Mechanical Derangements Research Articles

Arrhythmogenic Mitral Valve Prolapse: Can We Risk Stratify and Prevent Sudden Cardiac Death?

Ventricular arrhythmias associated with mitral valve prolapse (MVP) and the capacity to cause sudden cardiac death (SCD), referred to as 'malignant MVP', are an increasingly recognised, albeit rare, phenomenon. SCD can occur without significant mitral regurgitation, implying an interaction between mechanical derangements affecting the mitral valve apparatus and left ventricle. Risk stratification of these arrhythmias is an important clinical and public health issue to provide precise and targeted management. Evaluation requires patient and family history, physical examination and electrophysiological and imaging-based modalities. We provide a review of arrhythmogenic MVP, exploring its epidemiology, demographics, clinical presentation, mechanisms linking MVP to SCD, markers of disease severity, testing modalities and management, and discuss the importance of risk stratification. Even with recently improved understanding, it remains challenging how best to weight the prognostic importance of clinical, imaging and electrophysiological data to determine a clear high-risk arrhythmogenic profile in which an ICD should be used for the primary prevention of SCD.

Diabetes and Osteoporosis.

Bone fragility is an emerging complication of diabetes. People with diabetes are at a significantly higher risk of fractures compared to the general population. Bone fragility occurs in diabetes as a result of complex and poorly understood mechanisms occurring at the cellular level contributed by vascular, inflammatory and mechanical derangements. Bone mineral density (BMD) as assessed by DEXA is low in type 1 diabetes. Type 2 diabetes has a high risk of fracture despite a normal to raised BMD. DEXA thus underestimates the fracture risk in diabetes. Data are scare regarding the efficacy of the available therapies in this low bone turnover state.

Combined exercise training improved exercise capacity and lung inflammation in rats with hepatopulmonary syndrome

AimPhysical exercise training attenuates pulmonary inflammation, but its effects on impaired respiratory function caused by hepatopulmonary syndrome (HPS) have not been evaluated. We determined if the combination of moderate intensity aerobic and resistance training during HPS development modifies exercise capacity, respiratory system mechanics, and lung inflammation responses. Main methodsWistar rats were randomly divided into sham, HPS, and HPS + combined exercise training groups. Fifteen days after HPS induction, a moderate intensity aerobic plus resistance exercise training protocol was performed five times a week for 5 weeks on alternate days. Exercise capacity, respiratory system mechanics, lung inflammation, pulmonary morphology, and immunohistochemistry were evaluated. Key findingsOverall, our findings indicated that combined exercise training efficiently increased the maximal running and resistance capacity of HPS animals. The training regimen reduced the expression of P2X7 in parenchymal leukocytes (P < 0.01), partially restored the expression of interleukin-10 in airway epithelium (P < 0.01), and increased the expression of TFPI in the airway epithelium (P < 0.01) as well as reduced its expression in parenchymal leukocytes (P < 0.01). However, exercise training did not attenuate HPS-induced respiratory mechanical derangements or lung tissue remodeling. SignificanceCombined exercise training can elicit adaptation with regard to both maximal running capacity and maximum strength and modify the expression of P2X7 and TFPI in parenchymal leukocytes and that of IL-10 in airway epithelium.

Evaluation of Dynamic Respiratory Mechanical Abnormalities During Conventional CPET.

Assessment of the ventilatory response to exercise is important in evaluating mechanisms of dyspnea and exercise intolerance in chronic cardiopulmonary diseases. The characteristic mechanical derangements that occur during exercise in chronic respiratory conditions have previously been determined in seminal studies using esophageal catheter pressure-derived measurements. In this brief review, we examine the emerging role and clinical utility of conventional assessment of dynamic respiratory mechanics during exercise testing. Thus, we provide a physiologic rationale for measuring operating lung volumes, breathing pattern, and flow–volume loops during exercise. We consider standardization of inspiratory capacity-derived measurements and their practical implementation in clinical laboratories. We examine the evidence that this iterative approach allows greater refinement in evaluation of ventilatory limitation during exercise than traditional assessments of breathing reserve. We appraise the available data on the reproducibility and responsiveness of this methodology. In particular, we review inspiratory capacity measurement and derived operating lung volumes during exercise. We demonstrate, using recent published data, how systematic evaluation of dynamic mechanical constraints, together with breathing pattern analysis, can provide valuable insights into the nature and extent of physiological impairment contributing to exercise intolerance in individuals with common chronic obstructive and restrictive respiratory disorders.

Heart, lungs, and muscle interplay in worsening activity-related breathlessness in advanced cardiopulmonary disease.

Activity-related breathlessness is a key determinant of poor quality of life in patients with advanced cardiorespiratory disease. Accordingly, palliative care has assumed a prominent role in their care. The severity of breathlessness depends on a complex combination of negative cardiopulmonary interactions and increased afferent stimulation from systemic sources. We review recent data exposing the seeds and consequences of these abnormalities in combined heart failure and chronic obstructive pulmonary disease (COPD). The drive to breathe increases ('excessive breathing') secondary to an enlarged dead space and hypoxemia (largely COPD-related) and heightened afferent stimuli, for example, sympathetic overexcitation, muscle ergorreceptor activation, and anaerobic metabolism (largely heart failure-related). Increased ventilatory drive might not be fully translated into the expected lung-chest wall displacement because of the mechanical derangements brought by COPD ('inappropriate breathing'). The latter abnormalities, in turn, negatively affect the central hemodynamics which are already compromised by heart failure. Physical activity then decreases, worsening muscle atrophy and dysfunction. Beyond the imperative of optimal pharmacological treatment of each disease, strategies to lessen ventilation (e.g., walking aids, oxygen, opiates and anxiolytics, and cardiopulmonary rehabilitation) and improve mechanics (heliox, noninvasive ventilation, and inspiratory muscle training) might mitigate the burden of this devastating symptom in advanced heart failure-COPD.

Respiratory Mechanics and Diaphragmatic Dysfunction in COPD Patients Who Failed Non-Invasive Mechanical Ventilation.

BackgroundAlthough non-invasive mechanical ventilation (NIV) is the gold standard treatment for patients with acute exacerbation of COPD (AECOPD) developing respiratory acidosis, failure rates still range from 5% to 40%. Recent studies have shown that the onset of severe diaphragmatic dysfunction (DD) during AECOPD increases risk of NIV failure and mortality in this subset of patients. Although the imbalance between the load and the contractile capacity of inspiratory muscles seems the main cause of AECOPD-induced hypercapnic respiratory failure, data regarding the influence of mechanical derangement on DD in this acute phase are lacking. With this study, we investigate the impact of respiratory mechanics on diaphragm function in AECOPD patients experiencing NIV failure.MethodsTwelve AECOPD patients with respiratory acidosis admitted to the Respiratory ICU of the University Hospital of Modena from 2017 to 2018 undergoing mechanical ventilation (MV) due to NIV failure were enrolled. Static respiratory mechanics and end-expiratory lung volume (EELV) were measured after 30 mins of volume control mode MV. Subsequently, transdiaphragmatic pressure (Pdi) was calculated by means of a sniff maneuver (Pdisniff) after 30 mins of spontaneous breathing trial. Linear regression analysis and Pearson’s correlation coefficient served to assess associations.ResultsAverage Pdisniff was 23.3 cmH2O (standard deviation 29 cmH2O) with 3 patients presenting bilateral diaphragm palsy. Pdisniff was directly correlated with static lung elastance (r=0.69, p=0.001) while inverse correlation was found with dynamic intrinsic PEEP (r=−0.73, p=0.007). No significant correlation was found with static intrinsic PEEP (r=−0.55, p=0.06), EELV (r=−0.4, p=0.3), airway resistance (r=−0.2, p=0.54), chest wall, and total elastance (r=−0-01, p=0.96 and r=0.3, p=0.36, respectively). Significant linear inverse correlation was found between Pdisniff and the ratio between Pdi assessed at tidal volume and Pdi sniff (r=−0.82, p=0.02).ConclusionThe causes of extreme DD in AECOPD patients who experienced NIV failure might be predominantly mechanical, driven by a severe dynamic hyperinflation that overlaps on an elastic lung substrate favoring volume overload.

Mechanical-ventilatory responses to peak and ventilation-matched upper- versus lower-body exercise in normal subjects.

New Findings What is the central question of this study? To what extent are the mechanical‐ventilatory responses to upper‐body exercise influenced by task‐specific locomotor mechanics? What is the main finding and its importance? When compared with lower‐body exercise performed at similar ventilations, upper‐body exercise was characterized by tidal volume constraint, dynamic lung hyperinflation and an increased propensity towards neuromechanical uncoupling of the respiratory system. Importantly, these responses were independent of respiratory dysfunction and flow limitation. Thus, the mechanical ventilatory responses to upper‐body exercise are attributable, in part, to task‐specific locomotor mechanics (i.e. non‐respiratory loading of the thorax). The aim of this study was to determine the extent to which the mechanical ventilatory responses to upper‐body exercise are influenced by task‐specific locomotor mechanics. Eight healthy men (mean ± SD: age, 24 ± 5 years; mass, 74 ± 11 kg; and stature, 1.79 ± 0.07 m) completed two maximal exercise tests, on separate days, comprising 4 min stepwise increments of 15 W during upper‐body exercise (arm‐cranking) or 30 W during lower‐body exercise (leg‐cycling). The tests were repeated at work rates calculated to elicit 20, 40, 60, 80 and 100% of the peak ventilation achieved during arm‐cranking (V˙E, UBE ). Exercise measures included pulmonary ventilation and gas exchange, oesophageal pressure‐derived indices of respiratory mechanics, operating lung volumes and expiratory flow limitation. Subjects exhibited normal resting pulmonary function. Arm‐crank exercise elicited significantly lower peak values for work rate, O2 uptake, CO2 output, minute ventilation and tidal volume (p < 0.05). At matched ventilations, arm‐crank exercise restricted tidal volume expansion relative to leg‐cycling exercise at 60% V˙E, UBE (1.74 ± 0.61 versus 2.27 ± 0.68 l, p < 0.001), 80% V˙E, UBE (2.07 ± 0.70 versus 2.52 ± 0.67 l, p < 0.001) and 100% V˙E, UBE (1.97 ± 0.85 versus 2.55 ± 0.72 l, p = 0.002). Despite minimal evidence of expiratory flow limitation, expiratory reserve volume was significantly higher during arm‐cranking versus leg‐cycling exercise at 100% V˙E, UBE (39 ± 8 versus 29 ± 8% of vital capacity, p = 0.002). At any given ventilation, arm‐cranking elicited greater inspiratory effort (oesophageal pressure) relative to thoracic displacement (tidal volume). Arm‐cranking exercise is sufficient to provoke respiratory mechanical derangements (restricted tidal volume expansion, dynamic hyperinflation and neuromechanical uncoupling) in subjects with normal pulmonary function and expiratory flow reserve. These responses are likely to be attributable to task‐specific locomotor mechanics (i.e. non‐respiratory loading of the thorax).

The Effects of Prone with Respect to Supine Position on Stress Relaxation, Respiratory Mechanics, and the Work of Breathing Measured by the End-Inflation Occlusion Method in the Rat.

The working hypothesis is that the prone position with respect to supine may change the geometric configuration of the lungs inside the chest wall, thus their reciprocal mechanical interactions, leading to possible effects on stress relaxation phenomena and respiratory mechanics. The effects of changing body posture from supine to prone on respiratory system mechanics, particularly on stress relaxation, were investigated in the rat by the end-inflation occlusion method. In the prone with respect to supine position, an increment of the frictional resistance of the airway (from 0.13 ± 0.01 to 0.19 ± 0.02 cm H2O/l sec(-1), p < 0.05) and a decrement of the stress relaxation-linked pressure dissipation (from 0.51 ± 0.05 to 0.45 ± 0.05 cm H2O/l sec(-1), p < 0.01) were found. Respiratory system elastance and total resistive pressure dissipation did not change significantly. Accordingly, a significant increase of the frictional "ohmic" mechanical inspiratory work of breathing and a decrease of the visco-elastic work of inspiration were demonstrated, while no significant changes occurred for the total mechanical work of breathing and its total resistive and elastic components. It is concluded that postural changes affect the visco-elastic characteristics of the respiratory system and the related stress relaxation phenomena by influencing the disposition and relation of the lungs inside the chest wall and their relative geometrical configuration, and the interaction phenomena of the constitutive parenchymal structures, i.e., elastin and collagen fibers. Since the prone position resulted in no serious or disadvantageous respiratory system mechanical derangement, it is suggested it may be usefully applied in nursing or for therapeutic goals.

Geographical variation in incidence of knee arthroscopy for patients with osteoarthritis: a population‐based analysis of Victorian hospital separations data

To evaluate the frequency and geographical variation in knee arthroscopy for adults (>25 years) with a concomitant diagnosis of osteoarthritis. This was a retrospective cohort study of hospital separations involving an elective knee arthroscopy in public and private hospitals in Victoria, Australia. Participants included patients receiving knee arthroscopies with a diagnosis code indicating osteoarthritis (OA) from 1 July 2008 to 30 June 2009. Records were excluded if the patient was under 25 years or their arthroscopy involved a ligament reconstruction. Crude rates per 100 000 population and negative binomial regression offset by total knee arthroscopy volume were used to analyse differences by region. There were 9620 arthroscopic procedures meeting the inclusion criteria. There were 5500 (57.2%) admissions where the principal diagnosis was knee OA (gonarthrosis) and 3510 (36.5%) where the principal diagnosis indicated a mechanical derangement and there was a primary or associated diagnosis of OA. When we examined the incidence rate ratios (IRR) by region, after adjustment for relevant factors and accounting for the total knee arthroscopy volume within each region, we identified significant variation in knee arthroscopy rates for patients with OA. The region with the highest adjusted IRR was Barwon South Western (IRR: 1.26, 95% confidence interval (CI): 1.16-1.36) and the region with lowest adjusted incidence rate ratio was the Gippsland region (IRR: 0.89, 95% CI: 0.80-0.98). We identified considerable geographical variation in arthroscopies for people with OA across Victoria. Further investigation is needed to understand whether this variation is a reflection of differences in OA prevalence, clinical decision-making or access.

Interleukin-6 and Lung Inflammation: Evidence for a Causative Role in Inducing Respiratory System Resistance Increments

Interleukin-6 is a multifunctional cytokine that has been shown to be increased in some pathological conditions involving the respiratory system such as those experimentally induced in animals or spontaneously occurring in humans. Experimental data demonstrating that interleukin-6 plays a significant role in commonly occurring respiratory system inflammatory diseases are reviewed here. Those diseases, i.e. asthma and chronic obstructive pulmonary disease, are characterised by mechanical derangements of the respiratory system, for the most part due to increased elastance and airway resistance. Recent findings showing that interleukin-6 has a causative role in determining an increase in airway resistance are reviewed. The end-inflation occlusion method was used to study the mechanical properties of the respiratory system before and after interleukin-6 administration. The cytokine was shown to induce significant, dose-dependent increments in both the resistive pressure dissipation due to frictional forces opposing the airflow in the airway (ohmic resistance) and the additional resistive pressure dissipation due to the visco-elastic properties of the system, i.e. stress relaxation (visco-elastic resistance). There were no alterations in respiratory system elastance. Even when administered to healthy mammals, interleukin-6 determines a significant effect on respiratory system resistance causing an increase in the mechanical work of breathing during inspiration. IL-6 hypothetically plays an active role in the pathogenesis of respiratory system diseases and the mechanisms that may be involved are discussed here.

Bayesian inference of the lung alveolar spatial model for the identification of alveolar mechanics associated with acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is acute lung failure secondary to severe systemic inflammation, resulting in a derangement of alveolar mechanics (i.e. the dynamic change in alveolar size and shape during tidal ventilation), leading to alveolar instability that can cause further damage to the pulmonary parenchyma. Mechanical ventilation is a mainstay in the treatment of ARDS, but may induce mechano-physical stresses on unstable alveoli, which can paradoxically propagate the cellular and molecular processes exacerbating ARDS pathology. This phenomenon is called ventilator induced lung injury (VILI), and plays a significant role in morbidity and mortality associated with ARDS. In order to identify optimal ventilation strategies to limit VILI and treat ARDS, it is necessary to understand the complex interplay between biological and physical mechanisms of VILI, first at the alveolar level, and then in aggregate at the whole-lung level. Since there is no current consensus about the underlying dynamics of alveolar mechanics, as an initial step we investigate the ventilatory dynamics of an alveolar sac (AS) with the lung alveolar spatial model (LASM), a 3D spatial biomechanical representation of the AS and its interaction with airflow pressure and the surface tension effects of pulmonary surfactant. We use the LASM to identify the mechanical ramifications of alveolar dynamics associated with ARDS. Using graphical processing unit parallel algorithms, we perform Bayesian inference on the model parameters using experimental data from rat lung under control and Tween-induced ARDS conditions. Our results provide two plausible models that recapitulate two fundamental hypotheses about volume change at the alveolar level: (1) increase in alveolar size through isotropic volume change, or (2) minimal change in AS radius with primary expansion of the mouth of the AS, with the implication that the majority of change in lung volume during the respiratory cycle occurs in the alveolar ducts. These two model solutions correspond to significantly different mechanical properties of the tissue, and we discuss the implications of these different properties and the requirements for new experimental data to discriminate between the hypotheses.

Lung Stress and Strain During Mechanical Ventilation

Tidal volume (VT) and volume of gas caused by positive end-expiratory pressure (VPEEP) generate dynamic and static lung strains, respectively. Our aim was to clarify whether different combinations of dynamic and static strains, resulting in the same large global strain, constantly produce lung edema. Laboratory investigation. Animal unit. Twenty-eight healthy pigs. After lung computed tomography, 20 animals were ventilated for 54 hours at a global strain of 2.5, either entirely dynamic (VT 100% and VPEEP 0%), partly dynamic and partly static (VT 75-50% and VPEEP 25-50%), or mainly static (VT 25% and VPEEP 75%) and then killed. In eight other pigs (VT 25% and VPEEP 75%), VPEEP was abruptly zeroed after 36-54 hours and ventilation continued for 3 hours. Edema was diagnosed when final lung weight (balance) exceeded the initial weight (computed tomography). Mortality, lung mechanics, gas exchange, pulmonary histology, and inflammation were evaluated. All animals ventilated with entirely dynamic strain (VT 825±424 mL) developed pulmonary edema (lung weight from 334±38 to 658±99 g, p<0.01), whereas none of those ventilated with mainly static strain (VT 237±21 mL and VPEEP 906±114 mL, corresponding to 19±1 cm H2O of positive end-expiratory pressure) did (from 314±55 to 277±46 g, p=0.65). Animals ventilated with intermediate combinations finally had normal or largely increased lung weight. Smaller dynamic and larger static strains lowered mortality (p<0.01), derangement of lung mechanics (p<0.01), and arterial oxygenation (p<0.01), histological injury score (p=0.03), and bronchoalveolar interleukin-6 concentration (p<0.01). Removal of positive end-expiratory pressure did not result in abrupt increase in lung weight (from 336±36 to 351±77 g, p=0.51). Lung edema forms (possibly as an all-or-none response) depending not only on global strain but also on its components. Large static are less harmful than large dynamic strains, but not because the former merely counteracts fluid extravasation.

The functional neuroimaging correlates of psychogenic versus organic dystonia

The neurobiological basis of psychogenic movement disorders remains poorly understood and the management of these conditions difficult. Functional neuroimaging studies have provided some insight into the pathophysiology of disorders implicating particularly the prefrontal cortex, but there are no studies on psychogenic dystonia, and comparisons with findings in organic counterparts are rare. To understand the pathophysiology of these disorders better, we compared the similarities and differences in functional neuroimaging of patients with psychogenic dystonia and genetically determined dystonia, and tested hypotheses on the role of the prefrontal cortex in functional neurological disorders. Patients with psychogenic (n = 6) or organic (n = 5, DYT1 gene mutation positive) dystonia of the right leg, and matched healthy control subjects (n = 6) underwent positron emission tomography of regional cerebral blood flow. Participants were studied during rest, during fixed posturing of the right leg and during paced ankle movements. Continuous surface electromyography and footplate manometry monitored task performance. Averaging regional cerebral blood flow across all tasks, the organic dystonia group showed abnormal increases in the primary motor cortex and thalamus compared with controls, with decreases in the cerebellum. In contrast, the psychogenic dystonia group showed the opposite pattern, with abnormally increased blood flow in the cerebellum and basal ganglia, with decreases in the primary motor cortex. Comparing organic dystonia with psychogenic dystonia revealed significantly greater regional blood flow in the primary motor cortex, whereas psychogenic dystonia was associated with significantly greater blood flow in the cerebellum and basal ganglia (all P < 0.05, family-wise whole-brain corrected). Group × task interactions were also examined. During movement, compared with rest, there was abnormal activation in the right dorsolateral prefrontal cortex that was common to both organic and psychogenic dystonia groups (compared with control subjects, P < 0.05, family-wise small-volume correction). These data show a cortical–subcortical differentiation between organic and psychogenic dystonia in terms of regional blood flow, both at rest and during active motor tasks. The pathological prefrontal cortical activation was confirmed in, but was not specific to, psychogenic dystonia. This suggests that psychogenic and organic dystonia have different cortical and subcortical pathophysiology, while a derangement in mechanisms of motor attention may be a feature of both conditions.

Sociodemographic Comparison in Patients with Subjective and Objective Clinical Findings of Temporomandibular Dysfunctions

To investigate the differences in healthy persons and patients with myofacial pain without limitation, objective signs of temporomandibular dysfunctions (TMDs), and both subjective and objective features with respect to age, gender, effects of TMDs on daily life, economic condition, smoking habit, marital status, and education. Sociodemographic information of 296 persons (212 females and 84 males) was evaluated. Subjects were categorized into 4 groups according to clinical findings: no TMD symptoms (control, C); myofacial pain without limitation (MP); objective signs (PWOS); or both subjective and objective features (MP/PWOS). The C, MP, PWOS, and MP/PWOS groups comprised 64 (22%), 66 (22%), 68 (23%), and 98 (33%) subjects. PWOS and MP/PWOS differed significantly between the 15-30 and 30-45 year age groups. Although patients with PWOS were significantly higher in the 15-30 year age group, patients with MP/PWOS were significantly higher in the 30-45 year age group. A significant difference was observed with respect to gender in all groups except the control group. The effects of TMD symptoms on daily life differed statistically among the groups. Female gender is a risk factor for TMDs. Females are more vulnerable to subjective and objective signs than males. During general dental examinations, females should be checked for TMD symptoms. PWOS manifest before MP. Moreover, mechanical derangements can cause myofacial pain. MP can mostly affect daily life, but PWOS tend to be prohibitive.

Analysis of Regional Mechanics in Canine Lung Injury Using Forced Oscillations and 3D Image Registration

Acute lung injury is characterized by heterogeneity of regional mechanical properties, which is thought to be correlated with disease severity. The feasibility of using respiratory input impedance (Z rs) and computed tomographic (CT) image registration for assessing parenchymal mechanical heterogeneity was evaluated. In six dogs, measurements of Z rs before and after oleic acid injury at various distending pressures were obtained, followed by whole lung CT scans. Each Z rs spectrum was fit with a model incorporating variable distributions of regional compliances. CT image pairs at different inflation pressures were matched using an image registration algorithm, from which distributions of regional compliances from the resulting anatomic deformation fields were computed. Under baseline conditions, average model compliance decreased with increasing inflation pressure, reflecting parenchymal stiffening. After lung injury, these average compliances decreased at each pressure, indicating derecruitment, alveolar flooding, or alterations in intrinsic tissue elastance. However, average compliance did not change as inflation pressure increased, consistent with simultaneous recruitment and strain stiffening. Image registration revealed peaked distributions of regional compliances, and that small portions of the lung might undergo relative compression during inflation. The authors conclude that assessments of lung function using Z rs combined with the structural alterations inferred from image registration provide unique but complementary information on the mechanical derangements associated with lung injury.

Pulmonary-derived phosphoinositide 3-kinase gamma (PI3Kγ) contributes to ventilator-induced lung injury and edema

Ventilator-induced lung injury (VILI) occurs in part by increased vascular permeability and impaired alveolar fluid clearance. Phosphoinositide 3-kinase gamma (PI3Kγ) is activated by mechanical stress, induces nitric oxide (NO) production, and participates in cyclic adenosine monophosphate (cAMP) hydrolysis, each of which contributes to alveolar edema. We hypothesized that lungs lacking PI3Kγ or treated with PI3Kγ inhibitors would be protected from ventilation-induced alveolar edema and lung injury. Using an isolated and perfused lung model, wild-type (WT) and PI3Kγ-knockout (KO) mice underwent negative-pressure cycled ventilation at either -25 cmH₂O and 0 cmH₂O positive end-expiratory pressure (PEEP) (HIGH STRESS) or -10 cmH₂O and -3 cmH₂O PEEP (LOW STRESS). Compared with WT, PI3Kγ-knockout mice lungs were partially protected from VILI-induced derangement of respiratory mechanics (lung elastance) and edema formation [bronchoalveolar lavage (BAL) protein concentration, wet/dry ratio, and lung histology]. In PI3Kγ-knockout mice, VILI induced significantly less phosphorylation of protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), production of nitrate and nitrotyrosine, as well as hydrolysis of cAMP, compared with wild-type animals. PI3Kγ wild-type lungs treated with AS605240, an inhibitor of PI3Kγ kinase activity, in combination with enoximone, an inhibitor of phosphodiesterase-3 (PDE3)-induced cAMP hydrolysis, were protected from VILI at levels comparable to knockout lungs. Phosphoinositide 3-kinase gamma in resident lung cells mediates part of the alveolar edema induced by high-stress ventilation. This injury is mediated via altered Akt, eNOS, NO, and/or cAMP signaling. Anti-PI3Kγ therapy aimed at resident lung cells represents a potential pharmacologic target to mitigate VILI.

Reliability and Agreement of Measures Used in Radiographic Evaluation of the Adult Hip

Several mechanical derangements reportedly contribute to the development of noninflammatory arthritis of the hip. Diagnosis of these derangements involves the use of specific radiographic measures (eg, alpha angle, lateral center edge angle, cross-over sign). The reliability of some of these measures is not known, whereas others have not been confirmed. We examined the reproducibility of 20 radiographic parameters of the hip used in clinical practice. Twenty radiographic parameters on standardized digital AP and cross-table lateral radiographs were evaluated by two observers on two different occasions. The parameters were evaluated from the standpoint of reproducibility (reliability and agreement). The intraclass correlation coefficient (ICC), kappa coefficient, and standard error of measurement were calculated. The minimal detectable change was calculated where possible. Interrater reliability ranged from 0.45 to 0.90 for ICC depending on the measure. Intrarater reliability ranged from 0.55 to 0.99. Measurements that could be measured directly (femoral head diameter) were more reliable than measurements requiring estimation on the part of the observer (Tönnis angle, neck-shaft angle). Categorical parameters had interrater and intrarater reliability kappa values greater than 0.90 for all parameters measured. Agreement between repeated measurements, as given by the minimal detectable change, showed many parameters with low absolute reliability have clinical use in the context of the large changes seen in clinical practice. Radiographic hip measures show clinical utility when evaluated from the perspective of agreement and reliability. All measures investigated show clinical utility when evaluated from the perspective of reliability and agreement. Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.

Myocardial Structural, Perfusion, and Metabolic Correlates of Left Bundle Branch Block Mechanical Derangement in Patients With Dilated Cardiomyopathy

Background— Left bundle branch block (LBBB) influences on regional left ventricular (LV) structure, perfusion, and metabolism have not yet been thoroughly investigated in dilated cardiomyopathy patients. Methods and Results— Eleven dilated cardiomyopathy patients with LBBB (mean±SD age, 62±11 years; LV ejection fraction, 35±8%) and 7 dilated cardiomyopathy patients without LBBB (mean±SD age, 58±9 years; LV ejection fraction, 37±10%) were studied by cardiac magnetic resonance and positron emission tomography. The left ventricle was divided in 3 regions: septum, adjacent (anterior-inferior walls), and lateral. Regional midwall circumferential strain, maximum shortening, and strain rate were obtained from tagged cardiac magnetic resonance. The systolic stretch index was calculated as positive strain rate (stretching) divided by total strain rate. Myocardial metabolic rate of glucose and resting and hyperemic myocardial blood flow were quantified by 2-[ 18 F]fluoro-2-deoxyglucose and [ 13 N]ammonia positron emission tomography, respectively. Compared with non-LBBB patients, LBBB patients showed a highly inhomogeneous systolic deformation pattern that changed gradually, moving from a discoordinate [(systolic stretch index, 0.485 (0.284)] and poorly contracting (maximum shortening, −1.14±0.96%) septum to a coordinate [systolic stretch index, 0.002 (0.168)] and strongly contracting (maximum shortening, −13.63±2.58%) lateral region (both P &lt;0.0001). This pattern was closely matched to the myocardial metabolic rate of glucose, disclosing lowest, intermediate, and highest values in the septum, adjacent, and lateral regions, respectively ( P &lt;0.0001). Septal-to-lateral thickness ratio was lower in LBBB than in non-LBBB patients ( P =0.03). In both groups, the LV distribution of resting and hyperemic myocardial blood flow and myocardial blood flow reserve did not differ significantly. Conclusions— In dilated cardiomyopathy patients, the extensive LV contraction abnormalities induced by LBBB cause regional myocardial metabolic and structural remodeling, without consistent changes in blood flow.

Helping the homogeneous

The National Emphysema Treatment Trial (NETT) 1 helped clarify the patient selection criteria and expected risks and benefits of lung volume reduction surgery (LVRS) for patients with advanced emphysema. The NETT built on numerous earlier case series which showed that the greatest symptomatic and functional benefit accrued to patients with a predominantly upper lobe distribution of emphysema. In such patients who also had very low exercise tolerance, the surgery lowered their mortality risk over the next 5 yrs by about half. Importantly for patients in the USA, findings from the study were used to establish the criteria for Medicare coverage of the procedure. This opened the door for thousands of qualifying patients to undergo this life-enhancing and life-extending procedure. However, in the 6 yrs since, barely a trickle of emphysema patients has crawled through that door. In 2007 and 2008, only about a dozen lung volume reduction procedures per month were billed through Medicare (personal communication, J. Baldwin, Centers for Medicare and Medicaid Services). The reasons for this discrepancy are speculative, but could include concerns about the small but non-trivial operative mortality, the substantial morbidity of major surgery, the impermanence of improvement, and the difficulty predicting benefit for an individual despite propitious characteristics. Patients and their physicians have been making the intensely personal decision that the benefit of this surgery is not worth the risk. For patients whose emphysema is not in the upper lobe predominant distribution (about half of the patients enrolled in the NETT), the calculus is even less favourable. To redress this risk–benefit balance, a profusion of creative bronchoscopic approaches to the mechanical derangements of emphysema are under investigation. One method, primarily being studied for patients with diffuse, or “homogeneous” disease, creates holes, supported by drug-eluting stents, directly from segmental bronchi into the surrounding parenchyma. This “airway …

Pulmonary kinetic expression of the endothelin system in a swine model of endotoxic shock

Endothelin (ET)-1 is a potent vasoconstrictor peptide involved in the derangement of respiratory mechanics during endotoxic shock. We measured the kinetics of pulmonary mRNA expression of the key components of the ET system [i.e., ET-1, ET-converting enzyme (ECE), and ETA and ETB receptors] by quantitative real-time reverse transcriptase-polymerase chain reaction in a swine model of endotoxic shock (0, 1, 2, 3, and 4 h of continuous LPS infusion at 40 microg/kg/hour; sham group, 4 hour saline infusion). A significant increase in mRNA expression levels was observed for ET-1 in LPS-treated piglets; the increase began as early as 1 hour. In contrast, no significant variations were observed for the ECE, ETA, or ETB genes. Small gene expression differences observed with respect to our previous results suggest a possible effect of the anesthesia or surgical protocol on ET system regulation.