Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS. METHODS: The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO2/FiO2 ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 109/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0·9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 . FINDINGS: Between Sept 4, 2012, and Aug 23, 2018, 256 patients were randomised. Final follow-up was on Feb 25, 2019. We excluded three patients who revoked consent and one ineligible participant who received no intervention. Of 252 patients included in data analysis, the mean age was 58 years (SD 15), 157 (62%) were men, and 118 (47%) had ARDS. 128 (51%) patients were assigned to the heparin group and 124 (49%) to the placebo group, all of whom received their assigned intervention. Survivors in the heparin group (n=97) had similar SF-36 Physical Function Scores at day 60 compared to the placebo group (n=94; mean 53·6 [SD 31·6] vs 48·7 [35·7]; difference 4·9 [95% CI -4·8 to 14·5]; p=0·32). Compared with the placebo group, the heparin group had fewer cases of ARDS develop to day 5 among the at-risk patients (nine [15%] of 62 patients vs 21 [30%] of 71 patients; hazard ratio 0·46 [95% CI 0·22 to 0·98]; p=0·0431), less deterioration of the MLIS to day 5 (difference -0·14 [-0·26 to -0·02]; p=0·0215), similar day 60 mortality (23 [18%] of 127 patients vs 18 [15%] of 123 patients; odds ratio [OR] 1·29 [95% CI 0·66 to 2·53]; p=0·46), and more day 60 survivors at home (86 [87%] of 99 patients vs 73 [73%] of 100 patients; OR 2·45 [1·18 to 5·08]; p=0·0165). A similar number of serious adverse events occurred in each group (seven [5%] of 128 patients in the heparin group vs three [2%] of 124 patients in the placebo group; OR 2·33 [0·59 to 9·24]; p=0·23), which were a transient increase in airway pressure during nebulisation (n=3 in the heparin group), major non-pulmonary bleeding (n=2 in each group), haemoptysis (n=1 in the heparin group), tracheotomy site bleeding (n=1 in the heparin group), and hypoxaemia during nebulisation (n=1 in the placebo group). INTERPRETATION: In patients with or at risk of ARDS, nebulised heparin did not improve self-reported performance of daily physical activities, but was well tolerated and exploratory outcomes suggest less progression of lung injury and earlier return home. Further research is justified to establish if nebulised heparin accelerates recovery in those who have or are at risk of ARDS. FUNDING: Rowe Family Foundation, TR and RB Ditchfield Medical Research Endowment Fund, Patricia Madigan Charitable Trust, and The J and R McGauran Trust Fund.

Measuring dietary fatty acid intake:validation of a food-frequency questionnaire against 7 d weighed records.

There are few validated methods of measuring dietary fatty acid intake that are suitable for epidemiological research. The purpose of the present study was to develop and validate a food-frequency questionnaire (FFQ) developed to measure individual dietary fatty acid intakes against 7 d weighed dietary records, in a sample of thirty-one healthy adult volunteers. The FFQ was based on a previously validated questionnaire (DIETQ; Tinuviel Software, Warrington, Ches., UK), adapted to include greater detail on those foods from which the majority of dietary fatty acids are obtained. The FFQ and weighed records were analysed using food nutrient data from McCance and Widdowson's Food Composition Tables, supplemented with a food fatty acid content database (Foodbase, London, UK). Results from the two dietary assessment methods were compared by correlation coefficients and limits of agreement. The mean intake of individual fatty acids tended to be lower when assessed by FFQ. Correlation coefficients comparing unadjusted individual fatty acid intakes assessed by FFQ and weighed records ranged from 0.29 for 18 : 1n-9 to 0.71 for 20 : 4n-6. Adjusting for energy intake tended to increase the correlation coefficients between saturated fatty acids and decrease those between unsaturated fatty acids. In conclusion, this food-frequency method provides reliable estimates of dietary intake of many individual fatty acids for use in epidemiological studies.

Increase in the prevalence of allergen skin sensitization in successive birth cohorts.

BACKGROUND: Little is known about longitudinal trends in the prevalence of allergen skin sensitization in the general population. OBJECTIVE: We sought to measure the change in prevalence of allergen skin sensitization over a 9-year period in a cohort of adults and hence to determine whether cross-sectional differences in prevalence between age groups are due to an aging or cohort effect. METHODS: In 1991 and 2000, we measured skin sensitization, defined as a wheal diameter of 3 mm or larger than that elicited by a saline control, to Dermatophagoides pteronyssinus, cat fur, mixed grass, Aspergillus fumigatus, and Cladosporium herbarum in a cohort of 1339 adults from Nottingham aged between 18 and 71 years in 1991. Subjects were divided into six 9-year successive birth cohorts, and the effects of birth cohort and the within-subject change from 1991 to 2000 were analyzed in a generalized estimating equation logit model. RESULTS: The unadjusted prevalence of sensitization to any allergen was 30.5% in 1991 and 31.8% in 2000. In cross-sectional analyses the prevalence of sensitization decreased with increasing age at both surveys (risk ratio, 2.15; 95% confidence interval [CI], 1.45-3.17 for 18- to 26-year-old patients relative to 63- to 70-year-old patients in the 1991 survey). In longitudinal analysis there was no within-subject change in sensitization from 1991 to 2000 (adjusted odds ratio, 1.07; 95% CI, 0.97-1.19), but there was a significant cohort effect (adjusted odds ratio per successive 9 year cohort, 1.27; 95% CI, 1.18-1.37). CONCLUSION: The cross-sectional decrease in allergen sensitization with age in the general population arises predominantly from a secular increase in sensitization prevalence with successive birth cohorts and not to a loss of sensitization within subjects over time. As a result of this cohort effect, the prevalence of allergic sensitization has increased in this general adult population sample.

Prospective study of diet and decline in lung function in a general population.

We have investigated the relationship between decline in lung function and dietary intakes of magnesium, vitamin C, and other antioxidant vitamins in a general population cohort in Nottingham, United Kingdom. In 1991, we measured dietary intake by semiquantitative food frequency questionnaire, forced expiratory volume in 1 second (FEV1), and respiratory symptoms in a cross-sectional survey of 2,633 adults aged 18-70. Nine years later we repeated these measures in 1,346 of these individuals. In cross-sectional analyses, after adjustment for smoking and other confounders, higher intakes of vitamin C and magnesium, but not vitamins A or E, were associated with higher levels of FEV1 in both 1991 and 2000. In longitudinal analysis with adjustment for confounders, decline in FEV1 between 1991 and 2000 was lower amongst those with higher average vitamin C intake by 50.8 ml (95% confidence interval, 3.8-97.9) per 100 mg of vitamin C per day, but was unrelated to magnesium intake. There was no relationship between decline in FEV1 and intake of vitamins A or E. This study suggests that a high dietary intake of vitamin C, or of foods rich in this vitamin, may reduce the rate of loss of lung function in adults and thereby help to prevent chronic obstructive pulmonary disease.