Neurosciences-Intensive Care Unit Electrical Stimulation

The purpose of this pilot trial is to estimate the effect of electrical stimulation (e-stim) to the bilateral quadriceps on duration of intubation, ICU and hospital length of stay, and functional recovery in the NSICU in comparison to historical matched controls. The objectives of this initial pilot and feasibility study are to estimate the effect size to power a future full scale randomized controlled trial of this intervention and to optimize study logistics for a future full scale trial. The specific aims of the trial are:

Specific Aim 1 - Feasibility: Determine whether at least 4 of 5 planned treatments can be performed as described, and whether there is adequate patient population meeting inclusion criteria available for study

Specific Aim 2 - Efficacy: Evaluate efficacy of e-stim by comparing length of ICU stay (days from admission to "intermediate level of care" ordered in Epic) and duration of intubation (days) of subjects to that of historical controls.

Specific Aim 3 - Exploratory: Evaluate functional recovery (measured by modified Rankin Scale [mRS] and Extended Glasgow Outcome Scale [GOSE] at NSICU discharge) of subjects compared to that of historical controls.

Hypothesis: The investigators hypothesize that e-stim treatments will reduce the length of hospital stay and intubation and improve functional recovery.

The study will be a prospective, feasibility pilot study of 22 subjects enrolled from the NSICU to estimate the effect size to power a future, full scale randomized controlled trial of electrical stimulation. The information learned in the pilot will help the team optimize study logistics for a future full-scale trial. The controls used for comparison will be obtained from an NSICU patient database, using the average values of the outcomes for patients from the previous year who would have met inclusion criteria.

Patients admitted to the NSICU will be screened for eligibility through a review of medical records in Epic by study staff, and approached for consent. Patients with prognosticated prolonged stay will be approached on day 3 to 5 of their ICU stay for enrollment.

For the treatment procedure, electrical stimulation will be applied to the quadriceps muscle groups on both lower extremities simultaneously for 45 minutes at a time. The patient will be positioned either supine or sitting.

An Intelect Neuromuscular Electrical Stimulator (Chattanooga Group) device will be used to provide the stimulation. The stimulator will be set up and taken off the patients by a member of the study team or a trained ICU staff member. The stimulation parameters will be as follows:

Electrode location: Proximal and distal quadriceps Waveform: pulsed biphasic Pulse duration: 300 microseconds Pulse frequency: 35 pulses per second Amplitude: palpable, visible quadriceps muscle contraction On/off time: 5 seconds on, 15 seconds off Ramp up and down time: 2 seconds each Total treatment time: 45 ± 15 minutes/day, for a total of 5 treatments each week (Mon-Sun), for up to 14 days or until ICU discharge, whichever comes first.

At NSICU discharge, a member of the study team will assess functional recovery using the modified Rankin Scale (mRS) and the Extended Glasgow Outcome Scale (GOSE). Subjects who withdraw from e-stim treatment may still be assessed with these instruments at discharge, unless they request to withdraw from data collection as well. Subjects may be withdrawn from e-stim treatment without their consent if their physician or the study team decides that it is in their best interest (e.g. due to skin irritation or burns).

All procedures will be performed as part of the research study, and not as standard of care.

Data will be collected from the subjects' medical record in Epic, and from the mRS and GOSE instruments (completed by study staff). All data will be stored in RedCap. Data collected from the medical record will include demographics (sex, age, race), illness information (primary admission diagnosis, severity of critical illness as determined by the Sequential Organ Failure Score (SOFA) and/or APACHE II score), critical illness-associated complications (e.g. deep vein thrombosis, hospital acquired infection, etc.), and medications associated with neuromuscular weakness (e.g. steroids, neuromuscular blockers, etc.).

Analysis plan

Covariates: The following factors may impact outcome, and thus will be collected to assure the groups are comparable:

i. Demographics (sex, age, race) ii. Illness information: primary admission diagnosis, severity of critical illness (Sequential Organ Failure Score (SOFA), APACHE II score) iii. Critical Illness-Associated Complications: complications such as deep vein thrombosis, Hospital-acquired infection, etc. will be recorded as these conditions may impact outcome.

iv. Medications associated with neuromuscular weakness: including but not limited to steroids and neuromuscular blockers

Group Comparisons The study team statistician will analyze the data, and will be blinded to treatment assignment ("Group A" and "Group B", instead of "E-Stim Group" and "Historical Controls"). Descriptive statistics will be used to quantify feasibility. Mean length of stay and mean duration of intubation will be compared between the e-stim group and the historical controls using a t-test. If necessary, a linear regression model for length of stay and/or intubation duration will be used to compare groups while controlling for the potential confounding of covariates. A Wilcoxon rank-sum test will be used to compare the exploratory functional outcome measures between groups, as the mRS and GOSE are both ordinal scales.

The risks involved in the study are all small and mild:

1. Burns - electrical stimulation can cause burns, although this is very rare with the pulsed current that will be used in this study because electricity is only flowing for a very small proportion of the time with this type of current. The risk of burns is also increased if the electrodes have poor contact with the patients' skin. This will be avoided by closely inspecting the electrodes for good contact when applied, by cleaning the skin with water before applying the electrodes, clipping hair in the area of electrodes if present, and by using new electrodes at least weekly, or sooner if they start to adhere poorly.

2. Skin irritation or inflammation - the adhesive on electrical stimulation electrodes, which is similar to tape adhesive, can cause skin irritation in some individuals. Therefore, individuals with tape allergy will be excluded from this study. In addition, if a subject develops skin irritation, the investigators will switch to hypo-allergenic electrodes. If the skin irritation persists, the subject will be withdrawn from the study.

3. Discomfort during the stimulation - if the intensity is high enough an individual may experience discomfort during electrical stimulation. The investigators will limit the stimulation intensity to that sufficient to produce a visible muscle contraction and will discontinue the intervention if the subject either reports pain or has signs of pain e.g. elevated heart rate or blood pressure in response to the stimulation.

4. Delayed muscle soreness - there is a risk of delayed onset muscle soreness in the muscles stimulated. This is similar to the soreness experienced after exercise and will resolve without intervention. This is only likely if the exercise is substantially greater than the individual's usual activity. Although 30 minutes of visible quadriceps contraction is not generally likely to cause delayed onset muscle soreness, it is possible this will occur.

5. There is a small risk of breach of confidentiality.

It is hypothesized but unknown whether there are benefits to e-stim treatment. E-stim may result in reduced duration of hospitalization and intubation, and may improve recovery outcomes.

The device for this study is the Intelect® Portable Electrotherapy for Neuromuscular Electrical Stimulation, which is commercially manufactured by Chattanooga. The device is FDA approved for the prevention of disuse atrophy. It is also used for muscle re-education, increasing range of motion, and increasing circulation. This device is used in commonly in clinical Physical Therapy practice in other patient populations.