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).

Synchronized and proportional sub-diaphragmatic unloading in an animal model of respiratory distress.

BACKGROUND: A sealed abdominal interface was positioned below the diaphragm (the "NeoVest") to apply synchronized and proportional negative pressure ventilation (NPV) and was compared to positive pressure ventilation (PPV) using neurally adjusted ventilatory assist (NAVA). Both modes were controlled by the diaphragm electrical activity (Edi). METHODS: Eleven rabbits (mean weight 2.9 kg) were instrumented, tracheotomized, and ventilated with either NPV or PPV (sequentially) with different loads (resistive, dead space, acute lung injury). Assist with either PPV or NPV was titrated to reduce Edi by 50%. RESULTS: In order to achieve a 50% reduction in Edi, NPV required slightly more negative pressure (-8 to -12 cm H2O) than observed in PPV (+6 to +10 cm H2O). The efficiency of pressure transmission from the NeoVest into gastric pressure was 69.6% (range 61.3-77.4%). Swings in esophageal pressure were more negative during NPV than PPV, for all conditions, due to transmission of negative pressure. Transpulmonary pressure was lower during NPV. Transdiaphragmatic pressure swings were reduced similarly for PPV and NPV, suggesting equivalent unloading of the diaphragm. NPV did not affect hemodynamics. CONCLUSIONS: It is feasible to apply NPV sub-diaphragmatically in synchrony and in proportion to Edi in an animal model of respiratory distress. IMPACT: Negative pressure ventilation (NPV), for example, the "Iron Lung," may offer advantages over positive pressure ventilation. In the present work, we describe the "NeoVest," a system consisting of a sealed abdominal interface and a ventilator that applies NPV in synchrony and in proportion to the diaphragm electrical activity (Edi).

Estimation of transpulmonary driving pressure during synchronized mechanical ventilation using a single lower assist maneuver (LAM) in rabbits: a comparison to measurements made with an esophageal balloon.

BACKGROUND: Mechanical ventilation is applied to unload the respiratory muscles, but knowledge about transpulmonary driving pressure (ΔPL) is important to minimize lung injury. We propose a method to estimate ΔPL during neurally synchronized assisted ventilation, with a simple intervention of lowering the assist for one breath ("lower assist maneuver", LAM). METHODS: In 24 rabbits breathing spontaneously with imposed loads, titrations of increasing assist were performed, with two neurally synchronized modes: neurally adjusted ventilatory assist (NAVA) and neurally triggered pressure support (NPS). Two single LAM breaths (not sequentially, but independently) were performed at each level of assist by acutely setting the assist to zero cm H2O (NPS) or NAVA level 0 cm H2O/uV (NAVA) for one breath. NPS and NAVA titrations were followed by titrations in controlled-modes (volume control, VC and pressure control, PC), under neuro-muscular blockade. Breaths from the NAVA/NPS titrations were matched (for flow and volume) to VC or PC. Throughout all runs, we measured diaphragm electrical activity (Edi) and esophageal pressure (PES). We measured ΔPL during the spontaneous modes (PL_PES) and controlled mechanical ventilation (CMV) modes (PL_CMV) with the esophageal balloon. From the LAMs, we derived an estimation of ΔPL ("PL_LAM") using a correction factor (ratio of volume during the LAM and volume during assist) and compared it to measured ΔPL during passive (VC or PC) and spontaneous breathing (NAVA or NPS). A requirement for the LAM was similar Edi to the assisted breath. RESULTS: All animals successfully underwent titrations and LAMs for NPS/NAVA. One thousand seven-hundred ninety-two (1792) breaths were matched to passive ventilation titrations (matched Vt, r = 0.99). PL_LAM demonstrated strong correlation with PL_CMV (r = 0.83), and PL_PES (r = 0.77). Bland-Altman analysis revealed little difference between the predicted PL_LAM and measured PL_CMV (Bias = 0.49 cm H2O and 1.96SD = 3.09 cm H2O). For PL_PES, the bias was 2.2 cm H2O and 1.96SD was 3.4 cm H2O. Analysis of Edi and PES at peak Edi showed progressively increasing uncoupling with increasing assist. CONCLUSION: During synchronized mechanical ventilation, a LAM breath allows for estimations of transpulmonary driving pressure, without measuring PES, and follows a mathematical transfer function to describe respiratory muscle unloading during synchronized assist.

Reverse Triggering Dyssynchrony 24 h after Initiation of Mechanical Ventilation.

BACKGROUND: Reverse triggering is a delayed asynchronous contraction of the diaphragm triggered by passive insufflation by the ventilator in sedated mechanically ventilated patients. The incidence of reverse triggering is unknown. This study aimed at determining the incidence of reverse triggering in critically ill patients under controlled ventilation. METHODS: In this ancillary study, patients were continuously monitored with a catheter measuring the electrical activity of the diaphragm. A method for automatic detection of reverse triggering using electrical activity of the diaphragm was developed in a derivation sample and validated in a subsequent sample. The authors assessed the predictive value of the software. In 39 recently intubated patients under assist-control ventilation, a 1-h recording obtained 24 h after intubation was used to determine the primary outcome of the study. The authors also compared patients' demographics, sedation depth, ventilation settings, and time to transition to assisted ventilation or extubation according to the median rate of reverse triggering. RESULTS: The positive and negative predictive value of the software for detecting reverse triggering were 0.74 (95% CI, 0.67 to 0.81) and 0.97 (95% CI, 0.96 to 0.98). Using a threshold of 1 µV of electrical activity to define diaphragm activation, median reverse triggering rate was 8% (range, 0.1 to 75), with 44% (17 of 39) of patients having greater than or equal to 10% of breaths with reverse triggering. Using a threshold of 3 µV, 26% (10 of 39) of patients had greater than or equal to 10% reverse triggering. Patients with more reverse triggering were more likely to progress to an assisted mode or extubation within the following 24 h (12 of 39 [68%]) vs. 7 of 20 [35%]; P = 0.039). CONCLUSIONS: Reverse triggering detection based on electrical activity of the diaphragm suggests that this asynchrony is highly prevalent at 24 h after intubation under assist-control ventilation. Reverse triggering seems to occur during the transition phase between deep sedation and the onset of patient triggering.

Neurally adjusted ventilatory assist as a weaning mode for adults with invasive mechanical ventilation: a systematic review and meta-analysis.

BACKGROUND: Prolonged ventilatory support is associated with poor clinical outcomes. Partial support modes, especially pressure support ventilation, are frequently used in clinical practice but are associated with patient-ventilation asynchrony and deliver fixed levels of assist. Neurally adjusted ventilatory assist (NAVA), a mode of partial ventilatory assist that reduces patient-ventilator asynchrony, may be an alternative for weaning. However, the effects of NAVA on weaning outcomes in clinical practice are unclear. METHODS: We searched PubMed, Embase, Medline, and Cochrane Library from 2007 to December 2020. Randomized controlled trials and crossover trials that compared NAVA and other modes were identified in this study. The primary outcome was weaning success which was defined as the absence of ventilatory support for more than 48 h. Summary estimates of effect using odds ratio (OR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with accompanying 95% confidence interval (CI) were expressed. RESULTS: Seven studies (n = 693 patients) were included. Regarding the primary outcome, patients weaned with NAVA had a higher success rate compared with other partial support modes (OR = 1.93; 95% CI 1.12 to 3.32; P = 0.02). For the secondary outcomes, NAVA may reduce duration of mechanical ventilation (MD = - 2.63; 95% CI - 4.22 to - 1.03; P = 0.001) and hospital mortality (OR = 0.58; 95% CI 0.40 to 0.84; P = 0.004) and prolongs ventilator-free days (MD = 3.48; 95% CI 0.97 to 6.00; P = 0.007) when compared with other modes. CONCLUSIONS: Our study suggests that the NAVA mode may improve the rate of weaning success compared with other partial support modes for difficult to wean patients.

Duration of diaphragmatic inactivity after endotracheal intubation of critically ill patients.

BACKGROUND: In patients intubated for mechanical ventilation, prolonged diaphragm inactivity could lead to weakness and poor outcome. Time to resume a minimal diaphragm activity may be related to sedation practice and patient severity. METHODS: Prospective observational study in critically ill patients. Diaphragm electrical activity (EAdi) was continuously recorded after intubation looking for resumption of a minimal level of diaphragm activity (beginning of the first 24 h period with median EAdi > 7 µV, a threshold based on literature and correlations with diaphragm thickening fraction). Recordings were collected until full spontaneous breathing, extubation, death or 120 h. A 1 h waveform recording was collected daily to identify reverse triggering. RESULTS: Seventy-five patients were enrolled and 69 analyzed (mean age ± standard deviation 63 ± 16 years). Reasons for ventilation were respiratory (55%), hemodynamic (19%) and neurologic (20%). Eight catheter disconnections occurred. The median time for resumption of EAdi was 22 h (interquartile range 0-50 h); 35/69 (51%) of patients resumed activity within 24 h while 4 had no recovery after 5 days. Late recovery was associated with use of sedative agents, cumulative doses of propofol and fentanyl, controlled ventilation and age (older patients receiving less sedation). Severity of illness, oxygenation, renal and hepatic function, reason for intubation were not associated with EAdi resumption. At least 20% of patients initiated EAdi with reverse triggering. CONCLUSION: Low levels of diaphragm electrical activity are common in the early course of mechanical ventilation: 50% of patients do not recover diaphragmatic activity within one day. Sedatives are the main factors accounting for this delay independently from lung or general severity. Trial Registration ClinicalTrials.gov (NCT02434016). Registered on April 27, 2015. First patients enrolled June 2015.

Control of respiratory drive by extracorporeal CO2 removal in acute exacerbation of COPD breathing on non-invasive NAVA.

BACKGROUND: Veno-venous extracorporeal CO2 removal (vv-ECCO2R) and non-invasive neurally adjusted ventilator assist (NIV-NAVA) are two promising techniques which may prevent complications related to prolonged invasive mechanical ventilation in patients with acute exacerbation of COPD. METHODS: A physiological study of the electrical activity of the diaphragm (Edi) response was conducted with varying degrees of extracorporeal CO2 removal to control the respiratory drive in patients with severe acute exacerbation of COPD breathing on NIV-NAVA. RESULTS: Twenty COPD patients (SAPS II 37 ± 5.6, age 57 ± 9 years) treated with vv-ECCO2R and supported by NIV-NAVA were studied during stepwise weaning of vv-ECCO2R. Based on dyspnea, tolerance, and blood gases, weaning from vv-ECCO2R was successful in 12 and failed in eight patients. Respiratory drive (measured via the Edi) increased to 19 ± 10 µV vs. 56 ± 20 µV in the successful and unsuccessful weaning groups, respectively, resulting in all patients keeping their CO2 and pH values stable. Edi was the best predictor for vv-ECCO2R weaning failure (ROC analysis AUC 0.95), whereas respiratory rate, rapid shallow breathing index, and tidal volume had lower predictive values. Eventually, 19 patients were discharged home, while one patient died. Mortality at 90 days and 180 days was 15 and 25%, respectively. CONCLUSIONS: This study demonstrates for the first time the usefulness of the Edi signal to monitor and guide patients with severe acute exacerbation of COPD on vv-ECCO2R and NIV-NAVA. The Edi during vv-ECCO2R weaning was found to be the best predictor of tolerance to removing vv-ECCO2R.

A novel non-invasive method to detect excessively high respiratory effort and dynamic transpulmonary driving pressure during mechanical ventilation.

BACKGROUND: Excessive respiratory muscle effort during mechanical ventilation may cause patient self-inflicted lung injury and load-induced diaphragm myotrauma, but there are no non-invasive methods to reliably detect elevated transpulmonary driving pressure and elevated respiratory muscle effort during assisted ventilation. We hypothesized that the swing in airway pressure generated by respiratory muscle effort under assisted ventilation when the airway is briefly occluded (ΔPocc) could be used as a highly feasible non-invasive technique to screen for these conditions. METHODS: Respiratory muscle pressure (Pmus), dynamic transpulmonary driving pressure (ΔPL,dyn, the difference between peak and end-expiratory transpulmonary pressure), and ΔPocc were measured daily in mechanically ventilated patients in two ICUs in Toronto, Canada. A conversion factor to predict ΔPL,dyn and Pmus from ΔPocc was derived and validated using cross-validation. External validity was assessed in an independent cohort (Nanjing, China). RESULTS: Fifty-two daily recordings were collected in 16 patients. In this sample, Pmus and ΔPL were frequently excessively high: Pmus exceeded 10 cm H2O on 84% of study days and ΔPL,dyn exceeded 15 cm H2O on 53% of study days. ΔPocc measurements accurately detected Pmus > 10 cm H2O (AUROC 0.92, 95% CI 0.83-0.97) and ΔPL,dyn > 15 cm H2O (AUROC 0.93, 95% CI 0.86-0.99). In the external validation cohort (n = 12), estimating Pmus and ΔPL,dyn from ΔPocc measurements detected excessively high Pmus and ΔPL,dyn with similar accuracy (AUROC ≥ 0.94). CONCLUSIONS: Measuring ΔPocc enables accurate non-invasive detection of elevated respiratory muscle pressure and transpulmonary driving pressure. Excessive respiratory effort and transpulmonary driving pressure may be frequent in spontaneously breathing ventilated patients.

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.

Neural Breathing Pattern and Patient-Ventilator Interaction During Neurally Adjusted Ventilatory Assist and Conventional Ventilation in Newborns.

OBJECTIVE: To compare neurally adjusted ventilatory assist and conventional ventilation on patient-ventilator interaction and neural breathing patterns, with a focus on central apnea in preterm infants. DESIGN: Prospective, observational cross-over study of intubated and ventilated newborns. Data were collected while infants were successively ventilated with three different ventilator conditions (30 min each period): 1) synchronized intermittent mandatory ventilation (SIMV) combined with pressure support at the clinically prescribed, SIMV with baseline settings (SIMVBL), 2) neurally adjusted ventilatory assist, 3) same as SIMVBL, but with an adjustment of the inspiratory time of the mandatory breaths (SIMV with adjusted settings [SIMVADJ]) using feedback from the electrical activity of the diaphragm). SETTING: Regional perinatal center neonatal ICU. PATIENTS: Neonates admitted in the neonatal ICU requiring invasive mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Twenty-three infants were studied, with median (range) gestational age at birth 27 weeks (24-41 wk), birth weight 780 g (490-3,610 g), and 7 days old (1-87 d old). Patient ventilator asynchrony, as quantified by the NeuroSync index, was lower during neurally adjusted ventilatory assist (18.3% ± 6.3%) compared with SIMVBL (46.5% ±11.7%; p < 0.05) and SIMVADJ (45.8% ± 9.4%; p < 0.05). There were no significant differences in neural breathing parameters, or vital signs, except for the end-expiratory electrical activity of the diaphragm, which was lower during neurally adjusted ventilatory assist. Central apnea, defined as a flat electrical activity of the diaphragm more than 5 seconds, was significantly reduced during neurally adjusted ventilatory assist compared with both SIMV periods. These results were comparable for term and preterm infants. CONCLUSIONS: Patient-ventilator interaction appears to be improved with neurally adjusted ventilatory assist. Analysis of the neural breathing pattern revealed a reduction in central apnea during neurally adjusted ventilatory assist use.

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.

A diaphragmatic electrical activity-based optimization strategy during pressure support ventilation improves synchronization but does not impact work of breathing.

BACKGROUND: Poor patient-ventilator synchronization is often observed during pressure support ventilation (PSV) and has been associated with prolonged duration of mechanical ventilation and poor outcome. Diaphragmatic electrical activity (Eadi) recorded using specialized nasogastric tubes is a surrogate of respiratory brain stem output. This study aimed at testing whether adapting ventilator settings during PSV using a protocolized Eadi-based optimization strategy, or Eadi-triggered and -cycled assisted pressure ventilation (or PSVN) could (1) improve patient-ventilator interaction and (2) reduce or normalize patient respiratory effort as estimated by the work of breathing (WOB) and the pressure time product (PTP). METHODS: This was a prospective cross-over study. Patients with a known chronic pulmonary obstructive or restrictive disease, asynchronies or suspected intrinsic positive end-expiratory pressure (PEEP) who were ventilated using PSV were enrolled in the study. Four different ventilator settings were sequentially applied for 15 minutes (step 1: baseline PSV as set by the clinician, step 2: Eadi-optimized PSV to adjust PS level, inspiratory trigger, and cycling settings, step 3: step 2 + PEEP adjustment, step 4: PSVN). The same settings as step 3 were applied again after step 4 to rule out a potential effect of time. Breathing pattern, trigger delay (Td), inspiratory time in excess (Tiex), pressure-time product (PTP), and work of breathing (WOB) were measured at the end of each step. RESULTS: Eleven patients were enrolled in the study. Eadi-optimized PSV reduced Td without altering Tiex in comparison with baseline PSV. PSVN reduced Td and Tiex in comparison with baseline and Eadi-optimized PSV. Respiratory pattern did not change during the four steps. The improvement in patient-ventilator interaction did not lead to changes in WOB or PTP. CONCLUSIONS: Eadi-optimized PSV allows improving patient ventilator interaction but does not alter patient effort in patients with mild asynchrony. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT 02067403 . Registered 7 February 2014.

Assisted Ventilation in Patients with Acute Respiratory Distress Syndrome: Lung-distending Pressure and Patient-Ventilator Interaction.

BACKGROUND: In patients with acute respiratory distress syndrome (ARDS), the use of assisted mechanical ventilation is a subject of debate. Assisted ventilation has benefits over controlled ventilation, such as preserved diaphragm function and improved oxygenation. Therefore, higher level of "patient control" of ventilator assist may be preferable in ARDS. However, assisted modes may also increase the risk of high tidal volumes and lung-distending pressures. The current study aims to quantify how differences in freedom to control the ventilator affect lung-protective ventilation, breathing pattern variability, and patient-ventilator interaction. METHODS: Twelve patients with ARDS were ventilated in a randomized order with assist pressure control ventilation (PCV), pressure support ventilation (PSV), and neurally adjusted ventilatory assist (NAVA). Transpulmonary pressure, tidal volume, diaphragm electrical activity, and patient-ventilator interaction were measured. Respiratory variability was assessed using the coefficient of variation of tidal volume. RESULTS: During inspiration, transpulmonary pressure was slightly lower with NAVA (10.3 ± 0.7, 11.2 ± 0.7, and 9.4 ± 0.7 cm H2O for PCV, PSV, and NAVA, respectively; P < 0.01). Tidal volume was similar between modes (6.6 [5.7 to 7.0], 6.4 [5.8 to 7.0], and 6.0 [5.6 to 7.3] ml/kg for PCV, PSV, and NAVA, respectively), but respiratory variability was higher with NAVA (8.0 [6.4 to 10.0], 7.1 [5.9 to 9.0], and 17.0 [12.0 to 36.1] % for PCV, PSV, and NAVA, respectively; P < 0.001). Patient-ventilator interaction improved with NAVA (6 [5 to 8] % error) compared with PCV (29 [14 to 52] % error) and PSV (12 [9 to 27] % error); P < 0.0001. CONCLUSION: In patients with mild-to-moderate ARDS, increasing freedom to control the ventilator maintains lung-protective ventilation in terms of tidal volume and lung-distending pressure, but it improves patient-ventilator interaction and preserves respiratory variability.

Assessment of patient-ventilator breath contribution during neurally adjusted ventilatory assist in patients with acute respiratory failure.

INTRODUCTION: We previously showed in animals that the ratio of inspired tidal volume (Vtinsp) to inspiratory peak electrical activity of the diaphragm (EAdipk) can be used to quantify the respective patient and ventilator breath contributions (PVBCs) during neurally adjusted ventilatory assist (NAVA). The PVBC index has not been tested clinically. METHODS: We studied 12 intubated and mechanically ventilated patients with acute respiratory failure and measured EAdipk, airway (Paw) and inspiratory esophageal pressure (Pes) and Vtinsp. We applied 11 different NAVA levels, increasing them every 3 minutes in steps of 0.3 cm H2O/µV from 0 to 3.0 cmH2O/µV. At each NAVA level, one breath was non-assisted (NAVA level 0). PVBC indices were calculated by relating Vtinsp/EAdipk of the non-assisted breath to Vtinsp/EAdipk of the assisted breath(s) using one ((N1)PVBC) or the mean value of five preceding assisted breaths ((X5)PVBC). During assisted breaths, inspiratory changes in Pes (∆Pes) and transpulmonary (ΔPtp) pressures were used to calculate the relative contribution of patient to total inspiratory lung-distending pressures (ΔPes/ΔPtp). Matching of respiratory drive indices and squaring of the PVBC was evaluated for their effect on the correlation between PVBC and ΔPes/ΔPtp. Linear regression analysis and Bland-Altman analysis were applied to compare indices. RESULTS: Using an average of five assisted breaths prior to the non-assisted breath and squaring the PVBC ((X5)PVBC(2)) improved determination coefficients (P <0.05), adjusted the regression slope and intercept between PVBC and ΔPes/ΔPtp toward identity (P <0.05) and reduced bias (P <0.05). Matching EAdipk between non-assisted and assisted breaths within the range of 0.77 to 1.30 improved the relationship between (X5)PVBC(2) and ΔPes/ΔPtp (P <0.05) and abolished the need for EAdi normalization in the PVBC calculation (R(2) = 0.96; bias = 0.16 ± 0.06; precision = 0.33 ± 0.08 (mean and 95% confidence interval)). CONCLUSIONS: This clinical study confirms previous experimental results showing that the PVBC(2) predicts the contribution of the inspiratory muscles versus that of the ventilator during NAVA, when differences in effort (EAdi) between non-assisted and assisted breaths are limited. PVBC could help to quantify and standardize the adjustment of the level of assist, and hence reduce the risks of excessive ventilatory assist in patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01663480. Registered 9 August 2012.

Neural versus pneumatic control of pressure support in patients with chronic obstructive pulmonary diseases at different levels of positive end expiratory pressure: a physiological study.

INTRODUCTION: Intrinsic positive end-expiratory pressure (PEEPi) is a "threshold" load that must be overcome to trigger conventional pneumatically-controlled pressure support (PSP) in chronic obstructive pulmonary disease (COPD). Application of extrinsic PEEP (PEEPe) reduces trigger delays and mechanical inspiratory efforts. Using the diaphragm electrical activity (EAdi), neurally controlled pressure support (PSN) could hypothetically eliminate asynchrony and reduce mechanical inspiratory effort, hence substituting the need for PEEPe. The primary objective of this study was to show that PSN can reduce the need for PEEPe to improve patient-ventilator interaction and to reduce both the "pre-trigger" and "total inspiratory" neural and mechanical efforts in COPD patients with PEEPi. A secondary objective was to evaluate the impact of applying PSN on breathing pattern. METHODS: Twelve intubated and mechanically ventilated COPD patients with PEEPi ≥ 5 cm H2O underwent comparisons of PSP and PSN at different levels of PEEPe (at 0 %, 40 %, 80 %, and 120 % of static PEEPi, for 12 minutes at each level on average), at matching peak airway pressure. We measured flow, airway pressure, esophageal pressure, and EAdi, and analyzed neural and mechanical efforts for triggering and total inspiration. Patient-ventilator interaction was analyzed with the NeuroSync index. RESULTS: Mean airway pressure and PEEPe were comparable for PSP and PSN at same target levels. During PSP, the NeuroSync index was 29 % at zero PEEPe and improved to 21 % at optimal PEEPe (P < 0.05). During PSN, the NeuroSync index was lower (<7 %, P < 0.05) regardless of PEEPe. Both pre-trigger (P < 0.05) and total inspiratory mechanical efforts (P < 0.05) were consistently higher during PSP compared to PSN at same PEEPe. The change in total mechanical efforts between PSP at PEEPe0% and PSN at PEEPe0% was not different from the change between PSP at PEEPe0% and PSP at PEEPe80%. CONCLUSION: PSN abolishes the need for PEEPe in COPD patients, improves patient-ventilator interaction, and reduces the inspiratory mechanical effort to breathe. TRIAL REGISTRATION: Clinicaltrials.gov NCT02114567 . Registered 04 November 2013.

Feasibility of neurally adjusted positive end-expiratory pressure in rabbits with early experimental lung injury.

BACKGROUND: During conventional Neurally Adjusted Ventilatory Assist (NAVA), the electrical activity of the diaphragm (EAdi) is used for triggering and cycling-off inspiratory assist, with a fixed PEEP (so called "Triggered Neurally Adjusted Ventilatory Assist" or "tNAVA"). However, significant post-inspiratory activity of the diaphragm can occur, believed to play a role in maintaining end-expiratory lung volume. Adjusting pressure continuously, in proportion to both inspiratory and expiratory EAdi (Continuous NAVA, or cNAVA), would not only offer inspiratory assist for tidal breathing, but also may aid in delivering a "neurally adjusted PEEP", and more specific breath-by-breath unloading. METHODS: Nine adult New Zealand white rabbits were ventilated during independent conditions of: resistive loading (RES(1) or RES(2)), CO2 load (CO2) and acute lung injury (ALI), either via tracheotomy (INV) or non-invasively (NIV). There were a total of six conditions, applied in a non-randomized fashion: INV-RES(1), INV-CO2, NIV-CO2, NIV-RES(2), NIV-ALI, INV-ALI. For each condition, tNAVA was applied first (3 min), followed by 3 min of cNAVA. This comparison was repeated 3 times (repeated cross-over design). The NAVA level was always the same for both modes, but was newly titrated for each condition. PEEP was manually set to zero during tNAVA. During cNAVA, the assist during expiration was proportional to the EAdi. During all runs and conditions, ventilator-delivered pressure (Pvent), esophageal pressure (Pes), and diaphragm electrical activity (EAdi) were measured continuously. The tracings were analyzed breath-by-breath to obtain peak inspiratory and mean expiratory values. RESULTS: For the same peak Pvent, the distribution of inspiratory and expiratory pressure differed between tNAVA and cNAVA. For each condition, the mean expiratory Pvent was always higher (for all conditions 4.0 ± 1.1 vs. 1.1 ± 0.5 cmH2O, P < 0.01) in cNAVA than in tNAVA. Relative to tNAVA, mean inspiratory EAdi was reduced on average (for all conditions) by 19 % (range 14 %-25 %), p < 0.05. Mean expiratory EAdi was also lower during cNAVA (during INV-RES(1), INV-CO2, INV-ALI, NIV-CO2 and NIV-ALI respectively, P < 0.05). The inspiratory Pes was reduced during cNAVA all 6 conditions (p < 0.05). Unlike tNAVA, during cNAVA the expiratory pressure was comparable with that predicted mathematically (mean difference of 0.2 ± 0.8 cmH2O). CONCLUSION: Continuous NAVA was able to apply neurally adjusted PEEP, which led to a reduction in inspiratory effort compared to triggered NAVA.

Heart-lung interactions during neurally adjusted ventilatory assist.

INTRODUCTION: Assist in unison to the patient's inspiratory neural effort and feedback-controlled limitation of lung distension with neurally adjusted ventilatory assist (NAVA) may reduce the negative effects of mechanical ventilation on right ventricular function. METHODS: Heart-lung interaction was evaluated in 10 intubated patients with impaired cardiac function using esophageal balloons, pulmonary artery catheters and echocardiography. Adequate NAVA level identified by a titration procedure to breathing pattern (NAVAal), 50% NAVAal, and 200% NAVAal and adequate pressure support (PSVal, defined clinically), 50% PSVal, and 150% PSVal were implemented at constant positive end-expiratory pressure for 20 minutes each. RESULTS: NAVAal was 3.1 ± 1.1cmH2O/µV and PSVal was 17 ± 2 cmH20. For all NAVA levels negative esophageal pressure deflections were observed during inspiration whereas this pattern was reversed during PSVal and PSVhigh. As compared to expiration, inspiratory right ventricular outflow tract velocity time integral (surrogating stroke volume) was 103 ± 4%, 109 ± 5%, and 100 ± 4% for NAVAlow, NAVAal, and NAVAhigh and 101 ± 3%, 89 ± 6%, and 83 ± 9% for PSVlow, PSVal, and PSVhigh, respectively (p < 0.001 level-mode interaction, ANOVA). Right ventricular systolic isovolumetric pressure increased from 11.0 ± 4.6 mmHg at PSVlow to 14.0 ± 4.6 mmHg at PSVhigh but remained unchanged (11.5 ± 4.7 mmHg (NAVAlow) and 10.8 ± 4.2 mmHg (NAVAhigh), level-mode interaction p = 0.005). Both indicate progressive right ventricular outflow impedance with increasing pressure support ventilation (PSV), but no change with increasing NAVA level. CONCLUSIONS: Right ventricular performance is less impaired during NAVA compared to PSV as used in this study. Proposed mechanisms are preservation of cyclic intrathoracic pressure changes characteristic of spontaneous breathing and limitation of right-ventricular outflow impedance during inspiration, regardless of the NAVA level. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00647361, registered 19 March 2008.

Automated patient-ventilator interaction analysis during neurally adjusted non-invasive ventilation and pressure support ventilation in chronic obstructive pulmonary disease.

INTRODUCTION: Delivering synchronous assist during non-invasive ventilation (NIV) is challenging with flow- or pressure-controlled ventilators, especially in patients with chronic obstructive pulmonary disease (COPD). Neurally adjusted ventilatory assist (NAVA) uses diaphragm electrical activity (EAdi) to control the ventilator. We evaluated patient-ventilator interaction in patients with COPD during NIV with pressure support ventilation (PSV) and NAVA using a recently introduced automated analysis. METHODS: Twelve COPD patients underwent three 30-minute trials: 1) PSV with dedicated NIV ventilator (NIV-PSVVision), 2) PSV with intensive care unit (ICU) ventilator (NIV-PSVServo-I), and 3) with NIV-NAVA. EAdi, flow, and airway pressure were recorded. Patient-ventilator interaction was evaluated by comparing airway pressure and EAdi waveforms with automated computer algorithms. The NeuroSync index was calculated as the percentage of timing errors between airway pressure and EAdi. RESULTS: The NeuroSync index was higher (larger error) for NIV-PSVVision (24 (IQR 15 to 30) %) and NIV-PSVServo-I (21 (IQR 15 to 26) %) compared to NIV-NAVA (5 (IQR 4 to 7) %; P <0.001). Wasted efforts, trigger delays and cycling-off errors were less with NAVA (P <0.05 for all). The NeuroSync index and the number of wasted efforts were strongly correlated (r2 = 0.84), with a drastic increase in wasted efforts after timing errors reach 20%. CONCLUSIONS: In COPD patients, non-invasive NAVA improves patient-ventilator interaction compared to PSV, delivered either by a dedicated or ICU ventilator. The automated analysis of patient-ventilator interaction allowed for an objective detection of patient-ventilator interaction during NIV. In addition, we found that progressive mismatch between neural effort and pneumatic timing is associated with wasted efforts.

Lung protection during non-invasive synchronized assist versus volume control in rabbits.

INTRODUCTION: Experimental work provides insight into potential lung protective strategies. The objective of this study was to evaluate markers of ventilator-induced lung injury after two different ventilation approaches: (1) a "conventional" lung-protective strategy (volume control (VC) with low tidal volume, positive end-expiratory pressure (PEEP) and paralysis), (2) a physiological approach with spontaneous breathing, permitting synchrony, variability and a liberated airway. For this, we used non-invasive Neurally Adjusted Ventilatory Assist (NIV-NAVA), with the hypothesis that liberation of upper airways and the ventilator's integration with lung protective reflexes would be equally lung protective. METHODS: In this controlled and randomized in vivo laboratory study, 25 adult White New Zealand rabbits were studied, including five non-ventilated control animals. The twenty animals with aspiration-induced lung injury were randomized to ventilation with either VC (6 mL/kg, PEEP 5 cm H2O, and paralysis) or NIV-NAVA for six hours (PEEP = zero because of leaks). Markers of lung function, lung injury, vital signs and ventilator parameters were assessed. RESULTS: At the end of six hours of ventilation (n = 20), there were no significant differences between VC and NIV-NAVA for vital signs, PaO2/FiO2 ratio, lung wet-to-dry ratio and broncho-alveolar Interleukin 8 (Il-8). Plasma IL-8 was higher in VC (P <0.05). Lung injury score was lower for NIV-NAVA (P = 0.03). Dynamic lung compliance recovered after six hours in NIV-NAVA but not in VC (P <0.05). During VC, peak pressures increased from 9.2 ± 2.4 cm H2O (hour 1) to 12.3 ± 12.3 cm H2O (hour 6) (P <0.05). During NIV-NAVA, the tracheal end-expiratory pressure was similar to the end-expiratory pressure during VC. Two animals regurgitated during NIV-NAVA, without clinical consequences, and survived the protocol. CONCLUSIONS: In experimental acute lung injury, NIV-NAVA is as lung-protective as VC 6 ml/kg with PEEP.

Tidal volume delivery during nasal intermittent positive pressure ventilation: infant cannula vs. nasal continuous positive airway pressure prongs.

OBJECTIVE: To measure tidal volume delivery during nasal intermittent positive pressure ventilation with two nasal interfaces: infant cannula and nasal prongs. STUDY DESIGN: A single-center crossover study of neonates with mild respiratory distress. Fifteen preterm neonates were randomized to initial interface of infant cannula or nasal prongs and monitored on a sequence of pressure settings first on the initial interface, then repeated on the alternate interface. We compared relative tidal volumes between the two interfaces with two-way repeated measures ANOVA during three breath types: synchronized (I), patient effort without ventilator breaths (II), and ventilator breaths without patient effort (III). Clinical trial #NCT04326270. RESULTS: Type III breaths delivered no significant tidal volume. No significant difference was measured in relative tidal volume delivery between the interfaces when breath types were matched. CONCLUSIONS: Nasal intermittent positive pressure ventilation delivers neither clinically nor statistically significant tidal volume with either infant cannula or nasal prongs.