Robert J. O. Davies

Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial.

BACKGROUND Obstructive sleep apnoea is associated with raised blood pressure. If blood pressure can be reduced by nasal continuous positive airway pressure (nCPAP), such treatment could reduce risk of cardiovascular disease in patients with obstructive sleep apnoea. Our aim was to see whether nCPAP for sleep apnoea reduces blood pressure compared with the most robust control intervention subtherapeutic nCPAP. METHODS We did a randomised parallel trial to compare change in blood pressure in 118 men with obstructive sleep apnoea (Epworth score > 9, and a > 4% oxygen desaturation index of > 10 per h) who were assigned to either therapeutic (n=59) or subtherapeutic (59) nCPAP (about 1 cm H(2)O pressure) for 1 month. The primary outcome was the change in 24-h mean blood pressure. Secondary outcomes were changes in systolic, diastolic, sleep, and wake blood pressure, and relations between blood pressure changes, baseline blood pressure, and severity of sleep apnoea. FINDINGS Therapeutic nCPAP reduced mean arterial ambulatory blood pressure by 2.5 mm Hg (SE 0.8), whereas subtherapeutic nCPAP increased blood pressure by 0.8 mm Hg (0.7) (difference -3.3 [95% CI -5.3 to -1.3]; p=0.0013, unpaired t test). This benefit was seen in both systolic and diastolic blood pressure, and during both sleep and wake. The benefit was larger in patients with more severe sleep apnoea than those who had less severe apnoea, but was independent of the baseline blood pressure. The benefit was especially large in patients taking drug treatment for blood pressure. INTERPRETATION In patients with most severe sleep apnoea, nCPAP reduces blood pressure, providing significant vascular risk benefits, and substantially improving excessive daytime sleepiness and quality of life.

Comparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial

BACKGROUND Nasal continuous positive airway pressure (NCPAP) is widely used as a treatment for obstructive sleep apnoea. However, to date there are no randomised controlled trials of this therapy against a well-matched control. We undertook a randomised prospective parallel trial of therapeutic NCPAP for obstructive sleep apnoea compared with a control group on subtherapeutic NCPAP. METHODS Men with obstructive sleep apnoea, defined as an Epworth sleepiness score of 10 or more and ten or more dips per h of more than 4% SaO2 caused by obstructive sleep apnoea on overnight sleep study, were randomly assigned therapeutic NCPAP or subtherapeutic NCPAP (about 1 cm H2O) for 1 month. Primary outcomes were subjective sleepiness (Epworth sleepiness score), objective sleepiness (maintenance of wakefulness test), and SF-36 questionnaire measurements of self-reported functioning and well-being. FINDINGS 107 men entered the study: 53 received subtherapeutic NCPAP and 54 therapeutic NCPAP. Use of NCPAP by the two treatment groups was similar: 5.4 h (therapeutic) and 4.6 h (subtherapeutic) per night. Subtherapeutic NCPAP did not alter the overnight number of SaO2 dips per h compared with baseline, and thus acted as a control. Therapeutic NCPAP was superior to subtherapeutic NCPAP in all primary outcome measures. The Epworth score was decreased from a median of 15.5 to 7.0 on therapeutic NCPAP, and from 15.0 to 13.0 on subtherapeutic NCPAP (between treatments, p<0.0001). Mean maintenance-of-wakefulness time increased from 22.5 to 32.9 min on therapeutic NCPAP and, not significantly, from 20.0 to 23.5 min on subtherapeutic NCPAP (between treatments p<0.005). Effect sizes for SF-36 measures of energy and vitality were 1.68 (therapeutic) and 0.97 (subtherapeutic) NCPAP (between treatments p<0.0001). For mental summary score, the corresponding values were 1.02 and 0.4 (between treatments p=0.002). INTERPRETATION Therapeutic NCPAP reduces excessive daytime sleepiness and improves self-reported health status compared with a subtherapeutic control. Compared with controls, the effects of therapeutic NCPAP are large and confirm previous uncontrolled clinical observations and the results of controlled trials that used an oral placebo.

A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis.

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4–6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 × 10−8). We found that the Mal S180L variant attenuated TLR2 signal transduction.

Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials

Background: Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality and is an independent risk factor for hypertension. Novel circulating cardiovascular risk markers enabling a more accurate prediction of cardiovascular risk have been identified. Examination of these markers may clarify the increased risk in OSA and contribute to an analysis of the benefits of treatment. Methods: Plasma levels of total cholesterol and triglyceride and activated coagulation factors XIIa and VIIa, factors VII, VIII, XII, fibrinogen, thrombin-antithrombin (TAT), von Willebrand factor antigen (vWFAg), soluble P-selectin (sP-sel), and homocysteine were measured before and after treatment for 1 month with therapeutic or subtherapeutic (control) continuous positive airways pressure (CPAP) in 220 patients with OSA. Results: Levels of activated coagulation factors XIIa, VIIa, TAT and sP-sel were higher in OSA patients at baseline than in unmatched controls, but did not fall with 1 month of therapeutic CPAP treatment. The raised sP-sel levels correlated only with body mass index (p = 0.002). There was a trend towards a significant fall in total cholesterol with therapeutic CPAP (p = 0.06) compared with the control group. In the therapeutic group there was a clinically significant mean fall in total cholesterol of 0.28 mmol/l (95% confidence interval 0.11 to 0.45, p = 0.001) which may reduce cardiovascular risk by about 15%. Conclusion: A number of activated coagulation factors are increased in untreated OSA patients, potentially contributing to vascular risk, but they do not fall with 1 month of CPAP treatment. Nasal CPAP may produce a clinically relevant fall in total cholesterol level, potentially reducing cardiovascular risk, but this needs to be verified in a larger prospective study.

Effect of an Indwelling Pleural Catheter vs Chest Tube and Talc Pleurodesis for Relieving Dyspnea in Patients With Malignant Pleural Effusion: The TIME2 Randomized Controlled Trial

CONTEXT Malignant pleural effusion causes disabling dyspnea in patients with a short life expectancy. Palliation is achieved by fluid drainage, but the most effective first-line method has not been determined. OBJECTIVE To determine whether indwelling pleural catheters (IPCs) are more effective than chest tube and talc slurry pleurodesis (talc) at relieving dyspnea. DESIGN Unblinded randomized controlled trial (Second Therapeutic Intervention in Malignant Effusion Trial [TIME2]) comparing IPC and talc (1:1) for which 106 patients with malignant pleural effusion who had not previously undergone pleurodesis were recruited from 143 patients who were treated at 7 UK hospitals. Patients were screened from April 2007-February 2011 and were followed up for a year. INTERVENTION Indwelling pleural catheters were inserted on an outpatient basis, followed by initial large volume drainage, education, and subsequent home drainage. The talc group were admitted for chest tube insertion and talc for slurry pleurodesis. MAIN OUTCOME MEASURE Patients completed daily 100-mm line visual analog scale (VAS) of dyspnea over 42 days after undergoing the intervention (0 mm represents no dyspnea and 100 mm represents maximum dyspnea; 10 mm represents minimum clinically significant difference). Mean difference was analyzed using a mixed-effects linear regression model adjusted for minimization variables. RESULTS Dyspnea improved in both groups, with no significant difference in the first 42 days with a mean VAS dyspnea score of 24.7 in the IPC group (95% CI, 19.3-30.1 mm) and 24.4 mm (95% CI, 19.4-29.4 mm) in the talc group, with a difference of 0.16 mm (95% CI, −6.82 to 7.15; P = .96). There was a statistically significant improvement in dyspnea in the IPC group at 6 months, with a mean difference in VAS score between the IPC group and the talc group of −14.0 mm (95% CI, −25.2 to −2.8 mm; P = .01). Length of initial hospitalization was significantly shorter in the IPC group with a median of 0 days (interquartile range [IQR], 0-1 day) and 4 days (IQR, 2-6 days) for the talc group, with a difference of −3.5 days (95% CI, −4.8 to −1.5 days; P < .001). There was no significant difference in quality of life. Twelve patients (22%) in the talc group required further pleural procedures compared with 3 (6%) in the IPC group (odds ratio [OR], 0.21; 95% CI, 0.04-0.86; P = .03). Twenty-one of the 52 patients in the catheter group experienced adverse events vs 7 of 54 in the talc group (OR, 4.70; 95% CI, 1.75-12.60; P = .002). CONCLUSION Among patients with malignant pleural effusion and no previous pleurodesis, there was no significant difference between IPCs and talc pleurodesis at relieving patient-reported dyspnea. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN87514420.

CD56bright NK Cells Are Enriched at Inflammatory Sites and Can Engage with Monocytes in a Reciprocal Program of Activation

Human NK cells may be divided into a CD56dim subset and a CD56bright subset. In peripheral blood, CD56dim NK cells dominate, whereas in lymph nodes, CD56bright NK cells are more common. In this study we show that CD56bright NK cells accumulate within inflammatory lesions in a wide variety of clinical diseases affecting several different anatomical sites. We demonstrate that when activated by the monokines IL-12, IL-15, and IL-18, these NK cells promote TNF-α production by CD14+ monocytes in a manner that is dependent on cell:cell contact. Conversely, CD14+ monocytes synergize with monokines to promote IFN-γ production by these NK cells. Again, this interaction is dependent on cell:cell contact. The experiments show that CD56bright NK cells accumulate in inflammatory lesions and, in the appropriate cytokine environment, can engage with CD14+ monocytes in a reciprocal activatory fashion, thereby amplifying the inflammatory response. Such a positive feedback loop is likely to be important in the pathogenesis of chronic inflammatory conditions such as rheumatoid arthritis.

Case-control study of 24 hour ambulatory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects

BACKGROUND There is considerable debate regarding the relationship between obstructive sleep apnoea (OSA) and hypertension. It is unclear whether OSA is an independent vascular risk factor as studies attempting to assess this association have produced conflicting results because of confounding variables such as upper body obesity, alcohol, and smoking. A case-control study of 24 hour ambulatory blood pressure was undertaken in patients with OSA and matched controls to assess whether OSA is an independent correlate of diurnal hypertension. METHODS Forty five patients with moderate to severe OSA and excessive daytime sleepiness were matched with 45 controls without OSA in a sleep study. Matched variables included age, body mass index (BMI), alcohol, cigarette usage, treated hypertension, and ischaemic heart disease. Upper body obesity was compared by waist:hip and waist:height ratios; 24 hour ambulatory blood pressure recordings were performed (before treatment for OSA) in all subjects. RESULTS Patients with OSA had significantly increased mean (SD) diastolic blood pressure (mm Hg) during both daytime (87.4 (10.2) versus 82.8 (9.1); p=0.03, mean difference 4.6 (95% CI 0.7 to 8.6) and night time (78.6 (9.3) versus 71.4 (8.0); p<0.001, mean difference 7.2 (95% CI 3.7 to 10.6)), and higher systolic blood pressure at night (119.4 (20.7) versus 110.2 (13.9); p=0.01, mean difference 9.2 (95% CI 2.3 to 16.1)). The nocturnal reduction in blood pressure (“dipping”) was smaller in patients with OSA than in control subjects. CONCLUSIONS Compared with closely matched control subjects, patients with OSA have increased ambulatory diastolic blood pressure during both day and night, and increased systolic blood pressure at night. The magnitude of these differences is sufficient to carry an increased risk of cardiovascular morbidity. The slight excess of upper body fat deposition in the controls may make these results conservative.

Management of pleural infection in adults: British Thoracic Society pleural disease guideline 2010

Pleural infection is a frequent clinical problem with an approximate annual incidence of up to 80 000 cases in the UK and USA combined. The associated mortality and morbidity is high; in the UK 20% of patients with empyema die and approximately 20% require surgery to recover within 12 months of their infection.1 2 Prompt evaluation and therapeutic intervention appears to reduce morbidity and mortality as well as healthcare costs.3 This article presents the results of a peer-reviewed systematic literature review combined with expert opinion of the preferred management of pleural infection in adults for clinicians in the UK. The clinical guidelines generated from this process are presented in figure 1. The guidelines are aimed predominantly at physicians involved in adult general and respiratory medicine and specifically do not cover in detail the complex areas of tuberculous empyema, paediatric empyema or the surgical management of post-pneumonectomy space infection. Figure 1 Flow diagram describing the management of pleural infection. This section provides background information for reference, interest and to set the management guidelines in context. ### Historical perspective The Egyptian physician Imhotep initially described pleural infection around 3000 BC, although Hippocrates has been more famously credited with its recognition in 500 BC. Until the 19th century open thoracic drainage was the recommended treatment for this disorder but carried an associated mortality of up to 70%.4 5 This high mortality was probably due to respiratory failure produced by the large open pneumothorax left by drainage.5 This was particularly true of Streptococcus pyogenes infections which produce streptokinase and large alocular effusions free of adhesions.5 Closed tube drainage was first described in 1876 but was not widely adopted until the influenza epidemic of 1917–19. An Empyema Commission subsequently produced recommendations that remain the basis for treatment today. They advocated adequate pus drainage with a closed …

Sleep · 1: Obstructive sleep apnoea/hypopnoea syndrome: definitions, epidemiology, and natural history

Arguments over the definition of obstructive sleep apnoea/hypopnoea syndrome (OSAHS) have still not been satisfactorily resolved. As a result, robust estimates of the prevalence of OSAHS are not possible. New approaches are needed to identify those who have “CPAP responsive” disease, enabling more accurate estimates to be made of the prevalence of the sleep apnoea syndrome in the community.

Bacterial-induced release of inflammatory mediators by bronchial epithelial cells

This review focuses on bacterial induction and release of inflammatory cytokines and adhesion molecules by human bronchial epithelial cells, with special reference to Haemophilus influenzae, a pathogen commonly associated with chronic bronchitis. Studies investigating the mechanisms underlying bacterial colonization of the airways and bacterial-induced chronic airway inflammation have suggested that these are likely to involve localization of bacteria to the site(s) of infection in the respiratory tract and induction of a local airway inflammation resulting in the initiation of epithelial damage. We have hypothesized that the gross airway epithelial damage observed in chronic infective lung disease is an indirect consequence of proteolytic enzymes and toxic oxygen radicals generated by large numbers of neutrophils infiltrating the airways. Furthermore, the infiltration and activation of the neutrophils is a consequence of increased release of proinflammatory mediators from the host respiratory epithelium, induced by bacterial products, such as endotoxin. This hypothesis is based on studies which have demonstrated that the concentrations of circulating cytokines, such as interleukin (IL)-8 and tumour necrosis factor-alpha (TNF-alpha), which have profound effects on neutrophil activity, are increased in endotoxaemia and that airway epithelial cells are a rich source of these cytokines. Support for this hypothesis is provided by studies of cultured human bronchial epithelial cells incubated either in the absence or presence of purified endotoxin preparations from nontypable and type b H. influenzae strains which have demonstrated that these endotoxins lead to significantly increased expression and/or release of proinflammatory mediators, including IL-6, IL-8, TNF-alpha and intercellular adhesion molecule-1 (ICAM-1). Treatment of the cells with steroids can downregulate the expression and/or release of these inflammatory mediators. Additionally, these studies have demonstrated that culture medium collected from endotoxin-treated cultures, 24 h after treatment, significantly increases neutrophil chemotaxis and adhesion to human endothelial cells in vitro.