M u s c l e Was t i n g a n d E a r l y M o b i l i z a t i o n i n Ac u t e R e s p i r a t o r y D i s t res s S y n d ro m e Christopher J. Walsh, MD, FRCPCa, Jane Batt, MD, FRCPC, PhDa, Margaret S. Herridge, MD, FRCPC, MPHb, Claudia C. Dos Santos, MD, FRCPC, MSca,* KEYWORDS Muscle weakness Neuromuscular disease Critical illness ARDS Intensive care unit Early rehabilitation
KEY POINTS Patients with acute respiratory distress syndrome frequently develop persistent muscle weakness and poor functional outcome attributed to intensive care unit (ICU)–acquired weakness (ICUAW). Risk factors for ICUAW include sepsis, immobility, and hyperglycemia. Clinical diagnosis of ICUAW by physical examination has limitations, even in cooperative patients. Early rehabilitation programs in the ICU have been shown to be safe and feasible and have resulted in improved functional status after ICU discharge. Few interventions are available for prevention of ICUAW. Elucidating the molecular pathways that cause ICUAW is critical to develop novel targeted therapeutics.
Survivors of acute respiratory distress syndrome (ARDS) frequently develop substantial and persistent muscle weakness associated with impairments in physical function and health-related quality of life.1–4 Intensive care unit (ICU)–acquired weakness (ICUAW), well described in the acute phase of critical illness, is increasingly recognized to contribute to long-term disability in survivors of critical illness.2,4–6 Skeletal muscle wasting and weakness acquired during critical illness may result from muscle dysfunction, loss of myosin and less
commonly, frank myofiber necrosis (critical illness myopathy [CIM]), axonal sensory-motor axonopathy (critical illness polyneuropathy [CIP]), or a combination of both. Both processes manifest clinically as muscle weakness, induced by the resultant and variable combination of muscle wasting and impaired muscle contractility.6 In the acute phase, ICUAW is associated with failure of ventilator weaning, prolonged ICU stay, and increased mortality.7–10 In patients who survive, ICUAW may resolve completely over several weeks.11 However, a large proportion of patients
Funding Sources: This work was supported by the Canadian Institutes of Health Research (grant # MOP106545), the Ontario Thoracic Society (grants OTS2010/2011/2012), the Physicians’ Services Incorporated Foundation (grant # PSI 09–21), and the Early Research Award from the Ministry of Research and Innovation of Ontario (grant ERA/MRI 2011), Canada. a Department of Medicine, Institute of Medical Sciences, Keenan Centre for Biomedical Science, Li Ka Shing Knowledge institute, St. Michael’s Hospital, University of Toronto, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada; b Interdepartmental Division of Critical Care, University of Toronto, Toronto General Hospital, NCSB 11C-1180, 585 University Avenue, Toronto, ON M5G 2N2, Canada * Corresponding author. E-mail address: [email protected] Clin Chest Med 35 (2014) 811–826 http://dx.doi.org/10.1016/j.ccm.2014.08.016 0272-5231/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
INTRODUCTION
812
Walsh et al (40%–65%) have diminished functional capacity 5 years after ICU discharge (ie, reduced 6-minute walk [6MW]). The determinants of this persistent ICUAW remain inadequately defined.2,9 Inactivity has been shown to accelerate loss of muscle protein in severe illness and is a risk factor for ICUAW.12,13 Early rehabilitation is hypothesized to prevent disuse atrophy and improve muscle strength in both short-term and long-term ICU survivors. An increasing number of interventional studies have emerged over the past decade examining muscle function and ICUAW as outcomes, notably trials implementing early rehabilitation in the ICU setting. This article highlights the risk factors and molecular mechanisms associated with ICUAW and examines the current evidence for prevention and management of muscle weakness in critically ill patients, with a focus on early rehabilitation.
RISK FACTORS FOR INTENSIVE CARE UNIT– ACQUIRED WEAKNESS Classification of ICU patients within clinical phenotypes has the potential to accurately stratify patients by likelihood of persistent weakness.14 Several risks factors for ICUAW have been identified in multiple studies, including sepsis, immobility, and hyperglycemia. Age, burden of comorbid disease, and ICU length of stay have been recognized as major risk modifiers of
long-term recovery of function after critical illness (Fig. 1). Patients with sepsis and multiorgan dysfunction syndrome (MODS) are at high risk for ICUAW; a recent systematic review found a nearly 50% incidence of ICUAW in this population.12 The severity and duration of both systemic inflammatory response syndrome (SIRS) and MODS have been associated with ICUAW in several studies and several investigators have concluded that ICUAW is one manifestation of MODS.11,15–19 ICUAW has been associated with immobilization in several studies using the duration of mechanical ventilation (MV) and ICU stay as indirect measures of immobility.11,15,20 Hyperglycemia, a frequent complication of critical illness and inactivity, has been linked to ICUAW in multiple observational studies12 and in 2 large randomized controlled trials (RCTs) of insulin therapy that examined the effect of intensive insulin therapy (IIT) versus conventional insulin therapy (CIT) on ICUAW as a secondary outcome.21,22 The first RCT screened for ICUAW by electromyography weekly in 363 surgical patients requiring ICU stay for 1 week or more. The trial found a reduced incidence of ICUAW (28.7% vs 51.9%; P88%, and pH >7.25 Cardiovascular: No requirement for vasopressors Absence of symptomatic orthostasis Absence of cardiac ischemia or arrhythmias Absence of significant bleeding Absence of unstable fractures PT: initial assessment to measure activity and functional impairment. Determine appropriate exercises and advancement of activities Registered nurse: assess sedation, monitor vital signs, assist with care of tubes and arterial and venous catheters RT: alter ventilator settings, discontinue or reestablish MV as needed or ordered by treating physician Treating physician: assess readiness for early mobility and consult PT and multidisciplinary team. Order modifications to sedation, ventilator settings as needed Gait belts, portable telemetry and monitors Walkers and wheelchairs Portable ventilator, oxygen tank, and manual resuscitation bag Cycle ergometers Neuromuscular electrical stimulators In-bed exercises (eg, peripheral limb exercises, passive or active) Cycle ergometry Sitting (eg, at the edge of the bed) with or without support Transfer to the chair Pregait standing activities (eg, minisquats) Ambulation Physiologic deterioration/decompensation Extubation Dislodged or nonfunctional line Bleeding Minimizing/optimizing patient sedation Determining eligibility for early mobilization and consulting early mobilization services Assessing patients for safety early mobilization (starting, stopping, and altering physical activities)
A large number of research articles and documents related to implementing early mobilization of mechanically ventilated ICU patients can be found at www.mobilization-network.org. Abbreviations: PT, physical therapist; RT, respiratory therapist.
817
818
Walsh et al was provided to patients after discharge from ICU with instructions to perform their own physical therapy.82 A randomized trial compared the self-help manual versus control in a mixed population of 126 post-ICU patients and found that it improved physical function scores at 8 weeks and 6 months after ICU discharge versus usual care.
Cycle Ergometry and Neuromuscular Electrical Stimulation Novel rehabilitation devices are being studied that may have potential to improve muscle strength in the critically ill, particularly for those unable to move actively because of weakness or sedation. The bedside cycle ergometer may be used to perform active or passive cycling (for sedated patients) at multiple levels of resistance that are individually adjusted. One randomized trial found that patients using the cycle ergometer, in addition to standard mobilization therapies initiated early in ICU rehabilitation, showed no difference in quadriceps force or physical function at ICU discharge.83 However, it significantly improved quadriceps force, functional scores, and 6MW test (average of 56 m greater in the training group) at hospital discharge. Although this study did not rule out whether extra time spent performing standardized physical therapy was as beneficial as cycling ergometry, it does provide limited evidence associating increased physical activity in the ICU with improved functional outcomes. There is growing evidence that neuromuscular electrical stimulation (NMES) improves muscular function in the critically ill. NMES applies electrical stimulation using surface electrodes, typically on a target muscle of the lower limbs, to produce visible muscle contractions. It does not require active patient cooperation and has been shown in a small controlled study to increase protein synthesis and quadriceps cross-sectional area in orthopedic patients with knee immobilization.84 A randomized trial of NMES applied to the lower limb versus sham (52 ICU patients in total) found a significant reduction in ICUAW measured by MRC (27.3% vs 39.3%; P 5 .04).85 A systematic review of RCTs that compared NMES versus sham in ICU patients found 5 studies that evaluated strength of different muscle groups and 4 that evaluated muscle mass (thickness or volume).86 All 5 studies that evaluated muscle strength found an improvement with NMES, whereas only 2 of the 4 studies assessing muscle mass found an improvement. Meta-analysis of these 8 trials was not possible because of high inconsistency in the ICU patient characteristics between studies. However, the data point to moderate treatment effects on muscle strength, but
minimal impact on muscle wasting. Heterogeneity of NMES protocols across studies also limits the ability to generalize of the studies. Compliance and tolerability were generally high, without any adverse events reported in these studies. The only contraindication to use of NMES is the use of NMBAs.85 The major treatment modalities for early rehabilitation studied in prospective trials are summarized in Table 2.
Sedation Interruption The use of sedation in patients receiving MV has been found to increase the duration of MV and hinder early rehabilitation.87 A protocol that combined the interruption of sedation with spontaneous breathing trials (SBT) significantly reduced duration of MV versus routine sedation care with SBT in an RCT of 336 ICU patients with respiratory failure.88 Early rehabilitation performed during periods of interruption of sedation similarly resulted in a significant shortening of duration of MV and improved functional outcomes at hospital discharge and shorter periods of delirium versus interruption of sedation with routine care in one RCT.89 No differences in duration of ICU stay, hospital stay, or hospital mortality were detected.
Potential Limitations of Early Rehabilitation Therapy At present the most effective timing, mode, intensity, and frequency of early rehabilitation has not been established in clinical trials.90 To what extent clinical phenotypes at high risk for limited longterm functional improvement (advanced age, comorbid disease, and poor previous functional status) may benefit from even optimal physical therapies is controversial.81,91 The significant correlation between the degree of MODS and muscle wasting suggests that physical rehabilitation may only counteract a portion of lost muscle mass in severe critical illness.54 Although early rehabilitation may be able to attenuate muscle proteolysis and normalize muscle mass in some patients with ICUAW, it may be unable to restore normal muscle strength.92 Thus therapeutic interventions in addition to early rehabilitation therapy are crucial in order to improve management of ICUAW. Potential pharmacologic adjuncts to early rehabilitation are reviewed briefly later.
VENTILATOR-INDUCED DIAPHRAGM DYSFUNCTION Controlled MV (CMV) is frequently associated with patient sedation and NMBA, and leads to rapid diaphragmatic atrophy,7 termed ventilator-induced
Management of ICU–acquired Weakness
Table 2 Specific treatment modalities for early rehabilitation in the ICU studied in positive prospective trials Treatment Modality/Intervention
Study/Study Design
UE/LE exercise
Schweickert et al,89 2009 RCT N 5 104
Sedated adult ICU patients on MV 4 d of MV
Cycle ergometry (passive or active) combined with UE/LE exercise
Burtin et al,83 2009 RCT N 5 67
Single-center surgical and medical ICU patients with expected prolonged stay (at least 12 d after admission to ICU)
IMT with threshold inspiratory device
Martin et al,97 2011 RCT N 5 69
NMES
Routsi et al,85 2010 RCT N 5 52
Single-center medical and surgical ICU patients with failure to wean from MV with usual care Patients in the ICU with APACHE score 13 capable of assessment with MRC
Primary Outcome/Results Significantly higher rate of return to independent functional status at hospital discharge (59% in treatment group vs. 35%; P
KEY POINTS Patients with acute respiratory distress syndrome frequently develop persistent muscle weakness and poor functional outcome attributed to intensive care unit (ICU)–acquired weakness (ICUAW). Risk factors for ICUAW include sepsis, immobility, and hyperglycemia. Clinical diagnosis of ICUAW by physical examination has limitations, even in cooperative patients. Early rehabilitation programs in the ICU have been shown to be safe and feasible and have resulted in improved functional status after ICU discharge. Few interventions are available for prevention of ICUAW. Elucidating the molecular pathways that cause ICUAW is critical to develop novel targeted therapeutics.
Survivors of acute respiratory distress syndrome (ARDS) frequently develop substantial and persistent muscle weakness associated with impairments in physical function and health-related quality of life.1–4 Intensive care unit (ICU)–acquired weakness (ICUAW), well described in the acute phase of critical illness, is increasingly recognized to contribute to long-term disability in survivors of critical illness.2,4–6 Skeletal muscle wasting and weakness acquired during critical illness may result from muscle dysfunction, loss of myosin and less
commonly, frank myofiber necrosis (critical illness myopathy [CIM]), axonal sensory-motor axonopathy (critical illness polyneuropathy [CIP]), or a combination of both. Both processes manifest clinically as muscle weakness, induced by the resultant and variable combination of muscle wasting and impaired muscle contractility.6 In the acute phase, ICUAW is associated with failure of ventilator weaning, prolonged ICU stay, and increased mortality.7–10 In patients who survive, ICUAW may resolve completely over several weeks.11 However, a large proportion of patients
Funding Sources: This work was supported by the Canadian Institutes of Health Research (grant # MOP106545), the Ontario Thoracic Society (grants OTS2010/2011/2012), the Physicians’ Services Incorporated Foundation (grant # PSI 09–21), and the Early Research Award from the Ministry of Research and Innovation of Ontario (grant ERA/MRI 2011), Canada. a Department of Medicine, Institute of Medical Sciences, Keenan Centre for Biomedical Science, Li Ka Shing Knowledge institute, St. Michael’s Hospital, University of Toronto, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada; b Interdepartmental Division of Critical Care, University of Toronto, Toronto General Hospital, NCSB 11C-1180, 585 University Avenue, Toronto, ON M5G 2N2, Canada * Corresponding author. E-mail address: [email protected] Clin Chest Med 35 (2014) 811–826 http://dx.doi.org/10.1016/j.ccm.2014.08.016 0272-5231/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
INTRODUCTION
812
Walsh et al (40%–65%) have diminished functional capacity 5 years after ICU discharge (ie, reduced 6-minute walk [6MW]). The determinants of this persistent ICUAW remain inadequately defined.2,9 Inactivity has been shown to accelerate loss of muscle protein in severe illness and is a risk factor for ICUAW.12,13 Early rehabilitation is hypothesized to prevent disuse atrophy and improve muscle strength in both short-term and long-term ICU survivors. An increasing number of interventional studies have emerged over the past decade examining muscle function and ICUAW as outcomes, notably trials implementing early rehabilitation in the ICU setting. This article highlights the risk factors and molecular mechanisms associated with ICUAW and examines the current evidence for prevention and management of muscle weakness in critically ill patients, with a focus on early rehabilitation.
RISK FACTORS FOR INTENSIVE CARE UNIT– ACQUIRED WEAKNESS Classification of ICU patients within clinical phenotypes has the potential to accurately stratify patients by likelihood of persistent weakness.14 Several risks factors for ICUAW have been identified in multiple studies, including sepsis, immobility, and hyperglycemia. Age, burden of comorbid disease, and ICU length of stay have been recognized as major risk modifiers of
long-term recovery of function after critical illness (Fig. 1). Patients with sepsis and multiorgan dysfunction syndrome (MODS) are at high risk for ICUAW; a recent systematic review found a nearly 50% incidence of ICUAW in this population.12 The severity and duration of both systemic inflammatory response syndrome (SIRS) and MODS have been associated with ICUAW in several studies and several investigators have concluded that ICUAW is one manifestation of MODS.11,15–19 ICUAW has been associated with immobilization in several studies using the duration of mechanical ventilation (MV) and ICU stay as indirect measures of immobility.11,15,20 Hyperglycemia, a frequent complication of critical illness and inactivity, has been linked to ICUAW in multiple observational studies12 and in 2 large randomized controlled trials (RCTs) of insulin therapy that examined the effect of intensive insulin therapy (IIT) versus conventional insulin therapy (CIT) on ICUAW as a secondary outcome.21,22 The first RCT screened for ICUAW by electromyography weekly in 363 surgical patients requiring ICU stay for 1 week or more. The trial found a reduced incidence of ICUAW (28.7% vs 51.9%; P88%, and pH >7.25 Cardiovascular: No requirement for vasopressors Absence of symptomatic orthostasis Absence of cardiac ischemia or arrhythmias Absence of significant bleeding Absence of unstable fractures PT: initial assessment to measure activity and functional impairment. Determine appropriate exercises and advancement of activities Registered nurse: assess sedation, monitor vital signs, assist with care of tubes and arterial and venous catheters RT: alter ventilator settings, discontinue or reestablish MV as needed or ordered by treating physician Treating physician: assess readiness for early mobility and consult PT and multidisciplinary team. Order modifications to sedation, ventilator settings as needed Gait belts, portable telemetry and monitors Walkers and wheelchairs Portable ventilator, oxygen tank, and manual resuscitation bag Cycle ergometers Neuromuscular electrical stimulators In-bed exercises (eg, peripheral limb exercises, passive or active) Cycle ergometry Sitting (eg, at the edge of the bed) with or without support Transfer to the chair Pregait standing activities (eg, minisquats) Ambulation Physiologic deterioration/decompensation Extubation Dislodged or nonfunctional line Bleeding Minimizing/optimizing patient sedation Determining eligibility for early mobilization and consulting early mobilization services Assessing patients for safety early mobilization (starting, stopping, and altering physical activities)
A large number of research articles and documents related to implementing early mobilization of mechanically ventilated ICU patients can be found at www.mobilization-network.org. Abbreviations: PT, physical therapist; RT, respiratory therapist.
817
818
Walsh et al was provided to patients after discharge from ICU with instructions to perform their own physical therapy.82 A randomized trial compared the self-help manual versus control in a mixed population of 126 post-ICU patients and found that it improved physical function scores at 8 weeks and 6 months after ICU discharge versus usual care.
Cycle Ergometry and Neuromuscular Electrical Stimulation Novel rehabilitation devices are being studied that may have potential to improve muscle strength in the critically ill, particularly for those unable to move actively because of weakness or sedation. The bedside cycle ergometer may be used to perform active or passive cycling (for sedated patients) at multiple levels of resistance that are individually adjusted. One randomized trial found that patients using the cycle ergometer, in addition to standard mobilization therapies initiated early in ICU rehabilitation, showed no difference in quadriceps force or physical function at ICU discharge.83 However, it significantly improved quadriceps force, functional scores, and 6MW test (average of 56 m greater in the training group) at hospital discharge. Although this study did not rule out whether extra time spent performing standardized physical therapy was as beneficial as cycling ergometry, it does provide limited evidence associating increased physical activity in the ICU with improved functional outcomes. There is growing evidence that neuromuscular electrical stimulation (NMES) improves muscular function in the critically ill. NMES applies electrical stimulation using surface electrodes, typically on a target muscle of the lower limbs, to produce visible muscle contractions. It does not require active patient cooperation and has been shown in a small controlled study to increase protein synthesis and quadriceps cross-sectional area in orthopedic patients with knee immobilization.84 A randomized trial of NMES applied to the lower limb versus sham (52 ICU patients in total) found a significant reduction in ICUAW measured by MRC (27.3% vs 39.3%; P 5 .04).85 A systematic review of RCTs that compared NMES versus sham in ICU patients found 5 studies that evaluated strength of different muscle groups and 4 that evaluated muscle mass (thickness or volume).86 All 5 studies that evaluated muscle strength found an improvement with NMES, whereas only 2 of the 4 studies assessing muscle mass found an improvement. Meta-analysis of these 8 trials was not possible because of high inconsistency in the ICU patient characteristics between studies. However, the data point to moderate treatment effects on muscle strength, but
minimal impact on muscle wasting. Heterogeneity of NMES protocols across studies also limits the ability to generalize of the studies. Compliance and tolerability were generally high, without any adverse events reported in these studies. The only contraindication to use of NMES is the use of NMBAs.85 The major treatment modalities for early rehabilitation studied in prospective trials are summarized in Table 2.
Sedation Interruption The use of sedation in patients receiving MV has been found to increase the duration of MV and hinder early rehabilitation.87 A protocol that combined the interruption of sedation with spontaneous breathing trials (SBT) significantly reduced duration of MV versus routine sedation care with SBT in an RCT of 336 ICU patients with respiratory failure.88 Early rehabilitation performed during periods of interruption of sedation similarly resulted in a significant shortening of duration of MV and improved functional outcomes at hospital discharge and shorter periods of delirium versus interruption of sedation with routine care in one RCT.89 No differences in duration of ICU stay, hospital stay, or hospital mortality were detected.
Potential Limitations of Early Rehabilitation Therapy At present the most effective timing, mode, intensity, and frequency of early rehabilitation has not been established in clinical trials.90 To what extent clinical phenotypes at high risk for limited longterm functional improvement (advanced age, comorbid disease, and poor previous functional status) may benefit from even optimal physical therapies is controversial.81,91 The significant correlation between the degree of MODS and muscle wasting suggests that physical rehabilitation may only counteract a portion of lost muscle mass in severe critical illness.54 Although early rehabilitation may be able to attenuate muscle proteolysis and normalize muscle mass in some patients with ICUAW, it may be unable to restore normal muscle strength.92 Thus therapeutic interventions in addition to early rehabilitation therapy are crucial in order to improve management of ICUAW. Potential pharmacologic adjuncts to early rehabilitation are reviewed briefly later.
VENTILATOR-INDUCED DIAPHRAGM DYSFUNCTION Controlled MV (CMV) is frequently associated with patient sedation and NMBA, and leads to rapid diaphragmatic atrophy,7 termed ventilator-induced
Management of ICU–acquired Weakness
Table 2 Specific treatment modalities for early rehabilitation in the ICU studied in positive prospective trials Treatment Modality/Intervention
Study/Study Design
UE/LE exercise
Schweickert et al,89 2009 RCT N 5 104
Sedated adult ICU patients on MV 4 d of MV
Cycle ergometry (passive or active) combined with UE/LE exercise
Burtin et al,83 2009 RCT N 5 67
Single-center surgical and medical ICU patients with expected prolonged stay (at least 12 d after admission to ICU)
IMT with threshold inspiratory device
Martin et al,97 2011 RCT N 5 69
NMES
Routsi et al,85 2010 RCT N 5 52
Single-center medical and surgical ICU patients with failure to wean from MV with usual care Patients in the ICU with APACHE score 13 capable of assessment with MRC
Primary Outcome/Results Significantly higher rate of return to independent functional status at hospital discharge (59% in treatment group vs. 35%; P
