Correspondence
Mechanical Ventilation and Disuse Atrophy of the Diaphragm
N Engl J Med 2008; 359:89-92July 3, 2008
- Article
To the Editor:
In their article, Levine et al. (March 27 issue)1 conclude that atrophy of the human diaphragm occurs with mechanical ventilation; this finding is consistent with our observation of atrophy of the diaphragm in a patient with a high spinal cord injury after 8 months of mechanical ventilation necessitated by the failure of one diaphragmatic pacemaker.2 In this patient, atrophy of the diaphragm was prevented in the hemidiaphragm connected to the functioning pacemaker by stimulating the pacemaker for only 30 minutes per day. Levine et al. speculate as to whether there are functional implications due to atrophy and whether strategies can be used to prevent atrophy. Our study addresses both of these questions. First, we found that atrophy was associated with profound reductions in tidal volume. Second, we found that stimulation of the phrenic nerve of the diaphragm for 30 minutes per day was sufficient to prevent atrophy. From our observations and those of Levine et al., one major question arises: Is the diaphragmatic activation associated with the forms of ventilation commonly used in the intensive care unit sufficient to prevent disuse atrophy?
2 ReferencesDennis McCool, M.D.
Brown University, Providence, RI 02860
f_mccool@brown.edu Najib Ayas, M.D.
University of British Columbia, Vancouver, BC V6T 1Z4, CanadaRobert Brown, M.D.
Massachusetts General Hospital, Boston, MA 021141
Levine S ,Nguyen T ,Taylor N , et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med 2008;358:1327-1335
Full Text | Web of Science | Medline2
Ayas NT ,McCool FD ,Gore R ,Lieberman SL ,Brown R . Prevention of human diaphragm atrophy with short periods of electrical stimulation. Am J Respir Crit Care Med 1999;159:2018-2020
Web of Science | Medline
To the Editor:
Levine and colleagues confirm that in the absence of respiratory effort, mechanical ventilation for as little as 1 day causes profound atrophy of the diaphragm in adult humans, as it does in animals. Two decades ago, Knisely and others1 reported dramatic evidence of ventilation-induced atrophy in infants. They compared autopsy material obtained from 13 infants who died after mechanical ventilation for at least 12 days with that obtained from 26 infants who died after ventilation for 7 or days or less. Infants who were ventilated for a longer time had smaller diaphragm myofibers with histologic features of disuse atrophy, whereas strap and tongue muscles appeared to be normal.2 To control for the nutritional and catabolic effects of illness, they assessed ratios of the cross-sectional areas of myofibers in the diaphragm to those of the strap or tongue muscle; both ratios were much lower among the subjects who were ventilated for a longer time. The rapidity of disuse atrophy reported by Levine and colleagues militates against prolonged total rest of the diaphragm in many adults as well as infants who are at risk for hypercapnic respiratory failure.
2 ReferencesStephen H. Loring, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
sloring@bidmc.harvard. edu 1
Knisely AS ,Leal SM ,Singer DB . Abnormalities of diaphragmatic muscle in neonates with ventilated lungs. J Pediatr 1988;113:1074-1077
CrossRef | Web of Science | Medline2
Schild K ,Neusch C ,Schonhofer B . Ventilator-induced diaphragmatic dysfunction (VIDD). Pneumologie 2008;62:33-39
CrossRef | Medline
To the Editor:
Levine et al. report atrophy of the diaphragm muscle due to disuse in mechanically ventilated patients. Some issues have not been addressed appropriately. Brain death is associated with alteration in the mitochondrial function of skeletal muscle.1 This alteration may induce oxidative stress and subsequent protease activation resulting in myosin loss. Information about cellular energy failure in brain-dead patients may be provided by the ratio of lactate to pyruvate in plasma.1
Atrophy was investigated solely by measuring cross-sectional area. Levine and colleagues propose that a reduction in the cross-sectional area would predict an approximately 55% decrease in transdiaphragmatic pressure. However, a reduction in the cross-sectional area is not necessarily accompanied by reduced force generation.2 Conversely, we found that in patients with chronic obstructive pulmonary disease, the cross-sectional area of the diaphragm was not different from that of controls, but single-fiber force generation was significantly reduced (by approximately 27%), which could be explained by a loss of myosin of approximately 29%.3 Thus, a prediction of reduction in force should not be based on cross-sectional area, but rather on myosin content.3
3 ReferencesLeo M.A. Heunks, M.D., Ph.D.
Richard P.N. Dekhuijzen, M.D., Ph.D.
University Medical Center Nijmegen, 6500 HB Nijmegen, the Netherlands
l.heunks@ic. umcn. nl 1
Sztark F ,Thicoipe M ,Lassie P ,Petitjean ME ,Dabadie P . Mitochondrial energy metabolism in brain-dead organ donors. Ann Transplant 2000;5:41-44
Medline2
Trappe S ,Harber M ,Creer A , et al. Single muscle fiber adaptations with marathon training. J Appl Physiol 2006;101:721-727
CrossRef | Web of Science | Medline3
Ottenheijm CA ,Heunks LM ,Sieck GC , et al. Diaphragm dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172:200-205
CrossRef | Web of Science | Medline
To the Editor:
Levine and colleagues report on the effects of controlled mechanical ventilation on atrophy of the diaphragm. Although they cite other potential contributors to atrophy of the diaphragm (e.g., systemic inflammatory response syndrome and sepsis), they do not mention critical-illness polyneuropathy and myopathy and some of its risk factors, which also may lead to muscle atrophy and dysfunction of the diaphragm in these patients.1 Critical-illness polyneuropathy and myopathy is common, with a prevalence ranging from 30 to 90%, and it may develop quickly after the onset of critical illness.2,3 Glycemic control may be an important strategy to mitigate critical-illness polyneuropathy and myopathy.4 In this study, the blood glucose level was significantly higher in case patients versus controls (164 vs. 92 mg per deciliter, P<0.001), and only 4 of 14 patients received insulin infusions. We posit a potential “two-hit” hypothesis, with an interaction between muscle inactivity and the early development of subclinical critical-illness polyneuropathy and myopathy, contributing to rapid muscle atrophy in critically ill patients. This hypothesis requires investigation in future studies. Increasing awareness of critical-illness polyneuropathy and myopathy and further research on reversible risk factors and potential therapies are needed to ameliorate weakness and diaphragmatic dysfunction in critically ill patients.2,5
5 ReferencesEddy Fan, M.D.
Dale M. Needham, M.D., Ph.D.
Johns Hopkins University, Baltimore, MD 21205
eddy.fan@jhmi. edu 1
Kerbaul F ,Brousse M ,Collart F , et al. Combination of histopathological and electromyographic patterns can help to evaluate functional outcome of critically ill patients with neuromuscular weakness syndromes. Crit Care 2004;8:R358-R366
CrossRef | Web of Science | Medline2
Hough CL ,Needham DM . The role of future longitudinal studies in ICU survivors: understanding determinants and pathophysiology of weakness and neuromuscular dysfunction. Curr Opin Crit Care 2007;13:489-496
CrossRef | Web of Science | Medline3
Khan J ,Harrison TB ,Rich MM ,Moss M . Early development of critical illness myopathy and neuropathy in patients with severe sepsis. Neurology 2006;67:1421-1425
CrossRef | Web of Science | Medline4
Stevens RD ,Dowdy DW ,Michaels RK ,Mendez-Tellez PA ,Pronovost PJ ,Needham DM . Neuromuscular dysfunction acquired in critical illness: a systematic review. Intensive Care Med 2007;33:1876-1891
CrossRef | Web of Science | Medline5
Young GB ,Hammond RR . A stronger approach to weakness in the intensive care unit. Crit Care 2004;8:416-418
CrossRef | Web of Science | Medline
To the Editor:
In the article by Levine and colleagues, controls were patients with good general health and respiratory conditions that made them candidates for surgery. In the population of case subjects, four patients had been involved in motor vehicle accidents, which is a frequent cause of transient diaphragmatic paralysis and may cause long-term diaphragmatic eventration.1 In this case, a reduction in the diaphragmatic thickness is expected, even without intubation.2 Four other patients had a history of drug or alcohol abuse. In these subjects, malnutrition is frequent and muscular impairment may involve the diaphragm.
2 ReferencesFrancesco Leo, M.D., Ph.D.
European Institute of Oncology, 20141 Milan, Italy
francesco.leo@ieo. it Lorenzo Spaggiari, M.D., Ph.D.
University of Milan School of Medicine, 20141 Milan, Italy1
Mouroux J ,Venissac N ,Leo F ,Alifano M ,Guillot F . Surgical treatment of diaphragmatic eventration using video-assisted thoracic surgery: a prospective study. Ann Thorac Surg 2005;79:308-312
CrossRef | Web of Science | Medline2
Gottesman E ,McCool FD . Ultrasound evaluation of the paralyzed diaphragm. Am J Respir Crit Care Med 1997;155:1570-1574
Web of Science | Medline
Author/Editor Response
We agree with McCool and colleagues that the case report by Ayas et al.1 provides definitive evidence that unilateral phrenic-nerve stimulation can prevent atrophy — as assessed by ultrasound — in the ipsilateral hemidiaphragm. Therefore, bilateral phrenic-nerve stimulation may be useful in preventing atrophy of diaphragm fibers in patients with the combination of mechanical ventilation and diaphragmatic inactivity.
We also agree with Loring's comments about the article by Knisely et al.2 Since their infant study subjects were not brain-dead, their observations provide support for our concept that brain death per se was not playing a major role in eliciting the myofiber atrophy observed in the diaphragms of our case subjects.
With regard to the comments by Heunks and Dekhuijzen, because of the lack of clinical and histologic data in the article by Sztark et al.,3 the mitochondrial dysfunction that they observed in the long peroneal muscle of their brain-dead organ-donor subjects may represent early changes associated with disuse in this limb muscle. Second, myosin concentration was not measured in our diaphragm-biopsy specimens. Therefore, in our predictions of the maximum force-generating capacity of the diaphragm, we used measured cross-sectional areas, fiber-type proportions, and assumed normal specific force for the diaphragm-biopsy specimens from both case subjects and controls. If the increased proteolysis observed in the diaphragms of the case subjects was accompanied by a decrease in myosin concentration, as compared with the diaphragms of the controls, the diaphragms of the case subjects would have shown a greater decrease in force-generating capacity than that estimated in our article (i.e., a decrease in transdiaphragmatic pressure of >55%).
We agree with Fan and Needham that our case subjects had hyperglycemia, which is a risk factor for both critical-illness polyneuropathy and myopathy. Therefore, these conditions should be considered as possible causes of atrophy of diaphragm myofibers.4 The absence of necrosis and hypercellularity in the diaphragm-biopsy specimens of our case subjects rules out the myopathy associated with the critical-illness polyneuropathy and myopathy syndrome.5 Since we did not obtain sections of phrenic nerve, we cannot rule out a neural contribution to the atrophy of diaphragm fibers observed in our case subjects.
Regarding the concerns of Leo and Spaggiari, we do not believe that either trauma or malnutrition played a role in eliciting the atrophy of diaphragm fibers in the case subjects because we excluded subjects with thoracoabdominal trauma from our case cohort and because these patients showed no signs of malnutrition; indeed, our data indicate that case and control subjects did not differ with respect to body-mass index.
5 ReferencesSanford Levine, M.D.
Murat T. Budak, M.D., Ph.D.
Joseph B. Shrager, M.D.
University of Pennsylvania, Philadelphia, PA 19104
sdlevine@mail.med. upenn. edu 1
Ayas NT ,McCool FD ,Gore R ,Lieberman SL ,Brown R . Prevention of human diaphragm atrophy with short periods of electrical stimulation. Am J Respir Crit Care Med 1999;159:2018-2020
Web of Science | Medline2
Knisely AS ,Leal SM ,Singer DB . Abnormalities of diaphragmatic muscle in neonates with ventilated lungs. J Pediatr 1988;113:1074-1077
CrossRef | Web of Science | Medline3
Sztark F ,Thicoipe M ,Lassie P ,Petitjean ME ,Dabadie P . Mitochondrial energy metabolism in brain-dead organ donors. Ann Transplant 2000;5:41-44
Medline4
Stevens RD ,Dowdy DW ,Michaels RK ,Mendez-Tellez PA ,Pronovost PJ ,Needham DM . Neuromuscular dysfunction acquired in critical illness: a systematic review. Intensive Care Med 2007;33:1876-1891
CrossRef | Web of Science | Medline5
Kerbaul F ,Brousse M ,Collart F , et al. Combination of histopathological and electromyographic patterns can help to evaluate functional outcome of critically ill patients with neuromuscular weakness syndromes. Crit Care 2004;8:R358-R366
CrossRef | Web of Science | Medline
