A. Daniel Martin

Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.

CONTEXT Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. OBJECTIVE To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. DESIGN, SETTING, AND PATIENTS A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. INTERVENTION Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). MAIN OUTCOME MEASURES Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. RESULTS Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. CONCLUSION Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00824005.

Adherence to Exercise Prescriptions: Effects of Prescribing Moderate Versus Higher Levels of Intensity and Frequency

Sedentary adults (N = 379) were randomly assigned in a 2 x 2 design to walk 30 min per day at a frequency of either 3-4 or 5-7 days per week, at an intensity of either 45%-55% or 65%-75% of maximum heart rate reserve. Analyses of exercise accumulated over 6 months showed greater amounts completed in the higher frequency (p = .0001) and moderate intensity (p = .021) conditions. Analyses of percentage of prescribed exercise completed showed greater adherence in the moderate intensity(p = .02) condition. Prescribing a higher frequency increased the accumulation of exercise without a decline in adherence, whereas prescribing a higher intensity decreased adherence and resulted in the completion of less exercise.

Extended-Care Programs for Weight Management in Rural Communities: The Treatment of Obesity in Underserved Rural Settings (TOURS) Randomized Trial

BACKGROUND Rural counties in the United States have higher rates of obesity, sedentary lifestyle, and associated chronic diseases than nonrural areas, yet the management of obesity in rural communities has received little attention from researchers. METHODS Obese women from rural communities who completed an initial 6-month weight-loss program at Cooperative Extension Service offices in 6 medically underserved rural counties (n = 234) were randomized to extended care or to an education control group. The extended-care programs entailed problem-solving counseling delivered in 26 biweekly sessions via telephone or face to face. Control group participants received 26 biweekly newsletters containing weight-control advice. RESULTS Mean weight at study entry was 96.4 kg. Mean weight loss during the initial 6-month intervention was 10.0 kg. One year after randomization, participants in the telephone and face-to-face extended-care programs regained less weight (mean [SE], 1.2 [0.7] and 1.2 [0.6] kg, respectively) than those in the education control group (3.7 [0.7] kg; P = .03 and .02, respectively). The beneficial effects of extended-care counseling were mediated by greater adherence to behavioral weight-management strategies, and cost analyses indicated that telephone counseling was less expensive than face-to-face intervention. CONCLUSIONS Extended care delivered either by telephone or in face-to-face sessions improved the 1-year maintenance of lost weight compared with education alone. Telephone counseling constitutes an effective and cost-efficient option for long-term weight management. Delivering lifestyle interventions via the existing infrastructure of the Cooperative Extension Service represents a viable means of adapting research for rural communities with limited access to preventive health services. Trial Registration clinicaltrials.gov Identifier: NCT00201006.

Inspiratory muscle strength training improves weaning outcome in failure to wean patients: a randomized trial

IntroductionMost patients are readily liberated from mechanical ventilation (MV) support, however, 10% - 15% of patients experience failure to wean (FTW). FTW patients account for approximately 40% of all MV days and have significantly worse clinical outcomes. MV induced inspiratory muscle weakness has been implicated as a contributor to FTW and recent work has documented inspiratory muscle weakness in humans supported with MV.MethodsWe conducted a single center, single-blind, randomized controlled trial to test whether inspiratory muscle strength training (IMST) would improve weaning outcome in FTW patients. Of 129 patients evaluated for participation, 69 were enrolled and studied. 35 subjects were randomly assigned to the IMST condition and 34 to the SHAM treatment. IMST was performed with a threshold inspiratory device, set at the highest pressure tolerated and progressed daily. SHAM training provided a constant, low inspiratory pressure load. Subjects completed 4 sets of 6-10 training breaths, 5 days per week. Subjects also performed progressively longer breathing trials daily per protocol. The weaning criterion was 72 consecutive hours without MV support. Subjects were blinded to group assignment, and were treated until weaned or 28 days.ResultsGroups were comparable on demographic and clinical variables at baseline. The IMST and SHAM groups respectively received 41.9 ± 25.5 vs. 47.3 ± 33.0 days of MV support prior to starting intervention, P = 0.36. The IMST and SHAM groups participated in 9.7 ± 4.0 and 11.0 ± 4.8 training sessions, respectively, P = 0.09. The SHAM groups pre to post-training maximal inspiratory pressure (MIP) change was not significant (-43.5 ± 17.8 vs. -45.1 ± 19.5 cm H2O, P = 0.39), while the IMST groups MIP increased (-44.4 ± 18.4 vs. -54.1 ± 17.8 cm H2O, P < 0.0001). There were no adverse events observed during IMST or SHAM treatments. Twenty-five of 35 IMST subjects weaned (71%, 95% confidence interval (CI) = 55% to 84%), while 16 of 34 (47%, 95% CI = 31% to 63%) SHAM subjects weaned, P = .039. The number of patients needed to be treated for effect was 4 (95% CI = 2 to 80).ConclusionsAn IMST program can lead to increased MIP and improved weaning outcome in FTW patients compared to SHAM treatment.Trial RegistrationClinicalTrials.gov: NCT00419458

Inspiratory strengthening effect on resistive load detection and magnitude estimation.

PURPOSE This study investigated effects of inspiratory muscle training (IMT) on maximal inspiratory pressure (MIP), magnitude estimation (ME), and load detection (LD) of external resistive loads (deltaR) in healthy subjects. METHODS Ten adult volunteers IMT trained 5 d x wk(-1) for 4 wk. A training set consisted of six inspiratory efforts at 75% of MIP; daily training trials consisted of four sets. ME was calculated by linear regression, with actual and estimated deltaR loads plotted on log-log scale. LD was calculated by determining deltaR50/Ro fraction. Dependent measures were taken pre- and post-IMT. RESULTS MIP significantly increased from 87 to 139 cmH2O pre- to post-IMT, respectively. ME for individual loads significantly decreased post-IMT for all but the highest deltaR. There was no significant difference in LD deltaR50/Ro, post-IMT. CONCLUSIONS The results demonstrate that inspiratory muscle strength gains were associated with decreased ME of deltaRs without changing LD deltaR50/Ro. This suggests that the mechanisms mediating the detection of deltaRs may be different than the mechanisms for estimating deltaR size.

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.

Expiratory time constant for determinations of plateau pressure, respiratory system compliance, and total resistance.

IntroductionWe hypothesized the expiratory time constant (ƬE) may be used to provide real time determinations of inspiratory plateau pressure (Pplt), respiratory system compliance (Crs), and total resistance (respiratory system resistance plus series resistance of endotracheal tube) (Rtot) of patients with respiratory failure using various modes of ventilatory support.MethodsAdults (n = 92) with acute respiratory failure were categorized into four groups depending on the mode of ventilatory support ordered by attending physicians, i.e., volume controlled-continuous mandatory ventilation (VC-CMV), volume controlled-synchronized intermittent mandatory ventilation (VC-SIMV), volume control plus (VC+), and pressure support ventilation (PSV). Positive end expiratory pressure as ordered was combined with all aforementioned modes. Pplt, determined by the traditional end inspiratory pause (EIP) method, was combined in equations to determine Crs and Rtot. Following that, the ƬE method was employed, ƬE was estimated from point-by-point measurements of exhaled tidal volume and flow rate, it was then combined in equations to determine Pplt, Crs, and Rtot. Both methods were compared using regression analysis.ResultsƬE, ranging from mean values of 0.54 sec to 0.66 sec, was not significantly different among ventilatory modes. The ƬE method was an excellent predictor of Pplt, Crs, and Rtot for various ventilatory modes; r2 values for the relationships of ƬE and EIP methods ranged from 0.94 to 0.99 for Pplt, 0.90 to 0.99 for Crs, and 0.88 to 0.94 for Rtot (P <0.001). Bias and precision values were negligible.ConclusionsWe found the ƬE method was just as good as the EIP method for determining Pplt, Crs, and Rtot for various modes of ventilatory support for patients with acute respiratory failure. It is unclear if the ƬE method can be generalized to patients with chronic obstructive lung disease. ƬE is determined during passive deflation of the lungs without the need for changing the ventilatory mode and disrupting a patients breathing. The ƬE method obviates the need to apply an EIP, allows for continuous and automatic surveillance of inspiratory Pplt so it can be maintained ≤ 30 cm H2O for lung protection and patient safety, and permits real time assessments of pulmonary mechanics.

Comparing Costs of Telephone vs Face-to-Face Extended-Care Programs for the Management of Obesity in Rural Settings

BACKGROUND A major challenge after successful weight loss is continuing the behaviors required for long-term weight maintenance. This challenge can be exacerbated in rural areas with limited local support resources. OBJECTIVE This study describes and compares program costs and cost effectiveness for 12-month extended-care lifestyle maintenance programs after an initial 6-month weight-loss program. DESIGN We conducted a 1-year prospective randomized controlled clinical trial. PARTICIPANTS/SETTING The study included 215 female participants age 50 years or older from rural areas who completed an initial 6-month lifestyle program for weight loss. The study was conducted from June 1, 2003 to May 31, 2007. INTERVENTION The intervention was delivered through local Cooperative Extension Service offices in rural Florida. Participants were randomly assigned to a 12-month extended-care program using either individual telephone counseling (n=67), group face-to-face counseling (n=74), or a mail/control group (n=74). MAIN OUTCOME MEASURES Program delivery costs, weight loss, and self-reported health status were directly assessed through questionnaires and program activity logs. Costs were estimated across a range of enrollment sizes to allow inferences beyond the study sample. STATISTICAL ANALYSES PERFORMED Nonparametric and parametric tests of differences across groups for program outcomes were combined with direct program cost estimates and expected value calculations to determine which scales of operation favored alternative formats for lifestyle maintenance. RESULTS Median weight regain during the intervention year was 1.7 kg for participants in the face-to-face format, 2.1 kg for the telephone format, and 3.1 kg for the mail/control format. For a typical group size of 13 participants, the face-to-face format had higher fixed costs, which translated into higher overall program costs (

Phrenic Nerve Stimulation Increases Human Diaphragm Fiber Force after Cardiothoracic Surgery

420 per participant) when compared with individual telephone counseling (

Gene expression changes in the human diaphragm after cardiothoracic surgery

268 per participant) and control (