Time Course of Neuro-ventilatory Efficiency During a Spontaneous Breathing Training (TONES)

The TONES trial aims to evaluate the neuroventilatory efficiency (NVE = tidal volume / peak voltage of diaphragm contraction) measured during a zero-assist manoeuvre (ZAM, i.e. with PEEP but without pressure support). This novel parameter, NVE-ZAM, will be studied in a blocked, crossover, repeated measures design. Possible confounders, such as activity of respiratory muscles other than the diaphragm, are included. The investigators hypothesized that the NVE during a zero-assist maneuver has a low variability and high repeatability at the same level of PEEP (within subjects, within blocks) NVE-ZAM trends differ between participants (between subjects, within blocks) and between PEEP levels (within subjects, between blocks) The primary aim is to study the variability and repeatability of the NVE-ZAM within subjects and within blocks. Additionally, the effect of PEEP, muscle fatigue and recruitment of the accessory and expiratory muscles of respiration on the NVE-ZAM will be studied in an exploratory analysis (in multiple combinations of within and between subjects and/or blocks).

The respiratory muscles of all participants will be trained in 4 consecutive blocks of 30 minutes during ventilation in neural pressure support mode (NPS) with a pressure support of 7 cmH2O. During training A, the 4 blocks are A1. PEEP 10 cmH2O | A2. PEEP 5 cmH2O | A3. PEEP *5* cmH2O | A4. PEEP 5 cmH2O During the training, ventilator data will be recorded and respiratory muscles will be imaged using ultrasound. Before and after each training block, an inspiratory and an expiratory hold (both ≤ 30 seconds) will be performed to assess fatigue.

The respiratory muscles of all participants will be trained in 4 consecutive blocks of 30 minutes during ventilation in neural pressure support mode (NPS) with a pressure support of 7 cmH2O. During training B, the 4 blocks are B1. PEEP 10 cmH2O | B2. PEEP 5 cmH2O | B3. PEEP *0* cmH2O | B4. PEEP 5 cmH2O During the training, ventilator data will be recorded and respiratory muscles will be imaged using ultrasound. Before and after each training block, an inspiratory and an expiratory hold (both ≤ 30 seconds) will be performed to assess fatigue.

A short period (< 30 seconds) during which both inspiratory and expiratory valves of the ventilator circuit are closed at the end of inspiration. It is used to asses expiratory force generation (maximal expiratory pressure, MEP) and frequently used in clinical practice.

A short period (< 30 seconds) during which both inspiratory and expiratory valves of the ventilator circuit are closed at the end of expiration. It is used to asses static PEEP and inspiratory force generation (maximal inspiratory pressure, MIP & occlusion pressure, ∆Pocc) and is frequently used in clinical practice.

Ultrasound of the diaphragm, parasternal intercostal muscle and internal oblique muscle will be performed during each block. Thickening fractions, calculated as thickness at end-inspiration minus thickness at end-expiration divided by thickness at end-expiration, are used to assess the contribution of the muscle to the tidal volume. A median over 5 breaths will be calculated.

Neuroventilatory efficiency (NVE) during a zero-assist breath in neural pressure support mode with a pressure support level of 7cmH2O and a PEEP of 10 cmH2O

Measured using an Edi catheter (Maquet, Solna, Sweden) each 3 minutes as tidal volume / delta Edi. Zero assist is defined as a pressure support of 0 cmH2O during a single breath.

Measured each 3 mintues during blocks A1 and B1: initial 30 minutes of training in both trainings A and B (cumulative: 2x 30 minutes)

Neuroventilatory efficiency (NVE) during a zero-assist breath in neural pressure support mode with a pressure support level of 7cmH2O and a PEEP of 5 cmH2O

Measured using an Edi catheter (Maquet, Solna, Sweden) each 3 minutes as tidal volume / delta Edi. Zero assist is defined as a pressure support of 0 cmH2O during a single breath.

Measured each 3 mintues during blocks A2 and B2: second next 30 minutes of training in both trainings A and B (cumulative: 2x 30 minutes)

Neuroventilatory efficiency (NVE) during a zero-assist breath in neural pressure support mode with a pressure support level of 7cmH2O and a PEEP of 5 cmH2O

Measured using an Edi catheter (Maquet, Solna, Sweden) each 3 minutes as tidal volume / delta Edi. Zero assist is defined as a pressure support of 0 cmH2O during a single breath.

Measured each 3 mintues during block A3: third next 30 minutes of training in training A (cumulative: 1x 30 minutes)

Neuroventilatory efficiency (NVE) during a zero-assist breath in neural pressure support mode with a pressure support level of 7cmH2O and a PEEP of 0 cmH2O

Measured using an Edi catheter (Maquet, Solna, Sweden) each 3 minutes as tidal volume / delta Edi. Zero assist is defined as a pressure support of 0 cmH2O during a single breath.

Measured each 3 mintues during block B3: third next 30 minutes of training in training B (cumulative: 1x 30 minutes)

Neuroventilatory efficiency (NVE) during a zero-assist breath in neural pressure support mode with a pressure support level of 7cmH2O and a PEEP of 5 cmH2O

Measured using an Edi catheter (Maquet, Solna, Sweden) each 3 minutes as tidal volume / delta Edi. Zero assist is defined as a pressure support of 0 cmH2O during a single breath.

Measured each 3 mintues during blocks A4 and B4: fourth next 30 minutes of training in both trainings A and B (cumulative: 2x 30 minutes)

Diaphragm thickening fraction, calculated as (diaphragm thickness at end-inspiration - diaphragm thickness at end-expiration) / diaphragm thickness at end-expiration [dimensionless]. Muscle thickness will be measured in millimeters using M-mode ultrasound with the probe placed perpendicular to the muscle (not including the thickness of fascial muscle layers).

Parasternal intercostal muscle thickening fraction, calculated as (parasternal intercostal muscle thickness at end-inspiration - parasternal intercostal muscle thickness at end-expiration) / parasternal intercostal muscle thickness at end-expiration [dimensionless]. Muscle thickness will be measured in millimeters using M-mode ultrasound with the probe placed perpendicular to the muscle (not including the thickness of fascial muscle layers).

Internal oblique muscle thickening fraction, calculated as (internal oblique muscle thickness at end-inspiration - internal oblique muscle thickness at end-expiration) / internal oblique muscle thickness at end-expiration [dimensionless]. Muscle thickness will be measured in millimeters using M-mode ultrasound with the probe placed perpendicular to the muscle (not including the thickness of fascial muscle layers).

Measured during an expiratory hold of ≤ 30 seconds between each training block (AH0-4 & BH0-4; cumulative ≤ 5 minutes)

Measured during an inspiratory hold of ≤ 30 seconds between each training block (AH0-4 & BH0-4; cumulative ≤ 5 minutes)

Measured during an expiratory hold of ≤ 30 seconds between each training block (AH0-4 & BH0-4; cumulative ≤ 5 minutes)

Neuroventilatory efficiency, calculated as tidal volume divided by delta Edi. It is measured at a pressure support of 7 cmH2O, i.e. NOT during a zero assist manoeuvre.

Increase in electrical activity of the diaphragm (Edi) during inspiration, calculated as Edi high - Edi low.

Measured during an expiratory hold of ≤ 30 seconds between each training block (AH0-4 & BH0-4; cumulative ≤ 5 minutes)

Inclusion criteria: adult (18-80 yrs.) admitted to the ICU intubated and mechanically ventilated Edi catheter (Maquet, Solna, Sweden) in situ as part of their clinical care ventilated in a support mode (e.g. pressure support) with a support between 7 and 15 cmH2O, a PEEP ≤10 cmH2O and an Fi02 <0.6, all since ≥6 hours. can participate in the trial as judged by their attending physician Exclusion criteria: pregnancy refusal of participation pre-existing neuromuscular disorders (e.g., Guillain-Barré)