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

Inclusion Criteria:

- admitted to medicine, cardio-thoracic or trauma ICU

- initial primary or secondary diagnosis of acute respiratory distress/failure

- mechanical ventilation (predicted for at-least 72 hours)

Exclusion Criteria:

- receiving palliative treatment

- attending physician excluding due to high-risk of mortality

- neurological injury or event

- lower extremity amputee

- pregnant

- non-ambulatory prior to admission