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Mechanical Ventilation Weakens the Lungs
By Crystal Phend, Staff Writer, MedPage Today
Published: March 26, 2008
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine
http://www.medpagetoday.com/Surgery/GeneralSurgery/tb/8892
PHILADELPHIA, March 26
Slow-twitch fibers used for breathing and fast-twitch fibers used for coughing shrank by more than half after a prolonged period on full ventilatory support, reported Sanford Levine, M.D., of the University of Pennsylvania here, and colleagues in the March 27 issue of the New England Journal of Medicine.
This effect had been seen in prior animal studies but never confirmed in humans, the researchers said.
The findings argue against use of controlled mechanical ventilation as a protective strategy to "rest" the lungs and reverse diaphragm fatigue in the ICU, said Gary C. Sieck, Ph.D., and Carlos B. Mantilla, M.D., Ph.D., both of the Mayo Clinic in Rochester, Minn., in an accompanying editorial.
Patients on controlled ventilation during surgical anesthesia or other short-term procedures could also be at risk, they said. "It is likely that alternative ventilatory strategies will be necessary, especially for patients with decreased reserve capacity at baseline."
Their findings may help explain why some patients have so much trouble weaning off ventilation, Dr. Levine said.
However, the majority of patients go on assist-mode ventilation and synchronized intermittent mandatory ventilation with pressure support, which does require some work from the diaphragm, the editorialists noted.
Animal studies suggest these types of ventilation largely eliminate diaphragm atrophy, but the effect for human patients is still unclear, they said.
The researchers compared biopsy specimens from the costal diaphragms of 14 brain-dead organ donors before circulatory arrest and organ harvest with specimens from eight control patients collected during surgery for benign lesions or localized lung cancer.
Both groups had been on full mechanical ventilation with diaphragmatic inactivity before biopsy, but the duration was only two to three hours for control patients compared with 18 to 69 hours for organ donors.
Cases were younger than control subjects (mean 35 versus 57, P=0.008), but the gender ratio and average body-mass index was similar between groups.
Diaphragm tissue showed atrophy for those on longer-duration controlled ventilation. Mean cross-sectional areas of slow-twitch fibers were 57% lower for cases than controls (2,025 versus 4,725 μm2, P=0.001) and 53% lower for fast-twitch fibers (1,871 versus 3,949 μm2, P=0.01). The proportionate number of fibers did not differ.
Drs. Sieck and Mantilla noted that these combined effects would "almost certainly affect the ability of ventilated patients to sustain spontaneous breathing, requiring recruitment of more fatigable fast-twitch fibers," which would exacerbate muscle weakness.
The atrophy seen in organ donor patients was likely not caused by brain death or unmeasured humoral factors, as similar changes were not seen in pectoralis major muscle biopsies from case and control subjects the researchers said.
Specimens of pectoralis major muscle from a subgroup of organ donors and control patients showed no difference in cross-sectional areas of slow-twitch (3,084 versus 3,325 μm2) or fast-twitch fibers (2,933 versus 3,418 μm2).
Histology did not show inflammatory-cell infiltrate in the organ donor specimens, but these samples did show elevated oxidative stress and proteolysis, as would be expected with muscle inactivity, the researchers noted.
A longer duration of mechanical ventilation was associated with 23% lower total glutathione concentrations in diaphragm-biopsy specimens (1.03 versus 1.35 mM, P=0.01), which was "consistent with oxidative stress."
A protease involved in the first step of muscle breakdown, active caspase-3, was 154% elevated in cases compared with controls as well (1.52 versus 0.66 optical-density units, P=0.05).
Enzymes involved in breakdown of muscle proteins were also elevated. Organ donors had three-fold higher atrogin-1 expression (216 versus 72 arbitrary normalized copy units, P=0.002) and 6.9 times more MuRF-1 expression than control patients (885 versus 128 arbitrary normalized copy units, P=0.001).
For these reasons, the authors concluded that "our observations strongly suggest that increased proteolysis accounts for the fiber atrophy noted in the diagpragm-biopsy specimens from case subjects."
To help mitigate weaning problems, the researchers suggested, blocking or attenuating the pathways of proteolysis in the diaphragm might work.
The study was supported by grants from the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs Merit Review Program. The researchers and editorialists reported no conflicts of interest relevant to the study.
Primary source: New England Journal of Medicine
Source reference:
Levine S, et al "Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans" N Engl J Med 2008; 358: 1327-35.
Additional source: New England Journal of Medicine
Source reference:
Sieck GC, Mantilla CB "Effect of mechanical ventilation on the diaphragm" N Engl J Med 2008; 358: 1392-94.
By Crystal Phend, Staff Writer, MedPage Today
Published: March 26, 2008
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine
http://www.medpagetoday.com/Surgery/GeneralSurgery/tb/8892
PHILADELPHIA, March 26
A patient's diaphragm may atrophy quickly when mechanical ventilation takes all the pressure off it, researchers found.
Slow-twitch fibers used for breathing and fast-twitch fibers used for coughing shrank by more than half after a prolonged period on full ventilatory support, reported Sanford Levine, M.D., of the University of Pennsylvania here, and colleagues in the March 27 issue of the New England Journal of Medicine.
This effect had been seen in prior animal studies but never confirmed in humans, the researchers said.
The findings argue against use of controlled mechanical ventilation as a protective strategy to "rest" the lungs and reverse diaphragm fatigue in the ICU, said Gary C. Sieck, Ph.D., and Carlos B. Mantilla, M.D., Ph.D., both of the Mayo Clinic in Rochester, Minn., in an accompanying editorial.
Action Points
Explain to interested patients that diaphragm atrophy may make it more difficult to resume spontaneous breathing after mechanical ventilation.
Caution patients that the negative effects of mechanical ventilation on diaphragm strength may differ according to how much effort the ventilation protocol requires from the lungs.
Explain to interested patients that diaphragm atrophy may make it more difficult to resume spontaneous breathing after mechanical ventilation.
Caution patients that the negative effects of mechanical ventilation on diaphragm strength may differ according to how much effort the ventilation protocol requires from the lungs.
Patients on controlled ventilation during surgical anesthesia or other short-term procedures could also be at risk, they said. "It is likely that alternative ventilatory strategies will be necessary, especially for patients with decreased reserve capacity at baseline."
Their findings may help explain why some patients have so much trouble weaning off ventilation, Dr. Levine said.
However, the majority of patients go on assist-mode ventilation and synchronized intermittent mandatory ventilation with pressure support, which does require some work from the diaphragm, the editorialists noted.
Animal studies suggest these types of ventilation largely eliminate diaphragm atrophy, but the effect for human patients is still unclear, they said.
The researchers compared biopsy specimens from the costal diaphragms of 14 brain-dead organ donors before circulatory arrest and organ harvest with specimens from eight control patients collected during surgery for benign lesions or localized lung cancer.
Both groups had been on full mechanical ventilation with diaphragmatic inactivity before biopsy, but the duration was only two to three hours for control patients compared with 18 to 69 hours for organ donors.
Cases were younger than control subjects (mean 35 versus 57, P=0.008), but the gender ratio and average body-mass index was similar between groups.
Diaphragm tissue showed atrophy for those on longer-duration controlled ventilation. Mean cross-sectional areas of slow-twitch fibers were 57% lower for cases than controls (2,025 versus 4,725 μm2, P=0.001) and 53% lower for fast-twitch fibers (1,871 versus 3,949 μm2, P=0.01). The proportionate number of fibers did not differ.
Drs. Sieck and Mantilla noted that these combined effects would "almost certainly affect the ability of ventilated patients to sustain spontaneous breathing, requiring recruitment of more fatigable fast-twitch fibers," which would exacerbate muscle weakness.
The atrophy seen in organ donor patients was likely not caused by brain death or unmeasured humoral factors, as similar changes were not seen in pectoralis major muscle biopsies from case and control subjects the researchers said.
Specimens of pectoralis major muscle from a subgroup of organ donors and control patients showed no difference in cross-sectional areas of slow-twitch (3,084 versus 3,325 μm2) or fast-twitch fibers (2,933 versus 3,418 μm2).
Histology did not show inflammatory-cell infiltrate in the organ donor specimens, but these samples did show elevated oxidative stress and proteolysis, as would be expected with muscle inactivity, the researchers noted.
A longer duration of mechanical ventilation was associated with 23% lower total glutathione concentrations in diaphragm-biopsy specimens (1.03 versus 1.35 mM, P=0.01), which was "consistent with oxidative stress."
A protease involved in the first step of muscle breakdown, active caspase-3, was 154% elevated in cases compared with controls as well (1.52 versus 0.66 optical-density units, P=0.05).
Enzymes involved in breakdown of muscle proteins were also elevated. Organ donors had three-fold higher atrogin-1 expression (216 versus 72 arbitrary normalized copy units, P=0.002) and 6.9 times more MuRF-1 expression than control patients (885 versus 128 arbitrary normalized copy units, P=0.001).
For these reasons, the authors concluded that "our observations strongly suggest that increased proteolysis accounts for the fiber atrophy noted in the diagpragm-biopsy specimens from case subjects."
To help mitigate weaning problems, the researchers suggested, blocking or attenuating the pathways of proteolysis in the diaphragm might work.
The study was supported by grants from the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs Merit Review Program. The researchers and editorialists reported no conflicts of interest relevant to the study.
Primary source: New England Journal of Medicine
Source reference:
Levine S, et al "Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans" N Engl J Med 2008; 358: 1327-35.
Additional source: New England Journal of Medicine
Source reference:
Sieck GC, Mantilla CB "Effect of mechanical ventilation on the diaphragm" N Engl J Med 2008; 358: 1392-94.