ICU-Acquired Respiratory muscle Dysfunction (the ICARD study)

Severe sepsis, trauma, abdominal haemorrhage and vascular defects are the
leading causes of mortality in the intensive care unit. 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 inactivity of the respiratory muscle pump, is
an important cause of respiratory muscle weakness. This so-called
ventilator-induced respiratory muscle dysfunction is mainly caused by rapid
atrophy. Thus, after overcoming the perils of critical illness, continued
mechanical ventilation may be required because of profound respiratory muscle
weakness, leading to difficulties in discontinuing this ventilatory support
(i.e. weaning failure). Weaning failure is frequently encountered in
mechanically ventilated patients and contributes to mortality.

In our previous study that focused on the diaphragm, a profound effect of
mechanical ventilation was found. Diaphragm muscle fibers of mechanically
ventilated patients had a reduced cross-sectional area and lower normalized
force. These findings warrant further investigation into the underlying
molecular mechanisms to identify targets for pharmacological intervention.

The lateral abdominal wall muscles (expiratory muscles) are recruited with
active expiration during high breathing effort or inspiratory muscle weakness.
The effects of critical illness and mechanical ventilation on these muscles has
been assessed by bedside ultrasound. Changes in thickness occurred in 34
percent of patients. No data is available on histology and contractility of the
lateral abdominal muscles of critically ill patients.

In this observational study, we propose to elucidate the pathophysiology of
diaphragm weakness in critically ill patients and include in our evaluation
the role of the main components of the respiratory pump other than the
diaphragm .

Primary: To determine the contractile strength and the structure of single
muscle fibers isolated from biopsies of the diaphragm and lateral abdominal
muscles from mechanically-ventilated patients. Secondary: (i)To elucidate the
molecular mechanisms underlying ventilator-associated diaphragm dysfunction.
(ii) To determine whether respiratory muscle fiber weakness is part of a
generalized muscle weakness, or rather is specific to the respiratory muscles
and (iii) to determine the relationship between contractile properties of
single muscle fibers on one hand, and respiratory muscle thickness and
echogenicity as measured with ultrasound on the other hand.

Designated ICU physicians (surgeons, intensivists, anesthesiologists) at
participating centers will identify eligible mechanically-ventilated patients
who are planned for a laparotomy (~50 per year), or thoracotomy. As these
patients are incapacitated, the patient*s representative(s) will be contacted
by the responsible physician for possible recruitment. In case the
representative agrees with the study procedures, the informed consent form is
signed. At one point of time during the 24 hours before the surgery, 3 ml of
blood is collected. Diaphragm and expiratory muscle thickness, echogenicity and
layering are measured by an experienced physician or researcher using bedside
ultrasound.
Surgery: during the laparotomy or thoracotomy, the surgeon obtains a small
biopsy (~50 mg) from the diaphragm muscle. Moreover, a small biopsy from the
rectus abdominis and lateral abdominal muscles will be obtained; these muscles
will be readily accessible due to the already existing incision through the
abdominal wall (note that the rectus abdominis 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 Amsterdam UMC, location VUmc.
The majority of the experiments on the biopsies will be performed at the
Laboratory for Physiology at VUmc.

For the collection of the muscle biopsies from non-mechanically ventilated
patients (these will serve as controls), patients scheduled for thoracotomy for
removal of a small pulmonary tumor will be recruited by the thoracic surgeon.
Patients scheduled for abdominal surgery will be recruited by the abdominal
surgeon. The flow chart is comparable to that for critically ill mechanically
ventilated patients shown above, with the exception that these patients
are capacitated and will provide informed consent themselves, prior to surgery.
Additionally, in the thoracotomy group, the non-respiratory latissimus dorsi
muscle will be biopsied as this tissue is easily accessible through the
existing incision. In the abdominal surgery control group the surgeon will take
a small biopsy from the lateral abdominal muscles and the rectus abdominal
muscle through the existing incision the surgeon made to access the abdomen. In
this group, no diaphragm biopsy will be taken.

In the mechanically ventilated (ICU) group the burden associated with
participation consists of (1) the collection of a small (~50 mg) diaphragm
biopsy, (2) the collection of a biopsy of the lateral abdominal wall muscles,
(3) the collection of a biopsy from the rectus abdominis muscle ,(4) the
employment of bedside ultrasound to obtain insight in diaphragm and expiratory
muscle thickness, echogenicity and layering and (5) the collection of 3ml of
blood before the surgery. In the first control group the burden associated
with participation consists of (1) the collection of a small (~50 mg) diaphragm
biopsy, (2) the collection of a biopsy of the latissimus dorsi (LD) muscle,
(3) the employment of bedside ultrasound to obtain insight in diaphragm and
expiratory muscle thickness, echogenicity and layering and (4) the collection
of 3ml of blood before the surgery. In the abdominal surgery control group the
burden consists of (1) a small biopsy of the lateral abdominal muscles, (2) a
small biopsy of the rectus abdominis muscle and (3) the employment of bedside
ultrasound to obtain insight in expiratory muscle thickness, echogenicity and
layering and (4) the collection of 3 ml of blood before the surgery.
There will be no benefit for the subjects.