Pressure support ventilation attenuates ventilator-induced protein modifications in the diaphragm

Abstract

Introduction: Controlled mechanical ventilation (CMV) induces profound modifications of diaphragm protein metabolism, including muscle atrophy and severe ventilator-induced diaphragmatic dysfunction. Diaphragmatic modifications could be decreased by spontaneous breathing. We hypothesized that mechanical ventilation in pressure support ventilation (PSV), which preserves diaphragm muscle activity, would limit diaphragmatic protein catabolism.

Methods: Forty-two adult Sprague-Dawley rats were included in this prospective randomized animal study. After intraperitoneal anesthesia, animals were randomly assigned to the control group or to receive 6 or 18 hours of CMV or PSV. After sacrifice and incubation with 14C-phenylalanine, in vitro proteolysis and protein synthesis were measured on the costal region of the diaphragm. We also measured myofibrillar protein carbonyl levels and the activity of 20S proteasome and tripeptidylpeptidase II.

Results: Compared with control animals, diaphragmatic protein catabolism was significantly increased after 18 hours of CMV (33%, P = 0.0001) but not after 6 hours. CMV also decreased protein synthesis by 50% (P = 0.0012) after 6 hours and by 65% (P < 0.0001) after 18 hours of mechanical ventilation. Both 20S proteasome activity levels were increased by CMV. Compared with CMV, 6 and 18 hours of PSV showed no significant increase in proteolysis. PSV did not significantly increase protein synthesis versus controls. Both CMV and PSV increased protein carbonyl levels after 18 hours of mechanical ventilation from +63% (P < 0.001) and +82% (P < 0.0005), respectively.

Conclusions: PSV is efficient at reducing mechanical ventilation-induced proteolysis and inhibition of protein synthesis without modifications in the level of oxidative injury compared with continuous mechanical ventilation. PSV could be an interesting alternative to limit ventilator-induced diaphragmatic dysfunction.

Figure 1

Schematic illustration of the experimental design used.

Figure 2

In vitro diaphragmatic proteolysis. (a) Controlled mechanical ventilation (CMV) increased total diaphragmatic proteolysis after 18 hours, but not after 6 hours, of mechanical ventilation versus control (CON) and pressure support ventilation (PSV). Units in (a) are nanomoles of tyrosine per milligram of protein per hour. Both chymotrypsin-like activity (b) and tripeptidylpeptidase II activity (c) were increased by 18 hours of CMV. Units in (b) and (c) are relative fluorescence units (RFU) per microgram per minute. Values are mean ± standard error. *P < 0.05 compared with CON group. ^†P < 0.05 compared with PSV group at 6 and 18 hours. ^‡P < 0.05 compared with CMV group at 6 hours.

Figure 3

In vitro protein synthesis after 6 and 18 hours of controlled mechanical ventilation (CMV) and pressure support ventilation (PSV). Units are nanomoles of phenylalanine (Phe) per milligram of protein per hour. Values are mean ± standard error. *P < 0.05 compared with control (CON) group. ^†P < 0.05 compared with PSV group at 6 and 18 hours.

Figure 4

Protein-carbonyl content after 6 and 18 hours of controlled mechanical ventilation (CMV) and pressure support ventilation (PSV). Units are nanomoles per milligram of protein. Values are mean ± standard error. *P < 0.05 compared with control (CON) group.