Partial Neuromuscular Blockade for Lung Protective Mechanical Ventilation

Partial Neuromuscular Blockade to Facilitate Lung and Diaphragm Protective Mechanical Ventilation in Intensive Care Unit Patients: a Randomized Controlled Pilot Study

Controlled mechanical ventilation may lead to the development of diaphragm muscle atrophy, which is associated with weakness and adverse clinical outcome. Therefore, it seems reasonable to switch to partially supported ventilator modes as soon as possible. However, in patients with high respiratory drive, the application of partially supported modes may result in high lung distending pressures and diaphragm injury.

Recently, the investigators published a study that demonstrated that a low dose of neuromuscular blocking agents (NMBA) facilitates lung-protective ventilation and maintains diaphragm activity in intensive care unit (ICU) patients. That study was conducted in a small (N=10), selected group of patients and partial neuromuscular blockade was applied for only 2 hours (proof-of-concept study). Therefore, further research has to be done before this strategy can be applied in clinical practice.

The primary goal is to investigate the feasibility and safety of prolonged (24 hours) partial neuromuscular blockade in patients with high respiratory drive in partially supported mode. The secondary goals are to evaluate the effect of this strategy diaphragm function, lung injury, hemodynamics and systemic inflammation.

Study Overview

• Status: Unknown
• Conditions: Respiratory Insufficiency
• Intervention / Treatment: Drug: Rocuronium Bromide

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Diana Jansen, Drs.; Phone Number: +31(0)613225643; Email: diana.jansen@radboudumc.nl
• Study Contact Backup: Name: L.M.A. Heunks, prof.dr.; Email: l.heunks@vumc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • VUMC
    • Contact: L.M.A. Heunks, Prof.dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• high respiratory drive, defined as tidal volume > 8ml/kg PBW on inspiratory support of 12 cmH2O.
• sedation level: richmond agitation-sedation scale (RASS) ≤ -3
• ventilated in pressure support mode

Exclusion Criteria:

• recent use of NMBA (< 2 hrs)
• arterial pH < 7.25
• hemodynamic instability, i.e. high dose vasopressors (>0.5 μg/kg/min) or inotropes (dobutamine >15 μg/kg/min or enoximone >25 μg/kg/min)
• intracranial pressure > 20 cmH2O
• past medical history of neuromuscular disorders
• known pregnancy
• known previous anaphylactic reaction to NMBA's.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; Standard of care
Experimental: Rocuronium; Titration of rocuronium bromide until tidal volume of 6ml/kg predicted body weight (PBW) is reached	Drug: Rocuronium Bromide; Titration with rocuronium bromide until tidal volume 6ml/kg PBW; Other Names: Esmeron

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The percentage of breaths with tidal volume 6ml/kg predicted body weight (PBW)	During the study period we measure at five time points of 1 hour (T0, T1, T5, T12, T24) all breaths and determine the percentage of breaths with a tidal volume of 6ml/kg PBW.	At five time points of 1hr during the first 24hrs of the study period
Incidence of directly related serious adverse events	A serious adverse event is any untoward medical occurence or effect that: results in death; is life threatening; requires prolongation of existing inpatients' hospitalization; results in persistent or significatn disability or incapacity; is a new event of the trial medication to affect the safety of the subjects, such as adverse events which are not already were described	During the 48hrs study period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients completing the study without meeting the stopping criteria	After each time point (T0, T1, T5 and T12) we screen if the patient meets one of the stopping criteria, defined as: potential of hydrogen (pH) < 7.20; heart rate > 100 beats per minute or an increase of > 20% from baseline for more than 20 minutes; increase in mean arterial blood pressure of > 20% for more than 20 minutes	At four time points during the first 24hrs of the study period
Effect on partial carbon dioxide (pCO2)	At three time points (T0, T24, T48) during the study period we will collect a blood sample from the arterial catheter, to measure the effect of prolonged NMB administration on pCO2 (in kPa), in order to: determine if there were differences between the start and end of the study period; investigate if there were differences between both study groups	During the 48hrs study period
Effect on pH	At three time points (T0, T24, T48) during the study period we will collect a blood sample from the arterial catheter, to measure the effect of prolonged NMB administration on pH, in order to: determine if there were differences between the start and end of the study period; investigate if there were differences between both study groups.	During the 48hrs study period
Effect on heart rate	During the study period we will collect at six time points (T0, T1, T5, T12, T24 and T48) the heart rate (in beats per minute), in order to: determine if there were differences between the start and end of the study period; investigate if there were differences between both study groups.	During the 48hrs study period
Effect on blood pressure	During the study period we will collect at six time points (T0, T1, T5, T12, T24 and T48) the blood pressure (millimetre(s) of mercury (mmHg)), in order to: determine if there were differences between the start and end of the study period; investigate if there were differences between both study groups.	During the 48hrs study period
Effect on respiratory rate	During the study period we will collect at six time points (T0, T1, T5, T12, T24 and T48) the respiratory rate (in breaths per minute) in order to: determine if there were differences between the start and end of the study period; investigate if there were differences between both study groups.	During the 48hrs study period
Effect on peripheral capillary oxygen saturation (SpO2)	During the study period we will collect at six time points (T0, T1, T5, T12, T24 and T48) the SpO2 (%) in order to: determine if there were differences between the start and end of the study period; investigate if there were differences between both study groups.	During the 48hrs study period
Effect on partial oxygen pressure (pO2)	At three time points (T0, T24, T48) during the study period we will collect a blood sample from the arterial catheter, to measure the effect of prolonged NMB administration on pO2 (in kPa), in order to: determine if there were differences between the start and end of the study period; investigate if there were differences between both study groups.	During the 48hrs study period
Effect on work of breathing (WOB)	During the study period we will collect at five time points (T0, T1, T5, T12 and T24) the WOB (in Joule) in order to: determine if there were differences between the start and end of the study period; investigate if there were differences between both study groups.	During the first 24hrs of the study period
Effect on pressure time product (PTP)	During the study period we will collect at five time points (T0, T1, T5, T12 and T24) the PTP (in cmH2O per second) in order to: determine if there were differences between the start and end of the study period; investigate if there were differences between both study groups.	During the first 24hrs of the study period
Effect on tumor necrosis factor (TNF)-alfa	At three time points (T0, T24, T48) during the study period we will collect a blood sample from the arterial catheter, to measure the effect of prolonged NMB administration on TNF-alfa concentration (in pg/ml), in order to: determine if there were differences between the start and end of the study period; investigate if there were differences between both study groups.	During the first 24hrs of the study period
Effect on interleukin(IL)-6 and IL-8	At three time points (T0, T24, T48) during the study period we will collect a blood sample from the arterial catheter, to measure the effect of prolonged NMB administration on IL-6 and IL-8 concentration (in pg/ml), in order to: determine if there were differences between the start and end of the study period; investigate if there were differences between both study groups.	During the first 24hrs of the study period
Amount of days on mechanical ventilation	After 30 days we will investigate if there were differences between both groups in the duration of mechanical ventilation.	Until 30 days after the end of the study period

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2018
• Primary Completion (Anticipated): December 31, 2020
• Study Completion (Anticipated): December 31, 2020

Study Registration Dates

• First Submitted: July 26, 2018
• First Submitted That Met QC Criteria: August 22, 2018
• First Posted (Actual): August 24, 2018

Study Record Updates

• Last Update Posted (Actual): May 20, 2020
• Last Update Submitted That Met QC Criteria: May 19, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency; Physiological Effects of Drugs; Peripheral Nervous System Agents; Anticonvulsants; Neuromuscular Agents; Neuromuscular Nondepolarizing Agents; Neuromuscular Blocking Agents; Bromides; Rocuronium
• Other Study ID Numbers: NL65192.029.18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No