Paradoxical breathing during sleep is associated with increased sleep apnea and reduced ventilatory capacities in high-level spinal cord injury.

Sleep-disordered breathing is highly prevalent in individuals with high-level spinal cord injury. In addition, chest mechanics are known to be altered, leading to paradoxical breathing. Here we investigated the interaction between paradoxical breathing and sleep quality in these patients, and its association with measurements of respiratory function, hypercapnic ventilatory response and peak exercise ventilation. Home-based polysomnography was performed in 13 patients with spinal cord injury (C4 to T4) untreated for sleep-disordered breathing. We defined paradoxical breathing as counterphase between thoracic and abdominal movements during slow-wave and rapid eye movement sleep. Sleep quality, pulmonary function, hypercapnic ventilatory responses and peak exercise ventilation were compared between those with and without paradoxical breathing. Half of individuals presented with nocturnal paradoxical breathing. Despite similar age, body mass index, injury level, time since injury, and respiratory function, those with paradoxical breathing had higher apnea-hypopnea index (13 ± 8 versus 5 ± 3 events per hr) and average sleep heart rate (67 ± 12 versus 54 ± 4 bpm; p < 0.05). Moreover, paradoxical breathing was associated with lower hypercapnic ventilatory response (slope: 0.35 ± 0.17 versus 0.96 ± 0.38) and lower peak exercise ventilation (33 ± 4 versus 48 ± 12 L min-1 ; p < 0.05). Nocturnal respiratory muscle desynchronization could play a role in the pathophysiology of sleep apnea, and could relate to low ventilatory responses to both hypercapnia and exercise in high-level spinal cord injury. Polysomnography may be an important diagnostic tool for these patients for whom therapeutic approaches should be considered to treat this abnormality.

The effect of heart rate variability on blood pressure is augmented in spinal cord injury and is unaltered by exercise training.

PURPOSE: To define differences in heart rate and blood pressure variability (HRV/BPV) after spinal cord injury (SCI) compared with uninjured controls, and to determine whether variabilities are impacted by whole-body exercise after SCI. METHODS: Individuals with SCI (n = 40), aged 18-40, and uninjured age/sex-matched controls (n = 22) had HRV and BPV determined during supine paced (0.25 Hz) breathing. Spectral and cross-spectral values were derived for fluctuations at low (LF 0.05-0.15 Hz) and high (HF 0.20-0.30 Hz) frequencies. Thirty-two individuals with SCI further underwent either 6 months of whole-body exercise training (n = 17) or a control intervention (n = 15). RESULTS: Individuals with SCI had injuries graded A-C in severity, neurological levels of injury C1-T10. LF and HF HRV and LF BPV were significantly lower in individuals with SCI (p = 0.008-0.002), though HF BPV was similar. The LF cross-spectrum demonstrated similar phase and gain relationships between groups. The HF phase relationship between pressure and heart rate differed markedly: individuals with SCI demonstrated a -11.7 ± 3.4° phase lag (241 ± 70 ms feedback mechanism of pressure into heart rate), whereas uninjured controls demonstrated a +21.5 ± 10.8° phase lead (443 ± 224 ms feedforward mechanism of heart rate into pressure, p = 0.007). Whole-body exercise increased mean VO2peak by 2.09 ml/kg, whereas HRV, BPV, and their cross-spectral relationships were not significantly altered relative to the control intervention after SCI. CONCLUSION: After SCI, marked frequency-specific differences exist in the relationship between heart rate and blood pressure variabilities. The high-frequency cross-spectral relationship indicates that a feedback mechanism of blood pressure into heart rate may predominate in this range.

Serotonin 1A agonist and cardiopulmonary improvements with whole-body exercise in acute, high-level spinal cord injury: a retrospective analysis.

PURPOSE: High-level spinal cord injury (SCI) can result in spinal and supraspinal respiratory control deficits leading to insufficient ventilatory responses to exercise and training-related adaptations. We hypothesized a serotonin agonist, known to improve respiratory function in animal models, would improve adaptations to whole-body functional electrical stimulation (FES) exercise training in patients with acute high-level SCI. METHODS: We identified 10 patients (< 2 years of injury with SCI from C4 to T3) in our program who had performed 6 months of FES-row training while on Buspirone (29 ± 17 mg/day) between 2012 and 2018. We also identified well-matched individuals who trained for six months but not on Buspirone (n = 11). A peak incremental FES-rowing exercise test and resting pulmonary function test had been performed before and after training. RESULTS: Those on Buspirone demonstrated greater increases in peak oxygen consumption (VO2peak: + 0.24 ± 0.23 vs. + 0.10 ± 0.13 L/min, p = 0.08) and peak ventilation (VEpeak: + 6.5 ± 8.1 vs. - 0.7 ± 6.9 L/min, p < 0.05) compared to control. In addition, changes in VO2peak and VEpeak were correlated across all patients (r = 0.63, p < 0.01), but most strongly in those on Buspirone (r = 0.85, p < 0.01). Furthermore, changes in respiratory function correlated with increased peak tidal volume in the Buspirone group (r > 0.66, p < 0.05). CONCLUSION: These results suggest Buspirone improves cardiorespiratory adaptations to FES-exercise training in individuals with acute, high-level SCI. The strong association between increases in ventilatory and aerobic capacities suggests improved respiratory function is a mechanism; however, controlled studies are needed to determine if this preliminary finding is reproducible.

Gains in aerobic capacity with whole-body functional electrical stimulation row training and generalization to arms-only exercise after spinal cord injury.

STUDY DESIGN: Longitudinal study in adults (n = 27; 19-40 years old) with tetraplegic or paraplegic spinal cord injury (SCI). OBJECTIVES: Determine physiological adaptations and generalizable fitness effects of 6 months of whole-body exercise training using volitional arm and functional electrical stimulation (FES) leg rowing. SETTING: Outpatient hospital-based exercise facility and laboratory. METHODS: Participants enrolled in hybrid FES-row training (FESRT) and performed peak exercise tests with arms-only (AO; baseline and 6 months) and FES rowing (baseline, 3, 6 months). RESULTS: Participants demonstrated increased aerobic capacity (VO2peak) after FESRT (p < 0.001, np2 = 0.56) that tended to be higher when assessed with FES than AO rowing tests (0.15 ± 0.20 vs. 0.04 ± 0.22 L/min; p = 0.10). Changes in FES and AO VO2peak were significantly correlated (r = 0.55; p < 0.01), and 11 individuals demonstrated improvements (>6%) on both test formats. Younger age was the only difference between those who showed generalization of training effects and those who did not (mean age 26.6 ± 5.6 vs. 32.0 ± 5.7 years; p < 0.05) but changes in FES VO2peak correlated to time since injury in individuals <2 years post-SCI (r = -0.51, p < 0.01, n = 24). Lastly, VO2peak improvements were greater during the first 3 months vs. months 4-6 (+7.0% vs. +3.9%; p < 0.01) which suggests early training adaptations during FESRT. CONCLUSIONS: Gains in aerobic capacity after whole-body FESRT are better reflected during FES-row testing format. They relate to high-intensity exercise and appear early during training, but they may not generalize to equivalent increases in AO exercise in all individuals with SCI.

Automated O2 titration improves exercise capacity in patients with hypercapnic chronic obstructive pulmonary disease: a randomised controlled cross-over trial.

Automatically titrated O2 flows (FreeO2) was compared with constant O2 flow on exercise capacity, O2 saturation and risk of hyperoxia-related hypercapnia in patients with severe COPD with baseline hypercapnia and long-term oxygen therapy (LTOT). Twelve patients were enrolled in a randomised double-blind cross-over study to perform exercise with either FreeO2 or constant flow. Endurance time (primary outcome) and SpO2 were both significantly improved with FreeO2compared with constant flow (p<0.04), although pCO2 was similar in both conditions. Automated titration of O2 significantly and clinically improved endurance walking time in patients with severe COPD receiving LTOT, without worsening of pCO2 TRIAL REGISTRATION NUMBER: Results , NCT01575327.

Ventilatory support or respiratory muscle training as adjuncts to exercise in obese CPAP-treated patients with obstructive sleep apnoea: a randomised controlled trial.

BACKGROUND: Obstructive sleep apnoea (OSA) and obesity are interdependent chronic diseases sharing reduced exercise tolerance and high cardiovascular risk. INTERVENTION: A 3-month intervention with innovative training modalities would further improve functional capacity and cardiovascular health than usual cycle exercise training in already continuous positive airway pressure (CPAP)-treated obese patients with OSA. METHODS: Fifty three patients (35

Maximal exercise capacity in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis.

Maximal aerobic capacity is a strong health predictor and peak oxygen consumption (V'O2peak) is considered a reflection of total body health. No systematic reviews or meta-analyses to date have synthesised the existing data regarding V'O2peak in patients with obstructive sleep apnoea (OSA).A systematic review of English and French articles using PubMed/MEDLINE and Embase included studies assessing V'O2peak in OSA patients either in mL·kg-1·min-1 compared with controls or in % predicted. Two independent reviewers analysed the studies, extracted the data and assessed the quality of evidence.Mean V'O2peak expressed in mL·kg-1·min-1 was significantly lower in patients with OSA than in controls (mean difference -2.7 mL·kg-1·min-1; p<0.001; n=850). This reduction in V'O2peak was found to be larger in non-obese patients (body mass index <30 kg·m-2). Mean V'O2peak % pred was 89.9% in OSA patients (n=643).OSA patients have reduced maximal aerobic capacity, which can be associated with increased cardiovascular risks and reduced survival in certain patient subgroups. Maximal exercise testing can be useful to characterise functional limitation and to evaluate health status in OSA patients.

Clinical Use of Neuromuscular Electrical Stimulation for Neuromuscular Rehabilitation: What Are We Overlooking?

The clinical success of neuromuscular electrical stimulation (NMES) for neuromuscular rehabilitation is greatly compromised by the poor consideration of different physiological and methodological issues that are not always obvious to the clinicians. Therefore, the aim of this narrative review is to reexamine some of these fundamental aspects of NMES using a tripartite model perspective. First, we contend that NMES does not actually bypass the central nervous system but results in a multitude of neurally mediated responses that contribute substantially to force generation and may engender neural adaptations. Second, we argue that too much emphasis is generally placed on externally controllable stimulation parameters while the major determinant of NMES effectiveness is the intrinsically determined muscle tension generated by the current (ie, evoked force). Third, we believe that a more systematic approach to NMES therapy is required in the clinic and this implies a better identification of the patient-specific impairment and of the potential "responders" to NMES therapy. On the basis of these considerations, we suggest that the crucial steps to ensure the clinical effectiveness of NMES treatment should consist of (1) identifying the neuromuscular impairment with clinical assessment and (2) implementing algorithm-based NMES therapy while (3) properly dosing the treatment with tension-controlled NMES and eventually amplifying its neural effects.

Physiological correlates to spontaneous physical activity variability in obese patients with already treated sleep apnea syndrome.

BACKGROUND/OBJECTIVES: Physical activity is promoted in patients with sleep disorders and obesity. The aim of the present study was to assess physiological factors influencing objectively measured spontaneous physical activity in already treated patients for obstructive sleep apnea (OSA) by nocturnal continuous positive airway pressure (CPAP). SUBJECTS/METHODS: Fifty-five patients (age = 53 ± 3 years; body mass index (BMI) = 38 ± 3 kg/m2; compliance with CPAP >4 h/night) were prospectively included. Measurements were 5-day actigraphy with metabolic equivalent of task (METs) assessment, body composition, pulmonary function, quadriceps and respiratory muscle strength, exercise capacity (6-min walking distance and maximal aerobic capacity), as well as sleep parameters (sleepiness, duration, oxygen saturation, and micro-arousals during sleep) and quality of life (SF-36 questionnaire). RESULTS: As expected, the number of steps per day (6879 ± 2511) and mean intensity of physical activity (1.38 ± 0.15 METs) were below the recommendations for obese population. In age-adjusted stepwise regression models, peak oxygen consumption (VO2 peak) and peak dyspnea perception during incremental exercise test were independent predictors of the number of steps per day (r = 0.49, p = 0.001) although VO2 peak and peak minute ventilation were independent predictors of intensity of physical activity (in METs/day; r = 0.49, p = 0.001). CONCLUSIONS: In severe obese patients with OSA, exercise capacity, ventilatory requirement, and dyspnea perception were main physiological components of physical activity. These results emphasize the need to consider specific training interventions that increase ability to perform intense physical activity in obese OSA.

A new paradigm of neuromuscular electrical stimulation for the quadriceps femoris muscle.

PURPOSE: Neuromuscular electrical stimulation (NMES) with large electrodes and multiple current pathways (m-NMES) has recently been proposed as a valid alternative to conventional NMES (c-NMES) for quadriceps muscle (re)training. The main aim of this study was to compare discomfort, evoked force and fatigue between m-NMES and c-NMES of the quadriceps femoris muscle in healthy subjects. METHODS: Ten healthy subjects completed two experimental sessions (c-NMES and m-NMES), that were randomly presented in a cross-over design. Maximal electrically evoked force at pain threshold, self-reported discomfort at different levels of evoked force, and fatigue-induced force declines during and following a series of 20 NMES contractions were compared between c-NMES and m-NMES. RESULTS: m-NMES resulted in greater evoked force (P < 0.05) and lower discomfort in comparison to c-NMES (P < 0.05-0.001), but fatigue time course and magnitude did not differ between the two conditions. CONCLUSIONS: The use of quadriceps m-NMES appears legitimate for (re)training purposes because it generated stronger contractions and was less discomfortable than c-NMES (due to multiple current pathways and/or lower current density with larger electrodes).

Serotonin 1A Receptor Pharmacotherapy and Neuroplasticity in Spinal Cord Injury.

Spinal cord injury is associated with damage in descending and ascending pathways between brainstem/cortex and spinal neurons, leading to loss in sensory-motor functions. This leads not only to locomotor reduction but also to important respiratory impairments, both reducing cardiorespiratory engagement, and increasing cardiovascular risk and mortality. Moreover, individuals with high-level injuries suffer from sleep-disordered breathing in a greater proportion than the general population. Although no current treatments exist to restore motor function in spinal cord injury (SCI), serotoninergic (5-HT) 1A receptor agonists appear as pharmacologic neuromodulators that could be important players in inducing functional improvements by increasing the activation of spared motoneurons. Indeed, single therapies of serotoninergic 1A (5-HT1A) agonists allow for acute and temporary recovery of locomotor function. Moreover, the 5-HT1A agonist could be even more promising when combined with other pharmacotherapies, exercise training, and/or spinal stimulation, rather than administered alone. In this review, we discuss previous and emerging evidence showing the value of the 5HT1A receptor agonist therapies for motor and respiratory limitations in SCI. Moreover, we provide mechanistic hypotheses and clinical impact for the potential benefit of 5-HT1A agonist pharmacology in inducing neuroplasticity and improving locomotor and respiratory functions in SCI.

Diaphragmatic Activity and Respiratory Function Following C3 or C6 Unilateral Spinal Cord Contusion in Mice.

The majority of spinal cord injuries (SCIs) are cervical (cSCI), leading to a marked reduction in respiratory capacity. We aimed to investigate the effect of hemicontusion models of cSCI on both diaphragm activity and respiratory function to serve as preclinical models of cervical SCI. Since phrenic motoneuron pools are located at the C3-C5 spinal level, we investigated two models of preclinical cSCI mimicking human forms of injury, namely, one above (C3 hemicontusion-C3HC) and one below phrenic motoneuron pools (C6HC) in wild-type swiss OF-1 mice, and we compared their effects on respiratory function using whole-body plethysmography and on diaphragm activity using electromyography (EMG). At 7 days post-surgery, both C3HC and C6HC damaged spinal cord integrity above the lesion level, suggesting that C6HC potentially alters C5 motoneurons. Although both models led to decreased diaphragmatic EMG activity in the injured hemidiaphragm compared to the intact one (-46% and -26% in C3HC and C6HC, respectively, both p = 0.02), only C3HC led to a significant reduction in tidal volume and minute ventilation compared to sham surgery (-25% and -20% vs. baseline). Moreover, changes in EMG amplitude between respiratory bursts were observed post-C3HC, reflecting a change in phrenic motoneuronal excitability. Hence, C3HC and C6HC models induced alteration in respiratory function proportionally to injury level, and the C3HC model is a more appropriate model for interventional studies aiming to restore respiratory function in cSCI.

Cardiac, Autonomic, and Cardiometabolic Impact of Exercise Training in Spinal Cord Injury: A QUALITATIVE REVIEW.

INTRODUCTION: Direct and indirect effects of spinal cord injury lead to important cardiovascular (CV) complications that are further increased by years of injury and the process of "accelerated aging." The present review examines the current evidence in the literature for the potential cardioprotective effect of exercise training in spinal cord injury. REVIEW METHODS: PubMed and Web of Science databases were screened for original studies investigating the effect of exercise-based interventions on aerobic capacity, cardiac structure/function, autonomic function, CV function, and/or cardiometabolic markers. We compared the effects in individuals <40 yr with time since injury <10 yr with those in older individuals (≥40 yr) with longer time since injury (≥10 yr), reasoning that the two can be considered individuals with low versus high CV risk factors. SUMMARY: Studies showed similar exercise effects in both groups (n = 31 in low CV risk factors vs n = 15 in high CV risk factors). The evidence does not support any effect of exercise training on autonomic function but does support an increased peripheral blood flow, improved left ventricular mass, higher peak cardiac output, greater lean body mass, better antioxidant capacity, and improved endothelial function. In addition, some evidence suggests that it can result in lower blood lipids, systemic inflammation (interleukin-6, tumor necrosis factor α, and C-reactive protein), and arterial stiffness. Training intensity, volume, and frequency were key factors determining CV gains. Future studies with larger sample sizes, well-matched groups of subjects, and randomized controlled designs will be needed to determine whether high-intensity hybrid forms of training result in greater CV gains.

Ventilatory support during whole-body row training improves oxygen uptake efficiency in patients with high-level spinal cord injury: A pilot study.

High-level spinal cord injury (SCI) is characterized by profound respiratory compromise. One consequence is a limitation of whole-body exercise-based rehabilitation, reducing its cardioprotective effect. We investigated the use of ventilatory support during training on cardiorespiratory response to exercise. Nine subjects with high-level SCI (T3-C4) were included in this double-blind sham-controlled study. All had training adaptations plateauing for more than 6 months before enrolling in the study. After performing baseline assessment, participants were randomly assigned to continue training with non-invasive ventilation (NIV: n = 6: IPAP = 20 ± 2, EPAP: 3 cmH2O) or sham (n = 3: IPAP = 5, EPAP: 3 cmH2O) for 3 months and performed again maximal exercise tests. We compared the oxygen uptake efficiency slope (OUES, the rate of increases in VO2 in relation to increasing VE) before and after training. Training with NIV increased OUES both compared to baseline (4.1 ± 1.1 vs. 3.4 ± 1.0, i.e. +20 ± 12%, p < 0.05) and Sham (p = 0.01), representing an increase in ability to uptake oxygen for a given ventilation. This result was sustained without NIV during the test, suggesting improved cardiopulmonary reserve. Best responders were the youngest whose characteristics were very similar to sham participants. In addition, NIV tended to increase weekly rowing distance by 24% (p = 0.09, versus 10% in sham). Our results are very suggestive of a positive effect of ventilatory support during whole-body exercise in high-level SCI. Training adaptations found are of great importance since this sub-population of patients have the greatest need for exercise-based cardio-protection.

Acute Ventilatory Support During Whole-Body Hybrid Rowing in Patients With High-Level Spinal Cord Injury: A Randomized Controlled Crossover Trial.

BACKGROUND: High-level spinal cord injury (SCI) results in profound spinal and supraspinal deficits, leading to substantial ventilatory limitations during whole-body hybrid functional electrical stimulation (FES)-rowing, a form of exercise that markedly increases the active muscle mass via electrically induced leg contractions. This study tested the effect of noninvasive ventilation (NIV) on ventilatory and aerobic capacities in SCI. METHODS: This blinded, randomized crossover study enrolled 19 patients with SCI (level of injury ranging from C4 to T8). All patients were familiar with FES-rowing and had plateaued in their training-related increases in aerobic capacity. Patients performed two FES-rowing peak exercise tests with NIV or without NIV (sham). RESULTS: NIV increased exercise tidal volume (peak, 1.50 ± 0.31 L vs 1.36 ± 0.34 L; P < .05) and reduced breathing frequency (peak, 35 ± 7 beats/min vs 38 ± 6 beats/min; P < .05) compared with the sham test, leading to no change in alveolar ventilation but a trend toward increased oxygen uptake efficiency (P = .06). In those who reached peak oxygen consumption (Vo2peak) criteria (n = 13), NIV failed to significantly increase Vo2peak (1.73 ± 0.66 L/min vs 1.78 ± 0.59 L/min); however, the range of responses revealed a correlation between changes in peak alveolar ventilation and Vo2peak (r = 0.89; P < .05). Furthermore, those with higher level injuries and shorter time since injury exhibited the greatest increases in Vo2peak. CONCLUSIONS: Acute NIV can successfully improve ventilatory efficiency during FES exercise in SCI but may not improve Vo2peak in all patients. Those who benefit most seem to be patients with cervical SCI within a shorter time since injury. TRIAL REGISTRY: ClinicalTrials.gov; Nos.: NCT02865343 and NCT03267212; URL: www.clinicaltrials.gov.

Impact of preinduced quadriceps fatigue on exercise response in chronic obstructive pulmonary disease and healthy subjects.

Exercise intolerance in chronic obstructive pulmonary disease (COPD) results from a complex interaction between central (ventilatory) and peripheral (limb muscles) components of exercise limitation. The purpose of this study was to evaluate the influence of quadriceps muscle fatigue on exercise tolerance and ventilatory response during constant-workrate cycling exercise testing (CWT) in patients with COPD and healthy subjects. Fifteen patients with COPD and nine age-matched healthy subjects performed, 7 days apart, two CWTs up to exhaustion at 80% of their predetermined maximal work capacity. In a randomized order, one test was performed with preinduced quadriceps fatigue and the other in a fresh state. Quadriceps fatigue was produced by electrostimulation-induced contractions and quantified by maximal voluntary contraction and potentiated twitch force (TwQ(pot)). Endurance time and ventilatory response during CWT were compared between fatigued and fresh state. Endurance time significantly decreased in the fatigued state compared with the fresh condition in COPD (356 +/- 69 s vs. 294 +/- 45 s, P < 0.05) and controls (450 +/- 74 s vs. 340 +/- 45 s, P < 0.05). Controls showed significantly higher ventilation and end-exercise dyspnea scores in the fatigued condition, whereas, in COPD, fatigue did not influence ventilation or dyspnea during exercise. The degree of ventilatory limitation, as expressed by the Ve/maximum voluntary ventilation ratio, was similar in both conditions in patients with COPD. We conclude that it is possible to induce quadriceps fatigue by local electrostimulation-induced contractions. Our findings demonstrate that peripheral muscle fatigue is an additional important factor, besides intense dyspnea, that limits exercise tolerance in COPD.

Chronic neuromuscular electrical stimulation improves muscle mass and insulin sensitivity in a mouse model.

Muscle wasting reduces functional capacity and increases cardiometabolic risk in chronic disease. Neuromuscular electrical stimulation (NMES) of the lower limb has been shown to reverse muscle wasting in these patients but its effect on cardiometabolic health is unclear. We investigated a mouse model of in-vivo non-invasive chronic NMES on muscle mass, insulin sensitivity and arterial blood pressure (BP). Twenty-three C57BL6 mice underwent unilateral NMES or sham training over 2.5 weeks while anesthetized by isoflurane. Lower limb muscle mass and the stimulated limb to non-stimulated limb muscle mass ratio were compared between groups (NMES vs. sham). Insulin sensitivity was assessed 48 h after training using an intraperitoneal insulin tolerance test (ITT) and BP was assessed before and after training using the tail-cuff technique. After training, muscle mass increased in NMES vs. sham (416 ± 6 vs. 397 ± 6 mg, p = 0.04) along with the ratio of muscle mass (+3 ± 1% vs. -1 ± 1% p = 0.04). Moreover, insulin sensitivity improved in NMES vs. sham (average blood glucose during ITT: 139.6 ± 8.5 vs. 161.9 ± 9.0 mg/dl blood, p = 0.01). BP was decreased in both groups, although it is likely that the effect of NMES on BP was dampened by repetitive anesthesia. The metabolic benefit of NMES training could be of great utility in patients with chronic disease. Moreover, the clinical-like mouse model of NMES is an effective tool to investigate the systemic effects of local muscle strengthening.