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Critical Illness Neuromyopathy and Muscle Weakness in Patients in the Intensive Care Unit

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243 AACN Advanced Critical Care Volume 20, Number 3, pp.243–253 © 2009, AACN Critical Illness Neuromyopathy and Muscle Weakness in Patients in the Intensive Care Unit Eddy Fan, MD Jennifer M. Zanni, PT, MSPT Cheryl R. Dennison, RN, PhD, ANP Scott J. Lepre, MD Dale M. Needham, MD, PhD Neuromuscular complications of critical ill- ness are common and can be severe and per- sistent in some patients. Neuromyopathy from critical illness and disuse atrophy from prolonged immobility con
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  243 AACN Advanced Critical CareVolume 20, Number 3, pp.243–253© 2009, AACN Critical Illness Neuromyopathy andMuscle Weakness in Patients in theIntensive Care Unit Eddy Fan, MDJennifer M. Zanni, PT, MSPTCheryl R. Dennison, RN, PhD, ANPScott J. Lepre, MDDale M. Needham, MD, PhD Neuromuscular complications of critical ill-ness are common and can be severe and per-sistent in some patients. Neuromyopathyfrom critical illness and disuse atrophy fromprolonged immobility contribute to muscleweakness acquired while in the intensive careunit. Although various risk factors (eg, sever-ity of illness, corticosteroids, neuromuscularblocking agents) have been implicated incritical illness neuromyopathy (CINM), theevidence supporting these associations isinconsistent. Hyperglycemia may be animportant risk factor for CINM, with tightglycemic control through intensive insulintherapy reducing the incidence of CINM.Early mobility in the intensive care unit mayminimize disuse atrophy and possibly CINM,through exercise training and its anti-inflammatory effects. Although emergingdata have demonstrated the safety, feasi-bility, and benefit of early mobility in criticallyill patients, randomized controlled trials areneeded to thoroughly evaluate its potentialbenefits on patients’ muscle strength, physi-cal function, and quality of life. Future studiesare needed to elucidate the multiple mecha-nisms by which immobility, CINM, and otheraspects of critical illness lead to muscle lossand neuromuscular dysfunction. Keywords: bed rest, critical illness, earlyambulation, intensive care units, muscleweakness, neuromuscular diseases ABSTRACT T he decreasing mortality from critical ill-ness over recent decades has led to anincreasing number of intensive care unit (ICU)survivors. 1–4 As a result, there has been a shiftin focus from short-term mortality to longer-term morbidities within the field of criticalcare. Neuromuscular complications, leading tomuscle weakness and impaired physical func-tion, are common in survivors of critical ill-ness, with a prevalence 5 ranging from 9% to87%. Furthermore, these complications arefrequently severe and persistent, contributingto functional decline and significant decre-ments in health-related quality of life. 6–13 Eddy Fan is Instructor of Medicine, Division of Pulmonary &Critical Care Medicine, School of Medicine, Johns HopkinsUniversity, Baltimore, Maryland.Jennifer M. Zanni is Physical Therapist, Department of Physical Medicine and Rehabilitation, School of Medicine,Johns Hopkins University, Baltimore, Maryland.Cheryl R. Dennison is Associate Professor, Department of Health Systems and Outcomes, School of Nursing, JohnsHopkins University, Baltimore, MarylandScott J. Lepre is Clinical Associate, Department of PhysicalMedicine and Rehabilitation, School of Medicine, JohnsHopkins University, Baltimore, Maryland.Dale M. Needham is Assistant Professor of Medicine,Division of Pulmonary & Critical Care Medicine, School of Medicine, Johns Hopkins University, 1830 E Monument St,5th Floor, Baltimore, MD 21205 (dale.needham@jhmi.edu). NCI200050_243–253 7/6/09 9:55 PM Page 243  FAN ET AL AACN AdvancedCriticalCare 244 Reasons for muscle weakness followingcritical illness are multifactorial, including pre-morbid weakness associated with chronic dis-eases. Recently, there has been growingrecognition that both critical illness and itsassociated treatments are toxic to muscles andnerves, leading to pathologic changes termedcritical illness polyneuropathy (CIP) and criti-cal illness myopathy (CIM). 14–16 This reviewwill focus on the development, detection, pre-vention, and treatment of CIP/CIM and itsrole in the development of weakness in thecritically ill. Etiology and Pathophysiology of Weakness in ICU Patients Bed Rest, Immobilization, and Disuse Muscle Atrophy  Prolonged bed rest and immobilization is com-mon in many ICUs and may contribute to thedevelopment of ICU-acquired weakness. 17,18 Ameta-analysis of 39 randomized trials, exam-ining the effects of bed rest on 15 differentmedical conditions and procedures, demon-strated that bed rest was not beneficial andmay be associated with harm. 19 Prolonged bed rest leads to decreasedmuscle protein synthesis, increased musclecatabolism, and decreased muscle mass,especially in the lower extremities. 20,21 Exper-iments in healthy volunteers reveal that muscle atrophy begins within hours of immobility, 22 resulting in a 4% to 5% loss of muscle strength for each week of bed rest. 23 Immobility results in the activation of spe-cific biochemical pathways that lead toenhanced proteolysis and decreased proteinsynthesis, resulting in structural and meta-bolic changes in muscle. 24–28 These changesare manifested in a net loss in muscle mass,cross-sectional muscle area, and contractilestrength. Moreover, there is a general shiftfrom slow twitch (type I) to fast twitch (type II)muscle fibers, leading to reduced muscleendurance due to fewer fatigue-resistant(type I) fibers. 29–31 Consequently, disuse atro-phy results in deleterious effects on musclestrength, with 1% to 1.5% of quadricepsstrength lost for each day of bed rest inhealthy individuals. 32,33 In addition, the inter-action of bed rest and critical illness appearsto result in more significant muscle loss thandoes bed rest alone. 34–36 Furthermore, short-term immobility may impair microvascularfunction and induce insulin resistance, bothof which may further potentiate injuries tomuscle and nerves in the critically ill. 37 In addition to its direct effects on muscle,immobility can lead to a proinflammatory statevia increased proinflammatory cytokines. 38,39 This cytokine shift may potentiate the systemicinflammatory milieu commonly observed dur-ing critical illness, leadingto further muscledamage and loss. 40 The proinflammatory stateassociated with bed rest may also causeincreased production of reactive oxygenspecies (ROS), with a concomitant decrease inantioxidative defenses. 41,42 Reactive oxygenspecies play a role in oxidization of myofila-ments, resulting in contractile dysfunctionand atrophy. 43,44 This concomitant increase inROS and imbalance in the cytokine profilecan further disrupt the balance between mus-cle synthesis and proteolysis, with a net lossof muscle protein and subsequent muscleweakness.Finally, bed rest may produce indirect con-sequences that lead to further intolerance of physical activity. 45 Immobility may lead toincreased postural hypotension and tachycar-dia due to alterations in baroreceptor func-tion. 46,47 Furthermore, prolonged physicalinactivity can result in generalized pain andchanges in mood, which may limit physicalfunction. 15 Even in healthy adults, the effectsof prolonged immobilization and disuse atro-phy alone are often persistent and requireextensive physical reconditioning to allow areturn to their baseline level of functioning. 46,47 Critical Illness Polyneuropathy and Critical Illness Myopathy  Critical illness polyneuropathy, first describedin 1984, 48 is a diffuse and symmetric sensori-motor axonal neuropathy. Electrophysiologi-cal changes, detected with nerve conductionstudies (NCS) and electromyography (EMG),can occur within 24 hours after the onset of critical illness, with histological changes evi-dent shortly thereafter. 49 The development of axonal injury in CIP is likely multifactorial, 16 but a number of mechanistic hypotheses havebeen posited including (1) microcirculatorydysfunction in peripheral nerves due to sepsisand/or hyperglycemia, leading to impairedoxygen and nutrient delivery 50–52 ; (2) cytokine-induced changes in microvascular permeabi-lity, leading to increased endoneural edema withresultant hypoxemia and energy depletion 51 ;and(3) increased uptake of glucose, leading to NCI200050_243–253 7/6/09 9:55 PM Page 244  VOLUME 20 ã NUMBER 3 ã JULY–SEPTEMBER 2009 CINM AND WEAKNESS IN ICU 245 enhanced ROS generation contributing tomitochondrial dysfunction and neuronalbioenergetic failure. 52,53 Furthermore, cytokinesmay exert direct toxic effects on peripheralnerves, and there may be a role of a neurotoxicfactor in the pathogenesis of CIP. 54 The ulti-mate consequence of these cellular and ultra-structural disturbances in the peripheral nerveis the primary axonal degeneration seen inpatients with CIP.Critical illness myopathy represents a spec-trum of muscle pathology acquired duringcritical illness, involving metabolic, inflamma-tory, and bioenergetic derangements in musclesimilar to those seen in CIP. 16 Decreasedoxygen and nutrient delivery to muscles,upregulation of protein catabolism by proin-flammatory cytokines, and decreased expres-sion of myofibrillar repair genes all contributeto the muscle loss seen in patients withCIM. 15,16 An imbalance in anabolic and cata-bolic hormones may also contribute tomyofilament loss and enhanced muscle apop-tosis in CIM. 55 Functional inactivation of theremaining muscle may occur because of mem-brane inexcitability from acquired ion-channel dysfunction. 56–58 Further functionalimpairments may result from dysfunctionalexcitation-contraction coupling due toimpaired calcium release within musclefibers. 59 Functional denervation of muscle fromconcomitant CIP may provide a linkbetween CIP and CIM. 16 Experimental mod-els of CIP/CIM suggest that denervated mus-cle may be more susceptible to additionalinsults (eg, corticosteroid-induced myopa-thy). 60 Furthermore, the effects of CIP andCIM appear to be enhanced by immobility. 61 Critical illness polyneuropathy and criticalillness myopathy share many pathologicalmechanisms, often coexist, and may repre-sent a form of neuromuscular organ dys-function from systemic critical illness. 5,16 Therefore, CIP and CIM are commonlyreferred to collectively as critical illness neu-romyopathy (CINM).Although immobilization and the effects of critical illness traditionally have been consid-ered to predominantly affect peripheral mus-cles’ groups, recent preclinical and clinicalstudies have suggested diaphragmatic involve-ment, including reduced muscle force andincreased muscle atrophy. 62–64 A preliminarystudy in humans suggests that even short-termdiaphragmatic inactivity and controlledmechanical ventilation (with effective func-tional denervation) can result in markeddiaphragmatic atrophy. 65 We hypothesize thatthis “two-hit” combination of immobilizationand the early development of subclinicalCINM may contribute to the rapid develop-ment of muscle atrophy. 66 Risk Factors for CINM Although many studies have investigated riskfactors for CINM, most have been limited bysmall sample size, retrospective design, andsingle-center experiences. 5,15 Furthermore, lackof comparable patient populations and stan-dard definitions for CINM makes compar-isons across studies difficult. 5 Thus, althoughthere are a number of commonly cited risk fac-tors for CINM, many lack support from rigor-ous clinical investigations. Patient Demographics and Severity of Illness  Data conflict regarding the associationbetween patient age, sex, and severity of ill-ness with CINM. One multicenter, prospec-tive study (n  95) demonstrated that femalesex was significantly associated (odds ratio[OR] 4.7; 95% confidence interval [CI]1.2–18.3) with muscle weakness as deter-mined by clinical examination, but neitherage nor severity of illness (measured by theadmission Simplified Acute Physiology Score[SAPS]) was associated with the developmentof weakness. 6 However, in this study, multior-gan failure was significantly associated withweakness (OR 1.3; 95% CI 1.1–1.5 for eachadditional day of  2 organ failure). Twoother studies have also demonstrated an inde-pendent association between severity of ill-ness and the subsequent development of weakness. 67,68 A large, prospective secondary analysis(n  420) of a randomized controlled trial of intensive insulin therapy for tight glycemiccontrol in the ICU found that older age wasnegatively associated (OR 0.98; 95% CI0.96–0.99 per year) with weakness as definedby electrophysiological testing but that sexand severity of illness (admission Acute Phys-iology and Chronic Health Evaluation[APACHE] II and maximal daily SequentialOrgan Failure Assessment [SOFA] scores)were not associated with the development of weakness. 69 NCI200050_243–253 7/6/09 9:55 PM Page 245  FAN ET AL AACN AdvancedCriticalCare 246 Hyperglycemia  A recent systematic review found that hyper-glycemia is the most consistently identifiedrisk factor for CINM. 5 Two large randomizedcontrolled trials of intensive insulin therapyfor tight glycemic control in the ICU, 70,71 andassociated subanalyses, 52,69 demonstrated asubstantial decrease in the incidence of CINMin patients randomized to intensive insulintherapy. However, the overall safety and effi-cacy of intensive insulin therapy and tightglycemic control in a heterogeneous popula-tion of critically ill patients remains controver-sial. 72,73 Results from the recently completedNICE-SUGAR trial demonstrated increasedmortality with intensive insulin therapy (OR1.14; 95% CI 1.02–1.28). 74 Sepsis and Systemic Inflammation  Given the potential mechanistic relationshipbetween systemic inflammation (ie, the sys-temic inflammatory response syndrome[SIRS]), with or without concomitant infection(ie, sepsis), and the development of CINM,several studies have examined this issue. 67,68,75 Two prospective studies reported a significantassociation of CINM with the presence of SIRS 68 and the duration of SIRS (OR 1.05;95% CI 1.01–1.15 for each day in the firstweek). 67 However, another prospective studydemonstrated no association between the pres-ence of sepsis and CINM. 75 Corticosteroids  Substantial controversy exists regarding therole of systemic corticosteroids in the develop-ment of CINM. A prospective study reportedthat exposure to corticosteroids was the singlelargest risk factor for the development of weakness (OR 14.9; 95% CI 3.2–69.8). 6 How-ever, this study revealed no relationshipbetween the dose or duration of corticosteroidtherapy and the development of weakness. Anumber of other clinical studies, including asystematic review, have failed to demonstrate aconsistent association between corticosteroidsand CINM. 5,52,67,68,75–78 Conversely, a recentstudy demonstrated decreased CINM inpatients randomized to intensive insulin ther-apy who also received corticosteroids in theICU (OR 0.91; 95% CI 0.86–0.97). 69 Theinvestigators suggested that the deleteriouseffects of corticosteroids on the neuromuscu-lar system may be mediated through hyper-glycemia, such that when blood glucose isstrictly controlled, the anti-inflammatoryeffects of corticosteroids may be protectiveagainst CINM. Neuromuscular Blocking Agents  Despite early reports of persistent weaknessfollowing prolonged administration of neuro-muscular blockade, 4 prospective trials did notfind a significant association between their useand the development of CINM. 5,52,67,68 How-ever, 2 other studies did find a significant asso-ciation, possibly due to larger doses and longerduration of neuromuscular blockade use. 69,77 Clinical Manifestation and Diagnosis of CINM Physical Examination  Critical illness neuromyopathy is often diffi-cult to diagnose in critically ill patients duringthe acute phase of their illness because of thefrequent use of deep sedation. 79 As a result,CINM is usually recognized in 2 distinct con-texts: (1) prolonged or failed weaning frommechanical ventilation, despite otherwiseglobal improvement in other organ systems; or(2) profound weakness or quadriplegia in anawake patient recovering from critical illness. 14 In either scenario, neuromuscular dysfunctionis usually detected after the recovery of otherorgan systems.The bedside physical examination of theneuromuscular system in a critically ill patientis often difficult due to deep sedation or delir-ium. The standard physical examination of individual muscle groups is typically doneusing the Medical Research Council (MRC)scale, 80 which is dependent on patient effortand cooperation. This scale evaluates musclestrength with a score ranging from 0 (no mus-cle contraction) to 5 (normal strength). Physi-cal examination of 3 muscle groups in eachlimb, yielding a composite MRC score, hasdemonstrated excellent interrater reliabilitywithin specific non-ICU patient populations. 81 Clinically detectable muscle weakness hasbeen arbitrarily defined as a composite MRCscore of less than 80% of normal (eg, compos-ite MRC score less than 48 out of a maximumscore of 60 for 3 muscle groups in eachlimb). 6,81 Typically, symmetric motor weakness isobserved in all limbs, ranging from mild pare-sis to frank quadriplegia. In noncooperativepatients, noxious stimuli may be applied toeach extremity to grossly evaluate the strength NCI200050_243–253 7/6/09 9:55 PM Page 246
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