Dyssynchronous diaphragm contractions impair diaphragm function in mechanically ventilated patients.

BACKGROUND: Pre-clinical studies suggest that dyssynchronous diaphragm contractions during mechanical ventilation may cause acute diaphragm dysfunction. We aimed to describe the variability in diaphragm contractile loading conditions during mechanical ventilation and to establish whether dyssynchronous diaphragm contractions are associated with the development of impaired diaphragm dysfunction. METHODS: In patients receiving invasive mechanical ventilation for pneumonia, septic shock, acute respiratory distress syndrome, or acute brain injury, airway flow and pressure and diaphragm electrical activity (Edi) were recorded hourly around the clock for up to 7 days. Dyssynchronous post-inspiratory diaphragm loading was defined based on the duration of neural inspiration after expiratory cycling of the ventilator. Diaphragm function was assessed on a daily basis by neuromuscular coupling (NMC, the ratio of transdiaphragmatic pressure to diaphragm electrical activity). RESULTS: A total of 4508 hourly recordings were collected in 45 patients. Edi was low or absent (≤ 5 µV) in 51% of study hours (median 71 h per patient, interquartile range 39-101 h). Dyssynchronous post-inspiratory loading was present in 13% of study hours (median 7 h per patient, interquartile range 2-22 h). The probability of dyssynchronous post-inspiratory loading was increased with reverse triggering (odds ratio 15, 95% CI 8-35) and premature cycling (odds ratio 8, 95% CI 6-10). The duration and magnitude of dyssynchronous post-inspiratory loading were associated with a progressive decline in diaphragm NMC (p < 0.01 for interaction with time). CONCLUSIONS: Dyssynchronous diaphragm contractions may impair diaphragm function during mechanical ventilation. TRIAL REGISTRATION: MYOTRAUMA, ClinicalTrials.gov NCT03108118. Registered 04 April 2017 (retrospectively registered).

Combined frequency domain near-infrared spectroscopy and diffuse correlation spectroscopy system for comprehensive metabolic monitoring of inspiratory muscles during loading.

Significance: Mechanical ventilation (MV) is a cornerstone technology in the intensive care unit as it assists with the delivery of oxygen in critically ill patients. The process of weaning patients from MV can be long and arduous and can lead to serious complications for many patients. Despite the known importance of inspiratory muscle function in the success of weaning, current clinical standards do not include direct monitoring of these muscles. Aim: The goal of this project was to develop and validate a combined frequency domain near-infrared spectroscopy (FD-NIRS) and diffuse correlation spectroscopy (DCS) system for the noninvasive characterization of inspiratory muscle response to a load. Approach: The system was fabricated by combining a custom digital FD-NIRS and DCS system. It was validated via liquid phantom titrations and a healthy volunteer study. The sternocleidomastoid (SCM), an accessory muscle of inspiration, was monitored during a short loading period in fourteen young, healthy volunteers. Volunteers performed two different respiratory exercises, a moderate load and a high load, which consisted of a one-minute baseline, a one-minute load, and a six-minute recovery period. Results: The system has low crosstalk between absorption, reduced scattering, and flow when tested in a set of liquid titrations. Faster dynamics were observed for changes in blood flow index (BFi), and metabolic rate of oxygen (MRO2) compared with hemoglobin + myoglobin (Hb+Mb) based parameters after the onset of loads in males. Additionally, larger percent changes in BFi, and MRO2 were observed compared with Hb+Mb parameters in both males and females. There were also sex differences in baseline values of oxygenated Hb+Mb, total Hb+Mb, and tissue saturation. Conclusions: The dynamic characteristics of Hb+Mb concentration and blood flow were distinct during loading of the SCM, suggesting that the combination of FD-NIRS and DCS may provide a more complete picture of inspiratory muscle dynamics.

Clinical implications of frailty assessed in hospitalized patients with acute-exacerbation of interstitial lung disease.

BACKGROUND: Approximately 50% of patients with interstitial lung disease (ILD) experience frailty, which remains unexplored in acute exacerbations of ILD (AE-ILD). A better understanding may help with prognostication and resource planning. We evaluated the association of frailty with clinical characteristics, physical function, hospital outcomes, and post-AE-ILD recovery. METHODS: Retrospective cohort study of AE-ILD patients (01/2015-10/2019) with frailty (proportion ≥0.25) on a 30-item cumulative-deficits index. Frail and non-frail patients were compared for pre- and post-hospitalization clinical characteristics, adjusted for age, sex, and ILD diagnosis. One-year mortality, considering transplantation as a competing risk, was analysed adjusting for age, frailty, and Charlson Comorbidity Index (CCI). RESULTS: 89 AE-ILD patients were admitted (median: 67 years, 63% idiopathic pulmonary fibrosis). 31 were frail, which was associated with older age, greater CCI, lower 6-min walk distance, and decreased independence pre-hospitalization. Frail patients had more major complications (32% vs 10%, p = .01) and required more multidisciplinary support during hospitalization. Frailty was not associated with 1-year mortality (HR: 0.97, 95%CI: [0.45-2.10]) factoring transplantation as a competing risk. CONCLUSIONS: Frailty was associated with reduced exercise capacity, increased comorbidities and hospital complications. Identifying frailty may highlight those requiring additional multidisciplinary support, but further study is needed to explore whether frailty is modifiable with AE-ILD.

Lung- and diaphragm-protective strategies in acute respiratory failure: an in silico trial.

BACKGROUND: Lung- and diaphragm-protective (LDP) ventilation may prevent diaphragm atrophy and patient self-inflicted lung injury in acute respiratory failure, but feasibility is uncertain. The objectives of this study were to estimate the proportion of patients achieving LDP targets in different modes of ventilation, and to identify predictors of need for extracorporeal carbon dioxide removal (ECCO2R) to achieve LDP targets. METHODS: An in silico clinical trial was conducted using a previously published mathematical model of patient-ventilator interaction in a simulated patient population (n = 5000) with clinically relevant physiological characteristics. Ventilation and sedation were titrated according to a pre-defined algorithm in pressure support ventilation (PSV) and proportional assist ventilation (PAV+) modes, with or without adjunctive ECCO2R, and using ECCO2R alone (without ventilation or sedation). Random forest modelling was employed to identify patient-level factors associated with achieving targets. RESULTS: After titration, the proportion of patients achieving targets was lower in PAV+ vs. PSV (37% vs. 43%, odds ratio 0.78, 95% CI 0.73-0.85). Adjunctive ECCO2R substantially increased the probability of achieving targets in both PSV and PAV+ (85% vs. 84%). ECCO2R alone without ventilation or sedation achieved LDP targets in 9%. The main determinants of success without ECCO2R were lung compliance, ventilatory ratio, and strong ion difference. In silico trial results corresponded closely with the results obtained in a clinical trial of the LDP titration algorithm (n = 30). CONCLUSIONS: In this in silico trial, many patients required ECCO2R in combination with mechanical ventilation and sedation to achieve LDP targets. ECCO2R increased the probability of achieving LDP targets in patients with intermediate degrees of derangement in elastance and ventilatory ratio.

The influence of drugs used for sedation during mechanical ventilation on respiratory pattern during unassisted breathing and assisted mechanical ventilation: a physiological systematic review and meta-analysis.

Background: Sedation management has a major impact on outcomes in mechanically ventilated patients, but sedation strategies do not generally consider the differential effects of different sedatives on respiration and respiratory pattern. A systematic review was undertaken to quantitatively summarize the known effects of different classes of drugs used for sedation on respiratory pattern during both spontaneous breathing and assisted mechanical ventilation. Methods: This was a systematic review and meta-analysis conducted using Ovid MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials up to June 2020 to retrieve studies that measured respiratory parameters before and after the administration of opioids, benzodiazepines, intravenous and inhaled anaesthetic agents, and other hypnotic agents (PROSPERO #CRD42020190017). A random-effects meta-analytic model was employed to estimate the mean percentage change in each of the respiratory indices according to medication exposure with and without mechanical ventilation. Risk of bias was assessed using the Cochrane risk of bias assessment tools. Findings: Fifty-one studies were included in the analysis. Risk of bias was generally deemed to be low for most studies. Respiratory rate decreased with the administration of opioids in both non-ventilated patients (18% decrease, 95% CI 12-24%) and ventilated patients (26% decrease, 95% CI 15-37%) and increased with inhaled anaesthetics in non-ventilated patients (83% increase, 95% CI 49-118%) and ventilated patients (50% increase, 28-72%). In non-ventilated patients, tidal volume decreased following administration of inhaled aesthetics (55% decrease, 95% CI 25-86%), propofol (36% decrease, 95% CI 20-52%), and benzodiazepines (28% decrease, 95% CI 17-40%); in patients receiving assisted mechanical ventilation, tidal volume was not significantly affected by sedation. Administration of other hypnotic agents was not associated with changes in respiratory rate or tidal volume. Interpretation: Different classes of drugs used for sedation exert differential effects on respiratory pattern, and this may influence weaning and outcomes in mechanically ventilated patients. Funding: This study did not receive any funding support.

Impact of Supine Versus Semirecumbent Body Posture on the Distribution of Ventilation in Acute Respiratory Distress Syndrome.

In some patients with acute respiratory distress syndrome (ARDS), a paradoxical improvement in respiratory system compliance (CRS) has been observed when assuming a supine (head of bed [HOB] 0°) compared with semirecumbent (HOB 35-40°) posture. We sought to test the hypothesis that mechanically ventilated patients with ARDS would have improved CRS, due to changes in ventilation distribution, when moving from the semirecumbent to supine position. We conducted a prospective, observational ICU study including 14 mechanically ventilated patients with ARDS. For each patient, ventilation distribution (assessed by electrical impedance tomography) and pulmonary mechanics were compared in supine versus semirecumbent postures. Compared with semirecumbent, in the supine posture CRS increased (33 ± 21 vs. 26 ± 14 mL/cm H2O, p = 0.005), driving pressure was reduced (14 ± 6 vs. 17 ± 7 cm H2O, p < 0.001), and dorsal fraction of ventilation was decreased (48.5 ± 14.1% vs. 54.5 ± 12.0%, p = 0.003). Posture change from semirecumbent to supine resulted in a favorable physiologic response in terms of improved CRS and reduced driving pressure-with a corresponding increase in ventral ventilation, possibly related to reduced ventral overdistension.

A combined frequency domain near infrared spectroscopy and diffuse correlation spectroscopy system for comprehensive metabolic monitoring of inspiratory muscles during loading.

Significance: Mechanical ventilation (MV) is a cornerstone technology in the intensive care unit as it assists with the delivery of oxygen in critical ill patients. The process of weaning patients from MV can be long, and arduous and can lead to serious complications for many patients. Despite the known importance of inspiratory muscle function in the success of weaning, current clinical standards do not include direct monitoring of these muscles. Aim: The goal of this project was to develop and validate a combined frequency domain near infrared spectroscopy (FD-NIRS) and diffuse correlation spectroscopy (DCS) system for the noninvasive characterization of inspiratory muscle response to a load. Approach: The system was fabricated by combining a custom digital FD-NIRS and DCS system. It was validated via liquid phantom titrations and a healthy volunteer study. The sternocleidomastoid (SCM), an accessory muscle of inspiration, was monitored during a short loading period in fourteen young healthy volunteer. Volunteers performed two different respiratory exercises, a moderate and high load, which consisted of a one-minute baseline, a one-minute load, and a six-minute recovery period. Results: The system has low crosstalk between absorption, reduced scattering, and flow when tested in a set of liquid titrations. Faster dynamics were observed for changes in blood flow index (BFi), and metabolic rate of oxygen (MRO2) compared to hemoglobin + myoglobin (Hb+Mb) based parameters after the onset of loads in males. Additionally, larger percent changes in BFi, and MRO2 were observed compared to Hb+Mb parameters in both males and females. There were also sex differences in baseline values of oxygenated Hb+Mb, total Hb+Mb, and tissue saturation. Conclusion: The dynamic characteristics of Hb+Mb concentration and blood flow were distinct during loading of the SCM, suggesting that the combination of FD-NIRS and DCS may provide a more complete picture of inspiratory muscle dynamics.

Intermittent neck flexion induces greater sternocleidomastoid deoxygenation than inspiratory threshold loading.

PURPOSE: To compare deoxygenation of the sternocleidomastoid, scalenes, and diaphragm/intercostals (Dia/IC) during submaximal intermittent neck flexion (INF) versus submaximal inspiratory threshold loading (ITL) in healthy adults. METHODS: Fourteen participants performed a randomized, cross-over, repeated measures design. After evaluation of maximal inspiratory pressures (MIP) and maximum voluntary contraction (MVC) for isometric neck flexion, participants were randomly assigned to submaximal ITL or INF until task failure. At least 2 days later, they performed the submaximal exercises in the opposite order. ITL or INF targeted 50 ± 5% of the MIP or MVC, respectively, until task failure. Near-infrared spectroscopy (NIRS) was applied to evaluate changes of deoxy-hemoglobin (ΔHHb), oxy-hemoglobin (ΔO2Hb), total hemoglobin (ΔtHb), and tissue saturation of oxygen (StO2) of the sternocleidomastoid, scalenes, and Dia/IC. Breathlessness and perceived exertion were evaluated using Borg scales. RESULTS: Initially during INF, sternocleidomastoid HHb slope was greatest compared to the scalenes and Dia/IC. At isotime (6.5-7 min), ΔtHb (a marker of blood volume) and ΔO2Hb of the sternocleidomastoid were higher during INF than ITL. Sternocleidomastoid HHb, O2Hb, and tHb during INF also increased at quartile and task failure timepoints. In contrast, scalene ΔO2Hb was higher during ITL than INF at isotime. Further, Dia/IC O2Hb and tHb increased during ITL at the third quartile and at task failure. Borg scores were lower at task failure during INF compared to ITL. CONCLUSION: Intermittent INF induces significant metabolic activity of the sternocleidomastoid and a lower perception of effort, which may provide an alternative inspiratory muscle training approach for mechanically ventilated patients.

Measuring Diaphragm Thickness and Function Using Point-of-Care Ultrasound.

The diaphragm is the main component of the respiratory muscle pump. Diaphragm dysfunction can cause dyspnea and exercise intolerance, and predisposes affected individuals to respiratory failure. In mechanically ventilated patients, the diaphragm is susceptible to atrophy and dysfunction through disuse and other mechanisms. This contributes to failure to wean and poor long-term clinical outcomes. Point-of-care ultrasound provides a valid and reproducible method for evaluating diaphragm thickness and contractile activity (thickening fraction during inspiration) that can be readily employed by clinicians and researchers alike. This article presents best practices for measuring diaphragm thickness and quantifying diaphragm thickening during tidal breathing or maximal inspiration. Once mastered, this technique can be used to diagnose and prognosticate diaphragm dysfunction, and guide and monitor response to treatment over time in both healthy individuals and acute or chronically ill patients.

Therapeutic Heparin in Non-ICU Patients Hospitalized for COVID-19 in the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute Trial: Effect on 3-Month Symptoms and Quality of Life.

BACKGROUND: Therapeutic-dose heparin decreased days requiring organ support in noncritically ill patients hospitalized for COVID-19, but its impact on persistent symptoms or quality of life (QoL) is unclear. RESEARCH QUESTION: In the ACTIV-4a trial, was randomization of patients hospitalized for COVID-19 illness to therapeutic-dose vs prophylactic heparin associated with fewer symptoms and better QoL at 90 days? STUDY DESIGN AND METHODS: This was an open-label randomized controlled trial at 34 hospitals in the United States and Spain. A total of 727 noncritically ill patients hospitalized for COVID-19 from September 2020 to June 2021 were randomized to therapeutic-dose vs prophylactic heparin. Only patients with 90-day data on symptoms and QoL were analyzed. We ascertained symptoms and QoL by the EuroQol 5-Dimension 5-Level (EQ-5D-5L) at 90-day follow-up in a preplanned analysis for the ACTIV-4a trial. Individual domains assessed by the EQ-5D-5L included mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Univariate and multivariate analyses were performed. RESULTS: Among 571 patients, 288 (50.4%) reported at least one symptom. Among 410 patients, 148 (36.1%) reported moderate to severe impairment in one or more domains of the EQ-5D-5L. The presence of 90-day symptoms was associated with moderate-severe impairment in the EQ-5D-5L domains of mobility (adjusted OR [aOR], 2.37; 95% CI, 1.22-4.59), usual activities (aOR, 3.66; 95% CI, 1.75-7.65), pain (aOR, 2.43; 95% CI, 1.43-4.12), and anxiety (aOR, 4.32; 95% CI, 2.06-9.02), compared with patients reporting no symptoms There were no differences in symptoms or in the overall EQ-5D-5L index score between treatment groups. Therapeutic-dose heparin was associated with less moderate-severe impairment in all physical functioning domains (mobility, self-care, usual activities) but was independently significant only in the self-care domain (aOR, 0.32; 95% CI, 0.11-0.96). INTERPRETATION: In a randomized controlled trial of hospitalized noncritically ill patients with COVID-19, therapeutic-dose heparin was associated with less severe impairment in the self-care domain of EQ-5D-5L. However, this type of impairment was uncommon, affecting 23 individuals. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04505774; URL: www. CLINICALTRIALS: gov.

Simvastatin in Critically Ill Patients with Covid-19.

BACKGROUND: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2). RESULTS: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control. CONCLUSIONS: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

Phrenic Nerve Stimulation for Acute Respiratory Failure.

Diaphragm inactivity during invasive mechanical ventilation leads to diaphragm atrophy and weakness, hemodynamic instability, and ventilatory heterogeneity. Absent respiratory drive and effort can, therefore, worsen injury to both lung and diaphragm and is a major cause of failure to wean. Phrenic nerve stimulation (PNS) can maintain controlled levels of diaphragm activity independent of intrinsic drive and as such may offer a promising approach to achieving lung and diaphragm protective ventilatory targets. Whereas PNS has an established role in the management of chronic respiratory failure, there is emerging interest in how its multisystem putative benefits may be temporarily harnessed in the management of invasively ventilated patients with acute respiratory failure.