Muscle Dysfunction in Critical Illness

Patients surviving critical illness experience significant skeletal muscle dysfunction and weakness. Muscle atrophy suffered during critical illness has a long-term impact on the functionality and mobility of these individuals.1-6 The underlying etiology is multifactorial, but largely thought to be caused by immobility(bed-rest), severity of illness, prolonged mechanical ventilation, sepsis, systematic inflammation, and delirium.7-9 Additionally, these alterations are purported to impair recovery of muscle function following discharge from the intensive care unit (ICU) leading to long-term physical deficits. From previous randomized controlled trials, results have demonstrated that early rehabilitation focused on mobility may positively influence patient functional outcomes.10 However, a number of randomized controlled trials implementing early rehabilitation fail to demonstrate robust immediate or long-term benefits.11,12 Mixed results may in large part be due to inconsistency in early assessment and classification of these patients.

In recent years, researchers have utilized ultrasound to classify and track changes in muscle size and quality; demonstrating up to 30% decline in rectus femoris cross-sectional area in the first ten days of critical illness.13,14 In addition, muscle tissue analysis have elucidated morphological changes including myofiber necrosis in 40% of patients with acute respiratory distress syndrome. In the recovery phase, tissue analysis revealed a reduction in satellite cells within the muscle, sparking the hypothesis that these individuals have an impaired regenerative capacity.15 The absence of satellite cells may not be responsible for alterations in recovery solely, if at all.16 The investigators propose that increased collagen production within the muscle tissue is a major contributor to impaired or slow recovery of muscle tissue. The investigators hypothesize that distinct phenotypes of patients exist with different activation of physiologic pathways and therefore different clinical and functional presentations. The primary purpose of this study is to develop a model to classify patients based on markers of muscle function, clinical composition, and functional data. This classification is multifactorial which will enable improved prediction of the patient's recovery trajectory at very early time-points.

Moreover, studies elucidating the underlying muscle biology and physiologic mechanisms have yet to connect those changes to physical function and independence. Correlating specific markers of muscle health to functional outcome measures is a necessary step to provide clinicians with evidence to support and adapt their practice in relation to the pathophysiology of the muscle. Finally, muscular power has not been examined in this population. Muscular power is a key component of functional mobility that is not a current focus in critical care rehabilitation. Power may be a primary culprit of reductions in functionality specifically related to performing simple task such as sit-to-stand with adequate strength and velocity. Studying power in this population is novel and could lead to immediate changes in rehabilitation practice.

Aim 1: Examine and quantify changes in muscular power during critical illness and through the first six months of recovery. Hypothesis: Patients with longer times immobilized and higher severity of illness will have larger declines in muscle power during hospitalization with slower recovery of muscle power in the first six months after discharge. To test this hypothesis, the investigators will longitudinally record muscular power using a linear transducer with a standardized weight-apparatus. This is an innovative approach and novel in this population.

Aim 2: Determine the relationship of the physical function and independence to muscle function. The correlation between characteristics of muscle health to patient's functional status has not been performed to this extent. Hypothesis: Patients with the steepest declines in rectus femoris muscle cross-sectional area in the first seven days of ICU admission will have lower scores of functional outcomes requiring higher levels of assistance at hospital discharge. Researchers will compare findings from muscle ultrasound (size and structure), muscle strength, muscle power, and functional endurance to functional outcomes during critical illness and across the first six months of recovery. These data will be analyzed and stratified based on predictive functional recovery trajectories.

Aim 3: Elucidate the molecular and cellular mechanisms leading to muscle dysfunction and impaired recovery following critical illness. Specifically, to determine the effect of myofiber type on functional capacity and explore the role of collagen and lipid deposition in the capacity for muscle to regenerate. Hypothesis: Patients with higher severity of illness that require more days on mechanical ventilation (MV) will have increased collagen production in the extra-cellular matrix leading to larger disability at 6-month follow-up. To test this hypothesis, muscular biopsies will be performed within two weeks of hospital discharge and again at 6 months post hospitalization.

This study builds the understanding that clinicians have the knowledge and resources to predict which patients will suffer the largest deficits. Thus, these classifications will enable clinicians to identify, at very early-timepoints, which patients will benefit from rehabilitation interventions. Furthermore, this proposal starts to address classifying patients based on phenotypes, including the concept of responders and non-responders. Establishing a multi-factorial classification system with components of muscle function will support rehabilitation clinicians in their decision to allocate early interventions. Streamlined allocation of interventions will mitigate the negative consequences of critical illness and maximize long-term patient outcomes