Stroke is the leading cause of serious long-term disability in the United States [1]. A decrease in stroke mortality (36.9% decrease from 1999 to 2009), has led to a subsequent increase in those living with the consequences of stroke [2]. As such, it impacts the financial status of patients, families, and health care systems [3]. A retrospective study of inpatient stroke care costs from 2000 to 2020 revealed mean hospital costs per stay were US $15,781 (SD US $330) [4]. The mean lifetime cost of ischemic stroke is approximately US $140,048 in the United States, placing stroke among the top 10 most costly conditions among Medicare beneficiaries [5]. Recurrent stroke, cardiac disease, and respiratory complications are the leading causes of mortality in stroke survivors. Given these financial and health costs, there is therefore a critical need to prevent further cardiovascular and cardiorespiratory decline and reduce the incidence of cardiac and respiratory disease and functional disability.

Although stroke sequelae affect numerous body systems, automatic control of resting ventilation is typically spared in the majority of stroke cases, affected only in more severe brainstem strokes. Motor deficits are often the most debilitating to mobility and return to participation in life roles. Motor processing and the voluntary control of muscles of respiration engaged when speaking, upon exertion, coughing, or with exercise may be weakened following damage directly to the cerebral cortex or the descending axonal projections. Consequently, individuals after stroke may exhibit prolonged exercise intolerance, dyspnea, and airway clearance dysfunction. It is upon this conceptual framework we propose that respiratory muscle training is an important component in the rehabilitation of individuals following stroke. The purposes of this study are to (1) evaluate the effect of a combined exercise program (EP) with respiratory strength training (RST) on measures of impairment, activity, and participation; (2) evaluate its ability to maintain prospective respiratory health; and (3) explore the effect smoking history may have on these outcomes.

The primary objective of this trial is to test the hypothesis that a combined EP with RST improves physiologic, activity, and societal participation outcomes in chronic stroke survivors. In addition to limb and respiratory weakness, up to 78% of patients after stroke present with dysphagia [6], a significant risk factor for aspiration. Cough is a critical mechanism to guard against aspiration and is often impaired after stroke [7], resulting in greater incidences of aspiration and chest infection [8,9]. Furthermore, pneumonia is the leading cause of nonvascular death in acute [10] and chronic [11] phases after stroke. RST could improve airway clearance as a protective function. The adoption of interventions capable of preventing the occurrence of respiratory complications may substantially improve the long-term outcomes of these patients [12]. Several small-scale studies have demonstrated that inspiratory [13-16] and expiratory [14] muscles respond to strength training in patients after stroke, but the impacts of respiratory strengthening on function are less clear. In a systematic review of poststroke respiratory muscle training randomized controlled trials, Menezes et al [17] reported there were insufficient data to determine whether the benefits of respiratory muscle training are realized in gains in functional activity level or participation, concluding that future trials are needed to assess the effects of training on one’s activity and participation in life roles. RST for individuals after stroke has the potential to facilitate a return to these important societal roles.

Our secondary objective is to prospectively monitor health status for 1-year following the exercise intervention. There is a clear link between the presence of respiratory dysfunction in individuals after stroke and the incidence of respiratory complications such as aspiration or respiratory infections [18-20]. Menezes et al [17] revealed that respiratory muscle training reduced the relative risk of respiratory complications immediately and 6 months after the commencement of the intervention. Others have reported that expiratory muscle strength training exercises improve respiratory strength, cough, and swallowing function in stroke [21-23]. A 2016 meta-analysis [17] revealed that respiratory muscle training reduced the relative risk of respiratory complications immediately and 6 months after the commencement of the intervention. However, this conclusion was based on just 2 trials, and procedures for detecting the occurrence of respiratory complications were not sufficiently robust.

An exploratory objective will evaluate potential differential responses to respiratory muscle training based on smoke exposure. Cigarette smoking negatively impacts respiratory health and increases the risk of cardiovascular events. While direct cigarette smoking is a known risk factor for stroke and poststroke complications, individuals exposed to secondhand smoke also face high health risks. There is a strong, dose-dependent association between passive smoking and stroke [24].

This is a single-blind randomized controlled trial. Participants will be assessed at Brooks Rehabilitation Clinical Research Center and receive intervention sessions at the Brooks Family YMCA. Health status will be monitored monthly for 1 year following the intervention. This study is registered at ClinicalTrials.gov (NCT05819333). The trial will be reported according to SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials), TIDieR (Template for Intervention Description and Replication), and CONSORT (Consolidated Standards of Reporting Trials) guidelines (Figure 1).

This protocol and Informed Consent Form were reviewed and approved by the University of Florida’s institutional review board (IRB; #202000810). Participants will sign the IRB-approved informed consent form before enrollment. Participants will be assigned a unique numerical identifier to deidentify and assure the privacy and confidentiality of all collected data. Compensation of US $15/study visit will occur in the form of a debit card, with a total compensation of US $405.

To evaluate not simply how many steps participants take but to understand where those steps are taken (ie, within the confines of their home or actually outside their home in the community), participants will wear a GPS device for 7 days. These deidentified longitude and latitude coordinate data are not collected in real-time but rather will be downloaded to a password-protected computer at the completion of the 7-day wearing period. Safety of trial intervention and assessments will be monitored by reporting to the IRB any adverse events that occur from enrollment to trial completion at 12 months following the intervention.

Participants will be recruited from an IRB-approved clinical research registry and study flier. Power calculations determined a study population of 80 participants and are presented below. We will enroll up to 95 participants to allow for a potential attrition rate of up to 15% (14/95). Specific inclusion and exclusion criteria for study enrollment are presented in Textbox 1. The cardiovascular and respiratory exclusion criteria were adopted from a previous exercise study with individuals poststroke [25,26].

Participants will be randomized to the EP plus RST group or EP plus respiratory relaxation training (RRT group) using the Microsoft Excel (Microsoft Office Professional Plus 2016) RAND function. Participants and the intervention physical therapist will be aware of the group assignment due to the nature of the intervention; however, study evaluators will remain blinded.

In total, 24 intervention sessions will be delivered 3 times a week over 8 weeks. Intervention therapists will undergo standardized training and a structured intervention log with the 3 aspects of the EP, and the respiratory training outlined will be followed each session to assure intervention fidelity.

Both groups will participate in the EP consisting of 3 components recommended by American Heart Association (AHA) poststroke exercise recommendations [27], directed by the intervention physical therapist, and individualized to the participants’ ability.

Participants will be randomized to the RST or RRT group.

Participants will be assessed (1) at baseline, (2) after 12 sessions, and (3) after 24 sessions by a physical therapist blinded to group assignment. Blinded assessors will undergo standardized training to assure assessment fidelity. Following intervention completion participants will complete monthly health status questionnaires.

Results from this study will improve our understanding of the additive benefits of respiratory exercises on short and long-term physiologic, functional, and societal gains for these individuals. We hypothesize that the combined RST+EP will be more effective than the EP alone for stroke survivors with and without a smoking exposure history. Specifically, we hypothesize that combined RST+EP will be more effective in restoring poststroke maximal respiratory pressure, in restoring both physical (walking endurance) and respiratory (airway clearance) function, and in restoring poststroke life and social roles. We also hypothesize that RST+EP will be more effective than EP alone in reducing 1-year postintervention incidence of adverse respiratory events.

While multiple studies indicate the potential for respiratory muscle training to improve respiratory strength, airway protection, and dyspnea during acute stroke rehabilitation [14,65,66], limited information is available pertaining to the benefits of respiratory training in community-dwelling adults with chronic stroke [13,21,67]. This study approaches the research aims from a wellness perspective, as opposed to a medical model of rehabilitation. The AHA-informed EP and respiratory training sessions occur in a community-based gym that emphasizes wellness and secondary prevention of stroke. Previous respiratory training research has emphasized respiratory strength, with fewer studies reporting effects on activity-based metrics such as cough force, gait speed, or walking endurance [16,68]. This trial uses an impairment-based primary study outcome measure (MIP) as a comparator to other published respiratory training studies in stroke. However, activity- and participation-based outcome measures were also included to account for functional limitations participants might experience after stroke and to further quantify restrictions in their societal roles. Further, this study moves beyond patient-reported participation, by directly measuring impacts of the respiratory training on gains in community activity and societal roles for up to 1 year following the completion of the intervention. The carryover from a gain in body function or activity to improved community and societal participation is a recognized need in stroke rehabilitation research [17].

This research will also contribute novel exploratory information regarding effects of the EP and respiratory training in people with chronic stroke with and without daily cigarette smoke exposure. Smoking is an independent risk factor for stroke that directly increases the relative risk of stroke in a dose-dependent fashion [69]. Smoking induces vascular inflammation and endothelial dysfunction to accelerate the progression of atherosclerosis [70,71]. Secondhand smoke exposure also independently increases both the risk of stroke and obstructive pulmonary disease [72,73] and no level of passive smoke exposure is considered safe [24]. Chronic smoke exposure increases the work of breathing through dynamic hyperinflation and heightened airway resistance, despite an increased inspiratory neural drive, leading to dyspnea and airway clearance dysfunction [74,75]. Despite the negative impacts of smoking on cardiovascular and respiratory health, its impact on poststroke respiratory rehabilitation is poorly understood. Older adults with obstructive lung disease who completed 6 weeks of inspiratory strength training achieved significant improvements in MIP and dyspnea, and reported physical quality of life, yet in contrast to adults without lung disease, no gains in walking endurance occurred. These results suggest that individuals with lung disease recovering from stroke may require additional training time or combinatorial exercises to improve walking [76].

We recognize some limitations of the study design. The study was powered to distinguish the 8-week effects of RST from RRT on MIP. We acknowledge that societal participation is multidimensional, and longer-term changes may be influenced by many contributing factors beyond respiratory strength and walking endurance [77,78]. The use of patient-reported outcome measures and assessment of the Area Deprivation Index will help identify some factors that contribute to societal participation. Since group assignment will be based on the type of respiratory training, it is possible there may be unequal proportions of smoke-exposed and nonsmoking participants in each group. The monitoring of smoke exposure will enable us to explore whether the combined respiratory and whole-body exercise approaches offer distinct benefits to cigarette smoke-exposed individuals. While study assessors will be blinded to group assignment, patients and exercise supervisors will know their respiratory exercise assignment. A true control or “sham” respiratory training intervention was not included; rather, the RRT serves as an active comparator. The volume of respiratory exercises during exercise sessions will be the same for both groups, even though the physiological effects of RST and RRT exercises likely differ.

Since findings from this study may influence the health promotion, wellness, and secondary prevention societal roles of the physical therapy profession, dissemination efforts will be directed toward physical therapists and other rehabilitation providers. Study results will be presented at scientific conferences and published in peer-reviewed journals used by physical therapists and rehabilitation scientists.

This trial is an investigator-initiated, single-blind, randomized controlled trial designed to evaluate the effects of an AHA-informed EP and respiratory training on measures of impairment, activity, and societal participation. Implementation of this trial will help identify modes of exercise that lead to the greatest short- and long-term functional and societal gains in smoke-exposed and nonexposed, community-dwelling adults with chronic stroke.