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Ventilator-induced Diaphragm Dysfunction

From Mice (Hopefully) to Men

I

N the 60 yr since Danish anes-

thesiologist Bjorn Ibsen initi-ated the widespread use of positivepressure ventilation during theCopenhagen poliomyelitis epi-demic of 1951, the concerns haveshifted beyond saving lives to min-imizing iatrogenic harm. Webb andTierneys seminal 1974 report ofventilator-induced lung injury1 ini-tiated 3 decades of research culmi-nating in the ARDS (acute respira-tory distress syndrome) Network

trial thatconfirmed thesurvivalben-efit of lower versushigher tidal vol-umes.2Although efforts overthelast1020 yr have concentrated onminimizing damage to the lungs(i.e., ventilator-associated lung in-jury), harmto thediaphragm causedby mechanical ventilation (i.e., ven-tilator-induced diaphragm dysfunc-tion [VIDD]) is becoming morewidely appreciated. The study ofVIDD receives an important boost

with the report by Mrozeket al. inthe current issue of ANESTHESIOLOGYof a mouse model that enables reliable exploration of the mech-anisms involved.3

The association between mechanical ventilation and re-spiratory muscle weakness was first reported in baboons byAnzueto et al. in 1997 (although reported in abstract a de-cade before)4; several studies have since replicated these find-ings in multiple species. All the models demonstrate thatcontrolled mechanical ventilation results in significant loss ofrespiratory (but not peripheral skeletal) muscle strength andendurance after hours or 23 days. VIDD is likely an impor-tant clinical problem. Diaphragm biopsy specimens frombrain dead patients reveal characteristic histologic patterns; in-deed, rapidly progressive inspiratory muscle weakness has beenreported within 12 days of mechanical ventilation in intensivecare unit patients. Inspiratory muscle weakness is highly preva-

lent among mechanically ventilated

patients and is associated with a lon-ger duration of ventilation. Becauserespiratory muscle strength is a keydeterminant of weaning success (orfailure), VIDD probably prolongsmechanical ventilation and increasesits associated complications.5

The report by Mrozek et al.provides additional evidence thatsuppression of respiratory muscleactivity during controlled me-chanical ventilation leads rapidly

to diaphragmatic contractile dys-function.3 In the study, mice weresubjected to controlled mechani-cal ventilation, continuous posi-tive airway pressure, or controlconditions. The results are reassur-ingly similar to models reportedpreviously: controlled mechanicalventilated mice demonstrated40% lower maximal diaphrag-matic force versuscontrol, with noimpact from continuous positive

airway pressure; loss of diaphragmendurance paralleled these find-ings, and there were no effects on peripheral skeletal muscle.

Ventilator-induced diaphragm dysfunction is character-ized by atrophy of type 1 and 2 muscle fibers, as well as bymyofibrillar disarray, oxidative injury, and autophagy. Mo-lecular explanations include altered gene expression, withstress-response and proteolytic genes up-regulated and struc-tural andmetabolic genes down-regulated.6 Proteolytic systems,such as calcium-dependent proteases (calpain) and caspase,modulate disassembly of the myofilament framework; cleavingthese regulatory proteins renders muscle susceptible to ubiquiti-nation and destruction by the ubiquitin-proteasome system.Autophagy, a self-degradative proteolytic pathway has beendemonstrated in the diaphragms of brain dead organ donorsafter 1869 h of mechanical ventilation. The imbalance be-tween proteolysis and protein synthesis leads to atrophy; myo-fibrillar disarray produces loss of contractile force that is out of

Photo: J. P. Rathmell.

Accepted for publication March 29, 2012. Supported by a NewInvestigator Award from the Canadian Institutes of Health Research,Ottawa, Ontario, Canada (to Dr. Ferguson), and the Dr. GeoffreyBarker Research Chair in Critical Care Medicine, The Hospital for SickChildren, Toronto, Ontario, Canada (to Dr. Kavanagh). The authors arenot supported by, nor maintain any financial interest in, any commer-cial activity that may be associated with the topic of this article.

Copyright 2012, the American Society of Anesthesiologists, Inc. LippincottWilliams & Wilkins. Anesthesiology 2012; 117:4634

A pressing example await-

ing explanation is how mus-

cle inactivity triggers the cel-

lular changes associated with

[ventilator-induced diaphrag-

matic dysfunction].

This Editorial View accompanies the following article: Mrozek

S, Jung B, Petrof BJ, Pauly M, Roberge S, Lacampagne A,

Cassan C, Thireau J, Molinari N, Futier E, Scheuermann V,

Constantin J-M, Matecki S, Jaber S: Rapid onset of specific

diaphragm weakness in a healthy murine model of ventilator-

induced diaphragmatic dysfunction. ANESTHESIOLOGY 2012;

117:5607.

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proportion to the degree of atrophy. Although thepreciseeventsthat initiatethe cascade of injurywithin thediaphragm myocyteremain unidentified, oxidative stress resulting in injury to keycontractile elements (e.g., myosin and actin) appears to be a keyupstream trigger. That antioxidants such as N-acetylcysteine

significantly attenuate muscle injury in vitro suggests that oxi-dativeinjury plays a role; indeed, reactiveoxygen species seem tooriginate fromthemyocytemitochondria, anda mitochondrial-specific antioxidant may attenuate diaphragmatic injury. Manysuch mechanisms in the pathogenesis of VIDD need to be un-derstood to formulate strategies for prophylaxis or therapy.

In the murine model of VIDD described by Mrozeket al.there was no histologic evidence of muscle atrophy despite adramatic reduction in contractile function. Such uncouplingof muscle weakness from atrophy has been reported previ-ously in VIDD. This (early) weakness likely results from theinitial myofibril disassembly that is required before muscle pro-tein can be ubiquitinated and degraded.7 Consistent with pre-vious reports, the caspase-3 proteolytic system was found to beup-regulated in the controlled mechanically ventilated mice.Thus, this model seems to reflect well other models of VIDD.

How will this model facilitate increasing our understand-ing of VIDD? The beauty of a murine model is that a widevariety of molecular techniques and assays as well as geneti-cally modified animals are available, allowing dissection ofpotential molecular mechanisms. A pressing example await-ing explanation is how muscle inactivity triggers the cellularchanges associated with VIDD. A postulated candidate istitin, a long filamentous sarcomeric protein that functions asa mechanosensor by altering its signaling kinase domain ac-tivity in response to mechanical stretch8; selective expressionof this gene or mutation of its kinase domain would allowexploration of its role in VIDD.

The study also supports the interesting hypothesis thatthe risk of VIDD is proportional to the rate of protein turn-over. The authors predicted that the mice would developVIDD after only 6 h of mechanical ventilation by extrapo-lating protein turnover rates from previous VIDD animalmodels (piglet, rabbit, rat) to mice. They reported contractiledysfunction (but no atrophy) at the 6-h point, suggestingthat the muscle injury pathways are not simply related to alocal imbalance in cellular protein synthesis and catabolism,at least in the initial stages of VIDD. Nevertheless, organismswith higher protein turnover rates may develop the lesionmore quickly; this hypothesis merits further confirmation.Of course, some critically ill patients have extremely highrates of protein catabolism, and these patients may be athigher risk of VIDD; this could help to guide the selection ofhigh-risk patients for study.

One universally reported feature of VIDD is that it isinduced by suppression of diaphragm activity during me-chanical ventilation, so-called disuse atrophy. The report byMrozek et al. supports the theory of disuse atrophy; micesubjected to anesthesia and positive airway pressure that

maintained diaphragm activity (continuous positive airwaypressure mice) had no loss of contractile function. Becausemaintenance of some respiratory muscle activity attenuatesthe severity of VIDD, it has been suggested that spontaneousmodes of ventilation be used when possible.5 Multiple fac-

tors other than mechanical ventilation affect diaphragmfunction (e.g., sepsis, corticosteroids, neuromuscular block-ade, antibiotics, nutritional deficiency)9 and may compoundthe VIDD lesion or limit the benefit of maintaining respira-tory muscle activity; here the murine model might provideinsights into which conditions contribute most.

Whether attempts at preventing or treating VIDD ulti-mately will help critically ill patients remains to be seen. Butit is likely that insights enabled by careful development of avalid murine experimental model will help guide our pursuitof better care for patients receiving mechanical ventilation.Bjorn Ibsen would be pleased.

Ewan C. Goligher, M.D., F.R.C.P.(C),* Niall D. Ferguson,M.D., M.Sc., F.R.C.P.(C), Brian P. Kavanagh, M.B.,F.R.C.P.(C) *Interdepartmental Division of Critical CareMedicine, University of Toronto, Toronto, Ontario, Canada.Department of Medicine, Division of Respirology, Univer-sity Health Network and Mount Sinai Hospital, and theInterdepartmental Division of Critical Care Medicine, Uni-

versity of Toronto. Department of Critical Care Medicine,Hospital for Sick Children and the Department of Anesthe-sia, University of Toronto. brian.kavanagh@utoronto.ca

References1. Webb HH, Tierney DF: Experimental pulmonary edema due to

intermittent positive pressure ventilation with high inflation

pressures. Protection by positive end-expiratory pressure. AmRev Respir Dis 1974; 110:55665

2. Ventilation with lower tidal volumes as compared with tradi-tional tidal volumes for acute lung injury and the acute respi-ratory distress syndrome. The Acute Respiratory Distress Syn-drome Network. N Engl J Med 2000; 342:13018

3. Mrozek S, Jung B, Petrof BJ, Pauly M, Roberge S, LacampagneA, Cassan C, Thireau J, Molin ari N, Futier E, Scheuer mann V,Constantin J-M, Matecki S, Jaber S: Rapid onset of specificdiaphragm weakness in a healthy murine model of ventilator-induced diaphragmatic dysfunction. ANESTHESIOLOGY 2012;117:5607

4. Anzueto A, Peters JI, Tobin MJ, de los Santos R, Seidenfeld JJ,Moore G, Cox WJ, Coalson JJ: Effects of prolonged controlledmechanical ventilation on diaphragmatic function in healthyadult baboons. Crit Care Med 1997; 25:118790

5. Tobin MJ, Laghi F, Jubran A: Narrative review: Ventilator-induced respiratory muscle weakness. Ann Intern Med 2010;153:2405

6. Powers SK, Kavazis AN, Levine S: Prolonged mechanical ven-tilation alters diaphragmatic structure and function. Crit CareMed 2009; 37:S34753

7. Sassoon CS, Caiozzo VJ, Manka A, Sieck GC: Altered dia-phragm contractile properties with controlled mechanical

ventilation. J Appl Physiol 2002; 92:258595

8. Ottenheijm CA, van Hees HW, Heunks LM, Granzier H: Titin-based mechanosensing and signaling: Role in diaphragm atro-phy during unloading? Am J Physiol Lung Cell Mol Physiol2011; 300:L161 6

9. Laghi F, Tobin MJ: Disorders of the respiratory muscles. Am JRespir Crit Care Med 2003; 168:1048

Editorial Views

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