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).

Study Overview

• Status: Completed
• Conditions: Respiratory Failure; Critical Care; Respiration, Artificial; Ventilator Weaning; Respiratory Muscles
• Intervention / Treatment: Diagnostic test: Inspiratory hold; Diagnostic test: Expiratory hold; Diagnostic test: Ultrasound of respiratory muscles; Other: PEEP 10; Other: PEEP 5; Other: PEEP 0

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Antwerp
    • Edegem, Antwerp, Belgium, 2650
      • Antwerp University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Training A - PEEP 10-5-5-5; 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.	Diagnostic test: Inspiratory hold; 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.; Diagnostic test: Expiratory hold; 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.; Diagnostic test: Ultrasound of respiratory muscles; 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.; Other: PEEP 10; Positive End-Expiratory Pressure of 10cmH2O for 30 minutes; Other: PEEP 5; Positive End-Expiratory Pressure of 5cmH2O for 30 minutes
Experimental: Training B - PEEP 10-5-0-5; 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.	Diagnostic test: Inspiratory hold; 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.; Diagnostic test: Expiratory hold; 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.; Diagnostic test: Ultrasound of respiratory muscles; 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.; Other: PEEP 10; Positive End-Expiratory Pressure of 10cmH2O for 30 minutes; Other: PEEP 5; Positive End-Expiratory Pressure of 5cmH2O for 30 minutes; Other: PEEP 0; Positive End-Expiratory Pressure of 0cmH2O for 30 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in RSBI (ml*min)	Rapid shallow breathing index, calculated as tidal volume divided by respiratory rate	Measured at each breath during 30 minutes in block B3 (at zero PEEP; cumulative 30 minutes)
Change in P0.1 (cmH2O)	Airway pressure at the first 100 milliseconds of a breath	Measured at each breath during 30 minutes for each training block (A1-4 & B1-4; cumulative 4hours)
Change in Cdyn (ml / cmH2O)	Dynamic respiratory system compliance, calculated as tidal volume divided by driving pressure	Measured at each breath during 30 minutes for each training block (A1-4 & B1-4; cumulative 4hours)
Change in Raw (cmH2O * L / s)	Respiratory system resistance, calculated as (peak inspiratory pressure - plateau pressure) / flow	Measured at each breath during 30 minutes for each training block (A1-4 & B1-4; cumulative 4hours)
Change in PIP (cmH2O)	Peak Inspiratory Pressure	Measured at each breath during 30 minutes for each training block (A1-4 & B1-4; cumulative 4hours)
Change in DTF	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).	Measured for 5 breaths in the 30 minutes for each training block (A1-4 & B1-4; cumulative 4hours)
Change in ICTF	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).	Measured for 5 breaths in the 30 minutes for each training block (A1-4 & B1-4; cumulative 4hours)
Change in IOTF	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 for 5 breaths in the 30 minutes for each training block (A1-4 & B1-4; cumulative 4hours)
Change in MIP (cmH2O)	Maximal inspiratory pressure	Measured during an expiratory hold of ≤ 30 seconds between each training block (AH0-4 & BH0-4; cumulative ≤ 5 minutes)
Change in MEP (cmH2O)	Maximal expiratory pressure	Measured during an inspiratory hold of ≤ 30 seconds between each training block (AH0-4 & BH0-4; cumulative ≤ 5 minutes)
Change in ∆Pocc (cmH2O)	Airway occlusion pressure	Measured during an expiratory hold of ≤ 30 seconds between each training block (AH0-4 & BH0-4; cumulative ≤ 5 minutes)
Change in NVE (ml/µv)	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.	Measured at each breath during 30 minutes for each training block (A1-4 & B1-4; cumulative 4hours)
Change in TV (ml)	Tidal volume	Measured at each breath during 30 minutes for each training block (A1-4 & B1-4; cumulative 4hours)
Change in ∆Edi (µV)	Increase in electrical activity of the diaphragm (Edi) during inspiration, calculated as Edi high - Edi low.	Measured at each breath during 30 minutes for each training block (A1-4 & B1-4; cumulative 4hours)
Change in Pplat (cmH2O)	Airway plateau pressure	Measured at each breath during 30 minutes for each training block (A1-4 & B1-4; cumulative 4hours)
Change in static PEEP (cmH2O)	Postive end-expiratory pressure as measured during an expiratory hold.	Measured during an expiratory hold of ≤ 30 seconds between each training block (AH0-4 & BH0-4; cumulative ≤ 5 minutes)

Collaborators and Investigators

• Sponsor: University Hospital, Antwerp
• Collaborators: Research Foundation Flanders
• Investigators: Principal Investigator: Philippe G Jorens, MD, PhD, Head of the department of critical care medicine, Antwerp University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2022
• Primary Completion (Actual): December 31, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: May 9, 2022
• First Submitted That Met QC Criteria: May 13, 2022
• First Posted (Actual): May 19, 2022

Study Record Updates

• Last Update Posted (Actual): April 4, 2025
• Last Update Submitted That Met QC Criteria: April 3, 2025
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency
• Other Study ID Numbers: 002418

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Time series of NVE-ZAM will be plotted per participant and reported in a publication.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No