Diaphragm-protective mechanical ventilation in critically ill patients: A proof of concept study.

Despite being life-saving, mechanical ventilation can have detrimental effects
on respiratory muscle function of critically ill patients. Like any straited
skeletal muscle, disuse of the diaphragm caused by overassistance of the
ventilator leads to atrophy and contractile dysfunction. On the other hand,
excessive work of breathing caused by ineffective unloading by the ventilator
can also contribute to development of Weakness. Together, these processed are
refered to asventilator-induced diaphragm dysfunction (VIDD). Dysfunction of
the respiratory muscles is associated with adverse outcome, including prolonged
weaning from the ventilator and increased mortality. Finding strategies to
prevent respiratory muscle dysfunction is therefore of utmost importance.
We hypothesize that both inactivity and excessive activity of the diaphragm can
be prevented by monitoring diaphragm activity at the bedside and adjusting the
ventilator settings accordingly. This study aims to assess the effect of such a
'diaphragm-protective' ventilation strategy in a diverse ICU population.
Outcomes of this study will be used to conduct a large multi-center trial to
assess if diaphragm-protective ventilation leads to improved outcomes of
critically ill patients. If this strategy is effective and feasible, it can
quickly improve outcomes of critically ill patients worldwide, and reduce
healthcare costs.

Primary objective of this study is to assess the feasibility of using a
monitoring and a titration algorithm to prevent inactivity and excessive
activity of the diaphragm. This will be determined by comparing the fraction of
breaths where diaphragm activity was within physiological range in the
intervention group and control group.

Secundary objectives include:
- To assess if diaphragm protective ventilation can be combined with
lung-protective ventilation
- To assess the effect of diaphragm protective mechanical ventilation on
patient-ventilator interaction.
- To assess the effects of diaphragm-protective ventilation on various
clinically relevant parameters such as blood gas analysis, parameters of
inflammation and patient comfort.
- In a subgroup of patients where electrical activity of the diaphragm (EAdi)
is readily available: to evaluate te relationship between EAdi and Pdi.

The study is a single center, single blinded, randomized-controlled pilot
trial.

In both control and intervention group diaphragm activity will be monitored
continuously using esophageal and gastric pressure catheters. In the
intervention group, ventilator settings will be adjusted according to the
observed diaphragm activity in an attempt to prevent inactivity and excessive
activity of the diaphragm. Adjustments will be made using a specially designed
titration algorithm (see page 18 of the protocol). Adjustments will be made
within the current range used in current clinical practise. There is no further
intrusion on regular clinical care.

Risks and burden of the intervention are small and manageable. Adjustment of
ventilator settings is a standard procedure in the ICU. Other studies that
adjusted ventilator settings for various reason found that this is well
tolerated by patients. Furthermore, we wil abide to the general safety
guidelines of management of ventilator settings currently used in general
practise. As such, pressures and volumes administered to the subjects in the
intervention group will be within range of those used in general clinical
practise today. Furthermore, the attending physician can override the
ventilator settings suggested by the study algorithm at any point during the
study, if he/she thinks that this is in the patients best interest. These
events will be registered and analysed as a feasibility parameter. Risks of the
intervention are thus minimal.
The risk and burden of the additional measurements and monitoring instruments
are small. The esophageal and gastric pressure catheters are already used in
specific patient groups in clinical care today Research staff and nurses have
experience with placing these instruments and conducting the measurements. Some
subjects will thus have the required instruments available at the start of the
study and will no be subjected to additional risks or burden. In case subjects
need to be instrumented with esophageal and/or gastric pressure catheters for
this study, consent will be asked for this procedure. Placement is
uncomfortable, comparable to the burden and risks of placing a nasogastric
feeding tube, but generally well tolerated. From clinical experience and recent
literature it is regarded as a safe procedure. Furthermore, high risks groups
are excluded from participation in the study. The additional blood samples
required for this study are all drawn from indwelling arterial catheters and
thus pose no extra risk or burden on the subjects. The amount required is very
small (15ml in total), much less than is taken daily for regular clinical
practise.
A sound risk - benefit analysis is of utmost importance when conducting studies
in critically ill and mechanically ventilated patients. As outlined above,
risks posed on the subjects are small and manageable. Weakness of the
respiratory muscle is common in mechanically ventilated patients and is
associated with adverse outcome. It is therefore highly relevant to find
strategies that can effectively prevent the development of respiratory muscle
weakness. Such strategies can only be studied in mechanically ventilated
patients, making these studies group related. If the titration algorithm in
this study is indeed effective in preventing inactivity and excessive activity
of the diaphragm, then it will be of benefit to both subjects in this study and
to future patients requiring mechanical ventilation.