectively.Manually increasing, then decreasing, the FiO2 resulted in similar increases and then decreases in SpO2 and transcutaneous carbon dioxide (PtCO2) with NHF, bilevel and CPAP. CONCLUSION: The target SpO2 range was achieved more quickly when automated oxygen control was initiated with bilevel and CPAP compared with NHF while time spent within the range across the three therapies was similar. Manually changing the FiO2 had similar effects on SpO2 and PtCO2 across each of the three therapies. TRIAL REGISTRATION NUMBER: ACTRN12622000433707.

Acute Intermittent Hypoxia With High-Intensity Gait Training in Chronic Stroke: A Phase II Randomized Crossover Trial.

BACKGROUND: Studies in individuals with chronic stroke indicate high-intensity training (HIT) focused on walking improves locomotor function, which may be due to repeated activation of locomotor circuits and serotonin-dependent modulation of motor output. Separate studies in animals and individuals with spinal cord injury suggest acute intermittent hypoxia (AIH) can augment the effects of locomotor interventions through similar serotonin-dependent mechanisms, although no studies have coupled AIH with HIT in individuals poststroke. The goal of this study was to evaluate the safety and efficacy of AIH+HIT versus HIT alone in individuals with chronic stroke. METHODS: This phase II double-blind randomized, crossover trial recruited individuals between 18 and 85 years old, >6 months poststroke, and self-selected speeds <1.0 m/s. Participants received up to 15 sessions of AIH for 30 minutes using 15 cycles of hypoxia (60-90 seconds; 8%-9% O2) and normoxia (30-60 seconds; 21% O2), followed by 1 hour of HIT targeting >75% heart rate reserve. The control condition received normoxia for 30 minutes before HIT. Following the first training phase, participants performed the second phase >1 month later. The primary outcomes were self-selected speed and fastest speed, a 6-minute walk test, and peak treadmill speed. A 3-way mixed-model ANOVA assessed the effects of time, training, and order of interventions. RESULTS: Of 55 individuals screened, 35 were randomized to AIH+HIT or normoxia+HIT first, and 28 individuals completed both interventions, revealing greater gains in self-selected speeds (0.14 [0.08-0.18] versus 0.05 [0.01-0.10] m/s), fastest speed (0.16 [0.10-0.21] versus 0.06 [0.02-0.10] m/s), and peak treadmill speed (0.21 [0.14-0.29] versus 0.11 [0.06-0.16] m/s) following AIH+HIT versus normoxia+HIT (P<0.01) with no order effects. Greater gains in spatiotemporal symmetry were observed with AIH+HIT, with worse outcomes for those prescribed serotonin-mediated antidepressant medications. CONCLUSIONS: AIH+HIT resulted in greater gains in locomotor function than normoxia+HIT. Subsequent phase III trials should further evaluate the efficacy of this intervention. REGISTRATION: URL: https://clinicaltrials.gov/; Unique identifier: NCT04472442.

Comparison of venovenous extracorporeal membrane oxygenation, prone position and supine mechanical ventilation for severely hypoxemic acute respiratory distress syndrome: a network meta-analysis.

PURPOSE: Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 < 80 mmHg is a life-threatening condition. The optimal management strategy is unclear. The aim of this meta-analysis was to compare the effects of low tidal volumes (Vt), moderate Vt, prone ventilation, and venovenous extracorporeal membrane oxygenation (VV-ECMO) on mortality in severe ARDS. METHODS: We performed a frequentist network meta-analysis of randomised controlled trials (RCTs) with participants who had severe ARDS and met eligibility criteria for VV-ECMO or had PaO2/FiO2 < 80 mmHg. We applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to discern the relative effect of interventions on mortality and the certainty of the evidence. RESULTS: Ten RCTs including 812 participants with severe ARDS were eligible. VV-ECMO reduces mortality compared to low Vt (risk ratio [RR] 0.77, 95% confidence interval [CI] 0.59-0.99, moderate certainty) and compared to moderate Vt (RR 0.75, 95% CI 0.57-0.98, low certainty). Prone ventilation reduces mortality compared to moderate Vt (RR 0.78, 95% CI 0.66-0.93, high certainty) and compared to low Vt (RR 0.81, 95% CI 0.63-1.02, moderate certainty). We found no difference in the network comparison of VV-ECMO compared to prone ventilation (RR 0.95, 95% CI 0.72-1.26), but inferences were based solely on indirect comparisons with very low certainty due to very wide confidence intervals. CONCLUSIONS: In adults with ARDS and severe hypoxia, both VV-ECMO (low to moderate certainty evidence) and prone ventilation (moderate to high certainty evidence) improve mortality relative to low and moderate Vt strategies. The impact of VV-ECMO versus prone ventilation remains uncertain.

Transamniotic Stem Cell Therapy Modulates Uterine Natural Killer Cell Activity in the Hypoxia Model of Intrauterine Growth Restriction.

Intrauterine growth restriction (IUGR) pathophysiology is driven by abnormal uterine natural killer cell (uNK) activity leading to placental dysfunction. Transamniotic stem cell therapy (TRASCET) with mesenchymal stem cells (MSCs) can improve experimental IUGR by mechanisms not fully understood. We sought to examine TRASCET's effects in downstream products of uNKs in a model of IUGR: 15 Sprague-Dawley dams were exposed to alternating hypoxia (10.5% O2) from gestational day 15 (E15) until term (E21). Their fetuses (n = 189) were divided into four groups. One group remained untreated (n = 52), whereas three groups received volume-matched intraamniotic injections of either saline (sham, n = 44) or a suspension of amniotic fluid-derived MSCs, either in their native state (TRASCET, n = 50) or "primed" to an enhanced antiinflammatory phenotype (TRASCET-Primed, n = 43). Normal fetuses served as controls (n = 33). At term, various analyses were performed, including ELISA for surrogates of placental inflammation and uNK activity. Statistical comparisons included Bonferroni-adjusted criterion. Overall survival from hypoxia was 74% (140/189). Placental efficiency was lower in untreated and sham but normalized in both TRASCET groups (P < 0.01-0.47). Interleukin-17, a stimulator of uNKs, was elevated from normal in all groups (P < 0.01 for all). Interferon-gamma, released from activated uNKs, was elevated in all groups except sham but lower than the untreated in both TRASCET groups (P ≤ 0.01-0.06). Tumor necrosis factor-alpha, also produced by uNKs, was elevated in untreated and sham (P < 0.01 for both), but normalized by TRASCET (P = 0.05) and even lowered from normal in TRASCET-Primed (P < 0.01). Vascular endothelial growth factor, also released by uNKs, was elevated in untreated and sham but lower than normal in both TRASCET groups (P < 0.01 for all). We conclude that TRASCET with MSCs modulates the activity of placental uNKs in experimental IUGR, with distinct effects on their downstream products. This mechanistic insight may inform the development of novel strategies for the management of this disease.

High-flow nasal oxygen for children's airway surgery to reduce hypoxaemic events: a randomised controlled trial.

BACKGROUND: Tubeless upper airway surgery in children is a complex procedure in which surgeons and anaesthetists share the same operating field. These procedures are often interrupted for rescue oxygen therapy. The efficacy of nasal high-flow oxygen to decrease the frequency of rescue interruptions in children undergoing upper airway surgery is unknown. METHODS: In this multicentre randomised trial conducted in five tertiary hospitals in Australia, children aged 0-16 years who required tubeless upper airway surgery were randomised (1:1) by a web-based randomisation tool to either nasal high-flow oxygen delivery or standard oxygen therapy (oxygen flows of up to 6 L/min). Randomisation was stratified by site and age (<1 year, 1-4 years, and 5-16 years). Subsequent tubeless upper airway surgery procedures in the same child could be included if there were more than 2 weeks between the procedures, and repeat surgical procedures meeting this condition were considered to be independent events. The oxygen therapy could not be masked, but the investigators remained blinded until outcome data were locked. The primary outcome was successful anaesthesia without interruption of the surgical procedure for rescue oxygenation. A rescue oxygenation event was defined as an interruption of the surgical procedure to deliver positive pressure ventilation using either bag mask technique, insertion of an endotracheal tube, or laryngeal mask to improve oxygenation. There were ten secondary outcomes, including the proportion of procedures with a hypoxaemic event (SpO2 <90%). Analyses were done on an intention-to-treat (ITT) basis. Safety was assessed in all enrolled participants. This trial is registered in the Australian New Zealand Clinical Trials Registry, ACTRN12618000949280, and is completed. FINDINGS: From Sept 4, 2018, to April 12, 2021, 581 procedures in 487 children were randomly assigned to high-flow oxygen (297 procedures) or standard care (284 procedures); after exclusions, 528 procedures (267 assigned to high-flow oxygen and 261 assigned to standard care) in 483 children (293 male and 190 female) were included in the ITT analysis. The primary outcome of successful anaesthesia without interruption for tubeless airway surgery was achieved in 236 (88%) of 267 procedures on high-flow oxygen and in 229 (88%) of 261 procedures on standard care (adjusted risk ratio [RR] 1·02, 95% CI 0·96-1·08, p=0·82). There were 51 (19%) procedures with a hypoxaemic event in the high-flow oxygen group and 57 (22%) in the standard care group (RR 0·86, 95% CI 0·58-1·24). Of the other prespecified secondary outcomes, none showed a significant difference between groups. Adverse events of epistaxis, laryngospasm, bronchospasm, hypoxaemia, bradycardia, cardiac arrest, hypotension, or death were similar in both study groups. INTERPRETATION: Nasal high-flow oxygen during tubeless upper airway surgery did not reduce the proportion of interruptions of the procedures for rescue oxygenation compared with standard care. There were no differences in adverse events between the intervention groups. These results suggest that both approaches, nasal high-flow or standard oxygen, are suitable alternatives to maintain oxygenation in children undergoing upper airway surgery. FUNDING: Thrasher Research Fund, the Australian and New Zealand College of Anaesthetists, the Society for Paediatric Anaesthesia in New Zealand and Australia.

Cost-effectiveness of nasal high-flow in children with acute hypoxaemic respiratory failure.

AIM: A pilot randomised controlled trial assessed the early application of nasal high-flow (NHF) therapy compared with standard oxygen therapy (SOT), in children aged 0 to 16 years presenting to paediatric emergency departments with acute hypoxaemic respiratory failure (AHRF). The study estimated the need to escalate therapy and hospital length of stay in the NHF group compared with SOT. This sub-study then assessed the subsequent cost-effectiveness. METHODS: A decision tree-based model was developed, alongside the clinical study, to estimate cost-effectiveness, from the healthcare sector perspective. The primary health economics outcome is measured as incremental cost per length of hospital stay avoided. Incremental cost effectiveness ratios (ICER) measuring change in cost per change in length of stay, were obtained for four samples, depending on responder status and obstructive airways disease. These were (1) obstructive and responder, (2) non-obstructive and responder, (3) obstructive and non-responder and (4) non obstructive and non-responder. Bootstrapping of parameters accounted for uncertainty in estimates of cost and outcome. RESULTS: The ICER for patients randomised to NHF, indicated an additional A$367.20 for a lower hospital length of stay (in days) in the non-obstructive/non-responder sample. In the bootstrap sample, this was found to be cost effective above a willingness to pay threshold of A$10 000. The ICER was A$440.86 in the obstructive/responder sample and A$469.56 in the non-obstructive/responder sample - but both resulted in a longer length of stay. The ICER in the obstructive/non-responder sample was A$52 167.76, also with a longer length of stay, mainly impacted by a small sample of severe cases. CONCLUSION: As first-line treatment, NHF is unlikely to be cost-effective compared with SOT, but for non-obstructive patients who required escalation in care (non-obstructive non-responder), NHF is likely to be cost-effective if willingness-to-pay per reduced hospital length of stay is more than A$10 000 per patient.

When to intubate in acute hypoxaemic respiratory failure? Options and opportunities for evidence-informed decision making in the intensive care unit.

The optimal timing of intubation in acute hypoxaemic respiratory failure is uncertain and became a point of controversy during the COVID-19 pandemic. Invasive mechanical ventilation is a potentially life-saving intervention but carries substantial risks, including injury to the lungs and diaphragm, pneumonia, intensive care unit-acquired muscle weakness, and haemodynamic impairment. In deciding when to intubate, clinicians must balance premature exposure to the risks of ventilation with the potential harms of unassisted breathing, including disease progression and worsening multiorgan failure. Currently, the optimal timing of intubation is unclear. In this Personal View, we examine a range of parameters that could serve as triggers to initiate invasive mechanical ventilation. The utility of a parameter (eg, the ratio of arterial oxygen tension to fraction of inspired oxygen) to predict the likelihood of a patient undergoing intubation does not necessarily mean that basing the timing of intubation on that parameter will improve therapeutic outcomes. We examine options for clinical investigation to make progress on establishing the optimal timing of intubation.

Dyspnea is severe and associated with a higher intubation rate in de novo acute hypoxemic respiratory failure.

BACKGROUND: Dyspnea is a key symptom of de novo acute hypoxemic respiratory failure. This study explores dyspnea and its association with intubation and mortality in this population. METHODS: This was a secondary analysis of a multicenter, randomized, controlled trial. Dyspnea was quantified by a visual analog scale (dyspnea-VAS) from zero to 100 mm. Dyspnea was measured in 259 of the 310 patients included. Factors associated with intubation were assessed with a competing risks model taking into account ICU discharge. The Cox model was used to evaluate factors associated with 90-day mortality. RESULTS: At baseline (randomization in the parent trial), median dyspnea-VAS was 46 (interquartile range, 16-65) mm and was ≥ 40 mm in 146 patients (56%). The intubation rate was 45%. Baseline variables independently associated with intubation were moderate (dyspnea-VAS 40-64 mm) and severe (dyspnea-VAS ≥ 65 mm) dyspnea at baseline (sHR 1.96 and 2.61, p = 0.023), systolic arterial pressure (sHR 2.56, p < 0.001), heart rate (sHR 1.94, p = 0.02) and PaO2/FiO2 (sHR 0.34, p = 0.028). 90-day mortality was 20%. The cumulative probability of survival was lower in patients with baseline dyspnea-VAS ≥ 40 mm (logrank test, p = 0.049). Variables independently associated with mortality were SAPS 2 ≥ 25 (p < 0.001), moderate-to-severe dyspnea at baseline (p = 0.073), PaO2/FiO2 (p = 0.118), and treatment arm (p = 0.046). CONCLUSIONS: In patients admitted to the ICU for de novo acute hypoxemic respiratory failure, dyspnea is associated with a higher risk of intubation and with a higher mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier # NCT01320384.