Primary Objective: The primary goal is to investigate the feasibility and safety of prolonged (24 hours) partial neuromuscular blockade in ventilated patients with high respiratory drive in partially supported mode.Secondary Objectives: The…
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Middenrif / longfunctie
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Intervention
Outcome measures
Primary outcome
Feasibility to establish and maintain lung protective ventilation for 24 hours
with partial neuromuscular blockade in ventilated ICU patients with high
respiratory drive in partially supported mode. *Feasible* is define as: *the
ability to maintain tidal volume <6ml/kg PBW during the whole study protocol,
without developing any directly related serious adverse events.*
Therefore, the following parameters are collected:
Feasibility
• Percentage of breaths with tidal volume < 6ml/kg PBW
• Number of patients completing the study without meeting the stopping criteria
(see section 7.4.2) or serious adverse events.
• Number of patients that have been withdrawn after inclusion, and reason for
withdrawal.
• Number of eligible patients of the total ICU population, and reason why the
patient is not eligible for inclusion.
• Time needed to recruit patients and collect data.
Safety:
• Number of directly related adverse events
• Blood gas analysis: pCO2 and pH
• Hemodynamic parameters: heart rate and blood pressure
• Days on mechanical ventilation after the intervention
• ICU mortality
Secondary outcome
The effect of prolonged partial neuromuscular blocking on diaphragm function
and respiratory, hemodynamic and inflammatory parameters compared to standard
care. Therefore, the following parameters are collected:
• Respiratory and diaphragm function, assessed by measuring:
o respiratory rate, tidal volume and SpO2
o work of breathing (WOB) and pressure-time product (PTP)
o blood gas analysis: PaO2, PaCO2, pH
• Hemodynamic parameters, assessed by measuring clinical parameters such as
blood pressure and heart rate.
• Inflammatory parameters in blood; including TNF-α, IL-6 and IL-1β
7.1.3 Other study parameters
In addition, we recorded the following data:
• Sex, age and body mass index (BMI)
• Reason for admission and co-morbidity
• Amount of days on controlled mechanical ventilation before study period
• RASS, dose of sedatives and analgesics
• Ventilator settings: FiO2, PEEP, pressure support level and PaO2/FiO2 ratio
• If EAdi catheter in situ: EAdi signal and neuromuscular efficiency (NME)
Background summary
Mechanical ventilation is a life-saving intervention in patients with acute
respiratory failure (ARF) as it unloads the respiratory muscles and can
maintain adequate alveolar gas exchange. Mechanical ventilation can be
delivered in two ventilator modes: controlled mechanical ventilation, where all
the work of breathing is performed by the ventilator and partially supported
ventilation, where the work of breathing is shared between the patient and the
ventilator. The use of controlled mechanical ventilation requires high levels
of sedation, which is associated with adverse outcome. In addition, there is
increasing evidence that controlled mechanical ventilation itself could have
detrimental effects on the respiratory muscles due to prolonged inactivity
(disuse atrophy). Partially supported modes, have recognized beneficial
effects, including lung recruitment and reduced risk of ventilator-induces
diaphragm dysfunction (VIDD). Therefore, it seems reasonable to switch to a
partially supported mode as soon as feasible. However, in some patients this
transition may lead to an increased respiratory drive with high tidal volumes
(Vt) and transpulmonary pressures (Pl). In daily practice, these patients are
often re-sedated and ventilated in controlled mode, resulting in a vicious
circle in which they become difficult to wean from mechanical ventilation.
Recently, we have published a study in which a low-dose neuromuscular blocking
agent (NMBA) was administered to patients with lung injury and increased Vt (>
8ml/kg predicted body weight(PBW)) in partially supported modes. We
demonstrated that partial neuromuscular blockade facilitates lung-protective
ventilation (Vt <6ml/kg PBW and Pl reduced from 27cmH2O to 11cmH2O), reduces
work of breathing (WOB), while maintaining diaphragm activity. This
proof-of-concept study was well received by experts in the field and the study
was published in the highest ranked medical journal for intensive care
medicine. An important limitation of the study was that it was conducted in a
small, selected group of patients and during short period of time (2 hours). In
addition, in our proof of concept study no control group was evaluated.
Clearly, there is a need for a pilot study to demonstrate the feasibility and
safety of this strategy for prolonged period of time, before we can conduct a
large RCT with clinical relevant outcome parameters. Data obtained from this
pilot RCT are an important step towards innovative pharmacological intervention
in patients with high respiratory drives in partially assisted modes.
Study objective
Primary Objective:
The primary goal is to investigate the feasibility and safety of prolonged (24
hours) partial neuromuscular blockade in ventilated patients with high
respiratory drive in partially supported mode.
Secondary Objectives:
The secondary goal is to evaluate the effect of this strategy on diaphragm
function, lung injury, hemodynamics and systemic inflammation compared to
standard care.
Study design
The study is a single centre, clinical pilot RCT and will be performed during
one year period in an academic medical-surgical intensive care unit (ICU).
Intervention
Intervention group: titration until tidal volume of 6ml/kg predicted body
weight is reached, followed by continuous administration of partial
neuromuscular blockade with rocuronium bromide for 24 hrs.
Control group: receive standard of care
Study burden and risks
Based on results of our previous proof-of-concept study, patients may benefit
in participating in this study. There is a strong physiological rationale for
protecting patients against high tidal volumes and concomitant high
transpulmonary pressures [13, 14]. Ultimately, we want to perform a randomized
controlled trial to test if partial neuromuscular blockade will improve
outcome. However, first we need to investigate the feasibility of prolonged
administration of partial neuromuscular blocking agents on lung protective
ventilation and the effect of this strategy on diaphragm function, respiratory,
hemodynamic and inflammatory parameters compared to standard care. Data
obtained from this second proof-of-concept study are an important step towards
innovative pharmacological intervention in patients with high respiratory
drives in partially assisted modes.
Administration of rocuronium bromide
Risks of the use of rocuronium are the development of distress when the patient
is not adequately sedated. Therefore, partial neuromuscular blocking agents
will only be started when the patient is adequately sedated, indicated by a
RASS <= -3 used to assess sedation depth during the different phases of the
study. In our earlier performed study on partial neuromuscular blockade was
found that some patients developed a mild hypercapnic acidosis and mild
hemodynamic effects like tachycardia and hypertension. Therefore, we will not
include patients with a pH < 7.30 and/or hemodynamic instability.
*
Blood withdrawal
We will aim to combine blood gas analysis for the study with blood gas analysis
for clinical purpose. Only for analysis of the inflammatory parameters we will
require three samples of blood of maximum 5.0ml of blood per sample. All blood
samples will be withdrawn from the indwelling arterial catheter that is already
in situ for clinical purpose. No adverse events are anticipated from blood
withdrawal.
Risk - benefit analysis
A sound risk - benefit analysis is of great importance when studies are
performed in mechanically ventilated patients. As outlined in this section
risks for patients in the current study are minimized for administration of
rocuronium bromide (exclusion of patients with pH < 7.30 and / or hemodynamic
instability). These risks are negligible.
Studying the effect of prolonged administration of partially neuromuscular
blockade (with rocuronium bromide) in mechanically ventilated patients with
high respiratory drive in partially supported modes is highly needed.
Respiratory muscle atrophy and lung injury is common in this group of patients
and is associated with higher mortality rates and prolonged mechanical
ventilation. We reason that decreasing Vt to 6ml/kg PBW may reduce negative
effects of high drive and improve outcomes. As such, there is a potential
benefit for the participants, but this is not sure. The impact on outcome has
to be investigated with a randomized controlled trial. However, first we have
to investigate the feasibility of prolonged administration of partial
neuromuscular blocking agents on lung protective ventilation and the effect of
this strategy on diaphragm function and respiratory, hemodynamic and
inflammatory parameters compared to standard care. In conclusion, risks of the
intervention are negligible, and there is a potential benefit for
participating. As such, the risk-benefit ratio is acceptable.
De Boelelaan 1117
Amsterdam 1081HV
NL
De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
- high respiratory drive, defined as tidal volume > 8ml/kg PBW on inspiratory
support of 12cmH2O.
- sedation level: 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
- pregnancy
- known previous anaphylactic reaction to NMBA*s.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-000748-24-NL |
| CCMO | NL65192.029.18 |