Intraoperative Hemi-Diaphragm Electrical Stimulation Demonstrates Attenuated Mitochondrial Function without Change in Oxidative Stress in Cardiothoracic Surgery Patients.

Mechanical ventilation during cardiothoracic surgery is life-saving but can lead to ventilator-induced diaphragm dysfunction (VIDD) and prolong ventilator weaning and hospital length of stay. Intraoperative phrenic nerve stimulation may preserve diaphragm force production to offset VIDD; we also investigated changes in mitochondrial function after stimulation. During cardiothoracic surgeries (n = 21), supramaximal, unilateral phrenic nerve stimulation was performed every 30 min for 1 min. Diaphragm biopsies were collected after the last stimulation and analyzed for mitochondrial respiration in permeabilized fibers and protein expression and enzymatic activity of biomarkers of oxidative stress and mitophagy. Patients received, on average, 6.2 ± 1.9 stimulation bouts. Stimulated hemidiaphragms showed lower leak respiration, maximum electron transport system (ETS) capacities, oxidative phosphorylation (OXPHOS), and spare capacity compared with unstimulated sides. There were no significant differences between mitochondrial enzyme activities and oxidative stress and mitophagy protein expression levels. Intraoperative phrenic nerve electrical stimulation led to an acute decrease of mitochondrial respiration in the stimulated hemidiaphragm, without differences in biomarkers of mitophagy or oxidative stress. Future studies warrant investigating optimal stimulation doses and testing post-operative chronic stimulation effects on weaning from the ventilator and rehabilitation outcomes.

Effect of Telehealth Extended Care for Maintenance of Weight Loss in Rural US Communities: A Randomized Clinical Trial.

Importance: Lifestyle interventions for obesity produce reductions in body weight that can decrease risk for diabetes and cardiovascular disease but are limited by suboptimal maintenance of lost weight and inadequate dissemination in low-resource communities. Objective: To evaluate the effectiveness of extended care programs for obesity management delivered remotely in rural communities through the US Cooperative Extension System. Design, Setting, and Participants: This randomized clinical trial was conducted from October 21, 2013, to December 21, 2018, in Cooperative Extension Service offices of 14 counties in Florida. A total of 851 individuals were screened for participation; 220 individuals did not meet eligibility criteria, and 103 individuals declined to participate. Of 528 individuals who initiated a 4-month lifestyle intervention, 445 qualified for randomization. Data were analyzed from August 22 to October 21, 2019. Interventions: Participants were randomly assigned to extended care delivered via individual or group telephone counseling or an education control program delivered via email. All participants received 18 modules with posttreatment recommendations for maintaining lost weight. In the telephone-based interventions, health coaches provided participants with 18 individual or group sessions focused on problem solving for obstacles to the maintenance of weight loss. Main Outcomes and Measures: The primary outcome was change in body weight from the conclusion of initial intervention (month 4) to final follow-up (month 22). An additional outcome was the proportion of participants achieving at least 10% body weight reduction at follow-up. Results: Among 445 participants (mean [SD] age, 55.4 [10.2] years; 368 [82.7%] women; 329 [73.9%] white), 149 participants (33.5%) were randomized to individual telephone counseling, 143 participants (32.1%) were randomized to group telephone counseling, and 153 participants (34.4%) were randomized to the email education control. Mean (SD) baseline weight was 99.9 (14.6) kg, and mean (SD) weight loss after the initial intervention was 8.3 (4.9) kg. Mean weight regains at follow-up were 2.3 (95% credible interval [CrI], 1.2-3.4) kg in the individual telephone counseling group, 2.8 (95% CrI, 1.4-4.2) kg for the group telephone counseling group, and 4.1 (95% CrI, 3.1-5.0) kg for the education control group, with a significantly smaller weight regain observed in the individual telephone counseling group vs control group (posterior probability >.99). A larger proportion of participants in the individual telephone counseling group achieved at least 10% weight reductions (31.5% [95% CrI, 24.1%-40.0%]) than in the control group (19.1% [95% CrI, 14.1%-24.9%]) (posterior probability >.99). Conclusions and Relevance: This randomized clinical trial found that providing extended care for obesity management in rural communities via individual telephone counseling decreased weight regain and increased the proportion of participants who sustained clinically meaningful weight losses. Trial Registration: ClinicalTrials.gov Identifier: NCT02054624.

Patients alter power of breathing as the primary response to changes in pressure support ventilation.

INTRODUCTION: The patient-ventilator relationship is dynamic as the patient's health fluctuates and the ventilator settings are modified. Spontaneously breathing patients respond to mechanical ventilation by changing their patterns of breathing. This study measured the physiologic response when pressure support (PS) settings were modified during mechanical ventilation. METHODS: Subjects were instrumented with a non-invasive pressure, flow, and carbon dioxide airway sensor to estimate tidal volume, respiratory rate, minute ventilation, and end-tidal CO2. Additionally, a catheter was used to measure esophageal pressure and estimate effort exerted during breathing. Respiratory function measurements were obtained while PS settings were adjusted 569 times between 5 and 25 cmH2O. RESULTS: Data was collected on 248 patients. The primary patient response to changes in PS was to adjusting effort (power of breathing) followed by adjusting tidal volume. Changes in respiratory rate were less definite while changes in minute ventilation and end-tidal CO2 appeared unrelated to the change in PS. CONCLUSION: The data indicates that patients maintain a set minute ventilation by adjusting their breathing rate, volume, and power. The data indicates that the subjects regulate their Ve and PetCO2 by adjusting power of breathing and breathing pattern.

Breathing variability predicts the suggested need for corrective intervention due to the perceived severity of patient-ventilator asynchrony during NIV.

Patient-ventilator asynchrony is associated with intolerance to noninvasive ventilation (NIV) and worsened outcomes. Our goal was to develop a tool to determine a patient needs for  intervention by a practitioner due to the presence of patient-ventilator asynchrony. We postulated that a clinician can determine when a patient needs corrective intervention due to the perceived severity of patient-ventilator asynchrony. We hypothesized a new measure, patient breathing variability, would indicate when corrective intervention is suggested by a bedside practitioner due to the perceived severity of patient-ventilator asynchrony. With IRB approval data was collected on 78 NIV patients. A panel of experts reviewed retrospective data from a development set of 10 NIV patients to categorize them into one of the three categories. The three categories were; "No to mild asynchrony-no intervention needed", "moderate asynchrony-non-emergent corrective intervention required", and "severe asynchrony-immediate intervention required". A stepwise regression with a F-test forward selection criterion was used to develop a positive linear logic model predicting the expert panel's categorizations of the need for corrective intervention. The model was incorporated into a software tool for clinical implementation. The tool was implemented prospectively on 68 NIV patients simultaneous to a bedside practitioner scoring the need for corrective intervention due to the perceived severity of patient-ventilator asynchrony. The categories from the tool and the practitioner were compared with the rate of agreement, sensitivity, specificity, and receiver operator characteristic analyses. The rate of agreement in categorizing the suggested need for clinical intervention due to the perceived presence of patient-ventilator asynchrony between the tool and experienced bedside practitioners was 95% with a Kappa score of 0.85 (p < 0.001). Further analysis found a specificity of 84% and sensitivity of 99%. The tool appears to accurately match the suggested need for corrective intervention by a bedside practitioner. Application of the tool allows for continuous, real time, and non-invasive monitoring of patients receiving NIV, and may enable early corrective interventions to ameliorate potential patient-ventilator asynchrony.

Clinical decision support recommending ventilator settings during noninvasive ventilation.

NIV therapy is used to provide positive pressure ventilation for patients. There are protocols describing what ventilator settings to use to initialize NIV; however, the guidelines for titrating ventilator settings are less specific. We developed an advisory system to recommend NIV ventilator setting titration and recorded respiratory therapist agreement rates at the bedside. We developed an algorithm (NIV advisor) to recommend when to change the non-invasive ventilator settings of IPAP, EPAP, and FiO2 based on patient respiratory parameters. The algorithm utilized a multi-target approach; oxygenation, ventilation, and patient effort. The NIV advisor recommended ventilator settings to move the patient's respiratory parameters in a preferred target range. We implemented a pilot study evaluating the usability of the NIV advisor on 10 patients receiving critical care with non-invasive ventilation (NIV). Respiratory therapists were asked their agreement on recommendations from the NIV advisor at the patient's bedside. Bedside respiratory therapists agreed with 91% of the ventilator setting recommendations from the NIV advisor. The POB and VT values were the respiratory parameters that were most often out of the preferred target range. The IPAP ventilator setting was the setting most often considered in need of changing by the NIV advisor. The respiratory therapists agreed with the majority of the recommendations from the NIV advisor. We consider the IPAP recommendations informative in providing the respiratory therapist assistance in targeting preferred POB and Vt values, as these values were frequently out of the target ranges. This pilot implementation was unable to produce the results required to determine the value of the EPAP recommendations. The FiO2 recommendations from the NIV advisor were treated as ancillary information behind the IPAP recommendations.

Dynamic respiratory muscle function in late-onset Pompe disease.

Maximal inspiratory pressure (PIMAX) reflects inspiratory weakness in late-onset Pompe disease (LOPD). However, static pressure tests may not reveal specific respiratory muscle adaptations to disruptions in breathing. We hypothesized that dynamic respiratory muscle functional tests reflect distinct ventilatory compensations in LOPD. We evaluated LOPD (n = 7) and healthy controls (CON, n = 7) during pulmonary function tests, inspiratory endurance testing, dynamic kinematic MRI of the thorax, and ventilatory adjustments to single-breath inspiratory loads (inspiratory load compensation, ILC). We observed significantly lower static and dynamic respiratory function in LOPD. PIMAX, spirometry, endurance time, and maximal diaphragm descent were significantly correlated. During single-breath inspiratory loads, inspiratory time and airflow acceleration increased to preserve volume, and in LOPD, the response magnitudes correlated to maximal chest wall kinematics. The results indicate that changes in diaphragmatic motor function and strength among LOPD subjects could be detected through dynamic respiratory testing. We concluded that neuromuscular function significantly influenced breathing endurance, timing and loading compensations.

Design of the Rural LEAP randomized trial: An evaluation of extended-care programs for weight management delivered via group or individual telephone counseling.

Obesity is a major contributor to the greater prevalence of chronic disease morbidity and mortality observed in rural versus nonrural areas of the U.S. Nonetheless, little research attention has been given to modifying this important driver of rural/urban disparities in health outcomes. Although lifestyle treatments produce weight reductions of sufficient magnitude to improve health, the existing research is limited with respect to the long-term maintenance of treatment effects and the dissemination of services to underserved populations. Recent studies have demonstrated the feasibility of delivering lifestyle programs through the infrastructure of the U.S. Cooperative Extension Service (CES), which has >2900 offices nationwide and whose mission includes nutrition education and health promotion. In addition, several randomized trials have shown that supplementing lifestyle treatment with extended-care programs consisting of either face-to-face sessions or individual telephone counseling can improve the maintenance of weight loss. However, both options entail relatively high costs that inhibit adoption in rural communities. The delivery of extended care via group-based telephone intervention may represent a promising, cost-effective alternative that is well suited to rural residents who tend to be isolated, have heightened concerns about privacy, and report lower quality of life. The Rural Lifestyle Eating and Activity Program (Rural LEAP) is a randomized trial, conducted via CES offices in rural communities, targeted to adults with obesity (n = 528), and designed to evaluate the effectiveness and cost-effectiveness of extended-care programs delivered via group or individual telephone counseling compared to an education control condition on long-term changes in body weight.

Inspiratory Muscle Rehabilitation in Critically Ill Adults. A Systematic Review and Meta-Analysis.

RATIONALE: Respiratory muscle weakness is common in critically ill patients; the role of targeted inspiratory muscle training (IMT) in intensive care unit rehabilitation strategies remains poorly defined. OBJECTIVES: The primary objective of the present study was to describe the range and tolerability of published methods for IMT. The secondary objectives were to determine whether IMT improves respiratory muscle strength and clinical outcomes in critically ill patients. METHODS: We conducted a systematic review to identify randomized and nonrandomized studies of physical rehabilitation interventions intended to strengthen the respiratory muscles in critically ill adults. We searched the MEDLINE, Embase, HealthSTAR, CINAHL, and CENTRAL databases (inception to September Week 3, 2017) and conference proceedings (2012 to 2017). Data were independently extracted by two authors and collected on a standardized report form. RESULTS: A total of 28 studies (N = 1,185 patients) were included. IMT was initiated during early mechanical ventilation (8 studies), after patients proved difficult to wean (14 studies), or after extubation (3 studies), and 3 other studies did not report exact timing. Threshold loading was the most common technique; 13 studies employed strength training regimens, 11 studies employed endurance training regimens, and 4 could not be classified. IMT was feasible, and there were few adverse events during IMT sessions (nine studies; median, 0%; interquartile range, 0-0%). In randomized trials (n = 20), IMT improved maximal inspiratory pressure compared with control (15 trials; mean increase, 6 cm H2O; 95% confidence interval [CI], 5-8 cm H2O; pooled relative ratio of means, 1.19; 95% CI, 1.14-1.25) and maximal expiratory pressure (4 trials; mean increase, 9 cm H2O; 95% CI, 5-14 cm H2O). IMT was associated with a shorter duration of ventilation (nine trials; mean difference, 4.1 d; 95% CI, 0.8-7.4 d) and a shorter duration of weaning (eight trials; mean difference, 2.3 d; 95% CI, 0.7-4.0 d), but confidence in these pooled estimates was low owing to methodological limitations, including substantial statistical and methodological heterogeneity. CONCLUSIONS: Most studies of IMT in critically ill patients have employed inspiratory threshold loading. IMT is feasible and well tolerated in critically ill patients and improves both inspiratory and expiratory muscle strength. The impact of IMT on clinical outcomes requires future confirmation.

Decision support system facilitates rapid decreases in pressure support and appropriate inspiratory muscle workloads in adults with respiratory failure.

PURPOSE: A commercially available decision support system (DSS) provides guidance for setting inspiratory pressure support (PS) to maintain work of breathing (WOB/min), breathing frequency (f), and tidal volume (VT) in proper clinical ranges (VentAssist™). If these values are outside the proper clinical range patients may suffer fatigue, atrophy, hypoventilation, hyperventilation, volutrauma, or VT deficiency. The purpose of our study was to evaluate the increase of the percentage of breaths in the targeted clinical ranges when the DSS guidance for setting the PS was followed. MATERIALS AND METHODS: The study included 43 intubated adults with respiratory failure in an academic medical intensive care unit. Each of the patients had received ventilatory support for >24h with no weaning trials attempted. Clinicians switched the ventilator to PS then proceeded to utilize the guidance recommended by the DSS for setting PS for 21 patients (intervention group); while the clinicians caring for the remaining 23 patients did not have access to the DSS (control group). RESULTS: The use of a DSS to set PS level increased the percentage of breaths in the targeted clinical range [28% to 48%, p value<0.0001]. An unexpected result was that while following the DSS 18 of the 21 patients were rapidly weaned to minimal ventilator settings within 46±38min; however, when the DSS was not available weaning to minimal ventilator settings lasted 21±12h [p value<0.0001]. CONCLUSIONS: The DSS is successful at assisting clinicians on how to set PS specific to a patient's individual demands (VT and f) while accounting for their breathing effort (WOB/min). The DSS appears to promote rapid weaning of PS to minimal ventilator settings when appropriate.

Inspiratory muscle conditioning exercise and diaphragm gene therapy in Pompe disease: Clinical evidence of respiratory plasticity.

Pompe disease is an inherited disorder due to a mutation in the gene that encodes acid α-glucosidase (GAA). Children with infantile-onset Pompe disease develop progressive hypotonic weakness and cardiopulmonary insufficiency that may eventually require mechanical ventilation (MV). Our team conducted a first in human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory neural dysfunction in infantile-onset Pompe. Subjects (aged 2-15years, full-time MV: n=5, partial/no MV: n=4) underwent a period of preoperative inspiratory muscle conditioning exercise. The change in respiratory function after exercise alone was compared to the change in function after intramuscular delivery of AAV1-CMV-GAA to the diaphragm with continued exercise. Since AAV-mediated gene therapy can reach phrenic motoneurons via retrograde transduction, we hypothesized that AAV1-CMV-GAA would improve dynamic respiratory motor function to a greater degree than exercise alone. Dependent measures were maximal inspiratory pressure (MIP), respiratory responses to inspiratory threshold loads (load compensation: LC), and physical evidence of diaphragm activity (descent on MRI, EMG activity). Exercise alone did not change function. After AAV1-CMV-GAA, MIP was unchanged. Flow and volume LC responses increased after dosing (p<0.05 to p<0.005), but only in the subjects with partial/no MV use. Changes in LC tended to occur on or after 180days. At Day 180, the four subjects with MRI evidence of diaphragm descent had greater maximal voluntary ventilation (p<0.05) and tended to be younger, stronger, and use fewer hours of daily MV. In conclusion, combined AAV1-CMV-GAA and exercise training conferred benefits to dynamic motor function of the diaphragm. Children with a higher baseline neuromuscular function may have greater potential for functional gains.

Intraoperative hemidiaphragm electrical stimulation reduces oxidative stress and upregulates autophagy in surgery patients undergoing mechanical ventilation: exploratory study.

BACKGROUND: Mechanical ventilation (MV) during a cardio-thoracic surgery contributes to diaphragm muscle dysfunction that impairs weaning and can lead to the ventilator- induced diaphragm dysfunction. Especially, it is critical in older adults who have lower muscle reparative capacity following MV. Reports have shown that the intraoperative intermittent hemidiaphragm electrical stimulation can maintain and/or improve post-surgery diaphragm function. In particular, from a molecular point of view, intermittent ES may reduce oxidative stress and increase regulatory autophagy levels, and therefore improve diaphragm function in animal studies. We have recently shown in humans that intraoperative ES attenuates mitochondrial dysfunction and force decline in single diaphragm muscle fibers. The aim of this study was to investigate an effect of ES on oxidative stress, antioxidant status and autophagy biomarker levels in the human diaphragm during surgery. METHODS: One phrenic nerve was simulated with an external cardiac pacer in operated older subjects (62.4 ± 12.9 years) (n = 8) during the surgery. The patients received 30 pulses per min every 30 min. The muscle biopsy was collected from both hemidiaphragms and frozen for further analyses. 4-hydroxynonenal (4-HNE), an oxidative stress marker, and autophagy marker levels (Beclin-1 and the ratio of microtubule-associated protein light chain 3, I and II-LC3 II/I) protein concentrations were detected by the western blot technique. Antioxidant enzymatic activity copper-zinc (CuZnSOD) and manganese (MnSOD) superoxide dismutase were analyzed. RESULTS: Levels of lipid peroxidation (4-HNE) were significantly lower in the stimulated side (p < 0.05). The antioxidant enzyme activities (CuZnSOD and MnSOD) in the stimulated side of the diaphragm were not different than in the unstimulated side (p > 0.05). Additionally, the protein concentrations of Beclin-1 and the LC3 II/I ratio were higher in the stimulated side (p < 0.05). CONCLUSION: These results suggest that the intraoperative electrical stimulation decreases oxidative stress levels and upregulates autophagy levels in the stimulated hemidiaphragm. These results may contribute future studies and clinical applications on reducing post-operative diaphragm dysfunction.

Diaphragm Pacing as a Rehabilitative Tool for Patients With Pompe Disease Who Are Ventilator-Dependent: Case Series.

BACKGROUND AND PURPOSE: Pompe disease is an inherited disorder notable for severe, progressive ventilatory compromise. Although ventilatory failure has been attributed to myofiber dysfunction secondary to diaphragmatic glycogen accumulation, neural involvement of the phrenic motor system is also a prominent feature. Direct diaphragm pacing supplements respiratory function in other disorders of the phrenic motor system. Accordingly, it is hypothesized that augmented neuromuscular activity via diaphragm pacing would promote weaning from mechanical ventilation in patients with Pompe disease who are unresponsive to conventional, muscle-directed treatments. CASE DESCRIPTION: Three patients with Pompe disease developed diaphragm paresis that resulted in chronic mechanical ventilation dependence. After preoperative inspiratory muscle strengthening exercises failed to improve function, fine-wire pacing electrodes were laparoscopically implanted into the diaphragm. Diaphragm conditioning was initiated the first postoperative week and consisted of gradual increases in stimulation parameters, lengthening of stimulation sessions, and ventilator weaning. Ventilation and intramuscular electromyographic activity were recorded periodically during conditioning to quantify diaphragm neuromuscular function. OUTCOMES: During paced breathing without mechanical ventilation, tidal volumes increased, and 2 patients were weaned from daytime ventilator dependence within the first 3 months of pacing, which has been sustained over the long-term. A third patient reduced reliance on daytime ventilation, but weaning was delayed by malacia of the large airways. In all patients, pacing appeared to facilitate spontaneous phrenic motor unit activity during independent breathing without ventilator or pacer support. DISCUSSION: The findings are consistent with the view that diaphragm pacing has potential rehabilitative value to reduce reliance on mechanical ventilation in people with Pompe disease, but further study is needed. Diaphragm pacing represents a paradigm shift in the management of respiratory insufficiency for Pompe disease that warrants further controlled examination.

Altered activation of the diaphragm in late-onset Pompe disease.

Pompe disease is an inherited neuromuscular disorder that affects respiratory function and leads to dependence on external ventilatory support. We studied the activation of the diaphragm using bilateral phrenic magnetic stimulation and hypothesized that diaphragm compound muscle action potential (CMAP) amplitude and evoked transdiaphragmatic pressure (Twitch PDI) would correlate to disease severity. Eight patients with late onset Pompe disease (LOPD, aged 14-48 years) and four healthy control subjects completed the tests. Maximal Twitch PDI responses were progressively reduced in patients with LOPD compared to control subjects (1.4-17.1cm H2O, p<0.001) and correlated to voluntary functional tests (p<0.05). Additionally, CMAP amplitude (mA) was lower in the patients who used nighttime or fulltime ventilatory support, when compared to controls and patients who used no ventilatory support (p<0.005). However, the normalized (%peak) Twitch PDI and CMAP responses were similar between patients and controls. This suggests a loss of functional phrenic motor units in patients, with normal recruitment of remaining motor units.

Real time noninvasive estimation of work of breathing using facemask leak-corrected tidal volume during noninvasive pressure support: validation study.

We describe a real time, noninvasive method of estimating work of breathing (esophageal balloon not required) during noninvasive pressure support (PS) that uses an artificial neural network (ANN) combined with a leak correction (LC) algorithm, programmed to ignore asynchronous breaths, that corrects for differences in inhaled and exhaled tidal volume (VT) from facemask leaks (WOBANN,LC/min). Validation studies of WOBANN,LC/min were performed. Using a dedicated and popular noninvasive ventilation ventilator (V60, Philips), in vitro studies using PS (5 and 10 cm H2O) at various inspiratory flow rate demands were simulated with a lung model. WOBANN,LC/min was compared with the actual work of breathing, determined under conditions of no facemask leaks and estimated using an ANN (WOBANN/min). Using the same ventilator, an in vivo study of healthy adults (n = 8) receiving combinations of PS (3-10 cm H2O) and expiratory positive airway pressure was done. WOBANN,LC/min was compared with physiologic work of breathing/min (WOBPHYS/min), determined from changes in esophageal pressure and VT applied to a Campbell diagram. For the in vitro studies, WOBANN,LC/min and WOBANN/min ranged from 2.4 to 11.9 J/min and there was an excellent relationship between WOBANN,LC/breath and WOBANN/breath, r = 0.99, r(2) = 0.98 (p < 0.01). There were essentially no differences between WOBANN,LC/min and WOBANN/min. For the in vivo study, WOBANN,LC/min and WOBPHYS/min ranged from 3 to 12 J/min and there was an excellent relationship between WOBANN,LC/breath and WOBPHYS/breath, r = 0.93, r(2) = 0.86 (p < 0.01). An ANN combined with a facemask LC algorithm provides noninvasive and valid estimates of work of breathing during noninvasive PS. WOBANN,LC/min, automatically and continuously estimated, may be useful for assessing inspiratory muscle loads and guiding noninvasive PS settings as in a decision support system to appropriately unload inspiratory muscles.

Intrinsic transient tracheal occlusion training and myogenic remodeling of rodent parasternal intercostal fibers.

It is recognized that diaphragm muscle plasticity occurs with mechanical overloads, yet less is known about synergistic parasternal intercostal muscle fiber remodeling. We conducted overload training with intrinsic transient tracheal occlusion (ITTO) exercises in conscious animals. We hypothesized that ITTO would yield significant fiber hypertrophy and myogenic activation that would parallel diaphragm fiber remodeling. Sprague-Dawley rats underwent placement of a tracheal cuff and were randomly assigned to receive daily 10 min sessions of conscious ITTO or observation (sham) over 2 wk. After training, fiber morphology, myosin heavy chain (MHC) isoform composition, cross-sectional area, proportion of Pax7-positive nuclei, and presence of embryonic MHC (eMHC) were quantified. Type IIx/b fibers were 20% larger after ITTO training than with sham training (ITTO: 4,431 +/­ 676 µm2, sham: 3,689 +/­ 400 µm2, p < 0.05), and type I fibers were more prevalent after ITTO (p < 0.01). Expression of Pax7 was increased in ITTO parasternals and diaphragm (p < 0.05). In contrast, the proportion of eMHC-positive fibers was increased only in ITTO parasternals (1.2% [3.4%­0.6%], sham: 0% [0.6%­0%], p < 0.05). Although diaphragm and parasternal type II fibers hypertrophy to a similar degree, myogenic remodeling appears to differ between the two muscles.

Comparative effectiveness of three doses of weight-loss counseling: two-year findings from the rural LITE trial.

OBJECTIVE: To evaluate the effects and costs of three doses of behavioral weight-loss treatment delivered via Cooperative Extension Offices in rural communities. METHODS: Obese adults (N = 612) were randomly assigned to low, moderate, or high doses of behavioral treatment (i.e., 16, 32, or 48 sessions over two years) or to a control condition that received nutrition education without instruction in behavior modification strategies. RESULTS: Two-year mean reductions in initial body weight were 2.9% (95% Credible Interval = 1.7-4.3), 3.5% (2.0-4.8), 6.7% (5.3-7.9), and 6.8% (5.5-8.1) for the control, low-, moderate-, and high-dose conditions, respectively. The moderate-dose treatment produced weight losses similar to the high-dose condition and significantly larger than the low-dose and control conditions (posterior probability > 0.996). The percentages of participants who achieved weight reductions ≥ 5% at two years were significantly higher in the moderate-dose (58%) and high-dose (58%) conditions compared with low-dose (43%) and control (40%) conditions (posterior probability > 0.996). Cost-effectiveness analyses favored the moderate-dose treatment over all other conditions. CONCLUSIONS: A moderate dose of behavioral treatment produced two-year weight reductions comparable to high-dose treatment but at a lower cost. These findings have important policy implications for the dissemination of weight-loss interventions into communities with limited resources.

Effect of intermittent phrenic nerve stimulation during cardiothoracic surgery on mitochondrial respiration in the human diaphragm.

OBJECTIVES: Recent studies have shown that brief periods of mechanical ventilation in animals and humans can lead to ventilator-induced diaphragmatic dysfunction, which includes muscle atrophy, reduced force development, and impaired mitochondrial function. Studies in animal models have shown that short periods of increased diaphragm activity during mechanical ventilation support can attenuate ventilator-induced diaphragmatic dysfunction but corresponding human data are lacking. The purpose of this study was to examine the effect of intermittent diaphragm contractions during cardiothoracic surgery, including controlled mechanical ventilation, on mitochondrial respiration in the human diaphragm. DESIGN: Within subjects repeated measures study. SETTING: Operating room in an academic health center. PATIENTS: Five subjects undergoing elective cardiothoracic surgery. INTERVENTIONS: In patients (age 65.6 ± 6.3 yr) undergoing cardiothoracic surgery, one phrenic nerve was stimulated hourly (30 pulses/min, 1.5 msec duration, 17.0 ± 4.4 mA) during the surgery. Subjects received 3.4 ± 0.6 stimulation bouts during surgery. Thirty minutes following the last stimulation bout, samples of diaphragm muscle were obtained from the anterolateral costal regions of the stimulated and inactive hemidiaphragms. MEASUREMENTS AND MAIN RESULTS: Mitochondrial respiration was measured in permeabilized muscle fibers with high-resolution respirometry. State III mitochondrial respiration rates (pmol O2/s/mg wet weight) were 15.05 ± 3.92 and 11.42 ± 2.66 for the stimulated and unstimulated samples, respectively (p < 0.05). State IV mitochondrial respiration rates were 3.59 ± 1.25 and 2.11 ± 0.97 in the stimulated samples and controls samples, respectively (p < 0.05). CONCLUSION: These are the first data examining the effect of intermittent contractions on mitochondrial respiration rates in the human diaphragm following surgery/mechanical ventilation. Our results indicate that very brief periods (duty cycle ~1.7%) of activity can improve mitochondrial function in the human diaphragm following surgery/mechanical ventilation.

Effect of training on inspiratory load compensation in weaned and unweaned mechanically ventilated ICU patients.

BACKGROUND: While inspiratory muscle weakness is common in prolonged mechanical ventilation, inspiratory muscle strength training (IMST) can facilitate strengthening and ventilator weaning. However, the inspiratory load compensation (ILC) responses to threshold loads are not well characterized in patients. We retrospectively compared ILC responses according to the clinical outcomes of IMST (ie, maximum inspiratory pressure [PImax], weaning outcome), in difficult-to-wean ICU patients. METHODS: Sixteen tracheostomized subjects (10 weaned, 6 unweaned) from a previous clinical trial underwent IMST 5 days/week, at the highest tolerated load, in conjunction with daily, progressive spontaneous breathing trials. PImax and ILC with a 10 cm H2O load were compared in the subjects before and after IMST. Changes in ILC performance were further characterized (5, 10, 15 cm H2O loads) in the trained subjects who weaned. RESULTS: Demographics, respiratory mechanics, and initial PImax (52 ± 26 cm H2O vs 42 ± 13 cm H2O) did not significantly differ between the groups. Upon enrollment, PImax significantly correlated with flow ILC responses with the 10 cm H2O load (r = 0.64, P = .008). After IMST, PImax significantly increased in the entire sample (P = .03). Both before and after IMST, subjects who weaned generated greater flow and volume ILC than subjects who failed to wean. Additionally, ILC flow, tidal volume, and duty cycle increased upon ventilator weaning, at loads of 5, 10, and 15 cm H2O. CONCLUSIONS: Flow ILC at a threshold load of 10 cm H2O in ventilated, tracheostomized subjects positively correlated with PImax. Although PImax improved in both groups, the flow and volume ILC responses of the weaned subjects were more robust, both before and after IMST. The results suggest that ILC response is different in weaned and unweaned subjects, reflecting dynamic inspiratory muscular efforts that could be influential in weaning.