Trial design

This is a prospective multicentre observational study to evaluate longitudinal inpatient and outpatient measures of muscle mass and function in critically ill adults with AKI requiring CRRT and to compare these measurements with those of historical ICU controls without AKI-RRT. The study will have two phases, an ICU phase and a recovery phase for subjects who survive to discharge.

Study setting

This study will be conducted at the adult ICUs at the academic medical centres of the University of Kentucky, University of Iowa and University of New Mexico. Following discharge, survivors will return for outpatient evaluation of skeletal muscle and physical function.

Eligibility criteria

To be included in the study, patients are required to be ≥18 years old and have AKI-RRT with enrolment within 48 hours of CRRT initiation. Exclusion criteria include: (1) ICU admission for >7 days; (2) RRT of any kind at any time before ICU admission; (3) CKD with estimated glomerular filtration rate <20 mL/min/1.73 m² as calculated by the 2021 CKD-EPI equation;37 (4) underlying muscle disorders or muscle atrophy such as quadriplegia or hemiplegia, stroke with residual motor deficits, end-stage liver disease, active alcohol use disorder, active malignancy (other than non-melanoma skin cancer) within 1 year, burns or other baseline neuromuscular disease; (5) pregnancy; (6) concomitant use of other extracorporeal support devices such as ventricular assist devices or extracorporeal membrane oxygenation or (7) anticipated inability to engage in weight-bearing testing after discharge (eg, trauma or orthopaedic surgery). For outpatient testing, patients will be ineligible if they remain on RRT in the week prior to the research appointment.

Control population

Given the pilot nature of this study, we will use recent historical controls defined as critically ill adults without AKI-RRT in whom similar measurements of muscle size, quality and function were collected. Specifically, we have previously collected data on 41 ICU patients, of which 36 did not have AKI-RRT and will serve as the control group for the ICU phase of this study, and have published the results of MSKUS performed in the ICU and functional assessments performed at both ICU discharge and hospital discharge.38 The controls for the recovery phase will come from an ongoing prospective observational study being performed at the University of Kentucky, which will include outpatient functional assessments performed on 200 ICU survivors (NCT05537298). See table 1 for a summary of the demographic and clinical characteristics of the control cohorts which have been published thus far.21 38 39

Primary outcome (ICU phase)

The primary outcome is the change in RF CSA, mT and EI measured by MSKUS at baseline, assessed within 48 hours of CRRT initiation, to ICU days 3 and 7 of study enrolment (or at ICU discharge, if sooner). Operational and standardisation procedures have been previously published.35 38 In brief, patients are positioned supine with the lower extremity in neutral alignment. RF ultrasound images are acquired two-thirds of the distance from the anterior superior iliac spine to the superior border of the patella of the right lower extremity at all time points. Sonographers will use a linear probe (5–15 Hz) with the same machine for all time points and a minimal-to-no-compression technique. Sonographers will obtain three images per assessment to reduce variations in EI. Ultrasound images will be assessed for CSA, mT and EI at baseline within 48 hours of CRRT initiation, at days 3 and 7 from enrolment (or at ICU discharge, if sooner). A representative ultrasound image and the techniques for landmarking and probe pressure are provided in figure 1.

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Figure 1

Representative images of ultrasound acquisition techniques and the obtained image of the rectus femoris muscle. (A) is a representative ultrasound image with anatomical structures labelled for the quadriceps muscle. (B) demonstrates the technique to locate the anatomical landmarks for rectus femoris ultrasound (two-thirds of the distance from anterior superior iliac spine to the superior border of the patella). (C) depicts the-minimal-to-no-compression technique using the ultrasound probe with adequate ultrasound transmission gel to obtain images. These images were staged by the authors to demonstrate appropriate technique and were not taken from a patient encounter.

Secondary outcomes (ICU phase)

Patients will have blood collected at baseline (within 48 hours of CRRT initiation), at study days 3 and 7 (or ICU discharge, if sooner). Creatinine and cystatin C will be measured at each time point. In addition, 5 mL blood samples and CRRT effluent samples at each time point will be sent for gas chromatography-mass spectrometry evaluating a panel of analytes including amino acids, carbohydrates and fatty acids. Remaining samples will be stored for future analysis, though no genetic analysis will be conducted now or in the future.

Patients will be scored at the same time points as above using the ICU Mobility Scale, an 11-point scale ranging from 0 to 10 which involves the clinician scoring the patient’s maximum level of mobility in the prior 24-hour period.40 41

Outcomes (recovery phase)

Survivors will participate in skeletal muscle and physical function testing at hospital discharge and during the outpatient visit at 1–3 months postdischarge. Measurements will include MSKUS to determine RF CSA, mT and EI. We will also conduct an array of standardised and validated tests including:

• Medical Research Council Sum-score (MRC-ss): MRC-ss is a measure of global peripheral muscle strength that is the current clinical standard for diagnosing ICU-acquired weakness (ICU-AW).42 Muscle strength is assessed by physical exam and rated on an ordinal scale (0–5) at six bilateral muscle groups: shoulder abductors, elbow flexors, wrist extensors, hip flexors, knee extensors and ankle dorsiflexors. A score<48 is considered indicative of ICU-AW, with a score<36 indicative of severe weakness with the inability to act against resistance.43

• Muscle strength using hand-held dynamometry for knee extension: Maximal isometric knee extensor strength will be measured as peak force production and rate of force development following previously published standardised positions (figure 2).44

• Muscle strength using hand-grip dynamometry: Hand-grip dynamometers will be used to measure maximum isometric strength of the hand and forearm muscles at previously published standardised positions.42 43 The patient will undergo three repetitions with both the right and left hand, alternating between hands.

• Short Physical Performance Battery (SPPB): Physical function and physical frailty will be measured using the SPPB, a performance-based composite test with a total of 12 points including components of balance (side-by-side stand, semitandem stand and full-tandem stand), chair-to-stand test and 4 m habitual gait speed.45 46

• Timed Up and Go (TUG) Test: The TUG assesses the time (in seconds) for a subject to stand on command from a seated position, walk 3 m, turn around, walk back to the chair and sit down. The purpose of TUG is to assess mobility, physical function and fall risk. TUG has been validated in and recommended for patients with critical illness.47–49

• Six min walk test (6-MWT): The 6-MWT assesses the distance a subject can walk in 6 min, providing a global representation of physical function and cardiopulmonary endurance.50 51 Meta-analysis provides benchmark data for survivors of critical illness.52

• QoL testing using EuroQol Group 5-dimension 5-level (EQ-5D-5L) questionnaire: The EQ-5D is a standardised measure of health status developed by the Euro-Qol Group to provide an assessment of health for clinical and economic appraisal.53 It consists of two sections: the descriptive system and the Visual Analogue Scale (EQ VAS). The descriptive system assesses five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ VAS records the respondent’s self-rated health on a 20 cm vertical VAS with endpoints labelled the ‘best health you can imagine’ and the ‘worse health you can imagine’. This information can be used as a quantitative measure of health as judged by individual respondents.51 54 55

• Clinical Frailty Scale (CFS): The CFS is designed for clinical use and has been widely adopted as a judgement-based tool to screen for frailty and to broadly stratify degrees of fitness and frailty.56 57 It is not a questionnaire, but a way to summarise information from a clinical encounter to roughly quantify an individual’s overall health status. While CFS has traditionally been used specifically in older patients, recent data have demonstrated its utility in an ICU population demographically similar to our target population.58

• Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Questionnaire: The FACIT-F scale is a 13-item measure that assesses self-reported fatigue and its impact on daily activities and function.59 60

• Thirty-six-Item Short Form Health Survey Physical Function Scale (SF-36 Physical Function): The SF-36 is a 36-item patient-reported survey of health commonly used to evaluate adult patients which contains 8 domains, including a physical function scale based on 10 of the 36 items which has been shown to have high reliability.61

• Additional events: Finally, we will document the occurrence of the following events: return to driving, return to work or hobby, hospital readmission and need for emergency department care.

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Figure 2

Representative image of the performance of hand-held dynamometry to measure isometric knee extensor strength with a subject in the supine position with a towel roll keeping the knee in 20°–30° of flexion. This image was staged by the authors to demonstrate appropriate technique and was not taken from a patient encounter.

Assessor training

This multisite study is an interdisciplinary collaboration with expertise in critical care, nephrology, muscle biology and physical function. Physical therapist–scientists and exercise physiologists with established expertise in MSKUS and functional testing serve as coinvestigators at each site. Three 2-hour sessions of teleconference training will be performed to promote standardisation of ultrasound and outcome assessments. In addition, novice sonographers were instructed to perform and practice a minimum of 10 acquisitions of RF muscle images from healthy individuals before study initiation. To better establish inter-rater reliability of image acquisition, the first five patients at each site will have ultrasound studies conducted by two team members. The first sonographer will obtain images and leave the room, and the second will enter and repeat the test. After a 10 min wash-out period, the team members will sequentially repeat the ultrasound measurements, which will allow us to establish both interobserver and intraobserver variability. Finally, images will be blinded, coded (rater 1 or rater 2; site location) and sent securely to the University of Kentucky to be reviewed by an expert sonographer (KPM, who has >6 years of MSKUS experience) to ensure cross-site standardisation of measurements.35 All images will be analysed for muscle CSA, mT and EI by the same blinded expert sonographer. The images from the first five patients obtained by the two sonographers at each site will be examined with intraclass correlation coefficient (ICC). Sites with ICC<0.7 will receive additional training to improve reliability at each site. ICC values will be disseminated with our final results.

Participant timeline

Patients enrolled in the study will participate in up to two phases, an ICU phase and—for those who survive their critical illness—a recovery phase. The schedule of assessments for both phases is delineated in table 2.

Sample size

Our previous study reported a decrease in muscle RF CSA at ICU day 7 of 18.5%.38 To detect an absolute difference in per cent decrease in muscle size of 6% at 7 days (24.5% change at 7 days in AKI-RRT group vs 18.5% change in controls), 61 patients per group are needed assuming an alpha of 0.05 and a power of 80%. This will require inclusion of 20 AKI-RRT patients per site that provide all ICU datapoints. Our previous study also reported that RF CSA was 2.47±0.88 cm² at ICU day 7, down from a baseline on ICU day 1 of 2.99 cm².38 To detect a full return to baseline in the outpatient setting with an alpha of 0.05 and a power of 80%, 22 patients are required in each group. To detect a 75% recovery to baseline from day 7 values, 40 patients are required. We anticipate a 40%–50% in-hospital mortality rate which would leave 31–37 patients alive at discharge. Assuming 22 patients are needed, this provides room for attrition or lost to follow-up of 30%–40%.

Recruitment

Patients will be recruited in the multidisciplinary adult ICUs of the three sites involved in the study. Patients will be identified through communication with the nephrology consult services at each site, who will independently make decisions regarding indications for and timing of initiation of RRT. The enrolment will occur for a full year following institutional review board (IRB) approval at each site, with the funding dates ranging from 1 August 2022 to 31 July 2023, at the University of Kentucky and University of Iowa and from 1 October 2022 to 30 September 2023, at the University of New Mexico. To promote subject retention after discharge, we will allow for a 2-month window in which to schedule the postdischarge follow-up visit and subjects will be contacted by telephone a minimum of three times before being considered lost to follow-up. As stipulated in the informed consent form, though subjects may withdraw from the study at any point, all data collected prior to withdrawal will be retained for analysis.

Patient and public involvement

No formal patient advisory committee was established and there was no patient or public involvement in the design or planning of the study. However, to inform future study design, we will conduct a brief open-ended poststudy survey following the outpatient visit at 1–3 months to help discern which of the patient-reported outcome measures and functional assessments performed appear most valuable to the study subjects (online supplemental material 1).

Data collection methods

Ultrasound images will be transferred through secure link to the data coordinating site (University of Kentucky). One expert sonographer with clinical and research experience (KPM) will analyse the images for CSA, mT and EI. All muscle analyses will be performed blinded with all images coded by a different research coordinator. The blinded assessor will be unaware of the patient identification, the investigator obtaining the images or the time point of the MSKUS. Blood and effluent fluid will be collected at the defined time points. Plasma samples will be collected in EDTA tubes, centrifuged at 1000 g for 10 min at 4°C. Following extraction of supernatant and transfer into storage tubes, samples will be stored at −80°C. The specimens will be shipped to the biospecimen site (University of Iowa) where we will perform the metabolomic analysis on all samples in one batch. Patient data including demographics, data related to acute illness and comorbidity, and test results will be recorded using standardised case report forms and then uploaded to REDCap.

Data management

Data will be stored using REDCap software at each site. REDCap is a secure web application for building and managing online databases.62 REDCap is HIPAA compliant and is specifically geared to support online and offline data capture for research studies and operations.

Statistical methods

We will summarise descriptive statistics at each time point using frequencies and proportions for categorical variables and means and SD or medians and IQRs, as appropriate, for continuous variables. Binary outcome variables include the diagnosis of ICU-AW (defined as MRC-ss<48/60) and the additional recovery phase events (ie, return to driving, return to work or hobby, hospital readmission and need for emergency department care). Continuous variables include MSKUS parameters, strength testing and physical function testing. Ordinal variables include scores on the EQ-5D-5L, FACIT-F subquestion and CFS.

• ICU Phase: The primary outcome in the ICU phase of the study, corresponding to aim 1, will be the change in RF CSA, mT and EI from baseline to day 7 (or ICU discharge) within AKI-RRT patients and in comparison to historical ICU controls without AKI-RRT. Repeated measures analysis will be used with muscle parameters as fixed effects. Of note, in the cohort to be used as the historical control for the ICU phase, MSKUS was performed on ICU days 1, 3, 5 and 7 and muscle strength assessment (by MRC-ss, hand-held dynamometry and hand-grip dynamometry) was performed at ICU and hospital discharge.38 For AKI-RRT patients, time 0 is study enrolment (which must be within 48 hours of CRRT initiation). To account for the resulting differences in timing of assessments, time from ICU admission to MSKUS and muscle strength assessments will be included as covariables in our analyses. We will develop multivariable models for within-group comparisons (in AKI-RRT cases) and between-group comparisons (AKI-RRT cases vs controls). Additional variables entered in the analyses will include demographic variables including age and sex, Charlson Comorbidity Score, illness severity as measured by Sequential Organ Failure Assessment (SOFA) score63 and ICU variables (including mechanical ventilation, trauma, sepsis, corticosteroid use, use of paralytic agents and ICU type). We will conduct univariable analysis to determine if any of these variables are significantly associated with the primary outcomes. To avoid overfitting, only significant variables will be added in the subsequent adjusted model. We will use paired t-test to examine within-group differences and analysis of variance (ANOVA) for between-group differences of MSKUS parameters and other continuous measures. Binary outcomes will be compared by χ² test. Bonferroni adjustment will be used for multiple comparisons.

• Recovery Phase: The primary outcomes in the recovery phase of the study, corresponding to aim 2, will include both (1) the detailed characterisation of longitudinal changes in muscle mass and quality and functional status in AKI-RRT survivors, including comparison of postdischarge recovery of RF size and quality assessed by MSKUS and of muscle strength in AKI-RRT survivors as measured within 1–3 months of discharge compared with in-hospital baselines and (2) comparison of MSKUS parameters and of muscle strength assessed at 1–3 months after discharge in AKI-RRT survivors with the same parameters in historical controls of ICU survivors without AKI-RRT. The assessments of muscle strength at this phase will include MRC-ss, hand-held dynamometry for knee extension and hand-grip dynamometry. Using the same methods and covariables as outlined for the ICU phase analysis, we will generate multivariable models for within-group and between-group comparisons of MSKUS parameters and muscle strength, with the exception that lengths of ICU and hospital stay and time from hospital discharge to outpatient assessment will be included as covariables in this phase. For the SPPB, TUG, 6-MWT, EQ-5D-5L, CFS, FACIT-F, SF-36 and additional recovery phase events, differences between the AKI-RRT survivors and the historical ICU survivor controls without AKI-RRT will be compared using t-test, Wilcoxon rank sum test, Mann-Whitney U test and χ² test, as appropriate.

• Metabolomic analysis: The metabolomic analysis will have no control group. The primary outcome of the metabolomic analysis, corresponding to aim 3, will be the correlation between changes in plasma and effluent amino acid levels measured during CRRT treatment in the ICU phase and both the MSKUS parameters obtained throughout the study and muscle strength measured in AKI-RRT survivors at hospital discharge and 1–3 months postdischarge. The primary analysis will be performed using a mixed effects model with ANOVA using Sidak’s multiple comparison test for paired samples to compare baseline to subsequent samples. Correlations with muscle changes based on MSKUS measurements at days 3 and 7 and correlations with muscle mass, strength and function at hospital discharge and at 1–3 months will be assessed with Pearson correlation test for continuous variables and Spearman’s r test for non-parametric data.