Ethical Considerations: This study was reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines and approved by the Institutional Review Board at the University of Kentucky. Research subjects or legally authorized representative provided written informed consent before participating in the study. Consent was obtained from a legally authorized representative for patients unable to give consent due to sedation, mentation, and/or consciousness, re-consent was obtained once patient was awake, stable, and could provide informed consent themselves.
Study Design: A prospective, longitudinal observational study was conducted with adult patients admitted to Medicine ICU (MICU) or the Cardiothoracic ICU (CTICU) and enrollment occurred from November 15, 2018, to July 15, 2019. Eligibility criteria were: 18 years of age or older with a primary or secondary diagnosis of acute respiratory failure (ARF) or sepsis of any origin that were anticipated to spend more than 3 days in the MICU/CTICU and survive the current hospitalization and enrolled within 48 hours of admission. Patients were excluded from enrollment if they had baseline cognitive impairments, were non-ambulatory prior to hospitalization, had a pre-existing neurologic or neuromuscular disorder, new traumatic injury with lower-extremity fracture, one or more amputations of lower-extremity, were pregnant, admitted for substance abuse or were otherwise inappropriate for study procedures as determined by the primary attending physician. Patients with morbid obesity (body-mass index (BMI) > 45 kg/m2) were excluded to reduce distortion of ultrasound images.
Muscle Size and Echointensity: The Sonosite IViz (FUJIFILM SonoSite Inc. Bothell, WA) portable ultrasound with 8.5-MHz linear transducer was used to assess the right quadriceps femoris muscle and the right tibialis anterior (TA) muscle on ICU days 1, 3, 5, and 7. Ultrasound device settings were kept constant for subjects across time-points with the same sonographer (KM, physical therapist, PhD, >4 years of muscle ultrasound experience) acquiring all images.28 The methods for image acquisition and analysis of quadriceps and TA were previously reported1,29 and have good to excellent reliability28,30-32. Minimal probe compression and depth of 5.9 cm were utilized to obtained three images at all timepoints of both muscles. Quadriceps femoris muscle imaged at 2/3 distance from Anterior Superior Iliac Spine (ASIS) to superior patella border and TA muscle imaged at 1/3 distance from lateral tibial plateau to inferior border of the lateral malleolus. Images were saved on the device hard-drive and transferred to computer for analysis using ImageJ software (NIH, Bethesda, MD). The average value of three consecutive images was used in analyses.25,27 Quadriceps femoris ultrasound images were analyzed for quantification of rectus femoris (RF) muscle cross-sectional area (CSA), RF muscle thickness (mT), quadriceps complex (QC) muscle thickness (rectus femoris plus vastus intermedius thickness), and for muscle quality (Echogenicity- EI)28. TA muscle ultrasound images were analyzed for mT, CSA and EI. The final analyses included two approaches: CSA, mT and EI on ICU day one of admission to ICU (baseline) and parameters as percentage change from ICU day 1 to day 7.
Muscle strength, power and physical function: Prior to volitional assessments, patient had to be oriented (determined as ability to complete 3 of 4 domains of name, birthday, location, and date) and demonstrate ability to follow commands by scoring ≥ 3/5 on DeJonghe criteria.33
Muscular strength: Muscle strength was assessed using three different techniques at ICU discharge and hospital discharge:
1) The Medical Research Council sum score (MRC-ss) is a measure of global peripheral limb muscle strength that is standard of care for diagnosing ICU-AW with less than 48/60 denoting diagnosis.33-35 The MRC-ss six-consist of a 6-point scale measuring twelve muscles and has been described previously.36
2) Muscle strength force production and the rate of force development of the right knee extensors and right ankle dorsiflexors were recorded using a hand-held dynamometry (HHD) (Lafayette Manual Muscle Test System Model-01165, Lafayette Company, Lafayette, IN).37 HHD to assess isometric muscle strength is reliable and correlated to the gold standard of isokinetic dynamometry37. Knee extension was measured in supine or semi-reclined (head of bed <30 degrees) position with 20 degrees of knee flexion using a roll with dynamometer positioned proximal to the foot on the tibia38. Ankle dorsiflexion was measured with the knee in ~5 degrees of flexion (small towel under the knee) and supported on a hospital bed or leg-rest with the ankle in neutral with dynamometer positioned on the dorsum of the mid-foot. Patients unable to extend lower limb or dorsiflexion foot against gravity (<3/5 on MRC-ss for knee extension and ankle dorsiflexion) did not perform HHD. Patients participated in a minimum one practice repetition with therapist providing standardized verbal cues for activation, direction, and encouragement. The peak value of six second contraction was recorded and the average of three repetitions was used in analyses with patients resting a minimum of 30 seconds between repetitions.
3) Hand-grip strength of dominant hand was assessed at ICU discharge and hospital discharge using the Jamar Hydraulic dynamometer (Sammons Preston Rolyan, Bolingbrook, IL, USA) with technique, position and cues previously described.36,39 The average of the peak values for three repetitions was utilized in the analysis.
Muscle Power: Muscle power was assessed at ICU discharge and again at hospital discharge with a linear potentiometer (HUMAC-360, CSMi, Stoughton, MA) to record the velocity and peak-velocity of a unilateral lower-extremity press using a Shuttle MiniPress (Shuttle Systems, Bellingham, WA) while sitting in hospital bed or seated in hospital chair. Subjects performed three repetitions of the leg press at two pre-determined levels of resistance, 2 lbs and 10% of bodyweight. Patients were permitted to perform three repetitions for familiarization prior to formal testing.
Physical functional outcomes: The primary physical function outcome of interest was performance of 5-times sit to stand test (5x STS) at hospital discharge since it is a fundamental component of mobility and an independent measure of muscle strength and power.40 The Short Performance Physical Battery (SPPB)41,42, six-minute walk distance (6MWD)43,44 and clinical frailty scale (CFS) were assessed at hospital discharge. The CFS is validated tool assessing frailty based on mobility status, cognitive and physical function, and levels of independence.45
Standard rehabilitation and nutrition care: Patients admitted to MICU/CTICU receive physical therapy and occupational therapy as standard of care initiated by order at the discretion of the primary attending. This typically includes physical and occupational therapy 2-5 times per week lasting ~30 minutes and started upon weaning of sedation with physicians attempting to follow the ICU Liberation Bundle (A-F). The Physical Function in the ICU Test (PFIT-s) was performed by staff physical therapists according to routine care which includes performing the test upon initial evaluation in the ICU.46,47 Nutritional practice in our institution aligns with the SCCM/ASPEN guidelines for critically ill adults.48 Our nutrition support service assesses all ICU patients, providing a customized nutritional assessment, and enteral nutrition within 24h- 48h of ICU admission, for patients without volitional intake.
Clinical Variables: Baseline demographics (age, sex, BMI), Charlson Comorbidity Index (CCI), and critical illness data including ICU admission diagnosis, Sequential Organ Failure Assessment (SOFA), hours of mechanical ventilation (MV), ICU and hospital length of stay (LOS), time to first rehabilitation session, number of rehabilitation sessions, sedation (yes/no), use of inotropes and vasopressors (yes/no), and mortality (defined as in-hospital mortality plus transfer to inpatient hospice) were assessed.
Sample Size: A priori sample size calculation was not performed. The sample size was pragmatically based on 8-month time frame as well as previously published literature: Puthucheary et al previously reported a sample size of 32 patients to detect a 10% reduction in RF muscle CSA over first ten days of ICU admission.1 Parry et al utilized a pragmatic sample size (n=20) to demonstrate a 25% reduction in RF muscle CSA in first seven days25. Therefore, we utilized a pragmatic sample of 40 patients for this study.
Statistical Analysis: Data were assessed using descriptive statistics including mean and standard deviation (SD) or median and interquartile range (IQR), histograms, and Shapiro-Wilk test for normality. Ultrasound data were examined for change over time using a linear mixed-model approach. The relationships between muscle ultrasound parameters, muscle power, muscle strength, demographics, clinical, and physical function data were assessed with Spearman Rho tests. A multivariate logistic regression model was created to assess the effects of independent variables on development of ICU-AW at hospital discharge. Variables identified for the model included baseline demographics (age, sex, BMI) and other variables that are purported to be associated with weakness including muscle size and quality, severity of illness, ICU length of stay and muscle power. Stepwise backwards regression at the 0.2 level was used to minimize overfitting. Power assessment (10% BW) at ICU discharge was forced into the model, as this is our primary exploratory predictor variable. Using the same approach, a multivariate linear regression was used to assess the relationship between predictor variables with dependent variable of 5-times sit-to-stand performance at hospital discharge. The models were tested for assumptions of logistic and linear regression as appropriate. Multicollinearity was assessed using variance inflation factor; normality of errors was assessed with the IQR test. We assessed model fit with the Hosmer-Lemeshow and likelihood ratio tests. Heteroskedasticity of residuals was assessed with the Breusch-Pagan/Cook-Weisberg test, and standardized robust errors were used to adjust for heteroscedasticity in the models as appropriate. All other assumptions were met. Data were analyzed and visualized using GraphPad Prism 8.2 (GraphPad Software, San Diego, CA) and regression analyses were performed using Stata (version 14.2, Stata Corp, College Station, Texas, USA).