Inflammatory Signatures in ICU-Acquired Weakness*

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The onset of multifocal or generalized impairments in muscle and/or nerve function in the setting of critical illness, a heterogeneous spectrum of disorders collectively referred to as “ICU-acquired weakness” (ICU-AW), (1) is, alongside delirium, the most common neurologic syndrome seen in critically ill patients (2). ICU-AW is independently associated with adverse clinical outcomes in both the short and long term, including higher mortality and significant functional disability, and is recognized as a major driver of postintensive care syndromes (3). While patient- and treatment-specific risk variables for ICU-AW have been documented, efforts to account for the pathobiology underlying the clinical phenotype of ICU-AW have been inconclusive. Mechanisms implicated in critical illness myopathy include microvascular insufficiency, an acquired sodium channelopathy, increased myocyte proteolysis and apoptosis, failure of satellite cell recruitment, mitochondrial impairment, oxidative stress, and local inflammatory signaling (4). Many of the same processes have been linked with critical illness polyneuropathy although the pathogenesis of the latter is even less well understood.
A growing body of evidence indicates that maladaptive changes in immunologic or inflammatory signaling represent a common pathway responsible for triggering and subsequently perpetuating muscle and nerve dysfunction in critically ill patients. Dramatic adaptations in local and systemic inflammatory signaling are the ubiquitous hallmark of organ dysfunction and critical illness and injury, contributing in a time-dependent cycle to both cellular destruction and, importantly, to tissue remodeling and regeneration. Muscle biopsies in patients with ICU-AW reveal activated leukocytes and increased local expression of inflammatory mediators (5). There is an intriguing relationship between lack of physical activity and proinflammatory signaling (6, 7), and evidence suggests that immobility and systemic inflammation have independent but additive effects in inducing muscle weakness (8). Furthermore, recent work suggests that increased serum levels of proinflammatory markers can persist up to 3 months after critical illness and are associated with worse physical function as measured using a mobility score (9).
In this issue of Critical Care Medicine, Witteveen et al (10) investigate patterns of inflammatory protein expression and their association with clinically diagnosed ICU-AW in a prospective cohort of 204 patients admitted to a medical-surgical ICU and receiving at least 2 days of mechanical ventilation. Serum inflammatory signaling proteins were assayed on enrollment and 2 and 4 days following, and included interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-13, tumor necrosis factor-α, interferon-γ, granulocyte macrophage colony-stimulating factor, fractalkine, intercellular adhesion molecule-1, E-selectin, and P-selectin—molecules which have been implicated in the host response to sepsis, trauma, and surgery. The principal outcome was ICU-AW diagnosed with manual muscle testing (Medical Research Council [MRC] scale) when patients had awakened and were able to follow commands. Using this approach, ICU-AW was identified in nearly half of this cohort (99 patients). With the help of principal components analysis and partial least squares-discriminant analysis (PLS-DA), a proinflammatory signature was identified (IL-6, IL-8, IL-10, and fractalkine) which was independently associated with a higher risk of ICU-AW. PLS-DA demonstrated that the same biological signature predicted ICU-AW in patients regardless of whether they were clinically diagnosed with sepsis.
Results presented here do not allow direct inferences regarding causality, although the very early presence of a proinflammatory signature, prior to the clinical recognition of ICU-AW, indicates at least a plausible temporal sequence. Another limitation is that muscle strength was determined at only one time point, and this was done a median of 9 and 7 days after ICU admission (respectively in the ICU-AW and non-ICU-AW groups), suggesting that some patients may have been inaccurately classified. Earlier and repeat MRC assessments, as well as electrodiagnostic testing, would have increased confidence in the classification.
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