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1. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Globalstrategy for the diagnosis, management, and prevention of chronicobstructive pulmonary disease. NHLBI/WHO Global Initiative forChronic Obstructive Lung Disease (GOLD) workshop summary. AmJ Respir Crit Care Med 2001;163:1256–1276.

2. Celli BR, MacNee W; American Thoracic Society/European RespiratorySociety Task Force. Standards for the diagnosis and treatment ofpatients with COPD: a summary of the ATS/ERS position paper. EurRespir J 2004;23:932–946.

3. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L,Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al. The natureof small-airway obstruction in chronic obstructive pulmonary disease.N Engl J Med 2004;350:2645–2653.

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6. O’Shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK. Inflammationin bronchial biopsies of subjects with chronic bronchitis: inverse rela-tionship of CD8� T lymphocytes with FEV1. Am J Respir Crit CareMed 1997;155:852–857.

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Critical Illness NeuromyopathyFrom Risk Factors to Prevention

Critical illness neuromyopathy (CINM) can significantly delayweaning from mechanical ventilation and impair physical recov-ery (1, 2). CINM is often unrecognized and, depending on thepopulation studied, may affect between 25 and 75% of longer-stay intensive care unit (ICU) patients (3, 4). In this issue ofthe Journal (pp. 480–489), Hermans and colleagues report thatintensive insulin therapy prevented CINM in a subset of patientsenrolled in their medical ICU trial (5). That intensive insulintherapy may prevent CINM is exciting, but the report highlightsthe difficulty of diagnosing CINM in a research context andraises important issues of clinical trial methodology.

Hermans and colleagues diagnosed CINM solely on the pres-ence of spontaneous electrical activity in muscle on electro-neuromyography. They did not identify altered muscle mem-brane excitability, which is increasingly recognized as a cause ofmuscle weakness in critically ill patients (6). Had they done so,they may have reported a different result. In addition, they onlyreport outcomes in patients treated in the ICU for 7 days ormore and do not present an intention-to-treat analysis. The inci-dence of CINM in patients who received the study and controltreatments for up to 7 days goes unreported and this significantlyreduces the certainty of the findings (7). Furthermore, becausethe subgroup studied could not be identified at the start oftreatment, clinicians do not know to which of their patients thefindings apply (8).

Although selecting appropriate subgroups and reportingintention-to-treat analyses are essential components of clinicaltrial design, studying CINM presents particular difficulties. CINMcan be detected by clinical examination or electroneuromyogra-

Geerlings M, Hylkema MN, van den Berg A, Timens W, Kerstjens HA.Cigarette smoke–induced emphysema: a role for the B cell? Am JRespir Crit Care Med 2006;173:751–758.

9. Zhao MQ, Amir MK, Rice WR, Enelow RI. Type II pneumocyte-CD8�T-cell interactions: relationship between target cell cytotoxicity andactivation. Am J Respir Cell Mol Biol 2001;25:362–369.

10. Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med 2000;343:269–280.

11. Vernooy JHJ, Moller GM, van Suylen RJ, van Spijk MP, Cloots RHE,Hoet PH, Pennings HJ, Wouters EFM. Increased granzyme A expres-sion in type II pneumocytes of patients with severe chronic obstructivepulmonary disease. Am J Respir Crit Care Med 2007;175:464–472.

12. Chrysofakis G, Tzanakis N, Kyriakoy D, Tsoumakidou M, Tsiligianni I,Klimathianaki M, Siafakas NM. Perforin expression and cytotoxicactivity of sputum CD8� lymphocytes in patients with COPD. Chest2004;125:71–76.

13. Siafakas NM, Tzortzaki EG, Sourvinos G, Bouros D, Tzanakis N, KafatosA, Spandidos D. Microsatellite DNA instability in COPD. Chest1999;116:47–51.

14. Barnes PJ, Cosio MG. Characterization of T lymphocytes in chronicobstructive pulmonary disease. PLoS Med 2004;1:e20.

15. Vlachaki E, Tzortzaki EG, Koutsopoulos A, Dambaki K, Moniakis A,Drositis I, Tassopoulos D, Maltezakis G, Siafakas NM. Surfactant-A(SP-A) expression in COPD: preliminary results [abstract]. Proc AmThorac Soc 2006;3:A624.

16. Retamales I, Elliott WM, Meshi B, Coxson HO, Pare PD, Sciurba FC,Rogers M, Hayashi S, Hogg JC. Amplification of inflammation inemphysema and its association with latent adenoviral infection. AmJ Respir Crit Care Med 2001;164:469–473.

DOI: 10.1164/rccm.200612-1800ED

phy but usually not until patients have been treated with mechan-ical ventilation for several days. Clinical examination is focusedon detecting muscle weakness, which is a uniform manifestationof CINM, regardless of whether the axon, muscle contractileproteins, or muscle membrane excitability are involved alone orin combination (4, 9). As the patient must be cooperative, dailyassessment from the beginning of mechanical ventilation is rarelypossible. Electroneuromyography is the alternative diagnosticapproach. Electroneuromyography allows earlier diagnosis butits use requires considerable resources and can cause discomfort.It is neither practical nor ethical to conduct repeat testing on adaily basis for a clinical trial.

To date, only patients who remain in an ICU for 5 to 7 dayshave been assessed for CINM, and because many patients willhave been discharged or will have died by this time, an intention-to-treat analysis of a clinical trial may appear impractical. How-ever, the methodologic difficulties can be overcome by asking theright questions in the right population. We should ask whether atreatment reduces the incidence of CINM and does that resultin better outcomes for patients. The study population should bepatients likely to receive at least 5 days of mechanical ventilationand in whom the clinical diagnosis of CINM is feasible. This willlikely mean excluding patients with primary neurologic diseasesor brain injury. To determine if CINM is prevented, the outcomemeasure could be the number of patients discharged alive fromICU who were never diagnosed with CINM. To determine ifpatients’ outcomes are improved, time to recovery from CINMand long-term functional recovery of survivors should be re-ported.

Editorials 425

In our opinion, the diagnosis of CINM should be made byclinical examination conducted by a blinded observer using arecognized scoring system. For example, the Medical ResearchCouncil scale is a simple and robust score that quantifies muscleweakness (10). It has satisfactory interobserver reproducibility inventilated patients with Guillain-Barre syndrome (10), and inpatients with acute stroke (11). Although not yet validated in thegeneral ICU population, it appears to be an ideal tool for thediagnosis of CINM. The timing of clinical testing may be difficultbecause patients must be sufficiently recovered to cooperate;the earliest this is likely is at the start of weaning from mechanicalventilation. Serial testing should be conducted from the start ofweaning until the time of discharge from the ICU.

Having recognized the methodologic difficulties inherent insuch research, what are the implications of Hermans and col-leagues’ report for clinicians? Enthusiasm for intensive insulintherapy arose from the reduction in mortality in Van denBerghe’s first trial (12). This enthusiasm has been temperedsomewhat by the findings of the second trial (13), and becausethe Efficacy of Volume Substitution and Insulin Therapy inSevere Sepsis (VISEP) and Glucontrol studies have bothstopped early due to lack of efficacy and concerns about thesafety of intensive insulin therapy (14–16). A fourth, multicentertrial in Australasia and North America (the NICE-SUGAR[Normoglycaemia in Intensive Care Evaluation and SurvivalUsing Glucose Algorithm Regulation] study) plans to recruit6,100 patients and report its findings in 2008 (17). If NICE-SUGAR shows a clear mortality benefit, then intensive insulintherapy will likely become a standard of care. If not, then effectson secondary outcomes, such as the incidence of CINM andduration of mechanical ventilation, will assume considerable im-portance. Data from the two European trials may confirm orrefute Hermans and colleagues’ findings as the incidence ofCINM was assessed in the VISEP trial using electrophysiologyand in Glucontrol using clinical examination (F. Brunkhorst andJ.-C. Preiser, personal communications).

If intensive insulin therapy does prevent CINM, then thebenefit to patients should be a reduction in the duration ofmechanical ventilation and more rapid recovery from criticalillness. From the patient’s perspective, these outcomes are valu-able regardless of why they occur. Van den Berghe and col-leagues have reported that intensive insulin therapy significantlyreduced the time to weaning in their medical ICU trial (13), butnot the median duration of ventilation in their surgical ICU trial(12). The VISEP, Glucontrol, and NICE-SUGAR trials willreport the impact of intensive insulin therapy on duration ofmechanical ventilation in a large population of patients treatedin different ICUs. The collective findings should be broadlyapplicable in ICUs around the world.

Hermans and colleagues’ report that a metabolic therapy mayprevent CINM is exciting. From the clinicians’ viewpoint, thereport presents those who have adopted intensive insulin therapywith no reason to change their practice. Others may be concernedabout the methodologic issues and that intensive insulin therapyhas not yet been proven beneficial in multicenter trials. Thosewho remain skeptical may prefer to wait for the full reports ofthe VISEP and Glucontrol trials and possibly for the results ofthe NICE-SUGAR study.

It is hoped that other strategies to prevent CINM will bedeveloped and tested in randomized controlled trials. The diffi-culties of conducting such research should not be underestimatedand Hermans and colleagues are to be congratulated on theirwork. The results of future trials will be regarded with the great-est certainty if the outcomes most relevant to patients are re-ported in the intention-to-treat population.

Conflict of Interest Statement : Neither author has a financial relationship with acommercial entity that has an interest in the subject of this manuscript.

Bernard De Jonghe, M.D.Centre Hospitalier de Poissy-Saint-GermainPoissy, FranceSimon Finfer, F.R.C.P., F.J.F.I.C.M.Royal North Shore HospitalandNorthern Clinical SchoolUniversity of SydneySydney, Australia

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5. Hermans G, Wilmer A, Meersseman W, Milants I, Wouters PJ, BobbaersH, Bruyninckx F, Van den Berghe G. Impact of intensive insulin therapyon neuromuscular complications and ventilator dependency in the medi-cal intensive care unit. Am J Respir Crit Care Med 2007;175:480–489.

6. Bednarik J, Lukas Z, Vondracek P. Critical illness polyneuromyopathy:the electrophysiological components of a complex entity. IntensiveCare Med 2003;29:1505–1514.

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10. Kleyweg RP, van der Meche FG, Schmitz PI. Interobserver agreementin the assessment of muscle strength and functional abilities inGuillain-Barre syndrome. Muscle Nerve 1991;14:1103–1109.

11. Gregson JM, Leathley MJ, Moore AP, Smith TL, Sharma AK, WatkinsCL. Reliability of measurements of muscle tone and muscle power instroke patients. Age Ageing 2000;29:223–228.

12. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F,Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Inten-sive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359–1367.

13. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, WoutersPJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensiveinsulin therapy in the medical ICU. N Engl J Med 2006;354:449–461.

14. Brunkhorst FM, Kuhnt E, Engel C, Meier-Hellmann A, Ragaller M,Quintel M, Weiler N, Grundling M, Oppert M, Deufel T, et al. Inten-sive insulin therapy in patient with severe sepsis and septic shock isassociated with an increased rate of hypoglycemia: results from arandomized multicenter study (VISEP). Infection 2005;33(Suppl.):19–20.

15. Glucontrol Study. Comparing the effects of two glucose control regimensby insulin in intensive care unit patients [NIH clinical trials website].Available at: http://clinicaltrials.gov/ct/show/NCT00107601?order�1(last updated, July 3, 2006; accessed December 5, 2006).

16. Malhotra A. Intensive insulin in intensive care. N Engl J Med 2006;354:516–518.

17. Normoglycaemia in Intensive Care Evaluation and Survival UsingGlucose Algorithm Regulation (NICE-SUGAR Study) [NIH clinicaltrials website]. Available at: http://www.clinicaltrials.gov/ct/show/NCT00220987?order�1 (last updated, September 14, 2005; accessedDecember 5, 2006).

DOI: 10.1164/rccm.200612-1762ED