Breath-synchronized electrical stimulation of the expiratory muscles in mechanically ventilated patients: a randomized controlled feasibility study and pooled analysis.

BACKGROUND: Expiratory muscle weakness leads to difficult ventilator weaning. Maintaining their activity with functional electrical stimulation (FES) may improve outcome. We studied feasibility of breath-synchronized expiratory population muscle FES in a mixed ICU population ("Holland study") and pooled data with our previous work ("Australian study") to estimate potential clinical effects in a larger group. METHODS: Holland: Patients with a contractile response to FES received active or sham expiratory muscle FES (30 min, twice daily, 5 days/week until weaned). Main endpoints were feasibility (e.g., patient recruitment, treatment compliance, stimulation intensity) and safety. Pooled: Data on respiratory muscle thickness and ventilation duration from the Holland and Australian studies were combined (N = 40) in order to estimate potential effect size. Plasma cytokines (day 0, 3) were analyzed to study the effects of FES on systemic inflammation. RESULTS: Holland: A total of 272 sessions were performed (active/sham: 169/103) in 20 patients (N = active/sham: 10/10) with a total treatment compliance rate of 91.1%. No FES-related serious adverse events were reported. Pooled: On day 3, there was a between-group difference (N = active/sham: 7/12) in total abdominal expiratory muscle thickness favoring the active group [treatment difference (95% confidence interval); 2.25 (0.34, 4.16) mm, P = 0.02] but not on day 5. Plasma cytokine levels indicated that early FES did not induce systemic inflammation. Using a survival analysis approach for the total study population, median ventilation duration and ICU length of stay were 10 versus 52 (P = 0.07), and 12 versus 54 (P = 0.03) days for the active versus sham group. Median ventilation duration of patients that were successfully extubated was 8.5 [5.6-12.2] versus 10.5 [5.3-25.6] days (P = 0.60) for the active (N = 16) versus sham (N = 10) group, and median ICU length of stay was 10.5 [8.0-14.5] versus 14.0 [9.0-19.5] days (P = 0.36) for those active (N = 16) versus sham (N = 8) patients that were extubated and discharged alive from the ICU. During ICU stay, 3/20 patients died in the active group versus 8/20 in the sham group (P = 0.16). CONCLUSION: Expiratory muscle FES is feasible in selected ICU patients and might be a promising technique within a respiratory muscle-protective ventilation strategy. The next step is to study the effects on weaning and ventilator liberation outcome. TRIAL REGISTRATION: ClinicalTrials.gov, ID NCT03453944. Registered 05 March 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03453944 .

Respiratory Muscle Effort during Expiration in Successful and Failed Weaning from Mechanical Ventilation.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Respiratory muscle weakness in critically ill patients is associated with difficulty in weaning from mechanical ventilation. Previous studies have mainly focused on inspiratory muscle activity during weaning; expiratory muscle activity is less well understood. The current study describes expiratory muscle activity during weaning, including tonic diaphragm activity. The authors hypothesized that expiratory muscle effort is greater in patients who fail to wean compared to those who wean successfully. METHODS: Twenty adult patients receiving mechanical ventilation (more than 72 h) performed a spontaneous breathing trial. Tidal volume, transdiaphragmatic pressure, diaphragm electrical activity, and diaphragm neuromechanical efficiency were calculated on a breath-by-breath basis. Inspiratory (and expiratory) muscle efforts were calculated as the inspiratory esophageal (and expiratory gastric) pressure-time products, respectively. RESULTS: Nine patients failed weaning. The contribution of the expiratory muscles to total respiratory muscle effort increased in the "failure" group from 13 ± 9% at onset to 24 ± 10% at the end of the breathing trial (P = 0.047); there was no increase in the "success" group. Diaphragm electrical activity (expressed as the percentage of inspiratory peak) was low at end expiration (failure, 3 ± 2%; success, 4 ± 6%) and equal between groups during the entire expiratory phase (P = 0.407). Diaphragm neuromechanical efficiency was lower in the failure versus success groups (0.38 ± 0.16 vs. 0.71 ± 0.36 cm H2O/µV; P = 0.054). CONCLUSIONS: Weaning failure (vs. success) is associated with increased effort of the expiratory muscles and impaired neuromechanical efficiency of the diaphragm but no difference in tonic activity of the diaphragm.

Estimation of the diaphragm neuromuscular efficiency index in mechanically ventilated critically ill patients.

BACKGROUND: Diaphragm dysfunction develops frequently in ventilated intensive care unit (ICU) patients. Both disuse atrophy (ventilator over-assist) and high respiratory muscle effort (ventilator under-assist) seem to be involved. A strong rationale exists to monitor diaphragm effort and titrate support to maintain respiratory muscle activity within physiological limits. Diaphragm electromyography is used to quantify breathing effort and has been correlated with transdiaphragmatic pressure and esophageal pressure. The neuromuscular efficiency index (NME) can be used to estimate inspiratory effort, however its repeatability has not been investigated yet. Our goal is to evaluate NME repeatability during an end-expiratory occlusion (NMEoccl) and its use to estimate the pressure generated by the inspiratory muscles (Pmus). METHODS: This is a prospective cohort study, performed in a medical-surgical ICU. A total of 31 adult patients were included, all ventilated in neurally adjusted ventilator assist (NAVA) mode with an electrical activity of the diaphragm (EAdi) catheter in situ. At four time points within 72 h five repeated end-expiratory occlusion maneuvers were performed. NMEoccl was calculated by delta airway pressure (ΔPaw)/ΔEAdi and was used to estimate Pmus. The repeatability coefficient (RC) was calculated to investigate the NMEoccl variability. RESULTS: A total number of 459 maneuvers were obtained. At time T = 0 mean NMEoccl was 1.22 ± 0.86 cmH2O/µV with a RC of 82.6%. This implies that when NMEoccl is 1.22 cmH2O/µV, it is expected with a probability of 95% that the subsequent measured NMEoccl will be between 2.22 and 0.22 cmH2O/µV. Additional EAdi waveform analysis to correct for non-physiological appearing waveforms, did not improve NMEoccl variability. Selecting three out of five occlusions with the lowest variability reduced the RC to 29.8%. CONCLUSIONS: Repeated measurements of NMEoccl exhibit high variability, limiting the ability of a single NMEoccl maneuver to estimate neuromuscular efficiency and therefore the pressure generated by the inspiratory muscles based on EAdi.

Partial Neuromuscular Blockade during Partial Ventilatory Support in Sedated Patients with High Tidal Volumes.

RATIONALE: Controlled mechanical ventilation is used to deliver lung-protective ventilation in patients with acute respiratory distress syndrome. Despite recognized benefits, such as preserved diaphragm activity, partial support ventilation modes may be incompatible with lung-protective ventilation due to high Vt and high transpulmonary pressure. As an alternative to high-dose sedatives and controlled mechanical ventilation, pharmacologically induced neuromechanical uncoupling of the diaphragm should facilitate lung-protective ventilation under partial support modes. OBJECTIVES: To investigate whether partial neuromuscular blockade can facilitate lung-protective ventilation while maintaining diaphragm activity under partial ventilatory support. METHODS: In a proof-of-concept study, we enrolled 10 patients with lung injury and a Vt greater than 8 ml/kg under pressure support ventilation (PSV) and under sedation. After baseline measurements, rocuronium administration was titrated to a target Vt of 6 ml/kg during neurally adjusted ventilatory assist (NAVA). Thereafter, patients were ventilated in PSV and NAVA under continuous rocuronium infusion for 2 hours. Respiratory parameters, hemodynamic parameters, and blood gas values were measured. MEASUREMENTS AND MAIN RESULTS: Rocuronium titration resulted in significant declines of Vt (mean ± SEM, 9.3 ± 0.6 to 5.6 ± 0.2 ml/kg; P < 0.0001), transpulmonary pressure (26.7 ± 2.5 to 10.7 ± 1.2 cm H2O; P < 0.0001), and diaphragm electrical activity (17.4 ± 2.3 to 4.5 ± 0.7 µV; P < 0.0001), and could be maintained under continuous rocuronium infusion. During titration, pH decreased (7.42 ± 0.02 to 7.35 ± 0.02; P < 0.0001), and mean arterial blood pressure increased (84 ± 6 to 99 ± 6 mm Hg; P = 0.0004), as did heart rate (83 ± 7 to 93 ± 8 beats/min; P = 0.0004). CONCLUSIONS: Partial neuromuscular blockade facilitates lung-protective ventilation during partial ventilatory support, while maintaining diaphragm activity, in sedated patients with lung injury.

Strategies to optimize respiratory muscle function in ICU patients.

Respiratory muscle dysfunction may develop rapidly in critically ill ventilated patients and is associated with increased morbidity, length of intensive care unit stay, costs, and mortality. This review briefly discusses the pathophysiology of respiratory muscle dysfunction in intensive care unit patients and then focuses on strategies that prevent the development of muscle weakness or, if weakness has developed, how respiratory muscle function may be improved. We propose a simple strategy for how these can be implemented in clinical care.

Assessment of dead-space ventilation in patients with acute respiratory distress syndrome: a prospective observational study.

BACKGROUND: Physiological dead space (VD/VT) represents the fraction of ventilation not participating in gas exchange. In patients with acute respiratory distress syndrome (ARDS), VD/VT has prognostic value and can be used to guide ventilator settings. However, VD/VT is rarely calculated in clinical practice, because its measurement is perceived as challenging. Recently, a novel technique to calculate partial pressure of carbon dioxide in alveolar air (PACO2) using volumetric capnography (VCap) was validated. The purpose of the present study was to evaluate how VCap and other available techniques to measure PACO2 and partial pressure of carbon dioxide in mixed expired air (PeCO2) affect calculated VD/VT. METHODS: In a prospective, observational study, 15 post-cardiac surgery patients and 15 patients with ARDS were included. PACO2 was measured using VCap to calculate Bohr dead space or substituted with partial pressure of carbon dioxide in arterial blood (PaCO2) to calculate the Enghoff modification. PeCO2 was measured in expired air using three techniques: Douglas bag (DBag), indirect calorimetry (InCal), and VCap. Subsequently, VD/VT was calculated using four methods: Enghoff-DBag, Enghoff-InCal, Enghoff-VCap, and Bohr-VCap. RESULTS: PaCO2 was higher than PACO2, particularly in patients with ARDS (post-cardiac surgery PACO2 = 4.3 ± 0.6 kPa vs. PaCO2 = 5.2 ± 0.5 kPa, P < 0.05; ARDS PACO2 = 3.9 ± 0.8 kPa vs. PaCO2 = 6.9 ± 1.7 kPa, P < 0.05). There was good agreement in PeCO2 calculated with DBag vs. VCap (post-cardiac surgery bias = 0.04 ± 0.19 kPa; ARDS bias = 0.03 ± 0.27 kPa) and relatively low agreement with DBag vs. InCal (post-cardiac surgery bias = -1.17 ± 0.50 kPa; ARDS mean bias = -0.15 ± 0.53 kPa). These differences strongly affected calculated VD/VT. For example, in patients with ARDS, VD/VTcalculated with Enghoff-InCal was much higher than Bohr-VCap (VD/VT Enghoff-InCal = 66 ± 10 % vs. VD/VT Bohr-VCap = 45 ± 7 %; P < 0.05). CONCLUSIONS: Different techniques to measure PACO2 and PeCO2 result in clinically relevant mean and individual differences in calculated VD/VT, particularly in patients with ARDS. Volumetric capnography is a promising technique to calculate true Bohr dead space. Our results demonstrate the challenges clinicians face in interpreting an apparently simple measurement such as VD/VT.

Non-invasive method to detect high respiratory effort and transpulmonary driving pressures in COVID-19 patients during mechanical ventilation.

BACKGROUND: High respiratory drive in mechanically ventilated patients with spontaneous breathing effort may cause excessive lung stress and strain and muscle loading. Therefore, it is important to have a reliable estimate of respiratory effort to guarantee lung and diaphragm protective mechanical ventilation. Recently, a novel non-invasive method was found to detect excessive dynamic transpulmonary driving pressure (∆PL) and respiratory muscle pressure (Pmus) with reasonable accuracy. During the Coronavirus disease 2019 (COVID-19) pandemic, it was impossible to obtain the gold standard for respiratory effort, esophageal manometry, in every patient. Therefore, we investigated whether this novel non-invasive method could also be applied in COVID-19 patients. METHODS: ∆PL and Pmus were derived from esophageal manometry in COVID-19 patients. In addition, ∆PL and Pmus were computed from the occlusion pressure (∆Pocc) obtained during an expiratory occlusion maneuver. Measured and computed ∆PL and Pmus were compared and discriminative performance for excessive ∆PL and Pmus was assessed. The relation between occlusion pressure and respiratory effort was also assessed. RESULTS: Thirteen patients were included. Patients had a low dynamic lung compliance [24 (20-31) mL/cmH2O], high ∆PL (25 ± 6 cmH2O) and high Pmus (16 ± 7 cmH2O). Low agreement was found between measured and computed ∆PL and Pmus. Excessive ∆PL > 20 cmH2O and Pmus > 15 cmH2O were accurately detected (area under the receiver operating curve (AUROC) 1.00 [95% confidence interval (CI), 1.00-1.00], sensitivity 100% (95% CI, 72-100%) and specificity 100% (95% CI, 16-100%) and AUROC 0.98 (95% CI, 0.90-1.00), sensitivity 100% (95% CI, 54-100%) and specificity 86% (95% CI, 42-100%), respectively). Respiratory effort calculated per minute was highly correlated with ∆Pocc (for esophageal pressure time product per minute (PTPes/min) r2 = 0.73; P = 0.0002 and work of breathing (WOB) r2 = 0.85; P < 0.0001). CONCLUSIONS: ∆PL and Pmus can be computed from an expiratory occlusion maneuver and can predict excessive ∆PL and Pmus in patients with COVID-19 with high accuracy.

Patient-Ventilator Interaction During Noninvasive Ventilation in Subjects With Exacerbation of COPD: Effect of Support Level and Ventilator Mode.

BACKGROUND: Patient-ventilator synchrony in patients with COPD is at risk during noninvasive ventilation (NIV). NIV in neurally-adjusted ventilatory assist (NAVA) mode improves synchrony compared to pressure support ventilation (PSV). The current study investigated patient-ventilator interaction at 2 levels of NAVA and PSV mode in subjects with COPD exacerbation. METHODS: NIV was randomly applied at 2 levels (5 and 15 cm H2O) of PSV and NAVA. Patient-ventilator interaction was evaluated by comparing airway pressure and electrical activity of the diaphragm waveforms with automated computer algorithms. RESULTS: 8 subjects were included. Trigger delay was longer in PSV high (268 ± 112 ms) than in PSV low (161 ± 118 ms, P = .043), and trigger delay during NAVA was shorter than PSV for both low support (49 ± 24 ms for NAVA, P = .035) and high support (79 ± 276 ms for NAVA, P = .003). No difference in cycling error for low and high levels of PSV (PSV low -100 ± 114 ms and PSV high 56 ± 315 ms) or NAVA (NAVA low -5 ± 18 ms, NAVA high 12 ± 36 ms) and no difference between PSV and NAVA was found. CONCLUSIONS: Increasing PSV levels during NIV caused a progressive mismatch between neural effort and pneumatic timing. Patient-ventilator interaction during NAVA was more synchronous than during PSV, independent of inspiratory support level. (ClinicalTrials.gov registration NCT01791335.).

Effects of levosimendan on respiratory muscle function in patients weaning from mechanical ventilation.

PURPOSE: Respiratory muscle weakness frequently develops in critically ill patients and is associated with adverse outcome, including difficult weaning from mechanical ventilation. Today, no drug is approved to improve respiratory muscle function in these patients. Previously, we have shown that the calcium sensitizer levosimendan improves calcium sensitivity of human diaphragm muscle fibers in vitro and contractile efficiency of the diaphragm in healthy subjects. The main purpose of this study is to investigate the effects of levosimendan on diaphragm contractile efficiency in mechanically ventilated patients. METHODS: In a double-blind randomized placebo-controlled trial, mechanically ventilated patients performed two 30-min continuous positive airway pressure (CPAP) trials with 5-h interval. After the first CPAP trial, study medication (levosimendan 0.2 µg/kg/min continuous infusion or placebo) was administered. During the CPAP trials, electrical activity of the diaphragm (EAdi), transdiaphragmatic pressure (Pdi), and flow were measured. Neuromechanical efficiency (primary outcome parameter) was calculated. RESULTS: Thirty-nine patients were included in the study. Neuromechanical efficiency was not different during the CPAP trial after levosimendan administration compared to the CPAP trial before study medication. Tidal volume and minute ventilation were higher after levosimendan administration (11 and 21%, respectively), whereas EAdi and Pdi were higher in both groups in the CPAP trial after study medication compared to the CPAP trial before study medication. CONCLUSIONS: Levosimendan does not improve diaphragm contractile efficiency.

Glottic patency during noninvasive ventilation in patients with chronic obstructive pulmonary disease.

BACKGROUND: Non-invasive ventilation (NIV) provides ventilatory support for patients with respiratory failure. However, the glottis can act as a closing valve, limiting effectiveness of NIV. This study investigates the patency of the glottis during NIV in patients with acute exacerbation of Chronic Obstructive Pulmonary Disease (COPD). METHODS: Electrical activity of the diaphragm, flow, pressure and videolaryngoscopy were acquired. NIV was randomly applied in pressure support (PSV) and neurally adjusted ventilatory assist (NAVA) mode with two levels of support. The angle formed by the vocal cords represented glottis patency. RESULTS: Eight COPD patients with acute exacerbation requiring NIV were included. No differences were found in median glottis angle during inspiration or peak inspiratory effort between PSV and NAVA at low and high support levels. CONCLUSIONS: The present study showed that glottis patency during inspiration in patients with an acute exacerbation of COPD is not affected by mode (PSV or NAVA) or level of assist (5 or 15 cm H2O) during NIV.