Ventilator-Induced Diaphragm Dysfunction in ICU patients

Severe sepsis, trauma, abdominal haemorrhage and vascular injury are the
leading cause of mortality in the intensive care unit (5). Current treatment
modalities include the early institution of ventilation support, mainly to
support gas exchange. However, mechanical ventilation is clearly a two-edged
sword: a rapidly accumulating body of evidence suggests that mechanical
ventilation, with its attendant diaphragm muscle inactivity, is an important
cause of diaphragmatic weakness. Thus, after surviving the perils of sepsis,
trauma, abdominal haemorrhage and vascular injury, continued mechanical
ventilation may be required because of profound diaphragm weakness, leading to
difficulties in discontinuing ventilatory support (i.e. weaning failure).
Weaning failure is frequently encountered and a major clinical problem in
mechanically ventilated patients (1) and contributes to mortality (3).

How does prolonged mechanical ventilation weaken the human diaphragm? The
plethora of data suggesting that the ventilator causes damage to the diaphragm
are from animal studies. In rats, two days of controlled mechanical ventilation
reduced the pressure-generating capacity of the diaphragm by nearly fifty
percent (2). This decrease in diaphragmatic force is time-dependent, becoming
evident as early as twelve hours after onset of mechanical ventilation in rats
(15) and worsens as this ventilation is prolonged (16), and appears to be
specific for the diaphragm. This so-called ventilator-induced diaphragmatic
dysfunction (VIDD) is mainly caused by rapid atrophy of the diaphragm, in which
oxidative stress appears to play a key role (17) together with other factors
such as steroid (mis)use, malnutrition, hyperglycemia, and the type of
ventilatory support.

Whereas the evidence for VIDD in animal models is strong, this evidence for its
occurence in patients is lacking. The few studies directed at testing the
presence of VIDD in patients indicated that twitch transdiaphragmatic pressure
obtained via magnetic phrenic-nerve stimulation was reduced in mechanically
ventilated patients(4); however, such reduction of twitch pressure might very
well involve phenomena that reside outside the diaphragm.

In this observational study, we propose to determine whether VIDD occurs in
patients. To this end, studies on diaphragm muscle biopsies are indispensable:
these will allow to study directly the contractile strength of isolated muscle
fibers as well as the muscle fiber structure and the gene/protein expression
profiles. The diaphragm biopsies will be obtained during laparotomy or
thoracotomy performed on mechanically-ventilated patients for suspected or
proven intra-abdominal sepsis or trauma, abdominal haemorrhage, or patients
scheduled for vascular surgery. Thus, these biopsies will position us uniquely
to determine, for the first time, the effect of mechanical ventilation on
diaphragm fiber contractile performance.

Our study may provide rationale for the development of novel therapeutic
strategies aimed at preventing or treatment of diaphragm weakness (such as
Neurally Adjusted Ventilatory Assist (NAVA) ventilation technology and/or
calcium sensitizers), and ultimately weaning failure, in mechanically
ventilated septic and non-septic patients in the ICU.

PRIMARY OBJECTIVE
1. To determine the contractile strength and the (ultra)structure of single
diaphragm muscle fibers of mechanically ventilated patients

SECONDARY OBJECTIVE
1. To determine whether diaphragm muscle fiber weakness is part of a
generalized muscle weakness, or rather is specific to the diaphragm muscle .
2. To determine whether diaphragm muscle fiber strength correlates with the
duration of ventilatory support.
3. To determine whether diaphragm muscle fiber strength correlates with weaning
failure.

Note, that if these studies indicate diaphragm muscle fiber weakness in
mechanically ventilated septic and non-septic patients, future studies will
test whether this can be attenuated by NAVA ventilation technology to avoid
diaphragm disuse atrophy.

Study design:
•Prospective, observational study.
•The study will be performed in the VUmc in Amsterdam.

Study period:
•The study will end after 4 years or earlier when the required population size
for the mechanically ventilated and control patients is reached.

Flow chart:
Mechanically ventilated septic patients planned for a laparotomy and non-septic
patients planned for a laparotomy or thoracotomy for other reasons such as
trauma, abdominal haemorrhage, vascular surgery
•Designated ICU physicians (surgeons, intensivists, anaesthesiologists) at VUmc
or MST will identify eligible mechanically-ventilated septic and non-septic
patients who are planned for a laparotomy or thoracotomy for suspected or
proven intra-abdominal sepsis (~50 per year), abdominal haemorrhage, or patient
that need vascular surgery.
•As the majority of these patients is incapacitated, the patient*s
respresentative(s) will be contacted by the physician responsible for
recruitment.
•In case the representative agrees with the biopsy procedure, the informed
consent form is signed.
•Surgery: during the laparotomy or thoracotomoy, the surgeon obtains a small
biopsy (~50 mg) from the diaphragm muscle. Moreover, a small biopsy from the
rectus abdominus muscle or latissimus dorsi muscle will be obtained; this
muscle will be readily accessible due to the already existing incision (note
that the rectus abdominus biopsy will allow to compare the findings obtained
from the diaphragm to those from a non-respiratory muscle). The surgical
procedure will be attended by the coordinating investigator or by a trained
co-investigator for adequate storage of tissue and for subsequent
transportation to the Laboratory for Physiology at VUmc. Directly prior to the
biopsy, sidestream dark field imaging will be applied. The imaging takes place
by means of a sterile probe, with the size of a pen, and which will be placed
gently against the diaphragm via the already existing incision. The imaging
procedure is performed by well-trained researchers/physicians. The application
of the imaging is non-invasive and extends the surgery by ~1 minute.
•As soon as the patient regains consciousness, the patient will be informed
about the study, and will be asked for informed consent.
•The majority of the experiments on the biopsies will be performed at the
Laboratory for Physiology at VUmc.

Non-mechanically ventilated non-septic patients (these will serve as controls):
•The designated thoracic surgeon at VUmc will identify eligible patients who
are planned for a thoracotomy for removal of a small tumor (~30 per year).
•In case the patient agrees with the biopsy procedure, the patient will sign
the informed consent form prior to surgery.
•Surgery: during the thoracotomy, the surgeon obtains a small biopsy (~50 mg)
from the diaphragm muscle. Moreover, during surgery the surgeon will take a
small biopsy from the latissimus dorsi. The surgical procedure will be attended
by the coordinating investigator or by a trained co-investigator for adequate
storage of tissue and for subsequent transportation to the Laboratory for
Physiology at VUmc.
•The majority of the experiments on the biopsies will be performed at the
Laboratory for Physiology at VUmc.

The diaphragm (and rectus abdominal and latissimus dorsi) biopsy is very small
(~50 mg) and will induce only very little and reversible damage. Previous
studies performed by the coordinating investigator (CAC Ottenheijm) at the
Radboud University Nijmegen Medical Centre (dept of Pulmonary Diseases) using
diaphragm biopsies obtained by comparable procedures as described here) were
completed without any adverse events (~200 biopsies, obtained from Radboud
University Nijmegen Medical Centre, Rijnstate Hospital, and Catharina
Hospital).

Furthermore, an evaluation of the pain experienced after surgery by patients
from whom a diaphragm biopsy was obtained (n=30) revealed that these patients
did not observe more pain than patients (n=40) from whom no biopsy was
obtained. The coordinating investigator (CAC Ottenheijm) was involved in this
evaluation, which was performed at the Radboud University Nijmegen Medical
Centre (dept of Pulmonary Diseases) in 2001.

The sidestream dark field imaging takes place by means of a sterile probe, with
the size of a pen, and which will be placed gently against the diaphragm via
the already existing incision. The imaging procedure is performed by
well-trained researchers/physicians, is non-invasive and extends the surgery by
~1 minute.

Thus, we are confident that the risk for the patients are negligible and that
the burden can be considerd minimal (patients are already scheduled for, and
the biopsy collection/imaging procedure will not significantly delay the
duration of, the surgery; the average duration required for biopsy
collection/imaging procedure by the surgeon is one-two minutes).
Importantly, the knowledge obtained by experiments on these valuable biopsies
and by the imaging will provide extremely precious insights into the role of
diaphragm weakness in weaning failure in the ICU. This knowledge can
subsequently be used for novel treatment strategies to prevent diaphragm muscle
weakness in mechanically-ventilated septic and non-septic patients.

The proposed research can be regarded group-related, as the participation of
subjects belonging to the group in question is indispensable. Many of these
patients are mechanically ventilated for weeks/months; such research is
technically and financially not feasible in laboratory animals.