Acquired Neuromuscular Weakness and Early Mobilization in the Intensive Care Unit

MEDICINE has long turned to bedrest as an adjunct in the treatment of severe illness and convalescence after surgery. Hippocrates suggested that all pain is relieved by bedrest.1However, in the early 20th century, physicians and researchers began to recognize the “evil sequelae of complete bedrest,”2noting that “prolonged periods of recumbency in bed are anatomically, physiologically, and psychologically unsound and unscientific.”3More recently, a systematic review of 39 trials of bedrest for 15 different conditions showed no benefit and highlighted the potential for harm,1including atelectasis, venous thrombosis, pulmonary edema, bone atrophy, muscle-wasting, vasomotor instability, constipation, and backache.2,3Traditionally, healthcare providers working in intensive care units (ICUs) have focused their attention on normalizing the severe cardiopulmonary derangements that put their patients’ lives at risk. However, as survival from critical illness has improved, focus has shifted to include preventing the sequelae of critical illness, including neuromuscular weakness. Neuromuscular weakness occurs in approximately 25–50% of critically ill patients,4,5and persists for years after ICU discharge, such that only half of survivors return to work within a year.6,7Early mobilization of ICU patients has been touted as one intervention to decrease the weakness and deconditioning associated with critical illness. Recent studies have demonstrated that early mobilization is safe, feasible, and beneficial in the ICU population.8–11This review outlines the physiologic consequences of bedrest; the pathophysiology of neuromuscular weakness acquired in the ICU; and the safety, feasibility, and potential benefits of early mobilization during critical illness.It has been said that rest “of injured parts and of diseased bodies is the most valuable of all methods of treatment but may lead to untoward results when utilized either injudiciously or excessively.”12Indeed, in recent years, the medical community has increasingly acknowledged the adverse effects of physical inactivity, bedrest, and immobility.During bedrest, skeletal muscle utilization is decreased. Muscles are activated less frequently, for shorter periods of time, and are responsible for smaller loads. This mechanical unloading of muscles triggers a cascade of responses – slowed protein synthesis, accelerated proteolysis, and increased apoptosis – that alters skeletal muscle morphology, the proportion of slow and fast twitch muscle fibers, contractility, and aerobic capacity, ultimately resulting in catabolism, atrophy, and weakness.13,14Paddon-Jones et al. evaluated the effect of 28 days of bedrest on protein loss in young, healthy volunteers and found a 23% reduction in leg-extension strength.15Concomitant inflammation and stress exacerbate the weakness associated with bedrest. In a follow-up study, Paddon-Jones et al. administered hydrocortisone to achieve plasma cortisol levels consistent with acute illness in volunteers subjected to 28 days of bedrest and found a 28% loss of leg-extension strength and a 3-fold greater loss of lean leg mass compared with bedrest alone (P = 0.004).16A recent systematic review of 39 trials of bedrest (n = 5,777) for 15 different conditions evaluating a variety of outcomes including disability, pain, and mortality found no significant improvement in outcomes for any condition. In nine conditions, including acute myocardial infarction, low back pain, hepatitis, and pregnancy-induced hypertension, bedrest was associated with worsened outcomes.1Neuromuscular weakness in the ICU is common; approximately 50% of ICU patients with sepsis, multiorgan failure, or prolonged mechanical ventilation have electrophysiologic evidence of neuromuscular dysfunction.5The incidence increases to 100% in patients with both systemic inflammatory response syndrome/sepsis and multiorgan failure.17More than 25% of ICU patients undergoing mechanical ventilation for 7 or more days have clinical evidence of weakness on awakening.4Marked diaphragmatic atrophy can be seen 18 h after the onset of mechanical ventilation,18and the onset of weakness may occur as early as ICU day 2.17The differential diagnosis for neuromuscular weakness in the ICU is broad, and the mnemonic MUSCLES aids clinicians in remembering some of the most common causes (table 1).19A clinical algorithm for the evaluation of generalized weakness in the ICU, which includes laboratory testing, radiographic imaging, and electromyography, can also be helpful (fig. 1).Included in the long differential of weakness in the ICU is critical illness neuromyopathy (CINM). CINM is an umbrella term for a spectrum of neuromuscular disorders associated with critical illness, including critical illness polyneuropathy (CIP), critical illness myopathy (CIM), and disorders of the neuromuscular junction.5,19Differentiating between CIP and CIM often requires electrophysiology and/or direct muscle stimulation; although compound muscle action potential amplitudes are reduced in both conditions, sensory nerve action potential amplitudes are reduced or absent in CIP but normal in CIM (fig. 2).20In addition, creatine kinase levels are increased in about 50% of CIM patients, but normal in those with CIP. CIM can be further divided into four histologic subtypes: necrotizing, cachectic, acute rhabdomyolysis, and thick filament loss. The necrotizing subtype is associated with a poorer prognosis.19Because CIP and CIM frequently occur concurrently, they are often treated as one entity: CINM. The pathophysiology of CINM is complex and includes the sequelae of bedrest, the effects of critical illness-induced cytokine production, and possibly the interplay of drugs such as neuromuscular blockers and corticosteroids (fig. 3). Protein-energy malnutrition, electrolyte imbalances, and glutamine deficiency also play a role, highlighting the importance of nutritional supplementation in the critically ill.21,22ICU-acquired weakness (ICUAW), defined as bilateral symmetrical limb weakness, is the clinical manifestation of CINM.14The typical presentation is flaccid quadriparesis and hyporeflexia or areflexia, with sparing of the cranial nerves.19This acquired weakness is associated with respiratory muscle weakness, difficulty weaning from the ventilator, and prolonged ICU length of stay (LOS).14,23A prospective cohort study of 174 ICU patients in five academic medical centers requiring at least 5 days of mechanical ventilation without evidence of preexisiting neuromuscular disease revealed that ICUAW was independently associated with hospital mortality in both a multivariate logistic regression model (odds ratio OR: 7.8, 95% CI: 2.4–25.3) and in an analysis using propensity score matching (OR: 5.2, 95% CI: 1.5–18.3).24Several studies have evaluated the risk factors for CINM and ICUAW (table 2). The systemic inflammatory response syndrome, sepsis, and multiorgan failure have been repeatedly implicated. A systematic review of neuromuscular dysfunction acquired in critical illness included 1,421 ICU patients in 24 studies and identified hyperglycemia, the systemic inflammatory response syndrome, sepsis, multiorgan dysfunction, renal replacement therapy, and catecholamine administration as risk factors for the development of CINM. No consistent relationship between CINM and age, gender, severity of illness, or exposure to corticosteroids or neuromuscular blocking agents was found.5In a prospective cohort study of 95 ICU patients who underwent mechanical ventilation for 7 days or more in four hospitals in France, De Jonghe et al. found that the independent predictors of ICUAW were female sex (OR: 4.66, 95% CI: 1.19–18.30), the number of days with dysfunction of two or more organs (OR: 1.28, 95% CI: 1.11 to 1.49), duration of mechanical ventilation (OR: 1.10, 95% CI: 1.00 to 1.22), and administration of corticosteroids (OR: 14.90, 95% CI: 3.20–69.80).4Although corticosteroids inhibit protein synthesis in type II muscle fibers and contribute to severe protein catabolism,25the relationship between corticosteroids and CINM/ICUAW has been inconsistent, and corticosteroids were even found to be protective for the development of weakness in one study.26Whether the use of neuromuscular blocking agents increases the risk of CINM and ICUAW remains controversial; a dose-dependent response has been reported in patients with severe asthma requiring mechanical ventilation,27but this relationship has not borne out in the general adult ICU population.4,5,28Investigations of potential interventions to prevent CINM/ICUAW are relatively sparse. A recent Cochrane review identified only one successful intervention: intensive insulin therapy.21Unfortunately, despite its protective effect on the development of CINM/ICUAW, intensive insulin therapy may increase mortality in critically ill patients.29Because prolonged immobilization and bedrest have been shown to accelerate muscle loss and exacerbate ICUAW, mobility therapy has emerged as a potential preventative measure.15,16,23As survival from critical illness improves, and with preventative measures lacking, CINM and ICUAW present a grave public health problem. Herridge et al. studied long-term outcomes of 109 survivors of acute respiratory distress syndrome from four Canadian hospitals and found significant morbidity.6The patients tended to be young (median age, 45 y) and critically ill (median Acute Physiology, Age, and Chronic Health Evaluation APACHE II score, 23), and had prolonged mechanical ventilation (median duration, 21 days), ICU LOS (median duration, 25 days), and hospital LOS (median duration, 48 days). Lung function improved significantly during the first year after ICU discharge, with normalization of lung volumes and spirometry by 6 months, and improvement in carbon monoxide diffusion capacity to 72% predicted at 12 months. However, “all patients reported poor function and attributed this to the loss of muscle bulk, proximal weakness, and year after ICU discharge, the in 6 was of In a multivariate analysis of by in 6 the use of any systemic was the at months. 6 months, of lung and multiorgan dysfunction and of the most use was no at 12 months, of the and the model a poor of poor = only of survivors had to work after ICU 5 after ICU discharge, all patients reported weakness and capacity compared with ICU was no evidence of clinical weakness on the in 6 than on and sex of patients had to patients often a work back to or In addition, patients were with the of their severe illness, with more than half of survivors at least one of or the utilization of health care was with of year after ICU discharge, significantly more than by healthy et al. studied long-term and survivors of severe prospective cohort study included severe survivors and a of survivors of a all from the Health and The of severe was requiring both an and dysfunction during a patients were than and the of severe survivors was and were and after the with follow-up for to and The to independently complete of and of in to and on of and in to patients with no at severe was associated with the development of CI: as as a more of development of after = compared with The study also found that the incidence of severe was associated with to to severe (OR: 95% CI: of the effects of inflammation and on the The effects of severe were of the for mechanical the in physical function and function for at least the prolonged and associated with CINM and ICUAW, and of is of suggested is early physical therapy and mobilization of ICU of the of bedrest and the benefits of physical early mobilization in the ICU not as a therapy relatively are to ICU patients, by have severe derangements in physiologic healthcare providers to focus their attention on treatment of the that most of the of their critically ill patients are often to in physical early in their ICU the use of is often seen as a to physical therapy as patients are often to In addition, ICU patients often have and including venous even and and the risk of this increases with use of and renal replacement therapy have also been identified as ICU may in therapy to early mobilization in the ICU, studies have to the and of physical in the critically ill (table et al. a prospective cohort study of early in respiratory failure patients in an respiratory ICU study included patients who mechanical ventilation for more than A were to to of or or and of and catecholamine who not were included they were for of patients had been to ICU to the with a to of The most common diagnosis was of APACHE II score on to the was was defined as at physiologic included on the of the hospital bed without back in a after from and with the to more than ICU and were adverse to more than or less than less than and the incidence of adverse was less than and were no of patients were to more than the early to be and in one of the study by et al. is that patients to a are to be less ill by the relatively low APACHE II score on and that in the in not early at all when the to is more than recently, et al. a prospective study on the of early physical in the medical ICU at a ICU patients with ICU LOS of 7 days or more and duration of mechanical ventilation of days or more were included in a that included and was and Acute score a mortality of The most common diagnosis was acute respiratory failure and of patients had respiratory were the including less than or respiratory failure more than less than than or less than renal replacement therapy, and were present on of of interventions were during mechanical was during of The incidence of adverse was including one et al. a study of early physical and therapy in medical ICU patients at two care academic this the was and APACHE II score The most common diagnosis was acute lung and of patients were in were for of physical and therapy was with the and were for they not have any of the less than less than or more than respiratory less than 5 or more than less than evidence of increased myocardial undergoing a severe or The from to of therapy was days on of with in of or more to mobilization – acute lung renal replacement therapy, or mass more – were present in of or more during of on mechanical drugs were during of two or more during of and renal replacement therapy during of was present in of and may have patients from in such as adverse were reported during of including increased and but of therapy in only of No early mobilization is and to be in most medical ICU the of this intervention only be when the of early mobilization has and the number of patients in is to the incidence of but adverse patients have including pain, recent and on early mobilization in the ICU is et al. a prospective study of early mobilization in the ICU of a care academic the of the study was to the of mobilization in physical the study some into the and of early mobilization in patients to the ICU were The of patients were after including and were not in to or of mobility to or were both were with of in bed and to on the of the to a and A of mobilization therapy were as early as ICU day physical reported levels of mobilization than approximately of mobilization included No adverse were on the and of early mobilization in the ICU from the on the intervention in the and a number of have shown evidence that physical therapy and mobilization can be even in patients with requiring as patients requiring as a to lung ICU patients of or or to patients in the ICU is a more as the on this is lacking, and such patients from that may or The on of patients not in the ICU after of that although early mobilization is seen as a patients often from at increased risk of and to this to an ICU with is In a recent review the and benefits of early mobilization in medical ICU patients, et al. early mobilization in the ICU without on or treatment et al. a treatment for patients with acute in which they mobilization by or including to and of of the have been no studies of the intervention in this studies have the of early mobilization in the ICU on early study can decrease in critically ill patients requiring neuromuscular were as or leg of although the leg the of was between was muscle atrophy and protein loss in the limb that muscle a analysis of patients to a all of were and had clinical evidence of severe weakness on et al. found that of a was associated with increases in and strength on with to from the = included respiratory and medical including for than less than 5 more than no sepsis, no no or failure, and no this study was by its and of a et al. a prospective study including patients in a medical of a of one physical one and one for for early mobilization and administration of on an in of the ICU from to and to and were they were not only respiratory as of or less and or and had no increase in for at least h by its this study after of the the number of increased ICU and hospital LOS day 95% CI: and day 95% CI: et al. the first study the and benefits of early mobilization in the prospective cohort study included medical ICU patients with acute respiratory failure requiring mechanical were including to without acute illness, at neuromuscular acute mass more than 45 or mechanical ventilation more than 48 h from an more than cardiopulmonary at not at within days of therapy for within 6 of and to the were to a of therapy within 48 h of mechanical ventilation or care were no in between APACHE II were and in the care and (P = was no in the number of patients with to mobility venous neuromuscular blocking between the two The study found that the patients were out of bed and had shorter ICU and hospital LOS = and = was no in between the two A follow-up study the mortality and hospital of the patients in the cohort who to hospital were or within the first year after logistic regression was to from the that predicted hospital or within 12 of hospital of early mobilization in the ICU was one of four predictors identified (OR: 95% CI: including two have the benefit of early mobilization on ICU a of medical and ICU patients, et al. compared respiratory mobility of the and day of with respiratory and mobility of the were included only after ICU day they had ICU of at least 7 were as or or mass more than or length less than neuromuscular acute more than severe or cardiopulmonary as than than ventilation more than respiratory more than for significant and the treatment had a significantly ICU stay as compared with the days a of (median days and a of neuromuscular blocking agents were between the two with APACHE II score on 25 in the and 6 in the intervention hospital discharge, was greater in the treatment 25% and was a increased to in this patients in the treatment reported a significantly of time, ICU and hospital LOS were in the two et al. ICU patients who had been on mechanical ventilation for less than h and were to for at least 24 h to early during or with as by the were they had neuromuscular cardiopulmonary mortality to be more than increased or absent were between the two APACHE II score was in the intervention and in the The most common diagnosis in both was acute lung The return to independent at hospital discharge, was in of patients in the early as compared with of patients in the (P = the intervention also less days with = and more days = was a increased to in the intervention patients to = was no in the incidence of at hospital = although the study was not to this ICU hospital and hospital mortality were in the two on the evidence of the of prolonged and the potential benefits of early in the critically the and of a on for critically ill was the of from the trials of early most were levels and that and muscle be but that patients with or poor respiratory are not for patients who be the of and/or neuromuscular the evidence for use of early mobilization in the of early as with improvement requires a a significant in ICU evidence into requires the evidence for the intervention in the on early and to all patients the and and to early mobilization be acknowledged and evidence that the to mobilization and the of between and physical a mobilization that on the of healthcare providers may and a of acute care physical revealed that of hospitals a for of physical therapy in the ICU, with for of physical therapy in ICU patients present in only of and physical evaluating critically ill patients at only of and of for physical and of therapy benefit an early mobilization with physical therapy is a and et al. patients and after to a early is a and found that the number of patients after 48 h in the was 3-fold compared with (P = the APACHE II of the cohort during the study the improvement was not to the significant improvement in the that the patients had been to in early mobilization is not in the addition, successful requires the of and the intervention may be as a of a mobility has not been associated with increased direct the ICU and hospital LOS associated with early this intervention may to be the evidence that early mobilization is and in most ICU patients and may the on medical ICU on and ICU patients is of such as those in the and only evidence of the of this intervention in such In addition, all of the studies on the safety, feasibility, and outcomes of early mobilization in the critically ill had of mobilization may not be in patients with severe derangements or acute in or respiratory myocardial or severe or is a for mobilization of ICU patients has providers to the ICU be utilized on as an with on the clinical at that time, and providers to early mobilization in ICU the can be in clinical on early may in However, no for mobility at this et al. the ICU which of a that mobilization capacity of score from to with to no and to The found that the ICU predicted mortality as as ICU and hospital can be as a of severity of illness. is in the of and a mobility score on the mobility by the may of early mobilization therapy in the A variety of have been suggested for this medical including and mechanical are to patients to out of their ICU the of at The the for patients for includes a with a the to during therapy and an that a ventilator, and two of this the number of to therapy to a for or and has been shown to be safe, feasible, and in the critically muscle by atrophy in healthy and ill of in the critically ill have shown with some studies improved muscle incidence of no studies on are and of on for patients who are to and at risk of although is a attention has turned to the use of such as the for mobilization and in the can be or for use in the ICU et al. reported the use of in ICU use of muscle of and patients showed evidence of increased physical respiratory and No adverse were et al. a of using the in medical ICU this a of of which and The out the potential of therapy, including its duration, low and potential to and In their et al. reported no although their was The risk of from play is not of play have even a further is to the of therapy in the to increase of early mobilization as medical and more of mobility into the ICU has in ICU to decrease ICUAW and early mobilization in the ICU are also in care of the critically ill may the and benefit the of ICU and of in care found that 100% of ICU physicians and of the and of were to of in the in bed or to a However, only of in a care and may be to in early mobilization – with and of – and significantly increase the of therapy development of drugs to that atrophy and is was to be in this but was shown in a clinical to increase mortality in the critically is although are about and include of the and that atrophy, and of the and evaluation of is survival from critical illness improves, is increased for the sequelae of prolonged intensive during critical illness can no be a as is associated with catabolism, atrophy, and weakness. Neuromuscular weakness is in the ICU and can for years after mobilization is a and intervention for critically ill patients, and is associated with improved of an early mobilization requires and may be helpful in on early mobilization in the ICU and potential is

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