Key points In an anaesthetised animal model, independent stimulation of baroreceptors in the pulmonary artery elicits reflex sympathoexcitation. In humans, pulmonary arterial pressure is positively related to basal muscle sympathetic nerve activity (MSNA) under conditions where elevated pulmonary pressure is evident (e.g. high altitude); however, a causal link is not established. Using a novel experimental approach, we demonstrate that reducing pulmonary arterial pressure lowers basal MSNA in healthy humans. This response is distinct from the negative feedback reflex mediated by aortic and carotid sinus baroreceptors when systemic arterial pressure is lowered. Afferent input from pulmonary arterial baroreceptors may contribute to sympathetic neural activation in healthy lowland natives exposed to high altitude. Abstract In animal models, distension of baroreceptors located in the pulmonary artery induces a reflex increase in sympathetic outflow; however, this has not been examined in humans. Therefore, we investigated whether reductions in pulmonary arterial pressure influenced sympathetic outflow and baroreflex control of muscle sympathetic nerve activity (MSNA). Healthy lowlanders (n = 13; 5 females) were studied 4–8 days following arrival at high altitude (4383 m; Cerro de Pasco, Peru), a setting that increases both pulmonary arterial pressure and sympathetic outflow. MSNA (microneurography) and blood pressure (BP; photoplethysmography) were measured continuously during ambient air breathing (Amb) and a 6 min inhalation of the vasodilator nitric oxide (iNO; 40 ppm in 21% O2), to selectively lower pulmonary arterial pressure. A modified Oxford test was performed under both conditions. Pulmonary artery systolic pressure (PASP) was determined using Doppler echocardiography. iNO reduced PASP (24 ± 3 vs. 32 ± 5 mmHg; P < 0.001) compared to Amb, with a similar reduction in MSNA total activity (1369 ± 576 to 994 ± 474 a.u min−1; P = 0.01). iNO also reduced the MSNA operating point (burst incidence; 39 ± 16 to 33 ± 17 bursts·100 Hb−1; P = 0.01) and diastolic operating pressure (82 ± 8 to 80 ± 8 mmHg; P < 0.001) compared to Amb, without changing heart rate (P = 0.6) or vascular–sympathetic baroreflex gain (P = 0.85). In conclusion, unloading of pulmonary arterial baroreceptors reduced basal sympathetic outflow to the skeletal muscle vasculature and reset vascular–sympathetic baroreflex control of MSNA downward and leftward in healthy humans at high altitude. These data suggest the existence of a lesser‐known reflex input involved in sympathetic activation in humans.

ObjectiveThe passive leg raising (PLR) maneuver has become standard practice in fluid resuscitation. We aim to investigate the precision and consistency of the PLR for determining fluid responsiveness in critically ill patients and healthy volunteers using bioreactance non-invasive cardiac output monitoring (NiCOM™, Cheetah Medical, Inc., Newton Center, Massachusetts, USA).MethodsThis study is prospective, single-center, observational cohort with repeated measures in critically ill patients admitted to the medical intensive care unit and healthy volunteers at a tertiary academic medical center. Three cycles of PLR were performed, each at 20–30 minutes apart. Fluid responsiveness was defined as a change in stroke volume index (ΔSVI) > 10% with each PLR as determined by NiCOM™. Precision was the variability in ΔSVI after the 3 PLR’s, and determined by range, average deviation and standard deviation. Consistency was the same fluid responsiveness determination of “Yes” (ΔSVI > 10%) or “No” (ΔSVI ≤ 10%) for all 3 PLR’s.ResultsSeventy-five patients and 25 volunteers were enrolled. In patients, the precision was range of 17.2±13.3%, average deviation 6.5±4.0% and standard deviation 9.0±5.2%; and for volunteers, 17.4±10.3%, 6.6±3.8% and 9.0±6.7%, respectively. There was no statistical difference in the precision measurements between patients and volunteers. Forty-nine (65.3%) patients vs. twenty-four (96.0%) volunteers had consistent results, p < 0.01. Among those with consistent results, twenty-four (49.0%) patients and 24 (100%) volunteers were fluid responsive.ConclusionsThe precision and consistency of determining ΔSVI with NiCOM™ after PLR may have clinical implication if ΔSVI > 10% is the absolute cutoff to determine fluid responsiveness.

BackgroundMyotonic dystrophy (DM) is an inherited progressive muscle disorder caused by defects in muscle proteins. As the incidence of this condition is low, not many are familiar with the multisystem involvement. At times, cardiac disease may even be the predominant manifestation in the form of arrhythmias, conduction defects, and cardiomyopathies. The progression of the disease can lead to sudden, unpredictable death. Thus, it is important to identify this subgroup and treat accordingly.ObjectiveTo identify patients with DM and assess their risk for sudden cardiac death.MethodsNine patients previously diagnosed with muscular dystrophy were evaluated by cardiologists for various reasons, from a general follow-up to cardiac arrest. All of them had electrocardiograms (EKG) and 2-D echocardiograms, and seven of them had further electrophysiological (EP) studies.ResultsOf the nine patients with DM, eight had EKG evidence of conduction abnormalities ranging from first-degree heart block to complete heart block. Of the seven who had EP studies, five had inducible ventricular tachycardia requiring immediate cardioversion and implantable cardioverter defibrillator (ICD) implant. Two of them underwent permanent pacemaker placement due to complete heart block and infra-Hissian block. The remaining two patients opted for a conservative approach with yearly EKG monitoring.ConclusionBecause one-third of the cardiac deaths in patients with DM are sudden, there is a strong need to identify these patients and intervene in those at high risk. Prophylactic pacemaker placement is recommended even in those with minimal conduction system abnormality. However, the common practice is to identify patients at high risk of conduction abnormalities by EP studies and then provide them with prophylactic invasive strategies.

Excessive decrease in the flow of the late expiratory portion of a flow volume loop (FVL) or “flattening”, reflects small airway dysfunction. The assessment of the flattening is currently determined by visual inspection by the pulmonary function test (PFT) interpreters and is highly variable. In this study, we developed an objective measure to quantify the flattening. We downloaded 172 PFT reports in PDF format from the electronic medical records and digitized and extracted the expiratory portion of the FVL. We located point A (the point of the peak expiratory flow), point B (the point corresponding to 75% of the expiratory vital capacity), and point C (the end of the expiratory portion of the FVL intersecting with the x-axis). We did a linear fitting to the A-B segment and the B-C segment. We calculated: 1) the AB-BC angle (∠ABC), 2) BC-x-axis angle (∠BCX), and 3) the log ratio of the BC slope over the vertical distance between point A and x-axis [log (BC/A-x)]. We asked an expert pulmonologist to assess the FVLs and separated the 172 PFTs into the flattening and the non-flattening groups. We defined the cutoff value as the mean minus one standard deviation using data from the non-flattening group. ∠ABC had the best concordance rate of 80.2% with a cutoff value of 149.7°. We then asked eight pulmonologists to evaluate the flattening with and without ∠ABC in another 168 PFTs. The Fleiss’ kappa was 0.320 (lower and upper confidence intervals [CIs]: 0.293 and 0.348 respectively) without ∠ABC and increased to 0.522 (lower and upper CIs: 0.494 and 0.550) with ∠ABC. There were 147 CT scans performed within 6 months of the 172 PFTs. Twenty-six of 55 PFTs (47.3%) with ∠ABC &lt;149.7° had CT scans showing small airway disease patterns while 44 of 92 PFTs (47.8%) with ∠ABC ≥149.7° had no CT evidence of small airway disease. We concluded that ∠ABC improved the inter-rater agreement on the presence of the late expiratory flattening in FVL. It could be a useful addition to the assessment of small airway disease in the PFT interpretation algorithm and reporting.

Introduction Chronic obstructive pulmonary disease (COPD) patients have poor sleep quality, longer time to sleep onset and frequent nocturnal awakenings. Poor sleep quality in COPD is associated with poor quality of life (QoL), increased exacerbations and increased mortality. Pulmonary rehabilitation (PR) improves functional status and QoL in COPD but effects on sleep are unclear. PR improves subjective sleep quality but there is paucity of objective actigraphy data. We hypothesized that actigraphy would demonstrate subjective and objective improvement in sleep following PR. Paired comparisons (t-test or Wilcoxon-signed-rank test) were performed before and after PR data on all variables. Methods This retrospective study of COPD patients undergoing PR utilized actigraphy watch recordings before and after 8-weeks of PR to assess changes in sleep variables including total time in bed (TBT), total sleep time (TST), sleep onset latency (SOL), sleep efficiency (SE), wakefulness after sleep onset (WASO) and total nocturnal awakenings. A change in Pittsburg Sleep Quality Index (PSQI) was a secondary outcome. PSQI was performed before and after PR. Results Sixty-nine patients were included in the final analysis. Most participants were male (97%), non-obese (median BMI 27.5, IQR 24.3 to 32.4 kg/m2) with an average age of 69 ± 8 years and 71% had severe COPD (GOLD stage 3 or 4). Prevalence of poor sleep quality (PSQI ≥5) was 86%. Paired comparisons did not show improvement in actigraphic sleep parameters following 8-weeks PR despite improvements in 6-min-walk distance (6MWD, mean improvement 54 m, 95% CI 34 m to 74 m, p<0.0001) and St. George’s Respiratory Questionnaire scores (SGRQ, mean improvement 7.7 points, 95% CI 5.2 to 10.2, p<0.0001). Stratified analysis of all sleep variables by severity of COPD, BMI, mood, mental status, 6-MWD and SGRQ did not show significant improvement after PR. In Veterans with poor sleep quality (PSQI ≥ 5), PR improved subjective sleep quality (PSQI, mean difference 0.79, 95% CI 0.07 to 1.40, p = 0.03). Conclusions Pulmonary rehabilitation improved subjective sleep quality in Veterans who had poor sleep quality at the beginning of the PR but did not improve objective sleep parameters by actigraphy. Our findings highlight the complex interactions among COPD, sleep and exercise.

Background Sepsis mortality has remained unchanged for greater than a decade, and early recognition continues to be the most important factor in mortality outcome. Plasma resistin concentration is increased in sepsis, but its mechanism and clinical relevance is unclear. As one function, resistin interacts with toll-like receptor 4 in competition with lipopolysaccharide, a main component of the gram-negative bacterial cell wall. It is not known if the type of infection leading to sepsis influences resistin production. The objective of this study was to investigate whether 1) early plasma resistin concentration can predict mortality, 2) elevated plasma resistin concentration is associated with clinical disease severity scores, such as SOFA, mSOFA and APACHE II, and 3) plasma resistin concentrations differ between gram negative versus other etiologies of sepsis. Methods This was an exploratory study in the framework of a prospective observational design. Peripheral venous blood samples were obtained from subjects admitted to the intensive care unit at clinical recognition of sepsis (0 hour) and at 6 and 24 hours. Vasopressor utilization was not a requirement for inclusion. Plasma was analyzed for resistin concentration by ELISA. Cytokine concentrations including IL-6, IL-8, and IL-10 were determined by cytokine bead array. Cytokine data were evaluated against publicly available sepsis RNA expression datasets to compare protein versus RNA expression levels in predicting clinical disease state. Clinical data were collected from electronic health records for clinical severity index calculations and context for interpretation of resistin and cytokine concentrations. Subjects were followed up to 60 days, or until death, whichever came first. Statistical analysis was completed with R package and SPSS software. Results Resistin levels were elevated in subjects admitted to the intensive care unit with sepsis. Four-hundred subjects were screened with 45 subjects included in the final analysis. Thirteen of 45 patients were non-survivors. Mortality within 60 days correlated with significantly higher resistin concentrations than in survivors. A resistin concentration of >126 ng/mL at clinical recognition of sepsis and >197 ng/mL within the first 24 hours were associated with mortality within 60 days with an area under the curve of 0.82 and 0.88, respectively. Most subjects with resistin concentration greater than these threshold values were deceased prior to 30 days. Resistin concentrations correlated with SOFA, mSOFA, and APACHE II scores in addition to having association with increases in inflammatory and sepsis biomarkers. These associations were validated with analysis of RNA expression datasets. Conclusion Plasma resistin concentrations of >126 ng/mL at clinical recognition of sepsis and >197 ng/mL within the first 24 hours of clinical sepsis recognition are associated with all-cause mortality. Resistin concentration wi...

A 50-year-old woman presented with a three-month history of nonpruritic skin rash, weakness and myalgia. The skin rash, which preceded the weakness, started on her face and spread to her back, but spared the mucous membranes. Strength in her bilateral upper and lower extremities was decreased, and the proximal group muscles were tender and very painful on movement. Possible diagnoses included discoid lupus erythematosus, systemic lupus erythematosus and inflammatory myo pathies. Serum rheumatoid factor, antinuclear antibodies, creatinine phosphokinase, cortisol and aldolase levels were normal on two occasions; creatinine level was elevated at 144.89 (normal range 50-110) μmol/L.Pathognomonic skin findings of heliotrope rash, shawl sign, Gottron papules ( Figure 1) and periungual erythema suggested amyotrophic derma tomyositis, a variant of dermatomyositis with typical cutaneous features but lacking inflammatory myopathy. 1Skin biopsy showed mild, nonspecific interface dermatitis with increased deposition of dermal mucin (Appendix 1, available at www .cmaj.ca/lookup/suppl/ doi: 10.15 03/ cmaj .151448/ -/DC1). Despite the patient's muscle pain, creatinine phosphokinase and aldolase levels were normal, and she did not undergo muscle biopsy or electromyography.There is a fivefold higher incidence of malignancies with dermatomyositis, 2 and it is likely that the tumour and muscles express common auto antigens. The immune response aimed at tumour cells may also target autoantigens in the muscles, causing muscle inflammation. This makes dermatomyositis a paraneoplastic phenomenon. The cervix, lung, pancreas, ovaries and breast are common sites for such malignancies.3 All patients with newly diagnosed dermatomyositis should be evaluated for underlying malignancy. 2,3 In this patient, renal ultrasonography (performed because of the elevated creatinine level) showed bilateral hydronephrosis. Subsequent magnetic resonance imaging showed a cervical mass invading the bladder and ureters. Biopsy showed that it was infiltrative squamous cervical carcinoma. The patient had not undergone any prior cervical cytologic screening.The patient was treated with carboplatin and paclitaxel for the cervical cancer and oral prednisone for the dermatomyositis. Despite initial improvement in her symptoms, metastases developed in the brain and liver, and there was progresssively worsening renal failure. The patient died about one year after the initial diagnosis. References

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