Alteration of Lung Physiology with the Administration of Convalescent Plasma in ARDS Patients Intubated with COVID-19 Pneumonia

**Background:** It remains unknown to what degree lung physiology is altered by administration of convalescent plasma in patients intubated with ARDS due to COVID-19 pneumonia. Although no longer clinically used as treatment for COVID-19, convalescent plasma therapy could be deployed again should new virus threats emerge in the future. **Aim:** To evaluate changes in ventilator physiologic variables in response to convalescent plasma transfusion using a retrospective, observational, case control study of intubated patients with COVID-19 pneumonia. **Methods:** Patients who were receiving mechanical ventilation due to COVID-19 at the time of administration of convalescent plasma therapy (CPT) were matched to control patients who did not receive convalescent plasma. Ventilatory data such as compliance, positive end-expiratory pressure (PEEP), FiO~2~ administered, PaO~2~/FiO~2~ ratio, and tidal volume were collected pre and post administration. Panel-level random-effects linear regression models were used to assess the mean difference and interactions between CPT and cases vs controls over time. **Results:** 12 patients received CPT while intubated and were matched to 35 intubated control patients who did not receive CPT. In total, 857 separate measurements of static compliance were obtained over time. No significant difference in static compliance was seen after CPT. In cases, adjusted mean static compliance was 30.8 (95% CI (23.3, 38.4))mL/cm H~2~O before CPT and 28.2 (95% CI (20.7,35.6)) mL/cm H~2~O afterwards. Controls adjusted mean static compliance was 33.9 (95% CI (29.5, 38.4)) mL/cm H~2~O before versus 32.2 (95% CI (27.9, 36.5)) mL/cm H~2~O afterwards. Variables that had small but statistically significant differences pre vs post CPT among cases and controls were systolic and diastolic blood pressure, FiO~2~, heart rate, applied PEEP, and respiratory rate. **Conclusion:** While some statistically significant physiologic effects were seen with CPT in mechanically ventilated patients, these were deemed to be small and clinically insignificant. This is consistent with prior research on less acutely ill COVID-19 patients

Update to the study protocol for an implementation-effectiveness trial comparing two education strategies for improving the uptake of noninvasive ventilation in patients with severe COPD exacerbation

BACKGROUND: There is strong evidence that noninvasive ventilation (NIV) improves the outcomes of patients hospitalized with severe COPD exacerbation, and NIV is recommended as the first-line therapy for these patients. Yet, several studies have demonstrated substantial variation in NIV use across hospitals, leading to preventable morbidity and mortality. In addition, prior studies suggested that efforts to increase NIV use in COPD need to account for the complex and interdisciplinary nature of NIV delivery and the need for team coordination. Therefore, our initial project aimed to compare two educational strategies: online education (OLE) and interprofessional education (IPE), which targets complex team-based care in NIV delivery. Due to the impact of the COVID-19 pandemic on recruitment and planned intervention, we had made several changes in the study design, statistical analysis, and implementation strategies delivery as outlined in the methods. METHODS: We originally proposed a two-arm, pragmatic, cluster, randomized hybrid implementation-effectiveness trial comparing two education strategies to improve NIV uptake in patients with severe COPD exacerbation in 20 hospitals with a low baseline rate of NIV use. Due to logistical constrains and slow recruitment, we changed the study design to an opened cohort stepped-wedge design with three steps which will allow the institutions to enroll when they are ready to participate. Only the IPE strategy will be implemented, and the education will be provided in an online virtual format. Our primary outcome will be the hospital-level risk-standardized NIV proportion for the period post-IPE training, along with the change in rate from the period prior to training. Aim 1 will compare the change over time of NIV use among patients with COPD in the step-wedged design. Aim 2 will explore the mediators\u27 role (respiratory therapist autonomy and team functionality) on the relationship between the implementation strategies and effectiveness. Finally, in Aim 3, through interviews with providers, we will assess the acceptability and feasibility of the educational training. CONCLUSION: The changes in study design will result in several limitation. Most importantly, the hospitals in the three cohorts are not randomized as they enroll based on their readiness. Second, the delivery of the IPE is virtual, and it is not known if remote education is conducive to team building. However, this study will be among the first to test the impact of IPE in the inpatient setting carefully and may generalize to other interventions directed to seriously ill patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04206735 . Registered on December 20, 2019

Vascular pedicle width in acute lung injury: correlation with intravascular pressures and ability to discriminate fluid status

Abstract Introduction Conservative fluid management in patients with acute lung injury (ALI) increases time alive and free from mechanical ventilation. Vascular pedicle width (VPW) is a non-invasive measurement of intravascular volume status. The VPW was studied in ALI patients to determine the correlation between VPW and intravascular pressure measurements and whether VPW could predict fluid status. Methods This retrospective cohort study involved 152 patients with ALI enrolled in the Fluid and Catheter Treatment Trial (FACTT) from five NHLBI ARDS (Acute Respiratory Distress Syndrome) Network sites. VPW and central venous pressure (CVP) or pulmonary artery occlusion pressure (PAOP) from the first four study days were correlated. The relationships between VPW, positive end-expiratory pressure (PEEP), cumulative fluid balance, and PAOP were also evaluated. Receiver operator characteristic (ROC) curves were used to determine the ability of VPW to detect PAOP <8 mmHg and PAOP ≥18 mm Hg. Results A total of 71 and 152 patients provided 118 and 276 paired VPW/PAOP and VPW/CVP measurements, respectively. VPW correlated with PAOP (r = 0.41; P < 0.001) and less well with CVP (r = 0.21; P = 0.001). In linear regression, VPW correlated with PAOP 1.5-fold better than cumulative fluid balance and 2.5-fold better than PEEP. VPW discriminated achievement of PAOP <8 mm Hg (AUC = 0.73; P = 0.04) with VPW ≤67 mm demonstrating 71% sensitivity (95% CI 30 to 95%) and 68% specificity (95% CI 59 to 75%). For discriminating a hydrostatic component of the edema (that is, PAOP ≥18 mm Hg), VPW ≥72 mm demonstrated 61.4% sensitivity (95% CI 47 to 74%) and 61% specificity (49 to 71%) (area under the curve (AUC) 0.69; P = 0.001). Conclusions VPW correlates with PAOP better than CVP in patients with ALI. Due to its only moderate sensitivity and specificity, the ability of VPW to discriminate fluid status in patients with acute lung injury is limited and should only be considered when intravascular pressures are unavailable

Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited. METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed. RESULTS: A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups. CONCLUSIONS: Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028)

A phase I study evaluating the pharmacokinetics, safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung injury or acute respiratory distress syndrome

<p>Abstract</p> <p>Background</p> <p>The tissue factor (TF)-dependent extrinsic pathway has been suggested to be a central mechanism by which the coagulation cascade is locally activated in the lungs of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) and thus represents an attractive target for therapeutic intervention. This study was designed to determine the pharmacokinetic and safety profiles of ALT-836, an anti-TF antibody, in patients with ALI/ARDS.</p> <p>Methods</p> <p>This was a prospective, randomized, placebo-controlled, dose-escalation Phase I clinical trial in adult patients who had suspected or proven infection, were receiving mechanical ventilation and had ALI/ARDS (PaO₂/FiO₂≤ 300 mm). Eighteen patients (6 per cohort) were randomized in a 5:1 ratio to receive ALT-836 or placebo, and were treated within 48 hours after meeting screening criteria. Cohorts of patients were administered a single intravenously dose of 0.06, 0.08 or 0.1 mg/kg ALT-836 or placebo. Blood samples were taken for pharmacokinetic and immunogenicity measurements. Safety was assessed by adverse events, vital signs, ECGs, laboratory, coagulation and pulmonary function parameters.</p> <p>Results</p> <p>Pharmacokinetic analysis showed a dose dependent exposure to ALT-836 across the infusion range of 0.06 to 0.1 mg/kg. No anti-ALT-836 antibody response was observed in the study population during the trial. No major bleeding episodes were reported in the ALT-836 treated patients. The most frequent adverse events were anemia, observed in both placebo and ALT-836 treated patients, and ALT-836 dose dependent, self-resolved hematuria, which suggested 0.08 mg/kg as an acceptable dose level of ALT-836 in this patient population.</p> <p>Conclusions</p> <p>Overall, this study showed that ALT-836 could be safely administered to patients with sepsis-induced ALI/ARDS.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01438853">NCT01438853</a></p

The Association of Frailty With Long-Term Outcomes in Patients With Acute Respiratory Failure Treated With Noninvasive Ventilation

The objective of this study was to investigate the prevalence and impact of frailty on mortality in patients with acute respiratory failure (ARF) treated with noninvasive ventilation (NIV). This was a single-center, prospective study of patients who developed ARF (irrespective of etiology) and were treated with NIV support. Frailty was assessed using the Clinical Frailty Scale (CFS). We modeled the relationship of CFS with one-year mortality using Cox proportional hazards regression, adjusting for other clinical and demographic characteristics. Of the 166 patients enrolled, 48% had moderate to severe frailty. These patients were more likely to be female (67% versus 33%) and on oxygen therapy at home (46% versus 28%). The median CFS score was 5 (interquartile range (IQR): 5-6). Moderate to severe frailty was associated with a 60% higher risk of one-year mortality (hazard ratio (HR): 1.63, 95% confidence interval (CI): 1.15-2.31). Frailty assessment may identify patients in need of ventilatory support who are at increased risk of mortality and may be an important factor to consider when discussing goals of care in this vulnerable population. Keywords: acute respiratory failure; critical illness; frailty; mortality; noninvasive ventilation

Update to the study protocol for an implementation-effectiveness trial comparing two education strategies for improving the uptake of noninvasive ventilation in patients with severe COPD exacerbation

Background: There is strong evidence that noninvasive ventilation (NIV) improves the outcomes of patients hospitalized with severe COPD exacerbation, and NIV is recommended as the first-line therapy for these patients. Yet, several studies have demonstrated substantial variation in NIV use across hospitals, leading to preventable morbidity and mortality. In addition, prior studies suggested that efforts to increase NIV use in COPD need to account for the complex and interdisciplinary nature of NIV delivery and the need for team coordination. Therefore, our initial project aimed to compare two educational strategies: online education (OLE) and interprofessional education (IPE), which targets complex team-based care in NIV delivery. Due to the impact of the COVID-19 pandemic on recruitment and planned intervention, we had made several changes in the study design, statistical analysis, and implementation strategies delivery as outlined in the methods. Methods: We originally proposed a two-arm, pragmatic, cluster, randomized hybrid implementation-effectiveness trial comparing two education strategies to improve NIV uptake in patients with severe COPD exacerbation in 20 hospitals with a low baseline rate of NIV use. Due to logistical constrains and slow recruitment, we changed the study design to an opened cohort stepped-wedge design with three steps which will allow the institutions to enroll when they are ready to participate. Only the IPE strategy will be implemented, and the education will be provided in an online virtual format. Our primary outcome will be the hospital-level risk-standardized NIV proportion for the period post-IPE training, along with the change in rate from the period prior to training. Aim 1 will compare the change over time of NIV use among patients with COPD in the step-wedged design. Aim 2 will explore the mediators\u27 role (respiratory therapist autonomy and team functionality) on the relationship between the implementation strategies and effectiveness. Finally, in Aim 3, through interviews with providers, we will assess the acceptability and feasibility of the educational training. Conclusion: The changes in study design will result in several limitation. Most importantly, the hospitals in the three cohorts are not randomized as they enroll based on their readiness. Second, the delivery of the IPE is virtual, and it is not known if remote education is conducive to team building. However, this study will be among the first to test the impact of IPE in the inpatient setting carefully and may generalize to other interventions directed to seriously ill patients. Trial registration: ClinicalTrials.gov NCT04206735 . Registered on December 20, 2019

Exploring Patient Experience with Noninvasive Ventilation: A Human-Centered Design Analysis to Inform Planning for Better Tolerance

Background: This study brings a human-centered design (HCD) perspective to understand patient experience when using noninvasive ventilation (NIV) with the goal of creating better strategies to improve NIV comfort and tolerance. Methods: Using an HCD motivational approach, we created a semi-structured interview to uncover the patients\u27 journey while being treated with NIV. We interviewed 16 patients with COPD treated with NIV while hospitalized. Patients\u27 experience was captured in a stepwise narrative creating a journey map as a framework describing the overall experience and highlighting the key processes, tensions, and flows. We broke the journey into phases, steps, emotions, and themes to get a clear picture of the overall experience levers for patients. Results: The following themes promoted NIV tolerance: trust in the providers, the favorable impression of the facility and staff, understanding why the mask was needed, how NIV works and how long it will be needed, immediate relief of the threatening suffocating sensation, familiarity with similar treatments, use of mediation and mindfulness, and the realization that treatment was useful. The following themes deterred NIV tolerance: physical and psychological discomfort with the mask, impaired control, feeling of loss of control, and being misinformed. Conclusions: Understanding the reality of patients with COPD treated with NIV will help refine strategies that can improve their experience and tolerance with NIV. Future research should test ideas with the best potential and generate prototypes and design iterations to be tested with patients. Keywords: COPD; human-centered design; noninvasive ventilation; patient experience; qualitative analysis