Novel Transitional Rehabilitation Care in Coronary Artery Bypass Graft (CABG) Patients
Phase: NA
Conditions: Coronary Artery Disease, Coronary Artery Bypass Graft Surgery
Sponsor: University of Vermont

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Protocol and Statistical Analysis Plan 
 
 
Project Title: 
Version Date: 
Transitional rehabilitation in CABG patients
4-17-17
 
 
NCT number:
NCT03892460
Principal 
Investigator:  
Michael J. Toth 
Co-Investigator:  Philip A. Ades
Grant Sponsor:
University of Vermont, College of Medicine, Department of Medicine
 
 
 
 

 
Summary:  
Coronary artery bypass graft (CABG) surgery is a common surgical procedures and an important 
treatment option for coronary artery disease. As with any major surgical or medical procedure, the period 
of rest and recovery that follows is associated with cardiorespiratory and skeletal muscle deconditioning 
that can leave patients feeling weak and fatigued. Cardiac rehabilitation exercise training is recommended 
to recover lost strength and fitness. However, patients typically do not begin cardiac rehabilitation until 4-
6 weeks following CABG surgery. Rehabilitative interventions to bridge the period between discharge 
following CABG surgery and the start of cardiac rehabilitation could improve patient cardiorespiratory and 
their ability to perform daily activities. 
 
The goal of this research study is to understand whether an at-home exercise program started soon 
after CABG surgery, and continuing for 4 weeks following discharge from the hospital, can serve as a 
bridge between surgery and the start of cardiac rehabilitation to preserve physical function. Volunteers 
will be randomly assigned to receive neuromuscular electrical stimulation (NMES) of their quadriceps 
muscles or not to receive NMES (control group). Volunteers will be evaluated prior to CABG (Pre-
surgery testing), upon discharge and 4 weeks Post-CABG surgery. Assessments will include 
measurements of physical function by the Short Physical Performance Battery and 6 min walk tests, as 
well as assessment of subjective physical functional capacity and quality of life using the Medical 
Outcomes Short form 36. Additionally, accelerometry will be used to monitor weight-bearing physical 
activity during the 4 week treatment phase.  
 
If successful, results from these studies will advance knowledge by providing proof-of-principle 
evidence for the utility of NMES to counter physical functional deterioration in the early, post-surgical 
period following CABG. Additionally, our findings may advance postoperative care of CABG patients by 
providing a clinical intervention to bridge a gap in rehabilitation services prior to entry into formal CR. 
Maintaining functional capacity in patients post-discharge may reduce the risk for re-hospitalization and 
progression towards disability. Greater functionality upon entry into CR may permit greater functional 
and health benefits from exercise during CR.
 
Purpose:  
CR programs were initially developed to counter the deconditioning effects of medical and surgical 
interventions in cardiac patients and they have well-accepted health and survival benefits (1). Although 
CR is an important part of the care continuum (2), CABG patients typically do not start CR until ~4-6 wks 
after discharge (3). During this period, patients can experience further deterioration in physiological 
reserve, with increased risk for post-operative complications, readmission and development of physical 
disability (4-6). Whereas a large number of studies have focused on transitional care initiatives in 
medical and surgical cardiac populations to improve clinical outcomes and minimize costs (7), very few 
have focused on bridging this gap in physical rehabilitation care.  
     One reason for the absence of transitional rehabilitative care services in cardiac surgical patients is 
the inherent difficulty of intervening in a post-surgical population, as pain and limited mobility from 
surgical wounds diminishes motivation towards classical exercise. Moreover, reduced physical function 
related to surgery and hospitalization may render patients unable to perform basic activities of daily 
living at home, much less exercise. These hurdles represent a significant barrier to bridging the gap in 
rehabilitative care of cardiac surgical patients. Alternative exercise modalities that confer a training 
effect, but that do not have the physical requirements of classical aerobic or resistance training, could 
bridge this gap. Optimal candidates should induce an exercise training response, integrate easily into 
outpatient and home environments and be easy to use and inexpensive. 
      NMES is an intervention that fulfills many of these criteria. An inexpensive (~$500), FDA-approved, 
portable, hand-held NMES unit permits non-volitional initiation of muscle contractions that can mimic 
resistance- or aerobic-type exercise (8), producing a training response that is near comparable to 
classical aerobic training (9, 10). NMES improves muscle size, strength and performance in older adults 
with chronic disease (11), and counteracts muscle atrophy coincident with pathophysiologic catabolic 
stimuli (12-14) and muscle disuse (15), both of which occur in the post-operative period following CABG. 
Although NMES has been studied in stable heart failure patients (16), to our knowledge, it has never 
been employed in CABG or other cardiac surgical populations as a potential bridge therapy from post-

 
operative discharge to the start of CR. 
Transitional care following hospitalization has been recognized as a national priority (17, 18) and 
efforts to implement new services were incentivized by the Affordable Care Act (19). Numerous studies 
have shown the utility of transitional care services to improve outcomes, reduce unnecessary use of 
health services and decrease costs (20, 21), but few of these studies have focused on ways to extend 
rehabilitation services (22) and fewer still have focused on these services following CABG surgery.  
     CR is an important part of the rehabilitative care of cardiac medical and surgical patients that 
restores physiological reserve lost during the acute disease event and subsequent hospitalization and 
convalescence, as well as conferring long-term health benefits (23). Although this deterioration in 
physiological reserve is well-accepted, our current knowledge of such adaptations in CABG patients is 
limited and there are currently no evidence-based interventions that bridge rehabilitative care between 
discharge and the start of CR, aside from acute, in-patient rehabilitation facilities in cases of substantial 
frailty. Successful completion of our studies would impact the field of transitional care of CABG patients 
in several ways: 
Fill an important knowledge gap. Our results will provide the first characterization of early, post-
surgical functional and physiological adaptations to CABG (in patients randomized to control). Studies 
have noted that CABG patients have reduced self-reported or objectively-measured physical function 
post-surgery compared to non-surgically-treated patients. However, no study has systematically tracked 
the erosion of physical functional capacity from CABG surgery to the start of CR. Knowledge of the 
extent of the reduction in functional capacity due to CABG can spur the development of new transitional 
care services aimed at improving outcomes/costs. 
Define the utility of NMES to prevent early, post-surgical erosion in physiological capacity. 
Based on studies in other post-surgical populations, we anticipate uncovering novel effects of NMES to 
prevent the loss of physiological function, providing an important evidence base upon which to build 
support for further studies evaluating the utility of NMES in CABG recipients. Maintenance of 
physiological function in the post-CABG period may improve the response to CR, particularly in those 
with low baseline functionality (24). Because NMES is FDA-approved, inexpensive, portable to the 
outpatient and home environments and there are clinicians already trained in its use (PTs/OTs), barriers 
to its broader clinical application to the CABG population are minimal. 
Relevance to other surgical populations. Demonstration of the utility of NMES in the post-surgical 
CABG population has direct relevance to other older adult surgical populations beyond cardiac 
populations, where follow-up rehabilitative care, such as CR, is not available, as well as other non-
surgical populations (eg, heart failure, COPD patients). NMES may serve as an inexpensive, transitional 
care service that allows these patients to maintain/regain functional reserve.
References. 
1. 
Ades, P. A. (2001) Cardiac rehabilitation and secondary prevention of doronary heart disease. N Engl J Med 345, 892-902 
2. 
Balady, G. J., Williams, M. A., Ades, P. A., Bittner, V., Comoss, P., Foody, J. M., Franklin, B., Sanderson, B., and Southard, D. 
(2007) Core components of cardiac rehabilitation/secondary prevention programs: 2007 update. Circulation 115, 2675-2682 
3. 
Russell, K. L., Holloway, T. M., Brum, M., Caruso, V., Chessex, C., and Grace, S. L. (2011) Cardiac rehabilitation wait times: effect 
on enrollment. J Cardiopulm Rehabil Prev 31, 373-377 
4. 
Fisher, S. R., Kuo, Y.-F., Sharma, G., Raji, M. A., Kumar, A., Goodwin, J. S., Ostir, G. V., and Ottenbacher, K. J. (2013) Mobility after 
hospital discharge as a marker for 30-day readmission. J Gerontol A Biol Sci Med Sci 68, 805-810 
5. 
Singh, M., Stewart, R., and White, H. (2014) Importance of frailty in patients with cardiovascular disease. Eur Heart J 35, 1726-1731 
6. 
Gill, T. M., Allore, H. G., Gahbauer, E. A., and Murphy, T. E. (2010) Change in disability after hospitalization or restricted activity in 
older persons. JAMA 304, 1919-1928 
7. 
Bettger, J. P., Alexander, K. P., Dolor, R. J., Olson, D. M., Kendrick, A. S., Wing, L., Coeytaux, R. R., Graffagnino, C., and Duncan, 
P. W. (2012) Transitional care after hospitalization for acute stroke or myocardial infarction: a systematic review. Ann Intern Med 157, 
407-416 
8. 
Atherton, P. J., Babraj, J. A., Smith, K., Singh, J., Rennie, M. J., and Wackerhage, H. (2005) Selective activation of AMPK-PGC-1α or 
PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle 
stimulation. FASEB J 19, 786-788 
9. 
Deley, G., Eicher, J. C., Verges, B., Wolf, J. E., and Casillas, J. (2008) Do low-frequency electrical myostimulation and aerobic 
training similarly improve performance in chronic heart failure patients with different exercise capacities? J Rehabil Med 40, 219-224 
10. 
Harris, S., LeMaitre, J. P., Mackenzie, G., Fox, K. A. A., and Denvir, M. A. (2003) A randomised study of home-based electrical 
stimulation of the legs and conventional bicycle exercise training for patients with chronic heart failure. Eur Heart J 24, 871-878 
11. 
Maddocks, M., Gao, W., Higginson, I. J., and Wilcock, A. (2013) Neuromuscular electrical stimulation for muscle weakness in adults 
with advanced disease. In Cochrane Database Syst Rev Vol. 1 
12. 
Hirose, T., Shiozaki, T., Shimizu, K., Mouri, T., Noguchi, K., Ohnishi, M., and Shimazu, T. (2013) The effect of electrical muscle 
stimulation on the prevention of disuse muscle atrophy in patients with consciousness disturbance in the intensive care unit. J Crit 
Care 28, 536.e531-536.e537

 
13. 
Martin, T. P., Gundersen, L. A., Blevins, F. T., and Coutts, R. D. (1991) The influence of functional electrical stimulation on the 
properties of the vastus lateralis fibers following total knee arthroplasty. Scand J Rehabil Med 23, 207-210 
14. 
Gerovasili, V., Stefanidis, K., Vitzilaios, K., Karatzanos, E., Politis, P., Koroneos, A., Chatzimichail, A., Routsi, C., Roussos, C., and 
Nanas, S. (2009) Electrical muscle stimulation preserves the muscle mass of critically ill patients: a randomized study. Crit Care 13, 
R161 
15. 
Gibson, J. N. A., Smith, K., and Rennie, M. J. (1988) Prevention of disuse muscle atrophy by means of electrical stimulation: 
maintenance of protein synthesis. Lancet 332, 767-770 
16. 
Karavidas, A., Arapi, S., Pyrgakis, V., and Adamopoulos, S. (2010) Functional electrical stimulation of lower limbs in patients with 
chronic heart failure. Heart Fail Rev 15, 563-579 
17. 
Anonymous. (2009) Evaluating Efficiencey Across Patient-Focused Episodes of Care., National Quality Forum, Washington, DC 
18. 
Adams, K., and Corrigan, J. M. (2003) Committee on Identifying Priority Areas for Quality Improvement, Board on Health Care 
Services, Institute of Medicine., National Academic Press, Washington, DC 
19. 
Patient Protection and Affordable Care Act. Pub L No. 111-148.  (Government, U., ed), http://www.gpo.gov/fdsys/pkg/PLAW-
111publ148/content-detail.html 
20. 
Konetzka, R. T., Spector, W., and Limcangco, M. R. (2008) Reducing hospitalizations from long-term care settings. Med Care Res 
Rev 65, 40-66 
21. 
Naylor, M. D., Aiken, L. H., Kurtzman, E. T., Olds, D. M., and Hirschman, K. B. (2011) The importance of transitional care in 
achieving health reform. Health Aff 30, 746-754 
22. 
Mueller, E., Savage, P. D., Schneider, D. J., Howland, L. L., and Ades, P. A. (2009) Effect of a computerized referral at hospital 
discharge on cardiac rehabilitation participation rates. J Cardiopulm Rehabil Prev 29, 365-369 
23. 
Suaya, J. A., Stason, W. B., Ades, P. A., Normand, S.-L. T., and Shepard, D. S. (2009) Cardiac rehabilitation and survival in older 
coronary patients. J Am Coll Cardiol 54, 25-33 
24. 
Savage, P. D., Antkowiak, M., and Ades, P. A. (2009) Failure to improve cardiopulmonary fitness in cardiac rehabilitation. J 
Cardiopulm Rehabil Prev 29, 284-291 
 
Objectives:  
The goal of this application is to explore the utility of neuromuscular electrical stimulation (NMES) to 
counter the early, post-surgical deterioration in physical functional capacity. We chose NMES because it 
permits non-volitional initiation of muscle contractions that can produce an exercise training response 
similar to classical exercise training, with near comparable effects. We will test the ability of NMES to 
preserve physical function, as measured by the Short Physical Performance Battery (SPPB), a metric 
whose change in the first month post-hospitalization has been shown to predict re-hospitalization and 
death and that is validated for use in physically compromised elderly populations. We will also asses 6-
minute walk (6MW) performance as a secondary outcome, a metric that is commonly used for FDA 
approval of various interventions that seek to improve physical function/fitness. Our rationale for the 
proposed studies is that interventions directed towards preventing deleterious skeletal muscle changes 
during this period and maintaining functional capacity will enhance the effects of CR to improve 
functionality and future cardiovascular risk. We will accomplish these goals using a randomized, 
controlled design. Based on our preliminary data, we hypothesize that NMES will prevent deleterious 
reductions in physical function by preserving skeletal muscle size function. To address this hypothesis, 
we propose a single aim: 
Aim: Define the utility of NMES to preserve or increase physical functional capacity 
in patients during the period following CABG and prior to entry into CR. 
Primary Clinical Outcome: NMES will diminish CABG-induced erosion of physical functional 
capacity, as assessed by the SPPB. 
Secondary Clinical Outcome: NMES will diminish CABG-induced erosion of physical functional 
capacity, as assessed by the 6MW.  
 
METHODS AND PROCEDURES 
Study Design:  
We will use a prospective design, in which patients scheduled for elective CABG will be recruited 
and evaluated prior to CABG (Pre-surgery) and upon discharge (Discharge) for physical function (SPPB 
Testing and 6 min walk). Patients will be recruited for this study during the normal process of clinical 
recruitment for cardiac rehabilitation. This includes patients from cardiothoracic consultation lists and/or 
those scheduled for elective CABG. In some instances, we will identify patients from cardiothoracic 
consultation lists who are or will be scheduled for CABG, but are not on the surgical unit. We will contact 
these patients by phone regarding participation in cardiac rehabilitation and, at that time, introduce this 
research study. Patients will be randomized (1:1) to NMES or control intervention (n=18/group; 
Treatment Phase), with stratification for age and sex. Following completion of the 4 wk intervention, 

 
volunteers will undergo Post- Testing, which will be identical to Pre-surgery and Discharge testing. Each 
protocol phase is described below.  
Pre-surgery testing Baseline testing will occur prior to CABG surgery and at discharge and consist of 
functional assessment by the SPPB and a quality of life (QOL) questionnaire (MOS-SF36). Tests are 
described below.  
Discharge testing will repeat Pre-surgery testing and include a 6MW. At this time, volunteers will 
receive an accelerometer, which will be worn during three (3) 5-day periods during the Treatment 
phase.  
Treatment Phase 
Patients will be randomized (1:1) to NMES or control intervention and will continue in this Treatment 
phase until 4 weeks post-CABG surgery. 
4 wk Post-surgery testing will be identical to Discharge testing.  
Procedures:  
All of the procedures and interventions on volunteers recruited for these studies are carried out solely for 
research purposes, as none are part of standard therapy in CABG patients. 
Physiological Testing (during Pre-surgery (excluding 6 MW), Discharge and 4 wk Post-surgery testing)
SPPB will be measured, as described by us (1), as this assessment is prognostic for functional 
competence and mortality in cardiac surgical patients (2). This measure takes ~5 min to perform and 
is comprised of: 5 repeated chair stands, balance testing (3 tasks each 10 s long) and a   4 meter 
walk. As increasing SPPB score in the first month post-discharge in a sample of elderly patients with 
diverse clinical backgrounds was associated with lower risk for rehospitalization and death (3), 
improvements in, or maintenance of, this metric would provide strong evidence for the clinical utility 
of NMES. We have experience with this measure in cardiac populations (4). 
6 MW was developed to assess cardiopulmonary fitness in patients with lung and cardiac disease 
(5), but has been used widely to assess disability in older adults (6) and is the most common metric 
used when seeking FDA approval for interventions to improve physical function. We have 
experience with this measure in heart failure patients (7). 
Medical outcome survey short form 36 is a commonly used questionnaire to assess subjective 
quality of life and physical function.  
Accelerometry (Lifecorder Plus) will be used to monitor steps taken, caloric cost and minutes in 
activity and will be performed for three (3) 5-day periods during the Treatment phase of the study.  
Treatment phase 
NMES will be carried out bilaterally on the quadriceps using a portable stimulator (EMPI Continuum). 
Two adhesive electrodes will be affixed to the anterior surface of each thigh: ~1 cm distal to the inguinal 
crease and ~5 cm proximal to the patella, just lateral to the midline of the thigh to assure that it does not 
interfere with incisions for vein harvest. Symmetrical, biphasic pulses (400 µs duration at 25 Hz) will be 
used, with a duty cycle of 25% (10 s on, 30 s off). Patients will be trained to conduct NMES sessions 
and will select stimulation intensities sufficient to cause visible muscle contractions below their pain 
threshold. Training in the use of the NMES device will begin within 96 hrs of transfer to the surgical step 
down unit. This training will consist of one session per day of ~15 min to familiarize the volunteer with 
the unit and the exercise/contraction stimulus. Upon discharge, NMES sessions will occur 5 d/wk once 
per day for 45 min per occasion (5 min low-intensity warm-up, 40 min higher-intensity stimulation) for 4 
wks. This program is meant to mimic an aerobic-type exercise stimulus (8) and has been shown in heart 
failure patients to have functional benefits over a similar treatment period (9, 10). The 4 wk duration 
reflects the approximate average time that most CABG patients take to enter CR at our center. We 
acknowledge that the NMES training load is substantial, but have modeled this program on others that 
have shown morphological and functional effects in heart failure patients (11). At this exploratory stage, 
we feel that it is essential to use a stimulus that affects muscle size and function, with future studies 
modifying the NMES dose to establish a threshold that elicits a training effect with the highest subject 

 
compliance rate. Daily logs and weekly phone contacts will be used to track compliance, and 
compliance will be covertly monitored using the device software.  
Control patients will not receive an NMES device. We chose not to utilize a control NMES intervention 
(eg, stimulation below threshold to elicit contraction) to mitigate the possibility that patients may increase 
stimulation to produce muscle contractions if there is perceived benefit. Rigorous control over the NMES 
stimulus is preferable to controlling for any effects of sub-threshold, cutaneous electrical stimulation. 
Patients will be contacted weekly to assess their recovery and discuss issues related to general health 
to equate the degree of interaction with study personnel to that of the NMES intervention group. 
 
References cited above: 
1. 
Ades, P. A., Savage, P. D., Cress, M. E., Brochu, M., Lee, N. M., and Poehlman, E. T. (2003) Resistance training on 
physical performance in disabled older female cardiac patients. Med Sci Sports Exerc 35, 1265-1270 
2. 
Afilalo, J., Eisenberg, M. J., Morin, J.-F., Bergman, H., Monette, J., Noiseux, N., Perrault, L. P., Alexander, K. P., 
Langlois, Y., Dendukuri, N., Chamoun, P., Kasparian, G., Robichaud, S., Gharacholou, S. M., and Boivin, J.-F. (2010) 
Gait speed as an incremental predictor of mortality and major morbidity in elderly patients undergoing cardiac surgery. 
J Am Coll Cardiol 56, 1668-1676 
3. 
Volpato, S., Cavalieri, M., Sioulis, F., Guerra, G., Maraldi, C., Zuliani, G., Fellin, R., and Guralnik, J. M. (2011) 
Predictive value of the short physical performance battery following hospitalization in older patients. J Gerontol A Biol 
Sci Med Sci 66A, 89-96 
4. 
Rengo, J. L., Savage, P. D., and Ades, P. A. (in press) Directly measured physical function in cardiac rehabilitation. J 
Cardiopulm Rehabil Prev  
5. 
Guyatt, G. H., Sullivan, M. J., Thompson, P. J., Fallen, E. L., Pugsley, S. O., Taylor, D. W., and Berman, L. B. (1985) 
The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J 132, 
919-923 
6. 
Bean, J. F., Kiely, D. K., Leveille, S. G., Herman, S., Huynh, C., Fielding, R., and Frontera, W. R. (2002) The 6-minute 
walk test in mobility-limited elders: what is being measured? J Gerontol 57A, M751-M756 
7. 
Savage, P. D., Shaw, A. O., Miller, M. S., VanBuren, P., LeWinter, M. M., Ades, P. A., and Toth, M. J. (2011) Effect of 
resistance training on physical disability in chronic heart failure. Med Sci Sports Exer 43, 1379-1386 
8. 
Atherton, P. J., Babraj, J. A., Smith, K., Singh, J., Rennie, M. J., and Wackerhage, H. (2005) Selective activation of 
AMPK-PGC-1α or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance 
training-like electrical muscle stimulation. FASEB J 19, 786-788 
9. 
Harris, S., LeMaitre, J. P., Mackenzie, G., Fox, K. A. A., and Denvir, M. A. (2003) A randomised study of home-based 
electrical stimulation of the legs and conventional bicycle exercise training for patients with chronic heart failure. Eur 
Heart J 24, 871-878 
10. 
Karavidas, A., Parissis, J. T., Matzaraki, V., Arapi, S., Varounis, C., Ikonomidis, I., Grillias, P., Paraskevaidis, I., 
Pirgakis, V., Filippatos, G., and Kremastinos, D. T. (2010) Functional electrical stimulation is more effective in severe 
symptomatic heart failure patients and improves their adherence to rehabilitation programs. J Card Fail 16, 244-249 
11. 
Karavidas, A., Arapi, S., Pyrgakis, V., and Adamopoulos, S. (2010) Functional electrical stimulation of lower limbs in 
patients with chronic heart failure. Heart Fail Rev 15, 563-579 
Questionnaires:  
We will assess physical functionality/quality of life with the MOS-SF36 questionnaire. This questionnaire 
takes about ~10 min to complete and will be completed at Pre-surgery and Discharge and 4 wk Post-
surgery testing. 
Risks/Benefits:  
Potential risks: Below we have highlighted those procedures/measurements that have anything 
greater than negligible risk to the volunteers’ health for each phase of the study.  
Pre-surgery, Discharge and 4 wk Post-surgery Testing: Risks associated with functional testing are 
minimal. All of the activities are similar to those performed during the conduct of normal daily activities. 
If volunteers are unable to do any of the activities because of limitations of their heart condition, they will 
not be required to perform them and testing will be monitored by trained personnel. 
NMES intervention: NMES is a generally safe procedure, delivered in the proposed study by an FDA 
approved device. Although evidence is limited, some have suggested that NMES could increase the risk 
of DVT, which may have serious health consequences. However, several published reports show that 
NMES significantly reduces the risk of developing deep vein thromboses (DVT) (1) and we will actively 
exclude any individual with a known coagulopathy. Because of the location of the stimulating electrodes 
(upper leg), the risk of NMES dislodging a DVT is likely minimal. We will also exclude any volunteers 
that currently have an implanted cardiac defibrillator or pacemaker, as this is contraindicated for NMES 

 
use (1). Patients may experience some painful muscle contractions as they first adjust the stimulus to a 
tolerable level, which can be quickly corrected by reducing the stimulation intensity. After treatment, 
muscles soreness may occur. The level of fatigue and/or soreness, however, will be similar to that 
which occurs following a standard exercise training session and should dissipate over time as the 
volunteer’s muscles become accustomed to the electrically-stimulated contractions (ie, they become 
trained).  
Benefits: The direct benefit of the research to volunteers is minimal. NMES may improve skeletal 
muscle structure or function and, in turn, improve physical functional capacity. Because of this, patients 
may experience improved physiological capacity, which could reduce disability post-surgery and 
potentially enhance the beneficial effects of CR. If we find that NMES has beneficial effects on physical 
function, further research and application of the technique to CABG patients post-surgery may assist in 
the development of more effective transitional rehabilitative care approaches to mitigate long-term 
functional morbidity. 
References cited above: 
1. 
Houghton, P. E., Nussbaum, E. L., and Hoens, A. M. (2010) Electrophysical agents. Contraindications and 
precautions: an evidence-based approach to clinical decision making in physical therapy. Physiother Can 62, 1-80
Therapeutic Alternatives:   
There are no alternative rehabilitation regimens during the early, post-operative period in CABG 
patients.  
Data Safety and Monitoring:  
Drs. Toth and Ades will monitor the safety of the research procedures for this study. We have not 
set up a formal safety committee for several reasons. First, the PIs and the investigative team have a 
long history of performing the measurements proposed in this proposal. The procedures carry relatively 
low risk to the volunteers. Second, because of the small number of patients and track record of 
performing these procedures, it is highly unlikely that we will need to "stop" the study or significantly 
alter the procedures. If any problems/unanticipated events arise related to the NMES intervention, Dr. 
Ades will determine the nature of the problem and its relatedness to the NMES intervention and decide 
whether continued participation in the study is in the best interest of the patient. As detailed above, 
however, NMES is FDA-approved for this indication and we have taken precautions to minimize the 
potential for adverse effects. 
 
Adverse Event and Unanticipated Problem (UAP) Reporting:   
The PIs or the study coordinator (Jason Rengo) will monitor the safety of the research 
procedures/interventions for this study. Mr. Rengo or Dr. Toth will be available on-site for all 
assessments that may pose safety concerns for volunteers. In this context, study personnel will be 
readily available to monitor volunteer safety throughout the study. If an event occurs that affects 
participant safety, Dr. Toth or Mr. Rengo will alert Dr. Ades, who will adjudicate the event with respect to 
its severity, expectedness and relatedness to participation in the study. Because numerous studies in 
our laboratories and others have demonstrated the safety of this regimen of testing in patients from with 
a broad range of clinical backgrounds (eg, heart failure patients, cancer patients, advanced-stage, knee 
OA patients; healthy elderly), we expect minimal problems related to testing or the intervention. 
Considering the low risk nature of these studies, we have not incorporated "stoppage criteria" for the 
overall study. Instead, Dr. Ades will decide whether an individual participant should continue with the 
study following occurrence of any adverse events or unanticipated problems, taking into consideration 
what is in the best interest of each individual patient. 
Adverse events will be reported by one of 3 mechanisms. First, the joint University of 
Vermont/University of Vermont Medical Center (UVMMC) Committee for Human Subject Research 
Adverse Event Reporting Document. These reports will be sent to the office of the Committee for 
Human Research in the Medical Science (CHRMS) within 2 days of the event. Reporting any adverse 
events will be the responsibility of the PIs. The CHRMS will make a determination as to whether 
additional reporting requirements are indicated. Additionally, the UVMMC Patient Safety Reporting 
system (SAFE), which may be initiated by health care center staff or study personnel. These forms will 
be forwarded within 3 days to the PI, UVMMC Risk Management Office, CHRMS and other appropriate 
agencies, as indicated by the nature of the report. Reviews of protocol specific adverse events will be 

 
performed no less than annually. Additionally, any adverse event that occurs will be forwarded to the 
PIs for reporting to the Human Subject Research Protection Office within 1 week of occurrence. Of note, 
these protections against risk include both physical risks to the volunteers, as well as risks associated 
with any breach in confidentiality. 
On an annual basis, Drs. Toth and Ades will assess data being gathered and safety of volunteers to 
assess the pattern or frequency of events to identify occurrence of any event or problem that alters the 
safety profile of the procedures being performed. The exception would be occurrence of a serious 
adverse event or unanticipated problem that necessitates re-evaluation of the expected risk of the study 
procedures at an earlier time point. Additionally, they will evaluate data collection and storage to ensure 
the confidentiality of data and quality. Each of these evaluations will be followed by reports of study 
progress and patient safety to the University of Vermont CHRMS via yearly progress reports.  
Withdrawal Procedures:  
Volunteers will be withdrawn if the research team, clinician and/or safety officer feels that further 
participation in the study or performance of any procedure associated with this study would, in any way, 
put the volunteer at undue risk or not be in their best interest. Moreover, volunteers may be withdrawn if 
s/he fails to attend scheduled visits or do not comply with instructions from research staff. 
Sources of Materials:  
An individual research record will be kept on each volunteer in compliance with HIPAA standards. This 
record will contain identifying data, demographic information and results from all clinical research 
measurements and evaluations. The results of all testing will be kept confidential. All materials gathered 
in conjunction with the proposed studies will be used for research purposes only and will be available 
only to research personnel working on these studies, who have obtained proper training in human 
subjects research and privacy protection.  
 
Statistical Analysis Plan: 
Our primary goal is to assess changes in SPPB score and 6 MW between study groups to test 
whether NMES prevents the erosion of functionality from admission to 4 wk post-discharge 
(approximate time for starting CR). A general linear mixed model will be used, with group and time as 
fixed effects. The primary comparison will be between measures at admission and 4 wks post-
discharge, as changes over this time period will reflect the effects of the surgery, post-op recovery and 
post-discharge/pre-CR periods. Because function may be impaired pre-surgery due to 
angina/dyspnea/etc, post-surgery measures may be a better indicator of functional capacity and we 
have the ability to calculate the changes in these measures from Discharge to 4 wks post-surgery. We 
will assess QOL by questionnaire and activity by accelerometry as secondary outcomes to determine if 
NMES improves patient-reported QOL and free-living daily activity, respectively, vs. usual care. 
Covariates (eg, length of stay, time to start of CR, admission SPPB, etc) can be included in the models 
to control for potential confounders that might differ by group in the event that randomization fails to 
equate groups for these variables.  
 
DRUG AND DEVICE INFORMATION
Drug (s) 
X 
Not applicable 
Device (s)
 
Not applicable
 
The interventional device used in this study: EMPI Continuum complete electrotherapy system has 
received FDA approval (501K: K093324) for retarding disuse-related atrophy, which we believe is one of 
the primary mechanisms whereby CABG patients become more functional disabled in the early, post-
surgical period. That is, muscle disuse secondary to pain, limited range of motion and muscle weakness 
causes skeletal muscle fiber atrophy and weakness, as well as mitochondrial rarefaction and 
dysfunction that further impair physical fitness.
Is it FDA approved:
Yes. It is approved to mitigate muscle atrophy/dysfunction associated with muscle disuse (501K: 
K093324).  
Risk assessment:   

 
The device (and similar devices) has been used extensively in the orthopedic and neural rehabilitation 
settings by physical and occupational therapists and in numerous disease states (heart failure, chronic 
obstructive pulmonary disease, knee replacement) to improve muscle size and function in clinical trial 
settings. Thus, NMES is generally a safe modality, with a long safety record. Although evidence is 
limited, some have suggested that NMES could increase the risk of dislodging a DVT because of the 
rhythmic muscle contractions induced by the electrical stimulation. However, several published reports 
show that NMES significantly reduces the risk of developing DVTs. In fact, the device we are using is 
FDA-approved for prevention of DVT of the calf muscles immediately following surgery, as it would 
function similar to intermittent pneumatic compression. Moreover, we will actively exclude any individual 
with a known coagulopathy or DVT. Because of the location of the stimulating electrodes (upper leg), 
the risk of NMES dislodging a DVT is likely minimal. There are also several case reports that NMES 
may be sensed by cardiac defibrillators as an arrhythmia, causing the device to discharge 
inappropriately. However, interference with ICDs mostly involved low frequency stimulation of the upper 
or lower back. In contrast, a more recent study has shown that higher frequency stimulation of the leg 
muscles does not cause electromagnetic interference with the device (1). Regardless, consistent with 
current clinical practice guidelines (2), we will exclude any volunteers that currently have an implanted 
cardiac defibrillator or pacemaker. Finally, during the first couple of NMES sessions, muscle soreness 
may occur, but this is comparable to what might occur with classical exercise training and dissipates 
over time.  
Literature cited 
1. 
Kamiya, K., Satoh, A., Niwano, S., Tanaka, S., Miida, K., Hamazaki, N., Maekawa, E., Matsuzawa, R., Nozaki, K., 
Masuda, T., and Ako, J. Safety of neuromuscular electrical stimulation in patients implanted with cardioverter 
defibrillators. Journal of Electrocardiology 49, 99-101 
2. 
Houghton, P. E., Nussbaum, E. L., and Hoens, A. M. (2010) Electrophysical agents. Contraindications and 
precautions: an evidence-based approach to clinical decision making in physical therapy. Physiother Can 62, 1-80 
 
SUBJECT CHARACTERISTICS, IDENTIFICATION AND RECRUITMENT 
Prior to our rationale for subject selection, we provide a brief accounting of inclusion/exclusion criteria. 
Ambulatory patients (50-80 yrs of age) scheduled for elective CABG and able to give informed consent 
will be recruited. Patients will be excluded if they have: 1) rheumatoid arthritis or other 
inflammatory/autoimmune diseases; 2) cancer, excluding non-melanoma skin cancer; 3) exercise-
limiting peripheral vascular disease, neuromuscular disease or lower extremity neuromuscular 
dysfunction related to prior cerebrovascular event; 4) body mass index >38 kg/m2 or 5) significant 
(moderate or greater) valvular heart disease that was not corrected surgically. We will also exclude 
patients with an existing lower blood clot or an implanted pacemaker or ICD, as both are 
contraindications for NMES (1). Patients will be excluded from further study post-operatively if they have 
serious complications that prolong hospitalization beyond 7 d post-surgery (eg, stroke, prolonged 
intubation, infection, etc), although this will likely be a small proportion of the population. 
 
These criteria were chosen to obtain a cohort of CABG patients who are free of other clinical conditions 
that may complicate our ability to detect an effect of NMES on physical function (eg, cancer w/ its 
accompanying treatments or motor deficits due to CVA, etc) and who may have difficulty conducting the 
NMES (eg, very obese individuals may have difficulty obtaining muscle contractions with the NMES 
device because fat in their legs serves as an electrical insulator). Finally, we exclude those volunteers 
with contraindications for NMES use. 
Literature cited: 
1. 
Houghton, P. E., Nussbaum, E. L., and Hoens, A. M. (2010) Electrophysical agents. Contraindications and 
precautions: an evidence-based approach to clinical decision making in physical therapy. Physiother Can 62, 1-80 
Number of Subjects:   
We intend to enroll 48 volunteers. This will allow for n=36 to complete the study, conservatively 
assuming 25% total attrition rate: 15% dropout, 10% non-compliance, based on prior studies of NMES 
use in post-surgical populations (1) and compliance data in our prior training studies (85-95% 
compliance). 
Literature cited: 

 
1. 
Stevens-Lapsley, J. E., Balter, J. E., Wolfe, P., Eckhoff, D. G., and Kohrt, W. M. (2012) Early neuromuscular electrical 
stimulation to improve quadriceps muscle strength after total knee arthroplasty: a randomized controlled trial. Phys 
Ther 92, 210-226
Inclusion/Exclusion Criteria:
Patients will be excluded if they have: 1) rheumatoid arthritis or other inflammatory/autoimmune 
diseases; 2) cancer, excluding non-melanoma skin cancer; 3) exercise-limiting peripheral vascular 
disease, neuromuscular disease or lower extremity neuromuscular dysfunction related to prior 
cerebrovascular event; 4) body mass index >38 kg/m2 or 5) significant (moderate or greater) valvular 
heart disease that was not corrected surgically. We will also exclude patients with an existing lower 
extremity blood clot or an implanted pacemaker or ICD, as both are contraindications for NMES (1). 
Patients will be excluded from further study post-operatively if they have serious complications that 
prolong hospitalization beyond 7 d post-surgery (eg, stroke, prolonged intubation, infection, etc), 
although this will likely be a small proportion of the population. 
Literature cited: 
1. 
Houghton, P. E., Nussbaum, E. L., and Hoens, A. M. (2010) Electrophysical agents. Contraindications and 
precautions: an evidence-based approach to clinical decision making in physical therapy. Physiother Can 62, 1-80
Inclusion of Minorities and Women:  
Inclusion of Women 
     This study will seek to include equal numbers of men and women. 
Inclusion of Minorities 
     Every effort will be made to recruit minorities for the proposed studies. The contribution of minorities 
to the total population of Vermont is 3.2%, with a similar minority profile in Chittenden County (3.6%), 
where the University of Vermont (UVM) is located.  
Inclusion of Children:.
The proposed studies will not include children because elective CABG surgery is confined to the adult/ 
older adult population.
Recruitment:   
Patients will be recruited through the Cardiothoracic Surgery Clinic and local clinical practices.