Effect of Diaphragm Stimulation During Surgery

Although mechanical ventilation (MV) is life-sustaining, it comes with a cost. MV
dramatically reduces diaphragm contractility, induces ventilator-induced diaphragm
dysfunction (VIDD) and sometimes leads to weaning failure. VIDD includes reduced
mitochondrial respiration and increased oxidative stress, muscle fiber damage and decreased
diaphragm force production.

In animal models, intermittent diaphragm contraction during MV support attenuates VIDD.
However, there are only limited data addressing this problem in humans. Here, the study team
propose to directly test the hypothesis that intermittent electrical stimulation (ES) of the
human hemidiaphragm during prolonged cardiac surgeries with MV support prevents/attenuates
VIDD in the active hemidiaphragm. Mitochondrial function is central to energy metabolism and
skeletal muscle function in a chronically active muscle, such as the diaphragm. Although
abnormal mitochondrial function is thought to precipitate VIDD in animal models, limited data
are available concerning mitochondrial contributions to VIDD in humans. Of even greater
importance, there are no interventions available to attenuate these defects in humans. Here,
the study team will test the impact of an innovative experimental treatment, intermittent
electrical stimulation (ES) of the hemidiaphragm during prolonged surgeries with MV, on
mitochondrial function, single fiber contractile properties and catabolic muscle pathways in
human diaphragm. Using a within-subjects experimental design, muscle samples from a
stimulated hemidiaphragms will be compared with samples from the unstimulated hemidiaphragm.
The study team will investigate mitochondrial dysfunction and oxidative stress during
prolonged CTS/MV, and the potential of ES to attenuate or prevent VIDD. Next, the study team
will investigate the effects of ES on single fiber contractile properties and Titin
integrity. Finally, the study team will study the effect of ES on proteolytic pathways
(caspase, calpain and ubiquitin-proteasome) and ribosomal RNA markers of decreased protein
synthesis implicated in VIDD.

Inclusion Criteria:

- Patients undergoing complex, elective prolonged surgeries, usually lasting 5-8 hours
or longer, including lung transplants (e.g. valveoplasty, coronary artery bypass
and/or aortic repairs)

Exclusion Criteria:

- history of prior surgery to the diaphragm or pleura;

- a diagnosis of COPD will be determined from a clinical history consistent with chronic
bronchitis and/or emphysema, a long history of cigarette smoking, and pulmonary
function tests consistent with irreversible airflow obstruction (FEV1 < 40% predicted,
according to European Respiratory Society criteria [will not apply to transplant
patients]

- a diagnosis of chronic heart failure (NYHA class IV)

- clinical diagnosis of other lung disease (cystic fibrosis, bronchiectasis, lung
cancer; etc.) [will not apply to transplant patients]

- renal insufficiency (serum creatinine > 1.6 mg/dl);

- severe hepatic disease (any liver function tests > 1.5 times the upper limit of
normal);

- undernourishment (body mass index < 20 kg/m2),

- chronic uncontrolled or poorly controlled metabolic diseases (e.g., diabetes, hypo- or
hyperthyroidism)

- orthopedic diseases, suspected paraneoplastic or myopathic syndromes,

- if in the surgeons' judgment the patients' clinical status warrants, diaphragm
stimulation will be stopped and biopsies will not be obtained,