Clin Chest Med 27 (2006) 691–703
Neuromuscular Sequelae in Survivors of Acute Lung Injury Catherine Lee Hough, MD, MSc Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, 325 Ninth Avenue, Box 359762, Seattle, WA 98122, USA
Acute lung injury (ALI) is an important complication of pulmonary or systemic injury that is associated with signiﬁcant morbidity and mortality. Deﬁned by hypoxemic respiratory failure with bilateral inﬁltrates on chest radiograph without evidence of left atrial hypertension , ALI is common, aﬀecting nearly 200,000 in the United States alone each year . Mortality of patients with ALI has diminished sizably over the past 3 decades, from 60% to 70% to 30% to 40% in the present day [2,3]. As hospital survival of ALI patients improves and survivors become numerous, it is important to look beyond the traditional short-term outcomes of critical care research (such as 28-day survival and resolution of organ dysfunction) and consider longer-term outcomes of critical illness . In recent years, there has been an increase in research of longer-term outcomes after critical illness in general and ALI in particular. This research has included studies of patient-centered outcomes, including quality of life and functional status after hospital discharge. As discussed in the preceding article in this issue by Hopkins and Herridge, ALI survivors have signiﬁcant impairment in quality of life that is linked to problems with physical function. This article will focus on studies of impaired functional status after recovery from the acute phase of ALI and critical illness, with a discussion of potential etiologies of physical dysfunction, strategies for management
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and prevention, and potential targets for future research.
Pulmonary and physical function after acute lung injury: a brief history Pulmonary function Early studies of long-term outcome after the acute respiratory distress syndrome (ARDS) focused on resolution of pulmonary dysfunction. Following the ﬁrst case report in 1974 , there were many case reports and case series that described the change in pulmonary function over time after hospital discharge . These reports demonstrated signiﬁcant early decrements in lung volumes, airﬂow, and diﬀusing capacity that improved over time, leaving most patients with mild residual impairment, especially in diffusing capacity. A small group of ARDS survivors was identiﬁed with very severe reductions in lung volume and diﬀusing capacity that did not significantly improve over time. Decline in pulmonary function after initial improvement, a sign of upper airway obstruction from tracheal stenosis, was seen uncommonly . The ﬁrst study of pulmonary function after ARDS to perform testing at prespeciﬁed time points at and after hospital discharge (3, 6, and 12 months) was performed by McHugh and colleagues in Seattle, Washington . McHugh and colleagues found that most improvement in pulmonary function occurs by month 6, and residual impairment, when present, is predominantly mild. These results have been conﬁrmed by recent larger investigations with similar designs, including the study of 109 survivors by
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Herridge and colleagues in Toronto, Ontario [9,10]. Health-related quality of life and functional assessment In addition to studying pulmonary recovery, the McHugh and coworkers study  used the Sickness Impact Proﬁle, a measure of healthrelated quality of life (QOL), to assess general recovery of ALI survivors. This was the ﬁrst study of QOL after ALI that discovered profound reductions in QOL at the time of hospital discharge that improved over time but did not return to population norms at 1 year. Overall, subjects reported that breathing diﬃculties did not account for their impaired well-being. Despite improved pulmonary function and QOL, nearly half of these subjects had not returned to work at 1 year. Over the past decade, there have been larger studies of QOL after ALI, most using the Medical Outcomes Study 36-item short form health survey (SF-36) [9,11–17]. Using the SF-36, it has been shown that ALI survivors have profound decrements in QOL, particularly in physical health. As reviewed in the preceding article in this issue by Hopkins and Herridge, QOL improves over time, but most survivors remain impaired. Weinert and colleagues  describe the degree of physical impairment of their young cohort of ALI survivors (mean age of 40 years) with the statement, ‘‘Our ALI population’s physical component score of 37 is most comparable to a general population sample 75 years old or older.’’ The severity of physical impairment is also reﬂected in the ﬁndings that 1 year after hospital discharge, 57% of the patients studied by Heyland and colleagues still had not returned to ‘‘normal activity’’  and half of the patients studied by Herridge and colleagues  still had not returned to their original work. Reasons cited for not returning to work included persistent fatigue and weakness. While physical function may be most impaired in survivors with signiﬁcant residual pulmonary
deﬁcits , physical function may also be markedly impaired in those without any respiratory symptoms or pulmonary function testing abnormalities. It appears that neuromuscular problems resulting from critical illness are prominent contributors to functional disability and impaired health-related QOL after ALI. In a study of 132 ALI survivors using the Quality of Well-Being assessment, Angus and colleagues  found that 70% of subjects had persistent musculoskeletal symptoms at 6 months and 1 year. In a structured global assessment, Herridge and coworkers  discovered that all survivors in the Toronto cohort described poor function, which was ‘‘attributed to the loss of muscle bulk, proximal weakness, and fatigue.’’ These subjects performed a standardized 6-minute walk test at 3, 6, and 12 months as a functional assessment. As shown in Table 1, at 3 months, the median distance walked was 281 m, less than 50% of the predicted performance; one quarter of subjects could not even complete 60 m. Performance improved markedly by 6 months, but remained impaired at 1 year, with a median distance walked of 422 m (66% predicted). Factors associated with poor performance included corticosteroid treatment, slow resolution of lung injury and multiorgan dysfunction, and ICU-acquired complications. Is impaired quality of life a result of acute lung injury or critical illness? Studies of QOL after intensive care  as well as after speciﬁc critical illnesses such as sepsis , trauma , and renal failure  also demonstrate lasting impairment in physical function. It remains unclear to what extent ALI contributes to physical impairment beyond the general eﬀects of critical illness and inactivity. A case-control study conducted in Seattle compared the healthrelated QOL of survivors of ARDS due to either sepsis or trauma with age-matched survivors of either sepsis or trauma without ARDS, and showed
Table 1 Acute respiratory distress syndrome survivors’ distance walked in 6 minutes Time after hospital discharge (mo)
Median predicted (%)
Interquartile range (mo)
3 (n ¼ 80) 6 (n ¼ 78) 12 (n ¼ 81)
281 396 422
49 64 66
55–454 244–500 277–510
Data from Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003;348:683–93.
NEUROMUSCULAR SEQUELAE IN SURVIVORS OF ALI
that ARDS survivors had signiﬁcantly lower SF-36 scores (worse QOL) than matched controls at 2 years after acute illness . A small study with similar methodology did not support these results, but did ﬁnd that 48% of ARDS survivors described a decline in health state 1 year later, compared with 30% of matched controls [22,23]. Summary Most survivors of ALI have rapid return of normal pulmonary function within 6 months of critical illness. Despite this improvement in respiratory function, the overwhelming majority have problems with physical function that persist 1 year after acute illness. Muscle weakness, wasting, and fatigue are commonly described. Physical dysfunction is associated with poor QOL and inability to resume activities of daily living, and may be more severe in survivors of ALI than in other survivors of critical illness.
Causes of neuromuscular dysfunction after acute lung injury and critical illness Causes of functional impairment after acute lung injury There are many potential contributors to functional impairment and decreased QOL in survivors of acute lung injury. Prehospital disability and comorbidity may be diﬃcult to measure and generally will not be improved by an ICU stay (with the exception of ALI occurring in recovery from a corrective procedure, such as cardiac valve or bypass surgery, or an orthopedic procedure), and therefore are expected to contribute signiﬁcantly to posthospital impairment. Persistent organ dysfunction resulting from critical illness, such as heart failure, new lung pathology from pneumonia or ALI, or renal insuﬃciency, may be associated with long-term diminished QOL. Development of new neuromuscular pathology during the course of critical illness may be a signiﬁcant contributor to prolonged functional impairment. Nonpathological processes, such as the development of muscle atrophy and deconditioning associated with protracted inactivity and convalescence, may lead to diminished functional capacity and fatigue. Even in the absence of reduced muscle force, ongoing pain and psychological disturbances such as depression and posttraumatic stress may diminish the ability or will to perform physical tasks.
These are dynamic processes; coping with disability may improve perceived QOL over time in the absence of physical improvement, while depression or expectations of rapid return to health may lead to perceptions of worsening health status even as physical recovery progresses. Understanding of each of these factors is important in studying and treating survivors of acute lung injury. This review will focus on ICUacquired neuromuscular dysfunction, which is likely a sizeable contributor to post-ICU functional impairment. Neuromuscular dysfunction after acute lung injury Although there are an increasing number of studies that describe physical impairment in survivors of ALI, there have been no prospective studies published to date of the epidemiology of ICU-acquired weakness or its etiologies limited to ALI patients. Some early information is available from a retrospective analysis, a secondary study of a randomized controlled trial, and two abstracts. A chart review of 50 consecutive ARDS patients was performed in an ICU where neuromuscular assessment was part of routine clinical care and included at least one electrophysiologic evaluation as well as physical examination of strength at the time of recovery from sedation . Of the 45 patients who survived to undergo clinical assessment of strength, 27 were found to have signiﬁcant weakness (60%). Electrophysiologic abnormalities consistent with critical illness polyneuropathy/myopathy were seen in 25 of 27 of these weak subjects. ICU-acquired paresis was associated with increased duration of mechanical ventilation and increased blood glucose. The randomized controlled trial of corticosteroids for persistent ARDS by the National Institutes of Health, National Heart, Lung, and Blood Institute (NIH NHLBI) ARDS Network included a systematic chart review for evidence of neuromyopathy . Using this instrument, 48 of 180 subjects had evidence of myopathy, myositis, paralysis, muscle weakness, or neuropathy (classiﬁed as neuromyopathy) documented by treating clinicians. Neuromyopathy by this deﬁnition was not signiﬁcantly increased among subjects treated with corticosteroids, although all nine reported adverse events of weakness occurred in subjects randomized to corticosteroids. In a secondary analysis limited to 60-day survivors, neuromyopathy was found to be associated with hyperglycemia and increased concentration of
serum myoglobin . Clinical outcomes were also associated with neuromyopathy, including increases in return to mechanical ventilation (23% versus 9%, P ¼ .03), duration of mechanical ventilation after study day 1 (median of 17 days versus 11 days, P ¼ .02), and timing of eventual return to home (median 56 days versus 35 days, P ¼ .01) . A study to correlate the presence of neuromyopathy with long-term QOL of these subjects is ongoing. An early report of a third study shows that of 10 ARDS survivors, those with abnormalities on electrophysiological testing had lower scores on the physical functioning domain of the SF-36 than those without abnormal electrophysiology . These limited investigations provide preliminary evidence that neuromuscular dysfunction acquired in the ICU is common among patients with ALI, and is associated with metabolic factors such as hyperglycemia, and clinical outcomes, such as duration of mechanical ventilation and timing of return to home. History of studies of neuromuscular dysfunction associated with critical illness While there are few studies yet published that focus on ICU-acquired neuromuscular dysfunction among ALI patients, there is a growing body of epidemiologic and mechanistic literature reporting its incidence, risk factors, and pathophysiology in the critically ill. In 1892, Osler  reported that patients with sepsis develop muscle wasting and weakness, but little else connecting sepsis or critical illness with neuromuscular pathology appeared in the medical literature for decades. In 1977, a case report was published that described the onset of acute myopathy during treatment for status asthmaticus , and in 1983, there were three independent reports of polyneuropathy in critically ill patients [30–32]. These reports were followed by case series and retrospective studies that enrolled ICU patients who were clinically weak and examined combinations of clinical, histological, and electrodiagnostic features [33–35]. Pathologic ﬁndings included necrotizing myopathy, myopathy with thick ﬁlament loss without necrosis, and motor and sensory polyneuropathies with axonal degeneration and neurogenic myopathy. Since myopathy was initially described in patients with severe asthma  while polyneuropathy was described in long-term ICU patients presenting with failure to wean from mechanical
ventilation , myopathy and polyneuropathy of critical illness were initially regarded as two separate entities with diﬀering etiologies, populations at risk, and outcomes. Subsequent investigations showed that myopathy was not limited to asthmatics; muscle biopsies revealed necrosis and thick ﬁlament loss in ICU patients with sepsis and other illnesses, and in a number of patients, myopathy and polyneuropathy were coexistent . Although many terms have been used to describe these acquired neuromuscular disorders of critical illness, most are included by the terms ‘‘critical illness polyneuropathy’’ and ‘‘critical illness myopathy’’ , alone or in combination. Clinical features of critical illness polyneuropathy and myopathy The clinical signs of critical illness polyneuropathy and myopathy (CIPM) are often missed during the throes of acute critical illness during which the patient is usually sedated, restrained, and unable to communicate. In this period, clinicians may note lack of or weak withdrawal to painful stimuli with intact facial grimace. Diminished or absent deep tendon reﬂexes may be another sign, as is decreased spontaneous movement. Elevations in creatine kinase may be noted, or rarely, frank myoglobinuria. Once the patient clinically improves and wakefulness is regained, weakness may become more apparent. Diﬃculty liberating from the ventilator despite improved cardiopulmonary physiology may be the ﬁrst sign of CIPM; spontaneous breathing trials may result in rapid shallow breathing with CO2 retention and decreased inspiratory force and capacity. Critical illness polyneuropathy and myopathy are distinct conditions that often coexist and can be diﬃcult to diﬀerentiate, particularly when a patient is unable to cooperate with examination. Clinical, electrophysiological, and pathologic features of critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are outlined in Table 2. CIP is an axonal polyneuropathy that aﬀects both sensory and motor nerves. CIP is often preceded by septic encephalopathy . Physical examination of a cooperative patient may reveal distal sensory deﬁcits, distal weakness, and preserved (although sometimes decreased) deep tendon reﬂexes. Nerve conduction studies demonstrate decreased amplitudes of sensory and motor nerve action potentials. Electromyography may reveal reduced motor unit recruitment, but motor
NEUROMUSCULAR SEQUELAE IN SURVIVORS OF ALI
Table 2 Clinical, electrophysiologic, and pathologic ﬁndings of critical illness polyneuropathy and critical illness myopathy Findings
Critical illness polyneuropathy
Critical illness myopathy
Clinical and laboratory
Sensory deﬁcits Weakness (distal O proximal)a Diﬃculty weaning from the ventilatora Preserved deep tendon reﬂexes Decreased amplitudes of compound motor and sensory nerve action potentialsa Normal motor unit potentials with decreased recruitment Normal muscle excitability on direct stimulation
No sensory deﬁcitsa Weakness (proximal O distal) Decreased or absent deep tendon reﬂexes Elevated serum creatine kinase Preserved sensory nerve action potential amplitudesa Decreased compound muscle action potential amplitudesa Short, low-amplitude motor unit potentialsa Absence of decremental response on repetitive nerve stimulationa Muscle inexcitability on direct stimulation Myosin lossa Type II ﬁber atrophy Necrosis
Axonal degeneration with ﬁber loss Neurogenic atrophy
Suggested criteria for deﬁnitive diagnosis. Data from Bolton CF. Neuromuscular manifestations of critical illness. Muscle Nerve 2005;32:140–63; and Khan J, Burnham EL, Moss M. Acquired weakness in the ICU: critical illness myopathy and polyneuropathy. Minerva Anestesiol 2006;72:401–6.
unit potentials and muscle excitability should be normal. Pathologic evaluation reveals ﬁber loss and primary axonal degeneration of both motor and sensory ﬁbers, most severe distally . CIM describes a spectrum of muscle pathology seen in critically ill patients. Clinical signs include ﬂaccid tetraparesis, most severe proximally. Deep tendon reﬂexes are depressed or absent. Sensory function is not aﬀected. Nerve conduction studies reveal decreased amplitudes of compound muscle action potentials with preserved sensory nerve action potential. Electromyography shows small and short motor unit potentials. Direct stimulation of the muscle demonstrates reduced or absent muscle excitability . Several patterns may be seen on pathologic analysis of muscle. Most commonly, CIM has thick ﬁlament loss (seen on electron microscopy) with atrophy of the type II ﬁbers. Acute necrotizing myopathy develops less frequently, with diﬀuse necrosis of muscle ﬁbers. Additionally, atrophy from disuse and malnutrition may be seen predominantly in type II ﬁbers without other myopathic features . Evaluation of the noncooperative patient that is limited to physical examination and standard electrophysiologic studies is often unable to differentiate CIP from CIM. On physical examination, careful assessment of sensation is usually not possible due to sedation or encephalopathy. Serum creatine kinase may or may not be elevated, depending on the timing of evaluation and
the degree of muscle necrosis present, and has not been proven to be a reliable diagnostic tool, especially if normal. Diﬀuse edema, common to critical illness, may involve or surround nerves and may lead to decreased or absent sensory nerve action potentials that are consistent with the diagnosis of CIP, even without true nerve pathology. On the other hand, biopsy-proven CIP may occur in the presence of normal sensory nerve action potentials . Spontaneous activity seen as ﬁbrillations or positive sharp waves can been seen in both CIP and CIM, resulting from true denervation in the ﬁrst case and from ‘‘functional’’ denervation in the latter, where muscle necrosis separates the muscle from the end plate . Electromyographic diagnosis of myopathy traditionally relies on voluntary muscle contraction to assess motor unit potentials and recruitment; this is diﬃcult to accomplish in most ICU patients . Even muscle biopsy may be misinterpreted as isolated neurogenic atrophy if only light miscroscopy is performed, which cannot adequately assess thick ﬁlament myosin loss . Suggested diagnostic criteria for CIP and CIM are presented in Table 2. It is important to note that since both are common, occur in the same kind of patients, and often occur together, a deﬁnitive diagnosis is suspicious in many cases. CIP may be overdiagnosed while CIM is often underdiagnosed. As such, in reviewing the literature, it is often prudent to assume that the conditions
could not adequately be diﬀerentiated, and consider CIP and CIM together as CIPM . This is particularly true if direct muscle stimulation or muscle biopsy with electron microscopy is not part of the diagnostic strategy. Prospective studies of incidence of critical illness polyneuropathy and myopathy Prospective studies have improved the quality of knowledge about ICU-acquired neuromuscular disease. However, as summarized in Table 3, the study designs are variable, testing diﬀerent populations at diﬀerent time periods using diﬀerent methods of diagnosis. The ﬁrst investigations used electrophysiologic studies for diagnosis of CIPM in cohorts of septic patients, reporting incidences of 68% to 82% [38,46–48]. Cohort studies of mechanically ventilated ICU patients also found high incidences of CIPM by electrodiagnosis with rates of 47% to 58% [49,50]. Two recent studies of mechanically ventilated ICU patients found that 25% to 33% had clinical weakness on structured physical examination [51,52]. An additional study performed muscle biopsies on 31 consecutive ICU patients and found myopathic changes in 48% of patients . One multicenter prospective cohort study led by De Jonghe and colleagues  evaluated 332 consecutive ICU patients who required mechanical ventilation for 7 days or more. Patients were excluded for preexisting neurologic disease (101 patients) and for inability to pass a cognitive screen
before discharge from the ICU or death (111 patients). Study enrollment began on the day of passing the cognitive screen. All subjects underwent weekly muscle strength testing for 1 month, which consisted of strength testing of three muscle groups on each extremity. Strength was measured by physical exam using the Medical Research Council (MRC) 0- to 5-point scoring system, combined in a sum-score for all muscle groups tested, where 60 indicated full strength and 0 indicated inability to generate even a muscle twitch . Scores of 48 or less were used to indicate ‘‘ICU-acquired paresis’’ (ICUAP), a stringent deﬁnition of weakness. By protocol, all subjects with ICUAP had electrophysiologic testing performed within 72 hours of study entry; subjects still meeting criteria of ICUAP at day 14 of mechanical ventilation were referred for muscle biopsy. Ninety-ﬁve patients were included in the study, requiring prolonged ICU stays and ventilatory support for various medical-surgical reasons. The proportion of subjects meeting ALI criteria was not noted. Twenty-four (25%) subjects met the deﬁnition of ICUAP, with a mean proximal muscle group MRC score of 2 (indicating inability to oppose gravity). All subjects were followed until resolution of ICUAP (median 21 days). Electrophysiologic studies were performed on 22 ICUAP subjects, revealing reductions in compound muscle action potentials and sensory nerve action potentials in all subjects, and abnormal spontaneous muscle activity in 10 subjects. Muscle biopsies were performed in 10 of the 14 subjects
Table 3 Review of prospective studies of incidence of critical illness polyneuropathy and myopathy Author
Witt et al  Helliwell et al  Douglass et al  Coakley et al  Berek et al  Leijten et al  Tepper et al  Tennila et al  de Letter et al 
1991 1991 1992 1993 1996 1996 2000 2000 2001
Sepsis/MODS ICU patients Severe Asthma ICU patients Sepsis/MODS MV over 7 days Septic shock MV and SIRS MV over 7 days
43 31 25 23 22 38 25 9 98
30/43 15/31 9/25 22/23 18/22 18/38 19/25 9/9 32/98
Garnacho-Montero et al  Van den Berghe et al  de Jonghe et al 
Electrodiagnosis Muscle biopsy Clinical exam Muscle biopsy Electrodiagnosis Electrodiagnosis Electrodiagnosis Electrodiagnosis Electrodiagnosis, clinical exam Electrodiagnosis
MV, in ICU 7 days MV over 7 days, cooperative
Incidence (%) (70) (48) (36) (96) (82) (47) (76) (100) (33)
Abbreviations: MODS, mulitple organ dysfunction syndrome; MV, mechanical ventilation.
Clinical signs 15/43 (35%) Not reported Case deﬁnition 18/18 survivors weak 9/15 assessed (60%) Not reported (w50%) Not reported Case deﬁnition
NEUROMUSCULAR SEQUELAE IN SURVIVORS OF ALI
with persistent ICUAP at day 14; all had evidence of both primary myopathy (type II ﬁber atrophy with myolinolysis) and neurogenic muscle atrophy. Although limited by the small number of cases, the inability to assess cognitively impaired patients, and the lack of detailed assessment of subjects who did not meet ICUAP criteria, this study by De Jonghe and colleagues  is an important contribution. These results show that severe weakness is common among general ICU patients requiring a week or more of mechanical ventilation. By limiting invasive studies to ICUAP subjects, this study does not provide insight into the sensitivity of the clinical exam in detecting neuromyopathology in ICU patients. It appears, however, that the physical exam has high speciﬁcity in this population; all cases of ICUAP had evidence of both neuropathy and myopathy on subsequent invasive testing.
this was demonstrated in a large, randomized controlled trial . A second study of intensive insulin therapy performed in medical ICU patients apparently corroborates these results (Greet Van den Berghe, MD, PhD, personal communication, 2006). The results of the remaining association studies are contradictory, likely due to very small sample sizes, limited diﬀerential exposure between cases and controls, potential misclassiﬁcation of both diseased and disease-free subjects, and variations of tools and timing of evaluation of subjects, as shown in Table 4. It is also possible that there are diﬀerent risk factors for CIP and CIM, which were not diagnosed separately in most of these studies. Despite these conﬂicting results, sepsis, severity of multiple organ dysfunction, number of ICU and mechanical ventilation days, and treatment with corticosteroids or neuromuscular blocking agents may all be associated with CIPM, as is hyperglycemia. More conclusive studies are needed to establish these associations.
Analyses of risk factors for critical illness polyneuropathy and myopathy
Pathogenesis of critical illness polyneuropathy
Case reports and case series have described coincidence of acute neuromuscular abnormalities and sepsis, multiple organ dysfunction, hyperglycemia, treatment with corticosteroids [29,54,55], neuromuscular blocking agents [56–58] or aminoglycosides , and duration of mechanical ventilation . Each of these potential risk factors has been investigated in multiple studies, with conﬂicting results. Most compelling is the relationship between control of hyperglycemia with an intensive insulin regimen and prevention of CIPM, for
Signiﬁcant aspects of the pathogenesis of critical illness polyneuropathy can be grouped into three major categories: eﬀects of sepsis, eﬀects of treatment, and eﬀects of concomitant myopathy. First hypothesized by Bolton , it is now accepted that the axonal degeneration and ﬁber loss of CIP represents an additional organ dysfunction of sepsis and the systemic inﬂammatory response syndrome (SIRS). The pathophysiologic derangements associated with sepsis and SIRS aﬀect peripheral nerves in multiple ways.
Table 4 Review of risk factor analyses in prospective studies of critical illness polyneuropathy and myopathya Author (cases) Witt  (30, 70%) Helliwelll  (15, 48%) Douglass  (9, 36%) Coakley  (22, 96%) Leijten  (18, 47%) Tepper  (19, 76%) de Letter  (32, 33%) Garnacho-Montero  (50, 68%) Van den Berghe  (152, 42%) de Jonghe  (24, 25%)
ICU stay (days)
d Risk d No risk Risk Risk d No risk
d d d d No risk d Risk Risk
Risk d Risk d No risk d d d
d d Risk No risk No risk d No risk No risk
d d d No risk d d No risk No risk
Risk d d d d d d No risk
Abbreviation: MODS, multiple organ dysfunction syndrome. a Dashes indicate that exposure variable was not included in analysis.
Lacking autoregulation, the blood vessels that supply peripheral nerves may be especially susceptible to microthrombosis and other changes in the distal microcirculation . Recent data showing enhanced E-selectin expression in the vascular endothelium of peripheral nerves in patients with CIP provides another mechanism of altered microcirculation and associated sequelae . With increased capillary permeability, decreased serum albumin, and increased glucose, endoneural edema may develop, both aﬀecting nerve function and decreasing oxygen delivery to the nerve, leading to accelerated damage . Additionally, the inﬂammatory milieu of sepsis has deleterious eﬀects on peripheral nerves, with laboratory studies showing neuropathy induced by tumor necrosis factor, endotoxin, and fever [65– 67]. A speciﬁc endogenous neurotoxin has been identiﬁed in the circulation of patients with CIP and sepsis; this substance has not yet been further characterized, but has been shown to induce neuropathy in vitro . In the setting of increased capillary permeability and other factors damaging the peripheral nerves, critically ill patients may be particularly susceptible to the neurotoxic eﬀects of medications such as aminoglycosides. Changes in the muscle induced by critical illness also have deleterious eﬀects on peripheral nerves. It has been demonstrated that septic patients have mitochondrial dysfunction, which leads to bioenergetic failure and decreased ATP production . Lack of energy induces primary axonal degeneration that is more pronounced distally in long nerves . Pathogenesis of critical illness myopathy Most research of the pathogenesis of CIM has focused on myoﬁbrillar protein loss with increased proteolysis, decreased protein synthesis, and impaired myoﬁber repair and regeneration. Other important areas of research include derangements of energy delivery  and changes in the muscle membrane with primary inexcitability of muscle ﬁbers [70–72]. All three may contribute to easy fatigability and inability to generate normal muscle force. Muscle proteolysis in CIM may occur by several diﬀerent mechanisms. Calcium-dependent calpainmediated proteolysis has been implicated since studies have demonstrated an increase in calpain expression in aﬀected muscle ﬁbers; it is possible that alterations in calcium homeostasis play a role . There is also evidence that cathepsin-mediated
proteolysis by lysosomes plays a role in the muscle atrophy of CIM . Proteolysis is induced and accelerated by denervation of muscle, which may happen in the setting of critical illness through CIP, through segmental necrosis of muscle, and through pharmacologic denervation with neuromuscular blocking agents [39,75]. Activation of the ubiquitin-proteosome pathway appears to be an important contributor to muscle protein breakdown in CIM. This pathway is triggered by sepsis and associated inﬂammatory cytokines such as tumor necrosis factor-alpha, interferon gamma and interleukin-1 . Additionally, inﬂammatory mediators impair myoﬁber repair by decreasing the expression of MyoD, a gene that regulates muscle cell diﬀerentiation and myogenesis . Exciting new research has demonstrated that there are multiple ubiquitin-dependent pathways important to development of muscle atrophy in critical illness; one pathway is common to both neurogenic atrophy and primary myogenic atrophy (atogin-1), while another pathway is speciﬁc to CIM (induction of the transforming growth factor-beta/mitogenactivated protein kinase pathway) . Corticosteroids have a powerful direct eﬀect on skeletal muscle, and can lead to myosin loss, atrophy, and frank necrosis . Corticosteroids may also promote apoptosis in skeletal muscle, which contributes to cell and protein breakdown . Not only do steroids increase muscle breakdown, but also steroids decrease the synthesis of myosin, as detected by decreasing the production of myosin heavy chain mRNA .
Outcomes of critical illness polyneuropathy and myopathy Early diagnosis of critical illness polyneuropathy and myopathy and short-term outcomes It is not uncommon for patients with CIP or CIM to leave the ICU or even the hospital undiagnosed. It is likely that only a small minority of CIPM patients are diagnosed while receiving intensive care, usually in evaluation of failure to wean from mechanical ventilation . Although not part of current practice, early recognition of CIPM is valuable for the care of ALI patients. For the comatose or brain-injured patient, development of tetraplegia may be interpreted as deterioration of central nervous system function and decisions about care, speciﬁcally withdrawal of life-sustaining therapies, may be based on this
NEUROMUSCULAR SEQUELAE IN SURVIVORS OF ALI
interpretation . Diagnosis of CIPM in this patient population informs clinicians that aspects of physical exam may be unreliable assessments of brain function. Protracted mechanical ventilation may be both a risk factor for development of CIPM and a result of this condition [83,84]. CIP and CIM are commonly found in patients with diﬃculty weaning from the ventilator after resolution of acute cardiopulmonary issues . Assessment of the neuromuscular function of the diﬃcult-to-wean patient is important for treatment, prognostication, and discharge planning. Evidence of CIP in examination of the arms and legs correlates strongly with respiratory muscle involvement , and informs the clinician that the patient needs rest and ventilatory support while the respiratory muscles reinnervate. If isolated diaphragmatic weakness is suspected, phrenic nerve conduction or even diaphragm electromyography may guide management. Since CIPM is associated with need for return to assisted breathing after liberation from mechanical ventilation [26,84,86], these patients may beneﬁt from additional respiratory care and monitoring, including chest physiotherapy and augmented pulmonary toilet, daily vital capacity assessment, and placement in highly monitored locations after discharge from the ICU . It is likely that ALI itself is a risk factor for development of CIPM, as sepsis, prolonged mechanical ventilation, and high illness severity are all common among ALI patients. Therefore, it is recommended that all ALI patients are assessed for CIPM before ICU discharge. Currently, there is no evidence that evaluation in the clinical setting needs to be as rigorous as in the research setting. Clinical assessment should begin with a careful physical examination, particularly in the conscious patient, including assessment of proximal and distal strength, sensory exam of distal pain and proprioception, and evaluation of deep tendon reﬂexes. This evaluation may provide enough information for a presumptive diagnosis. In the uncooperative patient, or a patient with history or risk of other complicating neuromuscular disorders, electrophysiologic assessment of the limbs (nerve conduction testing and electromyography) may be informative. If limb studies are normal but respiratory muscle weakness appears likely, evaluation of the phrenic nerve and diaphragm may be warranted. Recognition of CIPM may help with coordination of early rehabilitation and physical therapy and preparations for hospital discharge. Early
recognition may also help the patient and informal caregivers prepare for protracted convalescence before and after leaving the hospital.
Long-term outcomes Little is known about the long-term outcomes of patients with CIPM. Only three prospective studies included follow-up evaluation. Of an inception cohort of 50 ICU patients enrolled after 7 days of mechanical ventilation in which 58% met criteria for CIPM, 24 of 32 survivors were followed through the rehabilitation period . CIPM was positively associated with rehabilitation delays, weakness in the legs, and sensory abnormalities in the feet. Five patients had persisting severe functional disabilities at 1 year: all ﬁve had evidence of CIPM in the acute setting. The second study began with 22 patients with sepsis and multiple organ failure; 82% met criteria for CIPM . At 3 months, electrodiagnostic study revealed improving but still diminished amplitudes of sensory nerve and compound muscle action potentials. Functionally, all patients had improved and were ambulatory. In the third study, only the 24 patients who were clinically weak during their ICU stay were followed; after 9 months, 7 died, all but 4 returned home, and all but 1 had only mild residual weakness. A recent follow-up study described the longterm outcomes of 22 survivors of a cohort of 195 patients who required ICU stays longer than 28 days . One year or more after ICU discharge, sensory defects were found in 29%, weakness in 18%, and both in 14%; electrodiagnostic evaluation was consistent with chronic partial denervation in more than 90% of subjects. Using the Barthel Index , a functional assessment tool that grades subjects’ abilities to perform activities of daily living with or without assistance, investigators found that 15 fo 22 patients were completely independent, whereas the remaining 7 patients required assistance. A systematic review of 36 studies compiled the long-term outcomes of 263 patients with CIPM . Most subjects were followed 3 to 6 months, but the sample included follow-up as long as 8 years. At hospital discharge most patients described profound muscle weakness, which improved over time beginning with the upper extremities. Over the course of follow-up, 68% of these subjects regained ability to walk independently, while 28% remained severely disabled,
unable to walk alone, or, in some cases, unable to breathe independently. While these investigations are intriguing, all are small and include biased samples that may not generalize to other populations, such as those who stay in the ICU for fewer than 28 days, or the patients similar to those lost to follow-up. Treatment and prevention of critical illness polyneuropathy and myopathy To date, there has been no conclusive study guiding treatment of patients with established CIPM. Two randomized, controlled trials have included prevention of CIPM as a secondary endpoint, and have demonstrated an impressive reduction in CIPM resulting from the use of an intensive insulin protocol to prevent hyperglycemia [61,89,90]. Other than intensive insulin therapy, current strategies for prevention of CIPM are based primarily on physiologic rationale. Since CIPM appears to be associated with sepsis, multiple organ failure, and duration of mechanical ventilation, practices that have been proven to prevent or minimize these complications are recommended. Daily interruption of sedation , low tidal volume ventilation , use of weaning protocols , activated protein C , and potentially ﬂuid-conservative management strategies  may directly or indirectly prevent or minimize the development of CIPM. Patients with known CIPM may beneﬁt from a multidisciplinary approach involving adequate nutrition, avoidance of additional myotoxins and neurotoxins (such as neuromuscular blocking agents and corticosteroids), rehabilitation and physical therapy, and attempts to prevent relapse of respiratory failure. Future directions While there has been a dramatic increase in knowledge of the biology and epidemiology of neuromuscular sequelae of ALI and critical illness over the past 10 years, there is still a long way to go. We continue to need high-quality epidemiologic studies of incidence, risk factors, and outcomes with standardized deﬁnitions of outcomes and regimented long-term follow-up at prespeciﬁed time points. We need improved and less involved diagnostic techniques to allow diagnosis reliable of CIPM outside of specialty centers. We need more interventional studies of prevention and therapy, including pharmacologic and physiatric interventions. Importantly, since the
mechanisms of ALI and sepsis are common to the pathogenesis of CIPM, interventional studies need to include incidence and severity of CIPM as standard measures of organ failure and outcome. ICU therapeutics may have unintended eﬀects on nerve and muscle, either beneﬁcial or harmful; it is essential that studies capture these short- and long-term functional eﬀects. And, in the meantime, we need to do a better job helping our patients understand the nature of their physical disability after critical illness and provide strategies to promote their recovery.
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