Use of effective contraception following provision of the progestogen-only pill for women presenting to community pharmacies for emergency contraception (Bridge-It): a pragmatic cluster-randomised crossover trial.

BACKGROUND: Unless women start effective contraception after oral emergency contraception, they remain at risk of unintended pregnancy. Most women in the UK obtain emergency contraception from community pharmacies. We hypothesised that pharmacist provision of the progestogen-only pill as a bridging interim method of contraception with emergency contraception plus an invitation to a sexual and reproductive health clinic, in which all methods of contraception are available, would result in increased subsequent use of effective contraception. METHODS: We did a pragmatic cluster-randomised crossover trial in 29 UK pharmacies among women receiving levonorgestrel emergency contraception. Women aged 16 years or older, not already using hormonal contraception, not on medication that could interfere with the progestogen-only pill, and willing to give contact details for follow-up were invited to participate. In the intervention group, women received a 3-month supply of the progestogen-only pill (75 µg desogestrel) plus a rapid access card to a participating sexual and reproductive health clinic. In the control group, pharmacists advised women to attend their usual contraceptive provider. The order in which each pharmacy provided the intervention or control was randomly assigned using a computer software algorithm. The primary outcome was the use of effective contraception (hormonal or intrauterine) at 4 months. This study is registered, ISRCTN70616901 (complete). FINDINGS: Between Dec 19, 2017, and June 26, 2019, 636 women were recruited to the intervention group (316 [49·6%], mean age 22·7 years [SD 5·7]) or the control group (320 [50·3%], 22·6 years [5·1]). Three women (one in the intervention group and two in the control group) were excluded after randomisation. 4-month follow-up data were available for 406 (64%) participants, 25 were lost to follow-up, and two participants no longer wanted to participate in the study. The proportion of women using effective contraception was 20·1% greater (95% CI 5·2-35·0) in the intervention group (mean 58·4%, 48·6-68·2), than in the control group (mean 40·5%, 29·7-51·3 [adjusted for recruitment period, treatment group, and centre]; p=0·011).The difference remained significant after adjusting for age, current sexual relationship, and history of effective contraception use, and was robust to the effect of missing data (assuming missingness at random). No serious adverse events occurred. INTERPRETATION: Provision of a supply of the progestogen-only pill with emergency contraception from a community pharmacist, along with an invitation to a sexual and reproductive health clinic, results in a clinically meaningful increase in subsequent use of effective contraception. Widely implemented, this practice could prevent unintended pregnancies after use of emergency contraception. FUNDING: National Institute for Health Research (Health Technology Assessment Programme project 15/113/01).

Hypothermia for Intracranial Hypertension after Traumatic Brain Injury.

BACKGROUND: In patients with traumatic brain injury, hypothermia can reduce intracranial hypertension. The benefit of hypothermia on functional outcome is unclear. METHODS: We randomly assigned adults with an intracranial pressure of more than 20 mm Hg despite stage 1 treatments (including mechanical ventilation and sedation management) to standard care (control group) or hypothermia (32 to 35°C) plus standard care. In the control group, stage 2 treatments (e.g., osmotherapy) were added as needed to control intracranial pressure. In the hypothermia group, stage 2 treatments were added only if hypothermia failed to control intracranial pressure. In both groups, stage 3 treatments (barbiturates and decompressive craniectomy) were used if all stage 2 treatments failed to control intracranial pressure. The primary outcome was the score on the Extended Glasgow Outcome Scale (GOS-E; range, 1 to 8, with lower scores indicating a worse functional outcome) at 6 months. The treatment effect was estimated with ordinal logistic regression adjusted for prespecified prognostic factors and expressed as a common odds ratio (with an odds ratio <1.0 favoring hypothermia). RESULTS: We enrolled 387 patients at 47 centers in 18 countries from November 2009 through October 2014, at which time recruitment was suspended owing to safety concerns. Stage 3 treatments were required to control intracranial pressure in 54% of the patients in the control group and in 44% of the patients in the hypothermia group. The adjusted common odds ratio for the GOS-E score was 1.53 (95% confidence interval, 1.02 to 2.30; P=0.04), indicating a worse outcome in the hypothermia group than in the control group. A favorable outcome (GOS-E score of 5 to 8, indicating moderate disability or good recovery) occurred in 26% of the patients in the hypothermia group and in 37% of the patients in the control group (P=0.03). CONCLUSIONS: In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN34555414.).

Mortality Risk Stratification After Traumatic Brain Injury and Hazard of Death With Titrated Hypothermia in the Eurotherm3235Trial.

OBJECTIVES: Hypothermia reduces intracranial hypertension in patients with traumatic brain injury but was associated with harm in the Eurotherm3235Trial. We stratified trial patients by International Mission for Prognosis and Analysis of Clinical Trials in [Traumatic Brain Injury] (IMPACT) extended model sum scores to determine where the balance of risks lay with the intervention. DESIGN: The Eurotherm3235Trial was a randomized controlled trial, with standardized and blinded outcome assessment. Patients in the trial were split into risk tertiles by IMPACT extended model sum scores. A proportional hazard analysis for death between randomization and 6 months was performed by intervention and IMPACT extended model sum scores tertiles in both the intention-to-treat and the per-protocol populations of the Eurotherm3235Trial. SETTING: Forty-seven neurologic critical care units in 18 countries. PATIENTS: Adult traumatic brain injury patients admitted to intensive care who had suffered a primary, closed traumatic brain injury; increased intracranial pressure; an initial head injury less than 10 days earlier; a core temperature at least 36°C; and an abnormal brain CT. INTERVENTION: Titrated Hypothermia in the range 32-35°C as the primary intervention to reduce raised intracranial pressure. MEASUREMENTS AND MAIN RESULTS: Three hundred eighty-six patients were available for analysis in the intention-to-treat and 257 in the per-protocol population. The proportional hazard analysis (intention-to-treat and per-protocol populations) showed that the treatment effect behaves similarly across all risk stratums. However, there is a trend that indicates that patients in the low-risk group could be at greater risk of suffering harm due to hypothermia. CONCLUSIONS: Hypothermia as a first line measure to reduce intracranial pressure to less than 20 mm Hg is harmful in patients with a lower severity of injury and no clear benefit exists in patients with more severe injuries.

Improving effective contraception uptake through provision of bridging contraception within community pharmacies: findings from the Bridge-it Study process evaluation.

OBJECTIVE: To present process evaluation results from the Bridge-it Study, a pragmatic cluster randomised cross-over trial to improve effective contraception uptake through provision of the progestogen only pill (POP) plus sexual and reproductive health (SRH) clinic rapid-access to women presenting to community pharmacies for emergency contraception (EC). RESEARCH DESIGN AND METHODS: A multimethod process evaluation was conducted to assess intervention implementation, mechanisms of change and contextual factors. Data were gathered from screening logs (n=599), observations of pharmacist training, analysis of data from 4-month follow-up questionnaires (n=406), monitoring of contemporaneous events and qualitative interviews with 22 pharmacists, 5 SRH clinical staff and 36 study participants in three participating UK sites in Lothian, Tayside and London. RESULTS: The intervention was largely delivered as intended and was acceptable. Pharmacists', SRH clinical staff and participants' accounts highlighted that providing a supply of POP with EC from the pharmacy as routine practice may have positive impacts on contraceptive practices in the short term, and potentially longer term. Key mechanisms of change included ease of access, increased awareness of contraception and services, and greater motivation and perceptions of self-efficacy. Few participants took up the offer to attend an SRH service (rapid-access component), and existing barriers within the SRH context were apparent (eg, lack of staff). Participant accounts highlight persistent barriers to accessing and using routine effective contraception remain. CONCLUSIONS: Implementation appeared to be acceptable and feasible, highlighting the potential for provision of POP within EC consultations as routine practice in community pharmacies. However, lack of engagement with the rapid access component of the intervention and existing barriers within the SRH context suggest that signposting to SRH services may be sufficient. Wider implementation should consider ways to address key implementation challenges to increase effectiveness and sustainability, and to overcome persistent barriers to accessing and using effective contraception. TRIAL REGISTRATION NUMBER: ISRCTN70616901.

Emergency contraception from the pharmacy 20 years on: a mystery shopper study.

BACKGROUND: Emergency contraception (EC) was approved in the UK as a pharmacy medicine for purchase without prescription in 2001. Twenty years later we conducted a study to characterise routine practice pharmacy provision of EC. STUDY DESIGN: Mystery shopper study of 30 pharmacies in Edinburgh, Dundee and London participating in a clinical trial of contraception after EC. METHODS: Mystery shoppers, aged ≥16 years, followed a standard scenario requesting EC. After the pharmacy visit, they completed a proforma recording the duration of the consultation, where it took place, and whether advice was given to them about the importance of ongoing contraception after EC. RESULTS: Fifty-five mystery shopper visits were conducted. The median reported duration of the consultation with the pharmacist was 6 (range 1-18) min. Consultations took place in a private room in 34 cases (62%) and at the shop counter in the remainder. In 27 cases (49%) women received advice about ongoing contraception. Eleven women (20%) left the pharmacy without EC due to lack of supplies or of a trained pharmacist. Most women were generally positive about the consultation. CONCLUSIONS: While availability of EC from UK pharmacies has undoubtedly improved access, the necessity to have a consultation, however helpful, with a pharmacist introduces delays and around one in five of our mystery shoppers left without getting EC. Consultations in private are not always possible and little advice is given about ongoing contraception. It is time to make EC available without a pharmacy consultation.

Provision of the progestogen-only pill by community pharmacies as bridging contraception for women receiving emergency contraception: the Bridge-it RCT.

INTRODUCTION: Unless women start effective contraception after using emergency contraception, they remain at risk of unintended pregnancy. Most women in the UK obtain emergency contraception from community pharmacies that are unable to provide ongoing contraception (apart from barrier methods which have high failure rates). This means that women need an appointment with a general practitioner or at a sexual and reproductive health clinic. We conducted a pragmatic cluster randomised cohort crossover trial to determine whether or not pharmacist provision of a bridging supply of a progestogen-only pill plus the invitation to attend a sexual and reproductive health clinic resulted in increased subsequent use of effective contraception (hormonal or intrauterine). METHODS: Twenty-nine pharmacies in three UK cities recruited women receiving emergency contraception (levonorgestrel). In the intervention, women received a 3-month supply of the progestogen-only pill (75 µg of desogestrel) plus a card that provided rapid access to a local sexual and reproductive health clinic. In the control arm, pharmacists advised women to attend their usual contraceptive provider. The primary outcome was reported use of an effective contraception (hormonal and intrauterine methods) at 4 months. Process evaluation was also conducted to inform any future implementation. RESULTS: The study took place December 2017 and June 2019 and recruited 636 women to the intervention (n = 316) and control groups (n = 320). There were no statistically significant differences in demographic characteristics between the groups. Four-month follow-up data were available for 406 participants: 63% (198/315) of the control group and 65% (208/318) of the intervention group. The proportion of participants reporting use of effective contraception was 20.1% greater (95% confidence interval 5.2% to 35.0%) in the intervention group (58.4%, 95% confidence interval 48.6% to 68.2%) than in the control group (40.5%, 95% confidence interval 29.7% to 51.3%) (adjusted for recruitment period, treatment arm and centre; p = 0.011). The proportion of women using effective contraception remained statistically significantly larger, when adjusted for age, current sexual relationship and history of past use of effective contraception, and was robust to the missing data. There were no serious adverse events. CONCLUSION: Provision of a bridging supply of the progestogen-only pill with emergency contraception from a pharmacist and the invitation to a sexual and reproductive health clinic resulted in a significant increase in self-reported subsequent use of effective contraception. This simple intervention has the potential to prevent more unintended pregnancies for women after emergency contraception. TRIAL REGISTRATION: Current Controlled Trials ISRCTN70616901. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 27. See the NIHR Journals Library website for further project information.

The emergency contraceptive pill can prevent pregnancy following unprotected sex or a burst condom; however, unless women start a regular method of contraception they remain at risk of pregnancy. Most women obtain emergency contraception from a community pharmacy (chemist), but then require an appointment with a general practitioner or at a sexual and reproductive health clinic for ongoing contraception. Getting an appointment can take time and unintended pregnancies can occur during this time. If a pharmacist could give women a small supply of a progestogen-only pill or 'mini-pill' with their emergency contraception, together with help to get an appointment at a clinic, then this might help more women to start effective contraception. We undertook a study in 29 pharmacies in Lothian, Tayside and London among women receiving emergency contraception. Pharmacists provided either their standard advice about contraception (control group) or the intervention. The intervention was a 3-month supply of the progestogen-only pill plus a rapid-access card, which, if presented at a sexual and reproductive health clinic, would help women get an appointment for contraception. The order in which the pharmacy provided either control or intervention was randomised. We conducted telephone interviews with the women 4 months later to find out what contraception they were using. A total of 636 women took part in the study, 316 in the intervention group and 320 in the control group. The proportion who said that they were using an effective method of contraception was around 20% larger in the intervention group. In addition, fewer women in this group said that they had used emergency contraception again. This study shows that community pharmacy provision of a small supply of progestogen-only pills and the invitation to attend a sexual and reproductive health clinic results in a large increase in the use of effective contraception after emergency contraception. If this became routine practice then it could help prevent unintended pregnancies.

Pragmatic cluster randomised cohort cross-over trial to determine the effectiveness of bridging from emergency to regular contraception: the Bridge-It study protocol.

INTRODUCTION: Oral emergency contraception (EC) can prevent unintended pregnancy but it is important to start a regular method of contraception. Women in the UK usually access EC from a pharmacy but then need a subsequent appointment with a general practitioner or a sexual and reproductive health (SRH) service to access regular contraception. Unintended pregnancies can occur during this time. METHODS AND ANALYSIS: Bridge-It is a pragmatic cluster randomised cohort cross-over trial designed to determine whether pharmacist provision of a bridging supply of a progestogen-only pill (POP) plus rapid access to a local SRH clinic, results in increased uptake of effective contraception and prevents more unintended pregnancies than provision of EC alone. Bridge-It involves 31 pharmacies in three UK regions (London, Lothian and Tayside) aiming to recruit 626-737 women. Pharmacies will give EC (levonorgestrel) according to normal practice and recruit women to both intervention and the control phases of the study. In the intervention phase, pharmacists will provide the POP (desogestrel) and offer rapid access to an SRH clinic. In the control phase, pharmacists will advise women to attend a contraceptive provider for contraception (standard care).Women will be asked 4 months later about contraceptive use. Data linkage to abortion registries will provide abortion rates over 12 months. The sample size is calculated on the primary outcome of effective contraception use at 4 months (yes/no) with 90% power and a 5% level of significance. Abortion rates will be an exploratory secondary analysis. Process evaluation includes interviews with pharmacists, SRH clinicians and women. Cost-effectiveness analysis will use a healthcare system perspective and be expressed as incremental cost-effectiveness ratio. ETHICS AND DISSEMINATION: Ethical approval was received from South East Scotland REC June 2017. Results will be published in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN70616901.

Study of therapeutic hypothermia (32 to 35°C) for intracranial pressure reduction after traumatic brain injury (the Eurotherm3235Trial): outcome of the pilot phase of the trial.

BACKGROUND: Clinical trials in traumatic brain injury (TBI) are challenging. Previous trials of complex interventions were conducted in high-income countries, reported long lead times for site setup and low screened-to-recruitment rates.In this report we evaluate the internal pilot phase of an international, multicentre TBI trial of a complex intervention to assess: design and implementation of an online case report form; feasibility of recruitment (sites and patients); feasibility and effectiveness of delivery of the protocol. METHODS: All aspects of the pilot phase of the trial were conducted as for the main trial. The pilot phase had oversight by independent Steering and Data Monitoring committees. RESULTS: Forty sites across 12 countries gained ethical approval. Thirty seven of 40 sites were initiated for recruitment. Of these, 29 had screened patients and 21 randomized at least one patient. Lead times to ethics approval (6.8 weeks), hospital approval (18 weeks), interest to set up (61 weeks), set up to screening (11 weeks), and set up to randomization (31.6 weeks) are comparable with other international trials. Sixteen per cent of screened patients were eligible. We found 88% compliance rate with trial protocol. CONCLUSION: The pilot data demonstrated good feasibility for this large international multicentre randomized controlled trial of hypothermia to control intracranial pressure. The sample size was reduced to 600 patients because of homogeneity of the patient group and we showed an optimized cooling intervention could be delivered. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN34555414.

Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients.

OBJECTIVE: To determine whether inclusion of glutamine, selenium, or both in a standard isonitrogenous, isocaloric preparation of parenteral nutrition influenced new infections and mortality among critically ill patients. DESIGN: Randomised, double blinded, factorial, controlled trial. SETTING: Level 2 and 3 (or combined) critical care units in Scotland. All 22 units were invited, and 10 participated. PARTICIPANTS: 502 adults in intensive care units and high dependency units for ≥ 48 hours, with gastrointestinal failure and requiring parenteral nutrition. INTERVENTIONS: Parenteral glutamine (20.2 g/day) or selenium (500 µg/day), or both, for up to seven days. MAIN OUTCOME MEASURES: Primary outcomes were participants with new infections in the first 14 days and mortality. An intention to treat analysis and a prespecified analysis of patients who received ≥ 5 days of the trial intervention are presented. Secondary outcomes included critical care unit and acute hospital lengths of stay, days of antibiotic use, and modified SOFA (Sepsis-related Organ Failure Assessment) score. RESULTS: Selenium supplementation did not significantly affect patients developing a new infection (126/251 v 139/251, odds ratio 0.81 (95% CI 0.57 to 1.15)), except for those who had received ≥ 5 days of supplementation (odds ratio 0.53 (0.30 to 0.93)). There was no overall effect of glutamine on new infections (134/250 v 131/252, odds ratio 1.07 (0.75 to 1.53)), even if patients received ≥ 5 days of supplementation (odds ratio 0.99 (0.56 to 1.75)). Six month mortality was not significantly different for selenium (107/251 v 114/251, odds ratio 0.89 (0.62 to 1.29)) or glutamine (115/250 v 106/252, 1.18 (0.82 to 1.70)). Length of stay, days of antibiotic use, and modified SOFA score were not significantly affected by selenium or glutamine supplementation. CONCLUSIONS: The primary (intention to treat) analysis showed no effect on new infections or on mortality when parenteral nutrition was supplemented with glutamine or selenium. Patients who received parenteral nutrition supplemented with selenium for ≥ 5 days did show a reduction in new infections. This finding requires confirmation. Trial registration Current Controlled Trials ISRCTN87144826.

European society of intensive care medicine study of therapeutic hypothermia (32-35 °C) for intracranial pressure reduction after traumatic brain injury (the Eurotherm3235Trial).

BACKGROUND: Traumatic brain injury is a major cause of death and severe disability worldwide with 1,000,000 hospital admissions per annum throughout the European Union.Therapeutic hypothermia to reduce intracranial hypertension may improve patient outcome but key issues are length of hypothermia treatment and speed of re-warming. A recent meta-analysis showed improved outcome when hypothermia was continued for between 48 hours and 5 days and patients were re-warmed slowly (1 °C/4 hours). Previous experience with cooling also appears to be important if complications, which may outweigh the benefits of hypothermia, are to be avoided. METHODS/DESIGN: This is a pragmatic, multi-centre randomised controlled trial examining the effects of hypothermia 32-35 °C, titrated to reduce intracranial pressure <20 mmHg, on morbidity and mortality 6 months after traumatic brain injury. The study aims to recruit 1800 patients over 41 months. Enrolment started in April 2010.Participants are randomised to either standard care or standard care with titrated therapeutic hypothermia. Hypothermia is initiated with 20-30 ml/kg of intravenous, refrigerated 0.9% saline and maintained using each centre's usual cooling technique. There is a guideline for detection and treatment of shivering in the intervention group. Hypothermia is maintained for at least 48 hours in the treatment group and continued for as long as is necessary to maintain intracranial pressure <20 mmHg. Intracranial hypertension is defined as an intracranial pressure >20 mmHg in accordance with the Brain Trauma Foundation Guidelines, 2007. DISCUSSION: The Eurotherm3235Trial is the most important clinical trial in critical care ever conceived by European intensive care medicine, because it was launched and funded by the European Society of Intensive Care Medicine and will be the largest non-commercial randomised controlled trial due to the substantial number of centres required to deliver the target number of patients. It represents a new and fundamental step for intensive care medicine in Europe. Recruitment will continue until January 2013 and interested clinicians from intensive care units worldwide can still join this important collaboration by contacting the Trial Coordinating Team via the trial website http://www.eurotherm3235trial.eu. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34555414.

Randomised trial of glutamine and selenium supplemented parenteral nutrition for critically ill patients. Protocol Version 9, 19 February 2007 known as SIGNET (Scottish Intensive care Glutamine or seleNium Evaluative Trial).

BACKGROUND: Mortality rates in the Intensive Care Unit and subsequent hospital mortality rates in the UK remain high. Infections in Intensive Care are associated with a 2-3 times increased risk of death. It is thought that under conditions of severe metabolic stress glutamine becomes "conditionally essential". Selenium is an essential trace element that has antioxidant and anti-inflammatory properties. Approximately 23% of patients in Intensive Care require parenteral nutrition and glutamine and selenium are either absent or present in low amounts. Both glutamine and selenium have the potential to influence the immune system through independent biochemical pathways. Systematic reviews suggest that supplementing parenteral nutrition in critical illness with glutamine or selenium may reduce infections and mortality. Pilot data has shown that more than 50% of participants developed infections, typically resistant organisms. We are powered to show definitively whether supplementation of PN with either glutamine or selenium is effective at reducing new infections in critically ill patients. METHODS/DESIGN: 2 x 2 factorial, pragmatic, multicentre, double-blind, randomised controlled trial. The trial has an enrollment target of 500 patients. Inclusion criteria include: expected to be in critical care for at least 48 hours, aged 16 years or over, patients who require parenteral nutrition and are expected to have at least half their daily nutritional requirements given by that route. Allocation is to one of four iso-caloric, iso-nitrogenous groups: glutamine, selenium, both glutamine & selenium or no additional glutamine or selenium. Trial supplementation is given for up to seven days on the Intensive Care Unit and subsequent wards if practicable. The primary outcomes are episodes of infection in the 14 days after starting trial nutrition and mortality. Secondary outcomes include antibiotic usage, length of hospital stay, quality of life and cost-effectiveness. DISCUSSION: To date more than 285 patients have been recruited to the trial from 10 sites in Scotland. Recruitment is due to finish in August 2008 with a further six months follow up. We expect to report the results of the trial in summer 2009. TRIAL REGISTRATION: This trial is registered with the International Standard Randomised Controlled Trial Number system. ISRCTN87144826.

Randomized, controlled trial on the effect of a 20% mannitol solution and a 7.5% saline/6% dextran solution on increased intracranial pressure after brain injury.

OBJECTIVE: The aim of this pilot study was to compare the effects of equimolar doses of hypertonic saline and dextran solution (HSD, Rescueflow) with 20% mannitol solution for reduction of increased intracranial pressure. DESIGN: Prospective, randomized, controlled, crossover trial in the intensive care unit of a large teaching hospital. SETTING: Academic hospital and tertiary referral center for neuroscience. PATIENTS: Nine patients with an intracranial pressure of >20 mm Hg were recruited and received two treatments of each, HSD and 20% mannitol, in a randomized order. INTERVENTION: Equimolar, rapid intravenous infusions of either 200 mL of 20% mannitol or 100 mL of 7.5% saline and 6% dextran-70 solution (HSD) over 5 mins. MEASUREMENTS: Intracranial pressure, blood pressure, serum and urine sodium and osmolality, and urine output. MAIN RESULTS: Treatments reduced intracranial pressure with both mannitol (median decrease, 7.5 mm Hg, 95% confidence interval, 5.8-11.8) and HSD (median decrease, 13 mm Hg; 95% confidence interval, 11.5-17.3). HSD caused a significantly greater decrease in intracranial pressure than mannitol (p = .044). HSD had a longer duration of effect than mannitol (p = .044). CONCLUSION: When given in an equimolar, rapid, intravenous infusion, HSD reduces intracranial pressure more effectively than mannitol.