Randolph W. Stroetz

Efficacy of Nocturnal Nasal Ventilation in Stable, Severe Chronic Obstructive Pulmonary Disease During a 3-Month Controlled Trial

OBJECTIVE To evaluate the efficacy of nocturnal nasal ventilation (NNV) in patients with rigidly defined, severe but stable chronic obstructive pulmonary disease (COPD) and hypercapnia. DESIGN By randomization, eligible patients were assigned to an active or a sham treatment arm. Data from these two groups were analyzed statistically. MATERIAL AND METHODS Initially, 35 patients with severe COPD (forced expiratory volume in 1 second [FEV1] of less than 40% predicted) and daytime hypercapnia (arterial carbon dioxide tension [PaCO2] of more than 45 mm Hg) were enrolled in a 3-month NNV trial. After a minimal observation period of 6 weeks, 13 patients were judged to be clinically stable and were randomized to NNV (N = 7) or sham (N = 6) treatment, consisting of nightly use of a bilevel positive airway pressure (PAP) device set to deliver an inspiratory pressure of either 10 or 0 cm of water (H2O). The device was used in the spontaneous or timed mode and set to a minimal expiratory pressure of 2 cm H2O. Patients underwent extensive physiologic testing including polysomnography and were introduced to the bilevel PAP system during a 2.5-day hospital stay. RESULTS The NNV and sham treatment groups were similar in mean age (71.0 versus 66.5 years), PaCO2 (54.7 versus 48.5 mm Hg), and FEV1 (0.62 versus 0.72 L). Only four of seven patients in the NNV group were still using the bilevel PAP device at the completion of the trial, as opposed to all six patients in the sham group. Only one patient had a substantial reduction in PaCO2 - from 50 mm Hg at baseline to 43 mm Hg after 3 months of NNV. He declined further NNV treatment with bilevel PAP. Sham treatment did not lower PaCO2. Lung function, nocturnal oxygen saturation, and sleep efficiency remained unchanged in both groups. CONCLUSION Disabled but clinically stable patients with COPD and hypercapnia do not readily accept and are unlikely to benefit from NNV.

Determinants of Plasma Membrane Wounding by Deforming Stress

Once excess liquid gains access to air spaces of an injured lung, the act of breathing creates and destroys foam and thereby contributes to the wounding of epithelial cells by interfacial stress. Since cells are not elastic continua, but rather complex network structures composed of solid as well as liquid elements, we hypothesize that plasma membrane (PM) wounding is preceded by a phase separation, which results in blebbing. We postulate that interventions such as a hypertonic treatment increase adhesive PM-cytoskeletal (CSK) interactions, thereby preventing blebbing as well as PM wounds. We formed PM tethers in alveolar epithelial cells and fibroblasts and measured their retractive force as readout of PM-CSK adhesive interactions using optical tweezers. A 50-mOsm increase in media osmolarity consistently increased the tether retractive force in epithelial cells but lowered it in fibroblasts. The osmo-response was abolished by pretreatment with latrunculin, cytochalasin D, and calcium chelation. Epithelial cells and fibroblasts were exposed to interfacial stress in a microchannel, and the fraction of wounded cells were measured. Interventions that increased PM-CSK adhesive interactions prevented blebbing and were cytoprotective regardless of cell type. Finally, we exposed ex vivo perfused rat lungs to injurious mechanical ventilation and showed that hypertonic conditioning reduced the number of wounded subpleural alveolus resident cells to baseline levels. Our observations support the hypothesis that PM-CSK adhesive interactions are important determinants of the cellular response to deforming stress and pave the way for preclinical efficacy trials of hypertonic treatment in experimental models of acute lung injury.

Experimental models to study cell wounding and repair.

Cell wounding, that is a loss of plasma membrane integrity, is a common everyday occurrence in load bearing organs such as muscle, skin, and bone. In general, these injuries trigger adaptive responses to either restore homeostasis or to protect the cells from further damage. The ability to restore plasma membrane integrity after injury is critical for cell survival and all cells posses a means to do so. However, the probability of plasma membrane wound repair depends on the cell type, as well as the size and nature of the lesion. Several in vitro experimental models of cell injury have been developed to simulate specific stresses cells experience in vivo. Motivated by our interest in studying the mechanisms of cell injury and repair relevant to ventilator associated lung injury, we review some of the most frequently used in vitro experimental models of cell wounding and present some new data pertaining to alveolar epithelium.

Contractile response to colonic distention is influenced by oscillation frequency.

Abstract  Static colonic mechanical properties are characterized by stepwise balloon distention. It is unclear whether the state of contractile activation affects frequency‐dependent differences in biomechanical properties. Our aim was to investigate the frequency‐dependence of colonic mechanical properties by sinusoidal oscillation. A descending colonic balloon was sinusoidally oscillated by 25 mL at 5, 10 and 20 cpm in randomized order for 20 min at each frequency in six healthy subjects before and after neostigmine. Volume oscillation was between 75–100 mL before, and 25–50 mL after neostigmine. Pressure waveforms were most variable shortly after commencing oscillation, reflecting an initial contractile response to distention. Elastance (i.e. pressure response to imposed volume) and hysteresivity were estimated; hysteresivity represents the proportion of energy added to the system during inflation, which cannot be recovered during deflation. Colonic elastance was frequency dependent, being highest and most variable at 10 cpm. In contrast, hysteresivity was not significantly different across frequencies. Neostigmine increased mean colonic elastance at all frequencies, and hysteresivity only at 5 cpm. Thus, colonic mechanical properties, particularly elastance are frequency‐dependent. The frequency‐dependence of colonic mechanical properties is worthy of future study because it may provide insights into reflex responses in health and disease.

A novel technique for bedside anorectal manometry in humans

Currently, anorectal manometry (ARM), which is used to diagnose defecatory disorders and identify anal weakness in fecal incontinence (FI) is generally conducted in specialized laboratories. Our aims were to compare anorectal functions measured with high‐resolution manometry (HRM) and a novel portable manometry device.

466 A Novel Portable Device to Measure Anorectal Pressures: Comparison With High Resolution Manometry

Abnormalities in rectal compliance have been identified in irritable bowel syndrome (IBS), wherein patients exhibit decreased rectal compliance in response to experimental distention (Kwan CL, et al. Neurogastroenterol Motil 2004; Shroff S, et al. DDW 2012). However, these differences in rectal physiology are not uniformly present in all IBS subjects. We sought to examine whether psychiatric comorbidity (e.g., depression, anxiety) in IBS has mechanistic relevance to rectal compliance. We hypothesized that dysregulation of autonomic tone inherent in mood disorders leads to decreased rectal compliance in IBS patients. Methods: 38 female subjects (43.6 ±11.1 yrs; 22 Rome III IBS/16 healthy controls) were recruited. Measures of mood (Beck Depression and Anxiety Inventories, [BDI, BAI]) and somatization (Patient Health Questionnaire [PHQ-15]) were collected. Both groups underwent 4 series of 6 pseudo-randomized, barostat-controlled rectal distentions using either high pressure (HPD, 50 mmHg) or low pressure (LPD, 25 mmHg) delivery. Dynamic rectal compliances (ΔV/ΔP) were derived from the ascending phase of the distention. Multivariate linear regression was employed to determine whether psychiatric comorbidity independently influenced rectal compliance. Results: Dynamic rectal compliance was significantly lower in IBS vs. controls for both LPD (8.1±1.8 vs. 9.4±1.6 ml/mmHg; p=0.03) and HPD (6.0±1.1 vs. 7.0±1.1 ml/mmHg; p =0.01). High ratings in anxiety (BAI≥16), depression (BDI≥14) and somatization (PHQ-15≥15) were identified in 31.8%, 40.9%, and 50.0% of IBS subjects, respectively. In high anxiety subjects, rectal compliance was significantly diminished with HPD (5.6±0.8 vs. 6.7±1.1 ml/mmHg; p =0.008), and trended lower during LPD (7.9±1.5 vs. 8.8±1.8 ml/ mmHg, P=0.18). High depression scores were also associated with decreased rectal compliance with HPD (5.6±1.0 vs. 6.8±1.2, p=0.02) and trended toward lower compliance during LPD (8.1±1.5 vs. 8.8±1.8 ml/mmHg, P=0.2). In contrast, degree of somatization did not influence rectal compliance with either distention stimulus (P.0.20 for each). Multivariate analyses suggested the effects of anxiety on rectal compliance were independent of IBS during HPD (B=-0.04, p=0.06), but not LPD (B=-0.008, p=0.8). Depression and somatization had no effect on rectal compliance independent of IBS at either pressure level (p .0.15 for each).Conclusions: Decreased dynamic rectal compliance is observed in IBS with both low pressure and high pressure rectal distensions. Mood symptoms common to IBS also are associated with diminished rectal compliance, particularly withmore noxious stimuli. Anxiety appears to influence rectal compliance independent of the functional GI diagnosis itself, an effect potentially mediated by sympathetic autonomic regulation of intestinal motor function.