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CHAPTER 15: Long-Term Outcomes After Critical Illness 107

evaluated using diagnostic tests (nerve conduction velocities, needle CRITICAL ILLNESS MYOPATHY
electromyography, direct muscle stimulation, histopathology of muscle
or nerve tissue) or a combination of these test findings and clinical ■ BACKGROUND AND INCIDENCE
findings of muscle weakness, decreased or absent deep tendon reflexes, Critical illness myopathy (CIM) encompasses a variety of descriptive
and/or failure to liberate from mechanical ventilation. Weakness may
initially be absent or difficult to detect clinically in these patients, but terms that include critical illness myopathy, acute quadriplegic myopa-
thy, thick filament myopathy, and necrotizing myopathy. Reported
subsequent electromyography (EMG) testing will demonstrate abnor-
malities showing an initial primary axonal degeneration of the motor incidence has varied between 48% and 96% in prospective studies that
have included muscle biopsy as part of their diagnostic evaluation.
58
neurons, followed by the sensory neural fibers, and this coincides with
acute and chronic changes of denervation noted on muscle biopsies in CIM is characterized pathologically by a nonnecrotizing myopathy that
is diffuse and associated with fatty degeneration of muscle fibers, fiber
affected patients. 40 atrophy, and fibrosis. This has been described in patients with sepsis
60
■ ETIOLOGY AND PATHOPHYSIOLOGY but also in those treated with corticosteroids and neuromuscular block-
may be indistinguishable from patients with CIP. Muscle biopsy allows
SIRS and Sepsis: CIP occurs in the context of SIRS and sepsis as shown ers. Patients will be weak, paretic, and have difficulties in weaning and
by multiple prospective and retrospective cohort studies. In sepsis, differentiation between these lesions.
41
the pathogenesis of CIP is linked to a perturbation in the microcircu- Thick filament myopathy shows a selective loss of myosin filaments in
lation with resultant axonal injury and degeneration. A recent report the context of significant corticosteroid or neuromuscular blocker exposure
61
describes increased expression of E-selectin on the endoneurial and and immobility. Some have speculated that this may represent a precursor
epineurial vessels of peripheral nerves in septic patients and this has to acute necrotizing myopathy since this form of CIM may show progres-
been shown to be mediated by proinflammatory cytokines such as sion to myonecrosis. Acute necrotizing myopathy is distinguished by exten-
TNF-α and IL-1. There is also evidence for a disruption of nerve sive myonecrosis with vacuolization and phagocytosis of muscle fibers and
42
action potential, which may be functional—and potentially entirely has been most often linked to corticosteroid and neuromuscular blocker
reversible early on—and not necessarily structural over the course of exposure and occurs in the context of multiple failed organ systems. 62
Hyperglycemia: ICUAW is consistently associated with hyperglycemia ■ ETIOLOGY AND PATHOPHYSIOLOGY
the disease.
43
in critically ill surgical and medical populations. 44-46 In their initial The pathophysiology of CIM entails catabolism, inflammation, and
landmark publication, Van den Berghe and colleagues demonstrated derangement of membrane excitability. Protein catabolism and an
that tight glycemic control reduced CIP, as defined by neurophysiologic increase in urinary nitrogen loss are observed in CIM. Muscle biopsies
testing, from 51.9% in control subjects to 28.7% among insulin-treated in affected patients show low glutamine, protein, and DNA levels. There
patients. Similar findings were noted in a predominantly medical is evidence for the upregulation of the calpain and ubiquitin proteolytic
44
population in a subsequent study by the same group of investigators. pathways and this occurs in concert with an increase in apoptosis. 63
45
The pathophysiologic link between glucose control and neuroprotec- Inactivity in critically ill patients is linked to propagation of inflam-
tion remains unclear, although there are some emerging data that may matory mediators, which result in direct stimulation of protein loss in
provide some new insights. Vanhorebeek and colleagues found that differentiated muscle cells, activation of a cascade of signaling events that
47
hyperglycemia causes mitochondrial dysfunction and ultrastructural promote oxidative injury, and disruption of insulin receptor signaling in
damage in the hepatocytes of critically ill patients. One might speculate muscle resulting in a reduction in substrate availability and impairment
64
that there is a similar effect on the peripheral nervous system and that of myofibril growth and repair. IL-1, IL-6, and TNF-α have proinflam-
protection of intact neuronal mitochondria may avert the deleterious matory properties and have all been implicated in muscle degradation
effects of oxidant injury and apoptosis that have also been implicated in critical illness and augment proteolysis and result in loss of muscle
in the pathophysiology of CIP. There may also be an important con- mass with a resultant decrease in muscle strength. The presence of IL-10
48
tribution from derangement of nitric oxide production. Asymmetric inhibits proinflammatory mediators and may have a role in mediating
65
dimethylarginine inhibits nitric oxide production and is an independent apoptosis and myocyte proteolysis. Some studies suggest evidence of
predictor of mortality in critically ill patients. Siroen and colleagues muscle membrane inexcitability, which may be related to inactivation
49
showed recently that insulin modulates levels of asymmetric dimethylar- of sodium channels at the resting potential (sodium channelopathy).
ginine and this may be an additional pathway by which insulin improves A recent report by Allen and colleagues found altered muscle-fiber excit-
this outcome. Some evidence indicates that insulin inhibits proinflam- ability and evidence for muscle membrane dysfunction as the principal
matory transcription factors and may actively promote neuroregenera- underlying abnormality in CIM. 66
tion during critical illness. 50,51
Pharmacologic Agents: Early reports suggested a link between neu- CLINICAL PHENOTYPES IN CRITICAL ILLNESS
romuscular dysfunction and the use of neuromuscular blockers and AND THE SPECTRUM OF DISABILITY
systemic corticosteroids. 52-54 This risk was highlighted by the observa-
tion of neuromuscular dysfunction in patients with status asthmaticus There are emerging data from recent cohort studies and administrative
who received treatment with both agents. However, these relation- datasets that the heterogeneity in disability after critical illness may be
55
ships have not been borne out in a recent, exhaustive systematic organized into discrete etiologically neutral clinical phenotypes with
review. Reports link aminoglycoside, vasopressor, and renal replace- different risks and recovery trajectories over weeks and months after
56
ment therapy use with neuromuscular dysfunction, but since most critical illness. These different clinical groups, when viewed together,
patients have sepsis or SIRS and will receive these therapies, it is very may comprise the spectrum of disability and facilitate the development of
difficult to determine any true causality. 57,58 Furthermore, in a recent rehabilitation interventions by understanding how common patient traits
randomized controlled trial on the early use of paralytic therapy in may be used to risk stratify and to inform the needs of that specific group.
paralysis did not appear to confer additional risk for weakness on ■ UBIQUITOUS INJURY
patients with severe ARDS, the exposure to 48 hours of continuous
the ICU survivors as assessed by the Medical Research Council score The imbalance between protein synthesis and protein degradation
assessing strength. 59 appears to be universal in critically ill patients. Proteolysis in diaphragm

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