Publications

BACKGROUND: Ventilator-induced diaphragmatic dysfunction (VIDD) occurs in up to 60% of mechanically ventilated patients and prolongs ventilatory dependance. The consequences of VIDD are muscle atrophy, reduction of strength, and injury of muscle fibers. Atrophy and contractile activity of the diaphragm can be estimated by ultrasound muscle thickness and thickening fraction. Prior experience demonstrates invasive electrical stimulation of the diaphragm helps preserve muscle thickness. This is the first study on a non-invasive phrenic nerve stimulator that aims to assess its feasibility, safety, and usefulness in preserving diaphragm thickness.

METHODS: A multi-center randomized clinical trial will be performed in four intensive care units (ICUs) in the United States of America and Canada. Inclusion criteria include patients older than 21 years, in the first 48 h of mechanical ventilation (MV) and predicted to remain on the ventilator for at least 48 h. Patients with contraindications for phrenic nerve stimulation, severe chronic pulmonary diseases, or impossibility to measure diaphragm thickness with ultrasound will be excluded. Patients enrolled will be randomized to standard care (control) or 30-min daily non-invasive phrenic nerve stimulation up to 10 days after enrollment (intervention). The primary effectiveness endpoint is the change in diaphragm thickness on day 10, extubation, or death whichever occurs first. Secondary endpoints include change in diaphragm thickness on day 4, maximal inspiratory pressure before extubation, and time-to rapid shallow breathing index (RSBI) <105. Safety objectives include the proportion of device- or procedure-related adverse events (SAE). The estimated sample size will be 40 patients (20 per group). DISCUSSION: The STIMIT ACTIVATOR trial is a randomized multi-center study powered to elucidate whether non-invasive phrenic nerve stimulation is feasible, safe, and preserves diaphragm thickness. Meeting the primary endpoint will demonstrate its applicability in clinical practice to prevent diaphragmatic atrophy in ventilated patients.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT05883163, August 29, 2023.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a heterogeneous condition with varying response to prone positioning. We aimed to identify subphenotypes of ARDS patients undergoing prone positioning using machine learning and assess their association with mortality and response to prone positioning.

METHODS: In this retrospective observational study, we enrolled 353 mechanically ventilated ARDS patients who underwent at least one prone positioning cycle. Unsupervised machine learning was used to identify subphenotypes based on respiratory mechanics, oxygenation parameters, and demographic variables collected in supine position. The primary outcome was 28-day mortality. Secondary outcomes included response to prone positioning in terms of respiratory system compliance, driving pressure, PaO2/FiO2 ratio, ventilatory ratio, and mechanical power.

RESULTS: Three distinct subphenotypes were identified. Cluster 1 (22.9% of whole cohort) had a higher PaO2/FiO2 ratio and lower Positive End-Expiratory Pressure (PEEP). Cluster 2 (51.3%) had a higher proportion of COVID-19 patients, lower driving pressure, higher PEEP, and higher respiratory system compliance. Cluster 3 (25.8%) had a lower pH, higher PaCO2, and higher ventilatory ratio. Mortality differed significantly across clusters (p = 0.03), with Cluster 3 having the highest mortality (56%). There were no significant differences in the proportions of responders to prone positioning for any of the studied parameters. Transpulmonary pressure measurements in a subcohort did not improve subphenotype characterization.

CONCLUSIONS: Distinct ARDS subphenotypes with varying mortality were identified in patients undergoing prone positioning; however, predicting which patients benefited from this intervention based on available data was not possible. These findings underscore the need for continued efforts in phenotyping ARDS through multimodal data to better understand the heterogeneity of this population.

OBJECTIVES: High mechanical power and driving pressure (ΔP) have been associated with postoperative respiratory failure (PRF) and may be important parameters guiding mechanical ventilation. However, it remains unclear whether high mechanical power and ΔP merely reflect patients with poor respiratory system mechanics at risk of PRF. We investigated the effect of mechanical power and ΔP on PRF in cohorts after exact matching by patients' baseline respiratory system compliance.

DESIGN: Hospital registry study.

SETTING: Academic hospital in New England.

PATIENTS: Adult patients undergoing general anesthesia between 2008 and 2020.

INTERVENTION: None.

MEASUREMENTS AND MAIN RESULTS: The primary exposure was high (≥ 6.7 J/min, cohort median) versus low mechanical power and the key-secondary exposure was high (≥ 15.0 cm H 2 O) versus low ΔP. The primary endpoint was PRF (reintubation or unplanned noninvasive ventilation within seven days). Among 97,555 included patients, 4,030 (4.1%) developed PRF. In adjusted analyses, high intraoperative mechanical power and ΔP were associated with higher odds of PRF (adjusted odds ratio [aOR] 1.37 [95% CI, 1.25-1.50]; p < 0.001 and aOR 1.45 [95% CI, 1.31-1.60]; p < 0.001, respectively). There was large variability in applied ventilatory parameters, dependent on the anesthesia provider. This facilitated matching of 63,612 (mechanical power cohort) and 53,260 (ΔP cohort) patients, yielding identical baseline standardized respiratory system compliance (standardized difference [SDiff] = 0.00) with distinctly different mechanical power (9.4 [2.4] vs 4.9 [1.3] J/min; SDiff = -2.33) and ΔP (19.3 [4.1] vs 11.9 [2.1] cm H 2 O; SDiff = -2.27). After matching, high mechanical power and ΔP remained associated with higher risk of PRF (aOR 1.30 [95% CI, 1.17-1.45]; p < 0.001 and aOR 1.28 [95% CI, 1.12-1.46]; p < 0.001, respectively).

CONCLUSIONS: High mechanical power and ΔP are associated with PRF independent of patient's baseline respiratory system compliance. Our findings support utilization of these parameters for titrating mechanical ventilation in the operating room and ICU.

Azizi BA, Munoz-Acuna R, Suleiman A, et al. Mechanical power and 30-day mortality in mechanically ventilated, critically ill patients with and without Coronavirus Disease-2019: a hospital registry study.. Journal of intensive care. 2023;11(1):14. doi:10.1186/s40560-023-00662-7

Publisher's Version

BACKGROUND: Previous studies linked a high intensity of ventilation, measured as mechanical power, to mortality in patients suffering from "classic" ARDS. By contrast, mechanically ventilated patients with a diagnosis of COVID-19 may present with intact pulmonary mechanics while undergoing mechanical ventilation for longer periods of time. We investigated whether an association between higher mechanical power and mortality is modified by a diagnosis of COVID-19.

METHODS: This retrospective study included critically ill, adult patients who were mechanically ventilated for at least 24 h between March 2020 and December 2021 at a tertiary healthcare facility in Boston, Massachusetts. The primary exposure was median mechanical power during the first 24 h of mechanical ventilation, calculated using a previously validated formula. The primary outcome was 30-day mortality. As co-primary analysis, we investigated whether a diagnosis of COVID-19 modified the primary association. We further investigated the association between mechanical power and days being alive and ventilator free and effect modification of this by a diagnosis of COVID-19. Multivariable logistic regression, effect modification and negative binomial regression analyses adjusted for baseline patient characteristics, severity of disease and in-hospital factors, were applied.

RESULTS: 1,737 mechanically ventilated patients were included, 411 (23.7%) suffered from COVID-19. 509 (29.3%) died within 30 days. The median mechanical power during the first 24 h of ventilation was 19.3 [14.6-24.0] J/min in patients with and 13.2 [10.2-18.0] J/min in patients without COVID-19. A higher mechanical power was associated with 30-day mortality (ORadj 1.26 per 1-SD, 7.1J/min increase; 95% CI 1.09-1.46; p = 0.002). Effect modification and interaction analysis did not support that this association was modified by a diagnosis of COVID-19 (95% CI, 0.81-1.38; p-for-interaction = 0.68). A higher mechanical power was associated with a lower number of days alive and ventilator free until day 28 (IRRadj 0.83 per 7.1 J/min increase; 95% CI 0.75-0.91; p < 0.001, adjusted risk difference - 2.7 days per 7.1J/min increase; 95% CI - 4.1 to - 1.3).

CONCLUSION: A higher mechanical power is associated with elevated 30-day mortality. While patients with COVID-19 received mechanical ventilation with higher mechanical power, this association was independent of a concomitant diagnosis of COVID-19.

Barrett CD, Moore HB, Moore EE, et al. Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial.. Chest. 2022;161(3):710-727. doi:10.1016/j.chest.2021.09.024

Publisher's Version

BACKGROUND: Pulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic heparin would improve pulmonary function in these patients.

RESEARCH QUESTION: Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe?

STUDY DESIGN AND METHODS: Adults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time [aPTT], 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao2 to Fio2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao2 to Fio2 ratio improvement of > 50% or Pao2 to Fio2 ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality.

RESULTS: Fifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao2 to Fio2 ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao2 to Fio2 ratio at 48 h (16.9% control [interquartile range (IQR), -8.3% to 36.8%] vs 29.8% tPA bolus [IQR, 4.5%-88.7%]; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 [IQR, 0.0-9.0] vs 12.0 [IQR, 0.0-19.0]; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit.

INTERPRETATION: The combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality.

TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04357730; URL: www.

CLINICALTRIALS: gov.