Routine low-dose continuous or nocturnal oxygen for people with acute stroke: three-arm Stroke Oxygen Supplementation RCT.

BACKGROUND: Stroke is a major cause of death and disability worldwide. Hypoxia is common after stroke and is associated with worse outcomes. Oxygen supplementation could prevent hypoxia and secondary brain damage. OBJECTIVES: (1) To assess whether or not routine low-dose oxygen supplementation in patients with acute stroke improves outcome compared with no oxygen; and (2) to assess whether or not oxygen given at night only, when oxygen saturation is most likely to be low, is more effective than continuous supplementation. DESIGN: Multicentre, prospective, randomised, open, blinded-end point trial. SETTING: Secondary care hospitals with acute stroke wards. PARTICIPANTS: Adult stroke patients within 24 hours of hospital admission and 48 hours of stroke onset, without definite indications for or contraindications to oxygen or a life-threatening condition other than stroke. INTERVENTIONS: Allocated by web-based minimised randomisation to: (1) continuous oxygen: oxygen via nasal cannula continuously (day and night) for 72 hours after randomisation at a flow rate of 3 l/minute if baseline oxygen saturation was ≤ 93% or 2 l/minute if > 93%; (2) nocturnal oxygen: oxygen via nasal cannula overnight (21:00-07:00) for three consecutive nights. The flow rate was the same as the continuous oxygen group; and (3) control: no routine oxygen supplementation unless required for reasons other than stroke. MAIN OUTCOME MEASURES: Primary outcome: disability assessed by the modified Rankin Scale (mRS) at 3 months by postal questionnaire (participant aware, assessor blinded). Secondary outcomes at 7 days: neurological improvement, National Institutes of Health Stroke Scale (NIHSS), mortality, and the highest and lowest oxygen saturations within the first 72 hours. Secondary outcomes at 3, 6, and 12 months: mortality, independence, current living arrangements, Barthel Index, quality of life (European Quality of Life-5 Dimensions, three levels) and Nottingham Extended Activities of Daily Living scale by postal questionnaire. RESULTS: In total, 8003 patients were recruited between 24 April 2008 and 17 June 2013 from 136 hospitals in the UK [continuous, n = 2668; nocturnal, n = 2667; control, n = 2668; mean age 72 years (standard deviation 13 years); 4398 (55%) males]. All prognostic factors and baseline characteristics were well matched across the groups. Eighty-two per cent had ischaemic strokes. At baseline the median Glasgow Coma Scale score was 15 (interquartile range 15-15) and the mean and median NIHSS scores were 7 and 5 (range 0-34), respectively. The mean oxygen saturation at randomisation was 96.6% in the continuous and nocturnal oxygen groups and 96.7% in the control group. Primary outcome: oxygen supplementation did not reduce disability in either the continuous or the nocturnal oxygen groups. The unadjusted odds ratio for a better outcome (lower mRS) was 0.97 [95% confidence interval (CI) 0.89 to 1.05; p = 0.5] for the combined oxygen groups (both continuous and nocturnal together) (n = 5152) versus the control (n = 2567) and 1.03 (95% CI 0.93 to 1.13; p = 0.6) for continuous versus nocturnal oxygen. Secondary outcomes: oxygen supplementation significantly increased oxygen saturation, but did not affect any of the other secondary outcomes. LIMITATIONS: Severely hypoxic patients were not included. CONCLUSIONS: Routine low-dose oxygen supplementation in stroke patients who are not severely hypoxic is safe, but does not improve outcome after stroke. FUTURE WORK: To investigate the causes of hypoxia and develop methods of prevention. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52416964 and European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2006-003479-11. FUNDING DETAILS: This project was funded by the National Institute for Health Research (NIHR) Research for Patient Benefit and Health Technology Assessment programmes and will be published in full in Health Technology Assessment; Vol. 22, No. 14. See the NIHR Journals Library website for further project information.

Effect of Routine Low-Dose Oxygen Supplementation on Death and Disability in Adults With Acute Stroke: The Stroke Oxygen Study Randomized Clinical Trial.

Importance: Hypoxia is common in the first few days after acute stroke, is frequently intermittent, and is often undetected. Oxygen supplementation could prevent hypoxia and secondary neurological deterioration and thus has the potential to improve recovery. Objective: To assess whether routine prophylactic low-dose oxygen therapy was more effective than control oxygen administration in reducing death and disability at 90 days, and if so, whether oxygen given at night only, when hypoxia is most frequent, and oxygen administration is least likely to interfere with rehabilitation, was more effective than continuous supplementation. Design, Setting, and Participants: In this single-blind randomized clinical trial, 8003 adults with acute stroke were enrolled from 136 participating centers in the United Kingdom within 24 hours of hospital admission if they had no clear indications for or contraindications to oxygen treatment (first patient enrolled April 24, 2008; last follow-up January 27, 2015). Interventions: Participants were randomized 1:1:1 to continuous oxygen for 72 hours (n = 2668), nocturnal oxygen (21:00 to 07:00 hours) for 3 nights (n = 2667), or control (oxygen only if clinically indicated; n = 2668). Oxygen was given via nasal tubes at 3 L/min if baseline oxygen saturation was 93% or less and at 2 L/min if oxygen saturation was greater than 93%. Main Outcomes and Measures: The primary outcome was reported using the modified Rankin Scale score (disability range, 0 [no symptoms] to 6 [death]; minimum clinically important difference, 1 point), assessed at 90 days by postal questionnaire (participant aware, assessor blinded). The modified Rankin Scale score was analyzed by ordinal logistic regression, which yields a common odds ratio (OR) for a change from one disability level to the next better (lower) level; OR greater than 1.00 indicates improvement. Results: A total of 8003 patients (4398 (55%) men; mean [SD] age, 72 [13] years; median National Institutes of Health Stroke Scale score, 5; mean baseline oxygen saturation, 96.6%) were enrolled. The primary outcome was available for 7677 (96%) participants. The unadjusted OR for a better outcome (calculated via ordinal logistic regression) was 0.97 (95% CI, 0.89 to 1.05; P = .47) for oxygen vs control, and the OR was 1.03 (95% CI, 0.93 to 1.13; P = .61) for continuous vs nocturnal oxygen. No subgroup could be identified that benefited from oxygen. At least 1 serious adverse event occurred in 348 (13.0%) participants in the continuous oxygen group, 294 (11.0%) in the nocturnal group, and 322 (12.1%) in the control group. No significant harms were identified. Conclusions and Relevance: Among nonhypoxic patients with acute stroke, the prophylactic use of low-dose oxygen supplementation did not reduce death or disability at 3 months. These findings do not support low-dose oxygen in this setting. Trial Registration: ISRCTN Identifier: ISRCTN52416964.

Statistical analysis plan for the Stroke Oxygen Study (SO2S): a multi-center randomized controlled trial to assess whether routine oxygen supplementation in the first 72 hours after a stroke improves long-term outcome.

BACKGROUND: The Stroke Oxygen Study (SO2S) is a multi-center randomized controlled trial of oxygen supplementation in patients with acute stroke. The main hypothesis for the trial is that fixed-dose oxygen treatment during the first 3 days after an acute stroke improves outcome. The secondary hypothesis is that restricting oxygen supplementation to night time only is more effective than continuous supplementation. This paper describes the statistical analysis plan for the study. METHODS AND DESIGN: Patients (n = 8000) are randomized to three groups: (1) continuous oxygen supplementation for 72 hours; (2) nocturnal oxygen supplementation for three nights; and (3) no routine oxygen supplementation. Outcomes are recorded at 7 days, 90 days, 6 months, and 12 months. The primary outcome measure is the modified Rankin scale at 90 days. Data will be analyzed according to the intention-to-treat principle. Methods of statistical analysis are described, including the handling of missing data, the covariates used in adjusted analyses, planned subgroups analyses, and planned sensitivity analyses. TRIAL REGISTRATION: This trial is registered with the ISRCTN register, number ISRCTN52416964 (30 September 2005).

The Stroke Oxygen Study (SO2S) - a multi-center, study to assess whether routine oxygen treatment in the first 72 hours after a stroke improves long-term outcome: study protocol for a randomized controlled trial.

BACKGROUND: Mild hypoxia is common in stroke patients and may have significant adverse effects on the ischemic brain after stroke. The use of oxygen treatment is rapidly increasing in European stroke units but is not without side effects. It impedes early mobilization, could pose an infection risk, and may encourage the formation of toxic free radicals, leading to further damage to the ischemic brain. In the Stroke Oxygen Pilot Study (2 or 3 L/min for 72 hours) neurological recovery at one week was better in the oxygen group than in controls, and after correction for difference in baseline stroke severity and prognostic factors, there was a trend to better outcome with oxygen at six months. Oxygen was as effective in mild as in severe strokes.Oxygen saturation is lower at night than during the day, and episodes of oxygen desaturation are common during sleep. Nocturnal oxygen supplementation is likely to reduce the burden of hypoxia without interfering with daytime mobilization and rehabilitation.Before wider use of oxygen supplementation becomes established it is important to obtain better evidence on which patients benefit from such treatment. METHODS: Participants will be randomized to one of three groups: the first will receive continuous oxygen for 72 hours (at a rate of 2 or 3 L/min depending on baseline oxygen saturation), the second group will receive nocturnal oxygen only (at a rate of 2 or 3 L/min depending on baseline oxygen saturation) and the third group will not receive any oxygen (control). A baseline assessment is performed at randomization and a one-week follow-up completed. Outcome data at three, six and twelve months will be obtained via a questionnaire sent to the patient by the trial center. DISCUSSION: This study will provide evidence on the effectiveness of oxygen supplementation for the treatment of stroke and whether nocturnal oxygen is a potentially beneficial therapy regimen. TRIAL REGISTRATION: This trial is registered with the ISRCTN register ID number ISRCTN52416964.

Validation of a new menstrual pictogram (superabsorbent polymer-c version) for use with ultraslim towels that contain superabsorbent polymers.

OBJECTIVE: To validate the menstrual pictogram (superabsorbent polymer-c version) for Always Ultra-slim feminine towels containing superabsorbent polymers. DESIGN: Prospective, multicenter, evaluator-blinded study. SETTING: Three gynecology research clinics in the United Kingdom. PATIENT(S): Women with self-perceived light, normal, or heavy menstrual periods who had not previously used a graphical method to assess their menstrual loss. INTERVENTION(S): One hundred twenty-two women were asked to complete the menstrual pictogram throughout two menstrual periods and collect their feminine towels for measurements of menstrual blood loss (MBL) by the alkaline hematin method and total menstrual fluid loss (MFL) by fluid weight. MAIN OUTCOME MEASURE(S): Agreement of menstrual pictogram MBL and MFL scores with alkaline hematin and towel weight, respectively. The percentage blood fraction was determined at various volumes of menstrual discharge. RESULT(S): Alkaline hematin and fluid weight were highly correlated (r = .97). However, the percentage blood fraction progressively increased with total MFL and MBL score. After correction for this incremental rise in blood fraction, the menstrual pictogram gave a sensitivity of 82% and a specificity of 92% for a diagnosis of heavy menstrual bleeding. CONCLUSION(S): The menstrual pictogram (superabsorbent polymer-c version) provides a simple means of measuring MBL in the clinical setting.

The stroke oxygen pilot study: a randomized controlled trial of the effects of routine oxygen supplementation early after acute stroke--effect on key outcomes at six months.

INTRODUCTION: Post-stroke hypoxia is common, and may adversely affect outcome. We have recently shown that oxygen supplementation may improve early neurological recovery. Here, we report the six-month outcomes of this pilot study. METHODS: Patients with a clinical diagnosis of acute stroke were randomized within 24 h of admission to oxygen supplementation at 2 or 3 L/min for 72 h or to control treatment (room air). Outcomes (see below) were assessed by postal questionnaire at 6 months. Analysis was by intention-to-treat, and statistical significance was set at p ≤ 0.05. RESULTS: Out of 301 patients randomized two refused/withdrew consent and 289 (148 in the oxygen and 141 in the control group) were included in the analysis: males 44%, 51%; mean (SD) age 73 (12), 71 (12); median (IQR) National Institutes of Health Stroke Scale score 6 (3, 10), 5 (3, 10) for the two groups respectively. At six months 22 (15%) patients in the oxygen group and 20 (14%) in the control group had died; mean survival in both groups was 162 days (p = 0.99). Median (IQR) scores for the primary outcome, the modified Rankin Scale, were 3 (1, 5) and 3 (1, 4) for the oxygen and control groups respectively. The covariate-adjusted odds ratio was 1.04 (95% CI 0.67, 1.60), indicating that the odds of a lower (i.e. better) score were non-significantly higher in the oxygen group (p = 0.86). The mean differences in the ability to perform basic (Barthel Index) and extended activities of daily living (NEADL), and quality of life (EuroQol) were also non-significant. CONCLUSIONS: None of the key outcomes differed at 6 months between the groups. Although not statistically significant and generally of small magnitude, the effects were predominantly in favour of the oxygen group; a larger trial, powered to show differences in longer-term functional outcomes, is now on-going. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN12362720; Eudract.ema.europa.eu 2004-001866-41.

A new menstrual pictogram for use with feminine products that contain superabsorbent polymers.

OBJECTIVE: To determine whether the menstrual pictogram (the superabsorbent polymer-c or SAP-c version) can reliably estimate blood and total menstrual fluid volumes on prestained Always Ultra slim feminine towels (Proctor & Gamble) that contain superabsorbent polymers. DESIGN: Randomized blinded study using simulated menstrual fluid (SMF: 50% blood, 50% saline mixture). SETTING: Gynecology research clinic. PATIENT(S): 12 premenopausal women with regular menstrual cycles who had not previously used a graphical method to assess menstrual loss. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Assignment of 135 prestained towels containing known volumes of 0.5-25.0 mL of SMF to five pictorial icons of the menstrual pictogram, and correlation of pictogram scores to blood recovered from towels by the alkaline hematin method and total fluid applied to towels by measurement of soiled towel weight. RESULT(S): There was a high level of agreement between individual scores. For 112 (83%) of 135 towels, the participants' readings either completely concurred or differed by only a single icon. There was a statistically significant correlation between the volume of blood applied (SMF/2) and that recovered by alkaline hematin, and volume of fluid applied and soiled towel weight. CONCLUSION(S): The menstrual pictogram (SAP-c version) is a potential diagnostic tool for heavy menstrual bleeding and would be suitable for testing in a clinical trial.

Incidence of venous thromboembolism in the wake of the Clots in Legs Or sTockings after Stroke (CLOTS) study.

BACKGROUND AND PURPOSE: In the United Kingdom, compressive stockings were standard care in all stroke units until the publication of the Clots in Legs Or sTockings after Stroke (CLOTS) trial results in May 2009, which concluded that stockings were ineffective. The aim of this audit was to assess whether this change in practice was associated with any change in venous thromboembolism incidence in routine clinical practice. METHOD: All stroke register entries at the University Hospital of North Staffordshire from 2 years before the publication of the CLOTS trial results to 2 years after were identified and included in this audit. The hospital radiology reporting system was then cross-checked for evidence of venous thromboembolism on computed tomography pulmonary angiogram, ventilation/perfusion lung scan, and leg Doppler reports. RESULTS: There were 773 patients in the before cohort and 861 in the after cohort (mean age, 74/74 years; men, 47%/45%; and ischemic stroke, 87%/85%, respectively). Symptomatic venous thromboembolism incidence was the same in both cohorts, 21 (2.7%) in the before cohort and 26 (3.0%) in the after cohort (P=0.8). There was a trend toward more deep vein thrombosis (9 [1.2%] versus 19 [2.2%]; P=0.1) and fewer pulmonary embolisms (12 [1.6%] versus 6 [0.7%]; P=0.2) in the after cohort. CONCLUSIONS: Discontinuation of compressive stockings did not increase venous thromboembolism incidence. There was a trend toward more deep vein thrombosis and fewer PEs after CLOTS, which might be because of increased clinical vigilance in the diagnosis of deep vein thrombosis, but a chance variation cannot be excluded.

ISPMD consensus on the management of premenstrual disorders.

The second consensus meeting of the International Society for Premenstrual Disorders (ISPMD) took place in London during March 2011. The primary goal was to evaluate the published evidence and consider the expert opinions of the ISPMD members to reach a consensus on advice for the management of premenstrual disorders. Gynaecologists, psychiatrists, psychologists and pharmacologists each formally presented the evidence within their area of expertise; this was followed by an in-depth discussion leading to consensus recommendations. This article provides a comprehensive review of the outcomes from the meeting. The group discussed and agreed that careful diagnosis based on the recommendations and classification derived from the first ISPMD consensus conference is essential and should underlie the appropriate management strategy. Options for the management of premenstrual disorders fall under two broad categories, (a) those influencing central nervous activity, particularly the modulation of the neurotransmitter serotonin and (b) those that suppress ovulation. Psychotropic medication, such as selective serotonin reuptake inhibitors, probably acts by dampening the influence of sex steroids on the brain. Oral contraceptives, gonadotropin-releasing hormone agonists, danazol and estradiol all most likely function by ovulation suppression. The role of oophorectomy was also considered in this respect. Alternative therapies are also addressed, with, e.g. cognitive behavioural therapy, calcium supplements and Vitex agnus castus warranting further exploration.

Clinical subtypes of core premenstrual disorders: a Delphi survey.

The purpose of this study was to classify the clinical subtypes of core premenstrual disorders during the International Society for Premenstrual Disorders' second consensus meeting. Multiple iterations were used to achieve consensus between a group of experts; these iterations included a two-generational Delphi technique that was preceded and followed by open group discussions. The first round was to generate a list of all potential clinical subtypes, which were subsequently prioritized using a Delphi methodology and then finalised in a final round of open discussion. On a six-point scale, 4 of the 12 potential clinical subtypes had a mean score of ≥5.0 following the second iteration and only 3 of the 4 still had a mean score of ≥5.0 after the third iteration. The final list consisted of these three subtypes and an additional subtype, which was introduced and agreed upon, in the final iteration. There is consensus amongst experts that core premenstrual disorder is divided into three symptom-based subtypes: predominantly physical, predominantly psychological and mixed. A proportion of psychological and mixed subtypes may meet the DSM-IV diagnostic criteria for premenstrual dysphoric disorder.

Validation of a rapid alkaline hematin technique to measure menstrual blood loss on feminine towels containing superabsorbent polymers.

OBJECTIVE: To validate the semiautomated alkaline hematin technique for rapid measurement of menstrual blood loss on ultrathin sanitary towels with a superabsorbent polymer component. DESIGN: Laboratory study using simulated menstrual fluid (SMF) and Always Ultra Normal, Long, and Night "with wings" sanitary towels. SETTING: Laboratorium für Klinische Forschung, Germany. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Linearity and blood recovery over a range of SMF volumes applied to towels, the lower limit of reliable detection, and the effect of storing soiled towels for up to 5 weeks at 20°C and 4°C before analysis, were determined. Recovery from 63 SMF samples comprising between 5% to 100% blood and 0.05-35 mL applied volume was compared with duplicates analyzed at Keele Menstrual Disorders Laboratory (manual reference method). RESULT(S): Linearity was confirmed, and ≥85% recovery was reproducibly achieved at up to 30 mL applied blood at all tested SMF compositions, except at low volume or high dilution equivalent to <4 mL blood. Samples could be stored for 3 weeks at 4°C without loss of recovery. Linear regression analysis showed good agreement with the reference method. CONCLUSION(S): The semiautomated alkaline hematin technique is a reliable method for measuring menstrual blood loss from Always Ultra sanitary towels containing superabsorbent polymers.

Menstrual blood loss measurement: validation of the alkaline hematin technique for feminine hygiene products containing superabsorbent polymers.

OBJECTIVE: To validate the alkaline hematin technique for measurement of menstrual blood loss using ultra-thin sanitary towels that contain superabsorbent polymer granules as the absorptive agent. DESIGN: Laboratory study using simulated menstrual fluid (SMF) and Always Ultra Normal, Long, and Night "with wings" sanitary towels. SETTING: Keele Menstrual Disorders Laboratory. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Recovery of blood, linearity, and interassay variation over a range of SMF volumes applied to towels. Because of the variable percentage of blood in menstrual fluid, blood recovery was assessed from SMF constituted as 10%, 25%, 50%, and 100% blood. The lower limit of reliable detection and the effect of storing soiled towels for up to 4 weeks at 15°C-20°C, 4°C, and -20°C before analysis were determined. RESULT(S): Ninety percent recovery was reproducibly achieved up to 30 mL applied volume at all tested SMF compositions, except at low volume or high dilution equivalent to <2 mL whole blood. Samples could be stored for 3 weeks at all tested temperatures without loss of recovery. The technique was suitable for processing towels individually or in batches. CONCLUSION(S): The alkaline hematin technique is a suitable and validated method for measuring menstrual blood loss from Always Ultra sanitary towels that contain superabsorbent polymers.