Markers of adipose tissue hypoxia are elevated in subcutaneous adipose tissue of severely obese patients with obesity hypoventilation syndrome but not in the moderately obese.

It has been suggested that metabolic dysfunction in obesity is at least in part driven by adipose tissue (AT) hypoxia. However, studies on AT hypoxia in humans have shown conflicting data. Therefore we aimed to investigate if markers of AT hypoxia were present in the subcutaneous AT of severly obese individuals (class III obesity) with and without hypoventilation syndrome (OHS) in comparison to moderately obese (class I obesity) and lean controls. To provide a proof-of-concept study, we quantified AT hypoxia by hypoxia inducible factor 1 A (HIF1A) protein abundance in human participants ranging from lean to severly obese (class III obesity). On top of that nightly arterial O2 saturation in individuals with obesity OHS was assessed. Subjects with class III obesity (BMI > 40 kg/m2) and OHS exhibited significantly higher adipose HIF1A protein levels versus those with class I obesity (BMI 30-34.9 kg/m2) and lean controls whereas those with class III obesity without OHS showed an intermediate response. HIF1A gene expression was not well correlated with protein abundance. Although these data demonstrate genuine AT hypoxia in the expected pathophysiological context of OHS, we did not observe a hypoxia signal in lesser degrees of obesity suggesting that adipose dysfunction may not be driven by hypoxia in moderate obesity.

Does either obesity or OSA severity influence the response of autotitrating CPAP machines in very obese subjects?

PURPOSE: The pressures delivered by autotitrating continuous positive airways pressure (CPAP) devices not only treat obstructive sleep apnoea (OSA) effectively but also give potentially interesting physiological information about the forces impinging on the pharynx. In earlier work from this unit, we used correlations between autoCPAP pressure and both OSA severity and obesity, to construct an algorithm to estimate the fixed CPAP pressure a patient required for subsequent clinical use. We wished to discover if these relationships could be reliably extended to a much more obese group. METHODS: We performed a prospective cohort study in an obese population. Measurements of obesity were made, OSA severity was recorded, and the 95th centile autoCPAP pressure was recorded during 1 week of autoCPAP. Spearman's rank correlation was performed between measurements of obesity and autoCPAP pressure, and between OSA severity and autoCPAP pressure. RESULTS: Fifty-four obese individuals (median body mass index (BMI) 43.0 kg/m(2)), 52 % of whom had OSA (apnoea-hypopnoea index (AHI) ≥ 15), had a median 95th centile autoCPAP pressure of 11.8 cmH2O. We found no significant correlation between autoCPAP pressure and neck circumference, waist circumference or BMI. There was a moderate correlation between autoCPAP pressure and OSA severity (AHI r = 0.34, p = 0.02; oxygen desaturation index (ODI) r = 0.48, p < 0.001). CONCLUSIONS: In this population, neither BMI nor neck circumference nor waist circumference is predictive of autoCPAP pressure. Therefore, the previously derived algorithm does not adequately predict the fixed CPAP pressure for subsequent clinical use in these obese individuals. In addition, some subjects without OSA generated high autoCPAP pressures, and thus, the correlation between OSA severity and autoCPAP pressure was only moderate.

Biomarkers of oxidative stress following continuous positive airway pressure withdrawal: data from two randomised trials.

There is conflicting evidence whether intermittent hypoxia in obstructive sleep apnoea (OSA) influences oxidative stress. We hypothesised that withdrawal of continuous positive airway pressure (CPAP) from patients with OSA would raise markers of oxidative stress.59 patients with CPAP-treated moderate-to-severe OSA (oxygen desaturation index (ODI) >20 events·h(-1)) were randomised 1:1 to either stay on CPAP (n=30) or change to sham CPAP (n=29) for 2 weeks. Using samples from two similar studies at two sites, we measured early morning blood malondialdehyde (MDA, a primary outcome in one study and a secondary outcome in the other), lipid hydroperoxides, total antioxidant capacity, superoxide generation from mononuclear cells and urinary F2-isoprostane. We also measured superoxide dismutase as a marker of hypoxic preconditioning. "Treatment" effects (sham CPAP versus CPAP) were calculated via linear regression.Sham CPAP provoked moderate-to-severe OSA (mean ODI 46 events·h(-1)), but blood markers of oxidative stress did not change significantly (MDA "treatment" effect (95% CI) -0.02 (-0.23 to +0.19) µmol·L(-1)). Urinary F2-isoprostane fell significantly by ~30% (-0.26 (-0.42 to -0.10) ng·mL(-1)) and superoxide dismutase increased similarly (+0.17 (+0.02 to +0.30) ng·mL(-1)).We found no direct evidence of increased oxidative stress in patients experiencing a return of their moderate-to-severe OSA. The fall in urinary F2-isoprostane and rise in superoxide dismutase implies that hypoxic preconditioning may have reduced oxidative stress.

Effect of continuous positive airway pressure treatment for obstructive sleep apnoea on visual processing of degraded words.

BACKGROUND: In a previous uncontrolled study, continuous positive airway pressure (CPAP) therapy for obstructive sleep apnoea (OSA) improved vision in patients with diabetic macular oedema. OBJECTIVES: We investigated whether the above improvement in vision (or visual processing) might have been due to reduced sleepiness, rather than a true improvement in retinal function. METHODS: Twelve normal control subjects and 20 patients with OSA were tested for their ability to recognise degraded words, by means of a computer programme displaying 5-letter words every 4 s for 10 min, with variable amounts of the bottom half of the word missing; the percentage of the word necessary to achieve correct identification on average half the time was 'hunted' (the test score). All subjects were tested twice, 2-3 weeks apart; the OSA group after the commencement of CPAP. The Epworth Sleepiness Score (ESS) in patients was measured at the same visit. RESULTS: The test score at visit 1 was 26.7% for normal subjects and 31.6% for patients with OSA. At visit 2, the test score was 25.0% for normal subjects and 29.9% for patients with OSA. The groups showed a small and identical improvement over the trial period in the test score, of 1.7% (p = 0.01 and p = 0.03 for the normal and OSA groups, respectively). The group with OSA experienced a drop in ESS of 7.5 (SD 5.5) points following treatment. CONCLUSION: The small and identical improvement in both groups suggests only a similar learning effect rather than any improvement due to reduced sleepiness.

The use of venous blood gas in assessing arterial acid-base and oxygenation status - an analysis of aggregated data from multiple studies evaluating the venous to arterial conversion (v-TAC) method.

BACKGROUND: Several methods exist toreduce the number of arterial blood gases (ABGs). One method, Roche v-TAC, hasbeen evaluated in different patient groups. This paper aggregates data from thesestudies, in different patient categories using common analysis criteria. RESEARCH DESIGN AND METHODS: We included studiesevaluating v-TAC based on paired arterial and peripheral venous blood samples.Bland-Altman analysis compared measured and calculated arterial values of pH, PCO2and PO2. Subgroup analyses were performed for normal, chronichypercapnia and chronic base excess, acute hyper- and hypocapnia, and acute andchronic base deficit. RESULTS: 811 samples from 12 studieswere included. Bias and limits of agreement for measured and calculated values:pH 0.001 (-0.029 to 0.031), PCO2 -0.08 (-0.65 to 0.49) kPa, and PO20.04 (-1.71 to 1.78) kPa, with similar values for all sub-group analyses. CONCLUSION: These data suggest thatv-TAC analysis may have a role in replacing ABGs, avoiding arterial puncture.Substantial data exists in patients with chronic hypercapnia and chronic baseexcess, acute hyper and hypocapnia, and in patients with relatively normal acidbase status, with similar bias and precision across groups and across studydata. Limited data exists for patients with acute and chronic base deficit.

Exploring the impact of excessive daytime sleepiness caused by obstructive sleep apnea on patient and partner quality of life: a time trade-off utility study in the UK general public.

STUDY OBJECTIVES: This study aimed to quantify the impact of excessive daytime sleepiness (EDS) on patient and patient's partner health-related quality of life in the form of utility values typically used in health economic evaluations. METHODS: A time trade-off study was conducted in a UK general population sample (representing a societal perspective) to elicit utility values, measured on a 0 to 1 scale, for health states with varying obstructive sleep apnea-associated EDS severity. In a time trade-off study, health states are described, and participants "trade off" time in a specific higher severity state for a shorter amount of time in full health. RESULTS: Overall, the sample consisted of 104 participants, who were interviewed and took part in the time trade-off exercise to elicit utility values for patient and partner residual EDS health states. The average utility score declined with increasing obstructive sleep apnea-associated EDS severity for both patient (no EDS, 0.926; mild EDS, 0.794; moderate EDS, 0.614; severe EDS, 0.546) and partner (no EDS, 0.955; mild EDS, 0.882; moderate EDS, 0.751; severe EDS, 0.670) health states. CONCLUSIONS: These results demonstrate the high impact that EDS in obstructive sleep apnea is estimated to have on patient and partner health-related quality of life. CITATION: Tolley K, Noble-Longster J, Mettam S, et al. Exploring the impact of excessive daytime sleepiness caused by obstructive sleep apnea on patient and partner quality of life: a time trade-off utility study in the UK general public. J Clin Sleep Med. 2022;18(9):2237-2246.

COVID-19 follow-up planning: what will we be missing?

There is a real need for a discharge plan for COVID-19 survivors in the UK. Follow-up imaging could help assess the resolution of infection, exclude underlying malignancy and identify post-inflammatory fibrosis. https://bit.ly/2YJ8hyg.

Targeting coagulation activation in severe COVID-19 pneumonia: lessons from bacterial pneumonia and sepsis.

Novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has rapidly spread throughout the world, resulting in a pandemic with high mortality. There are no effective treatments for the management of severe COVID-19 and current therapeutic trials are focused on antiviral therapy and attenuation of hyper-inflammation with anti-cytokine therapy. Severe COVID-19 pneumonia shares some pathological similarities with severe bacterial pneumonia and sepsis. In particular, it disrupts the haemostatic balance, which results in a procoagulant state locally in the lungs and systemically. This culminates in the formation of microthrombi, disseminated intravascular coagulation and multi-organ failure. The deleterious effects of exaggerated inflammatory responses and activation of coagulation have been investigated in bacterial pneumonia and sepsis and there is recognition that although these pathways are important for the host immune response to pathogens, they can lead to bystander tissue injury and are negatively associated with survival. In the past two decades, evidence from preclinical studies has led to the emergence of potential anticoagulant therapeutic strategies for the treatment of patients with pneumonia, sepsis and acute respiratory distress syndrome, and some of these anticoagulant approaches have been trialled in humans. Here, we review the evidence from preclinical studies and clinical trials of anticoagulant treatment strategies in bacterial pneumonia and sepsis, and discuss the importance of these findings in the context of COVID-19.

Randomised, cOntrolled Multicentre trial of 26 weeks subcutaneous liraglutide (a glucagon-like peptide-1 receptor Agonist), with or without contiNuous positive airway pressure (CPAP), in patients with type 2 diabetes mellitus (T2DM) and obstructive sleep apnoEa (OSA) (ROMANCE): study protocol assessing the effects of weight loss on the apnea-hypnoea index (AHI).

INTRODUCTION: Obstructive sleep apnoea (OSA) and type 2 diabetes mellitus (T2DM) often occur concurrently, and untreated OSA may potentially amplify the high risk of cardiovascular disease in T2DM. Compliance with continuous positive airway pressure (CPAP), the conventional treatment for OSA, can be poor and considering weight loss is the most effective treatment for OSA. This trial examines whether the glucagon-like peptide-1 receptor agonist liraglutide, a glucose-lowering therapy associated with significant weight loss used in T2DM, can improve the severity and symptoms of OSA. METHODS AND ANALYSIS: This is an outpatient, single-centred, open-labelled, prospective, phase IV randomised controlled trial in a two-by-two factorial design. One hundred and thirty-two patients with newly diagnosed OSA (apnoea-hypopnoea index (AHI) ≥15 events/hour), and existing obesity and T2DM (glycated haemoglobin (HbA1c) ≥47 mmol/mol), will be recruited from diabetes and sleep medicine outpatient clinics in primary and secondary care settings across Liverpool. Patients will be allocated equally, using computer-generated random, permuted blocks of unequal sizes, to each of the four treatment arms for 26 weeks: (i) liraglutide (1.8 mg once per day) alone, (ii) liraglutide 1.8 mg once per day with CPAP, (iii) CPAP alone (conventional care) or (iv) no treatment (control). The primary outcome measure is change in OSA severity, determined by AHI. Secondary outcome measures include effects on glycaemic control (glycated haemoglobin (HbA1c)), body weight and quality of life measures. Exploratory measures include measures of physical activity, MRI-derived measures of regional body composition including fat mass (abdominal subcutaneous, visceral, neck and liver fat) and skeletal muscle mass (cross-sectional analysis of thigh), indices of cardiac function (using transthoracic echocardiography) and endothelial function. ETHICAL APPROVAL: The study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1019) and it is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. TRIAL REGISTRATION NUMBERS: ISRCTN16250774. EUDRACT No. 2014-000988-41. UTN U1111-1139-0677.

Correlates of obesity-related chronic ventilatory failure.

INTRODUCTION: Only a third of obese patients develop chronic ventilatory failure. This cross-sectional study assessed multiple factors potentially associated with chronic ventilatory failure. MATERIALS/PATIENTS AND METHODS: Participants had a body mass index (BMI) >30 kg/m(2), with or without chronic ventilatory failure (awake arterial partial pressure of carbon dioxide >6 kPa or base excess (BE) ≥2 mmols/L). Factors investigated were grouped into domains: (1) obesity measures, (2) pulmonary function, (3) respiratory and non-respiratory muscle strength, (4) sleep study derivatives, (5) hypoxic and hypercapnic responses, and (6) some hormonal, nutritional and inflammatory measures. RESULTS: 71 obese participants (52% male) were studied over 27 months, 52 (SD 9) years and BMI 47 (range 32-74) kg/m(2). The best univariate correlates of BE from each domain were: (1) dual-energy X-ray absorptiometry measurement of visceral fat (r=+0.50, p=0.001); (2) supine forced expiratory volume in 1 s (r=-0.40, p=0.001); (3) sniff maximum pressure (r=-0.28, p=0.02); (4) mean overnight arterial oxygen saturation (r=-0.50, p<0.001); (5) ventilatory response to 15% O2 breathing (r=-0.28, p=0.02); and (6) vitamin D (r=-0.30, p=0.01). In multivariate analysis, only visceral fat and ventilatory response to hypoxia remained significant. CONCLUSIONS: We have confirmed that in the obese, BMI is a poor correlate of chronic ventilatory failure, and the best independent correlates are visceral fat and hypoxic ventilatory response. TRIAL REGISTRATION NUMBER: NCT01380418.

Exploratory study into the effect of abdominal mass loading on airways resistance and ventilatory failure.

OBJECTIVE: We hypothesised that the airway resistance during tidal breathing would correlate with a particular pattern of increasing obesity, particularly when supine, and would differ between participants with and without ventilatory failure. METHODS: In our cross-sectional cohort study, 72 morbidly obese patients (40 males, 32 females, mean body mass index (BMI) 47.2) had measurements of both airways resistance (by impulse oscillometry (IOS)) and adiposity (by dual-energy X-ray absorptiometry (DXA)). RESULTS: All measures of airways resistance increased in the supine position: total airways resistance (R5) +37% (p<0.0005); large airways resistance (R20) +29% (p<0.0005); and small airways resistance (R5-R20) +52% (p<0.0005). BMI was correlated with seated R5, seated R5-R20, supine R5 and supine R5-R20 (r=0.33 p<0.006, r=0.32 p<0.004, r=0.30 p<0.02 and r=0.36 p<0.04, respectively). Visceral adipose tissue mass was correlated with supine R5-20 (r=0.46 p<0.05). Supine measures of total airways resistance (R5) and large airways resistance (R20) differed between those with and without ventilatory failure, as did mean weight and BMI. CONCLUSIONS: Our study identifies a potentially detrimental effect of the supine posture on tidal breathing airways resistance in obese patients. This change is correlated most with visceral adipose tissue mass and the small airways. We were able to demonstrate that supine increases in airways resistance during tidal breathing, within obese patients, are different between those with and without ventilatory failure. TRIAL REGISTRATION NUMBER: NCT01380418; pre-results.