Neuromuscular Electrical Stimulation to Improve the Muscle Health of Individuals With Acute Kidney Injury (NMES-AKI)

Acute Kidney Injury (AKI) is a serious, common illness that is defined as a sudden loss in kidney function. AKI is associated with poor clinical outcomes such as increased morbidity, mortality and prolonged hospitalisation. Clinical research has tended to explore prevalence, risk of recurrence of AKI and prevention, leaving patient-focused outcomes such as physical function and quality of life understudied. AKI is also associated with increased muscle catabolism, and this is coupled with longer hospital stays that prolong immobilisation. As a result, many older patients experience a significant reduction in muscle mass, strength, and functional capacity, sometimes to the extent of a diagnosis of sarcopenia (age-associated loss of skeletal muscle mass, strength and function), which can extend far beyond the duration of their hospitalisation. Skeletal muscle disuse atrophy is known to occur within 4 days, and the average AKI patient's stay in hospital is approximately 12 days. These factors are therefore significant contributors to losses in skeletal muscle mass, strength and function in AKI.

Neuromuscular Electrical Stimulation (NMES) is an alternative, passive form of exercise that involves attaching electrodes to the belly of a specified anatomical site of skeletal muscle, through which a device transcutaneously applies intermittent electrical stimuli which then produces a strong, tetanic isometric muscle contraction, with the aim of retaining neuromuscular function. It has been used in studies investigating its use in geriatric patients who presented with sarcopenia and frailty, in which a significant improvement in knee extensor strength was identified. It has also been used for patients who were critically ill, with a previous study identifying that NMES at low and medium frequencies in combination with a standard physical therapy program was associated with a significant improvement in knee extensor strength and handgrip strength, functional capacity, and quality of life during hospitalisation. Another study found that NMES in addition to early mobilisation significantly improved isometric quadriceps strength as well as functional capacity and ability to engage in activities of daily living. A study that examined the use of bilateral NMES in patients with heart failure found that there was a significant improvement in functional capacity and exercise tolerance. Another study that examined the use of bilateral NMES in hospitalised patients with chronic obstructive pulmonary disorder found that there was a significant improvement in quadriceps force production and exercise tolerance. However, the feasibility of NMES intervention has not been tested within the context of AKI. The aims and objectives of this study are to investigate the feasibility of using bilateral quadriceps NMES in people who have AKI and to generate preliminary data on whether NMES can attenuate losses in muscle strength, mass, and function.

This is to be a single-centre, parallel-group, single-blind, randomised controlled trial. Participants will be randomised to either the intervention (max 10 days of NMES) or the control group (sham NMES) in a 1:1 approach, with a block size of 4. Participants will undergo randomisation for arm allocation by using sealed envelope (sealedenvelope.com). Minimisation factors of age (< 60 years and ≥ 61 years) and Pre-existing Clinical Frailty Scale score (2 or ≥3) will be applied to ensure balanced groups.

Having been screened as potential participants meeting the inclusion/exclusion criteria, the patient will be approached to have the study explained, as well as have any questions answered. Patients will be provided with a participant information sheet and allowed time to make an informed decision. If screened patient does not decide to participate, this will be recorded for measurement of feasibility outcomes

Following the formalisation of consent, confirmation of eligibility, and randomisation, the baseline measurements will commence. We intend to record demographic and clinical information from the participant's electronic health records in the participant's case report form such as age, height, weight, sex, ethnicity, Charlson comorbidity score, AKI stage, Clinical Frailty Score, Length of Stay (days), laboratory data from routine clinical care (daily blood tests are performed in patients with severe AKI), and previous medical history. We also intend to use questionnaires and basic questioning to record information such as physical activity levels assessed by a retrospective, prior to hospitalisation International Physical Activity Questionnaire (IPAQ), and smoking status (never, former, current). These basic questions will be asked to the participant and recorded by the researcher. The participant will then have assessments of muscle strength, mass, and function.

On the morning of the intervention, participants will be visited by a member of the research team and have the NMES device electrodes fitted just above the proximal and distal heads of the vastus lateralis (VL) muscle, the proximal pad will be placed longitudinally across the upper outside area of the thigh just above the midzone of the VL and the distal pad will be placed longitudinally on the lower outside area of the thigh just below the midzone. Anatomical landmarks will be marked with a skinsafe marker pen. These will be identified by palpation of anatomical landmarks and marked with a skin-safe marker for the consistency of placement throughout the intervention. The device will be preset to the following specified settings: Electrical Muscle Stimulation (EMS); Synchronous; duration - 30 mins; Frequency - 30 hertz (Hz); Pulse Width - 300 microseconds (µs); Duty Cycle - 1:3 (2 seconds on, 6 seconds off); Intensity - Max tolerable - from 1 up to 99 milliamps (mA) (10 mA for CON/sham group); ramp time - 2 seconds. The first session will last 30 mins, during which a member of the research team will stay with the participant throughout. At the end of the first session, participants will be asked of their preferred time in the afternoon for their second session, it is recommended that at least 3 hours should elapse between each session. The second session will also last for 30 minutes.

Food/drink intake assessment will be conducted via 24-hour dietary recalls on days 1, 5 and 10 (or hospital discharge) in both the NMES and CON groups. The information collected will be used to assess energy and protein intake. On the final day, following the cessation of NMES either due to the participant staying the full 10 days or due to imminent discharge, measurements of muscle strength, mass, and function will be taken. Feasibility data on acceptability and tolerability would be collected via visual analogue scale (VAS) pain report and an average of scores will be calculated for all days they were able to report this.

Study procedures will be the same for 1-month and 3-month study visits. Participants will be asked to attend the Renal Department at Royal Derby Hospital (RDH) on a further two separate occasions. This will be at 1 month following the cessation of NMES/hospital discharge (whichever occurs first) and at 3-months following the cessation of NMES/hospital discharge (whichever occurs first). Both of these visits will coincide with routine clinic visits.

Participants will be contacted by a member of the research team to arrange the date and time of the first study visit within two weeks of hospital discharge. Once they have confirmed a date they will be reminded a week and 24h before their visit by email or phone call, whichever the participant prefers.

On the day of the visit, participants will have measurements of muscle strength knee extensor strength (KES) (5-10 mins), muscle function via the modified sit-to-stand 30 test (M-STS-30) (5-10 mins), vastus lateralis ultrasound (30 mins), appendicular skeletal muscle mass (ASM) via bioelectrical impedance analysis (BIA) (2mins), EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L) (5-10 mins) and Barthel Index (5-10 mins) questionnaires by a trained member of the research team. Body composition will be assessed using the BIA device (2 mins).

As per routine clinical pathways, blood and urine tests will be requested by the clinical team and collected in advance of their clinic visit. This will include routine biochemistry and haematology tests and cystatin-C (which is used clinically to assess kidney function after AKI in patients in whom sarcopenia is suspected). All blood tests will be analysed in local NHS pathology laboratories. The creatinine muscle index (CMI) will be calculated from these results. The chief investigator will review all blood tests measured at 1-month and 3-month visits in parallel with their entry into the CRF. The blood samples will be collected as per routine clinical care (e.g. National Health Service [NHS] phlebotomy services, or by trained clinical staff in the renal department).

Following these measurements being taken, another follow-up will be scheduled 2 months after the 1-month follow-up visit, (i.e. 3 months following the cessation of NMES [+/- 10 days]).

The primary outcomes, being the feasibility findings will be used to inform the design of a potential larger study and the secondary outcomes to discover whether the study methods need refining.