Ethnic pharmacokinetic comparison of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) between Asian and Western healthy subjects.

BACKGROUND: The Phase III KRONOS study (NCT02497001) found the fixed-dose combination triple therapy budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) to be efficacious and well tolerated versus corresponding dual therapies in patients with moderate-to-very severe COPD from North America, China and Japan. However, pharmacokinetic (PK) studies of other drugs have shown that ethnic factors (e.g. genetic factors affecting drug metabolism) can affect the bioavailability of drugs which may impact upon efficacy and safety outcomes. METHODS: This was a post-hoc analysis of data from four randomised, double-blind Phase I studies of BGF MDI 320/18/9.6 µg and 160/18/9.6 µg in Chinese (NCT03075267), Japanese (NCT02197975) and Western (NCT01980615, NCT02189304) healthy subjects. PK properties (area under the plasma concentration-time curve 0-12 h post-dose [AUC0-12] and maximum plasma concentration, [Cmax]) were recorded following single and repeated dosing of BGF MDI 320/18/9.6 µg or 160/18/9.6 µg. Potential ethnic differences in the PK properties of budesonide, glycopyrrolate and formoterol in Chinese, Japanese and Western healthy subjects were derived by non-compartmental analysis, and ethnic insensitivity factors evaluated based on criteria from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Guideline E5 Ethnic Factors in the Acceptability of Foreign Clinical Data. RESULTS: The analyses included data from 64 Chinese, 31 Japanese and 169 Western subjects. Overall, PK properties following single or repeated dosing of BGF MDI were similar across Chinese, Japanese and Western subjects. After single dosing at either dose level, AUC0-12 and Cmax for budesonide, glycopyrrolate and formoterol appeared generally similar for Asian (Chinese and Japanese) versus Western subjects, with most geometric least squares mean ratios within the range of 0.92-1.22. The exception was that Cmax for glycopyrrolate was slightly lower in Asian versus Western subjects (0.6-0.7). Of the 10 ethnic insensitivity factors evaluated, six were met for budesonide, nine for glycopyrrolate and nine for formoterol, suggesting that BGF MDI can be classified as an ethnically insensitive drug. CONCLUSIONS: Overall, these analyses suggest no appreciable ethnic differences in the PK of BGF MDI across Chinese, Japanese and Western healthy subjects.

Efficacy and Safety of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler in Chinese Patients with COPD: A Subgroup Analysis of KRONOS.

INTRODUCTION: This pre-specified subgroup analysis evaluated the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) triple therapy versus corresponding dual therapies in the China subgroup of the phase III, double-blind KRONOS study in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). METHODS: Patients were randomized 2:2:1:1 to BGF MDI 320/18/9.6 µg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 µg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 µg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 µg twice daily for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over weeks 12-24. Secondary endpoints included symptoms, health-related quality of life, and safety. Rate of moderate/severe COPD exacerbations was an additional efficacy endpoint. RESULTS: In the China subgroup (n = 432; 22.7% of the KRONOS population), BGF MDI demonstrated nominally significant improvements in the primary endpoint versus BFF MDI (least squares mean (LSM) difference 68 mL; P = 0.0035) and BUD/FORM DPI (LSM difference 78 mL; P = 0.0010) but not GFF MDI (LSM difference - 4 mL; P = 0.8316). BGF MDI demonstrated at least numerical improvements versus comparators in secondary lung function and symptom endpoints. BGF MDI reduced the rate of moderate/severe COPD exacerbations versus GFF MDI (rate ratio 0.41; P = 0.0030), with numerical benefits versus BFF MDI and BUD/FORM DPI. All treatments were well tolerated. CONCLUSIONS: Results demonstrated that BGF MDI showed benefits on lung function (vs inhaled corticosteroid/long-acting ß2-agonist), as well as symptoms and exacerbations relative to dual therapies. Findings support BGF MDI use in Chinese patients with moderate to very severe COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02497001.

Glycopyrrolate/formoterol fumarate metered dose inhaler for maintenance-naïve patients with chronic obstructive pulmonary disease: a post-hoc analysis of the randomized PINNACLE trials.

BACKGROUND: Glycopyrrolate (GP)/formoterol fumarate (FF; GFF) metered dose inhaler is a fixed-dose combination dual bronchodilator for patients with chronic obstructive pulmonary disease (COPD); however, whether the efficacy in patients without current maintenance treatment is consistent with currently maintenance-treated patients is unclear. METHODS: Data from patients who were not maintenance-treated at screening (NMT) (n = 1943) and patients who were maintenance-treated at screening (MT) patients (n = 3040) receiving GFF, FF, GP, or placebo were pooled from the Phase III PINNACLE studies (NCT01854645, NCT01854658, NCT02343458) for post-hoc analysis. MT patients had received long-acting bronchodilators and/or inhaled corticosteroids in the 30 days prior to screening, and/or prior to randomization. NMT patients had received short-acting bronchodilators or no treatment. Outcomes included forced expiratory volume over 1 s (FEV1), clinically important deterioration (CID), rescue medication use, and safety. RESULTS: GFF provided significant lung function improvements at Week 24 versus placebo, GP, and FF for NMT patients, with pre-dose trough FEV1 treatment differences of 152 (117-188) mL, 73 (45-100) mL, and 56 (29-84) mL, respectively (least squares mean change from baseline versus comparators [95% CI]; all P < 0.0001). GFF reduced the risk of CID by 17-43% in NMT (P ≤ 0.0157) and 18-52% (P ≤ 0.0012) in MT patients compared with monotherapy and placebo, and reduced rescue medication use by 1.5 puffs/day over 24 weeks for both cohorts. Safety profiles for all cohorts were consistent with each other and the parent studies. CONCLUSIONS: NMT patients achieved better lung function with GFF versus monotherapy and placebo, without increased safety risk. Dual bronchodilator therapy may offer better outcomes than monotherapy for COPD patients when administered as first-line treatment.

A Community-Based Intervention for Managing Hypertension in Rural South Asia.

BACKGROUND: The burden of hypertension is escalating, and control rates are poor in low- and middle-income countries. Cardiovascular mortality is high in rural areas. METHODS: We conducted a cluster-randomized, controlled trial in rural districts in Bangladesh, Pakistan, and Sri Lanka. A total of 30 communities were randomly assigned to either a multicomponent intervention (intervention group) or usual care (control group). The intervention involved home visits by trained government community health workers for blood-pressure monitoring and counseling, training of physicians, and care coordination in the public sector. A total of 2645 adults with hypertension were enrolled. The primary outcome was reduction in systolic blood pressure at 24 months. Follow-up at 24 months was completed for more than 90% of the participants. RESULTS: At baseline, the mean systolic blood pressure was 146.7 mm Hg in the intervention group and 144.7 mm Hg in the control group. At 24 months, the mean systolic blood pressure fell by 9.0 mm Hg in the intervention group and by 3.9 mm Hg in the control group; the mean reduction was 5.2 mm Hg greater with the intervention (95% confidence interval [CI], 3.2 to 7.1; P<0.001). The mean reduction in diastolic blood pressure was 2.8 mm Hg greater in the intervention group than in the control group (95% CI, 1.7 to 3.9). Blood-pressure control (<140/90 mm Hg) was achieved in 53.2% of the participants in the intervention group, as compared with 43.7% of those in the control group (relative risk, 1.22; 95% CI, 1.10 to 1.35). All-cause mortality was 2.9% in the intervention group and 4.3% in the control group. CONCLUSIONS: In rural communities in Bangladesh, Pakistan, and Sri Lanka, a multicomponent intervention that was centered on proactive home visits by trained government community health workers who were linked with existing public health care infrastructure led to a greater reduction in blood pressure than usual care among adults with hypertension. (Funded by the Joint Global Health Trials scheme; COBRA-BPS ClinicalTrials.gov number, NCT02657746.).

Efficacy And Safety Of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (GFF MDI) Formulated Using Co-Suspension Delivery Technology In Chinese Patients With COPD.

Background: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) is a long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination therapy delivered by MDI, formulated using innovative co-suspension delivery technology. The PINNACLE-4 study evaluated the efficacy and safety of GFF MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) from Asia, Europe, and the USA. This article presents the results from the China subpopulation of PINNACLE-4. Methods: In this randomized, double-blind, placebo-controlled, parallel-group Phase III study (NCT02343458), patients received GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI (all twice daily) for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second at Week 24. Secondary lung function endpoints and patient-reported outcome measures were also assessed. Safety was monitored throughout the study. Results: Overall, 466 patients from China were included in the intent-to-treat population (mean age 63.6 years, 95.7% male). Treatment with GFF MDI improved the primary endpoint compared to GP MDI, FF MDI, and placebo MDI (least squares mean differences: 98, 104, and 173 mL, respectively; all P≤0.0001). GFF MDI also improved daily total symptom scores and time to first clinically important deterioration versus monocomponents and placebo MDI, and Transition Dyspnea Index focal score versus placebo MDI. Rates of treatment-emergent adverse events were similar across the active treatment groups and slightly higher in the placebo MDI group. Conclusion: GFF MDI improved lung function and daily symptoms versus monocomponents and placebo MDI and improved dyspnea versus placebo MDI. All treatments were well tolerated with no unexpected safety findings. Efficacy and safety results were generally consistent with the global PINNACLE-4 population, supporting the use of GFF MDI in patients with COPD from China.

Comparison of Supreme laryngeal mask airway versus endotracheal intubation for airway management during general anesthesia for cesarean section: a randomized controlled trial.

BACKGROUND: The obstetric airway is a significant cause of maternal morbidity and mortality. Endotracheal intubation is considered the standard of care but the laryngeal mask airway (LMA) has gained acceptance as a rescue airway and has been incorporated into the obstetric airway management guidelines. In this randomized controlled equivalence trial, we compared the Supreme LMA (SLMA) with endotracheal intubation (ETT) in managing the obstetric airway during cesarean section. METHODS: Parturients who underwent elective cesarean section under general anesthesia were randomized to receive either an SLMA or ETT as their airway device. Our primary outcome was first-attempt insertion success. Successful insertion was defined as adequate bilateral air entry with auscultation and the presence of end-tidal carbon dioxide on the capnogram. The first-attempt insertion success rate was compared using the Chi-Square test. Secondary outcomes included time-to-ventilation, seal pressure, ventilation/hemodynamic parameters, occurrence of clinical aspiration, fetal outcomes, and maternal side effects associated with the airway device. RESULTS: We recruited 920 parturients (460 SLMA, 460 ETT) who underwent elective cesarean section under general anesthesia. Patient characteristics were similar between the groups. First attempt success was similar (Odds Ratio--ORSLMA/ETT: 1.00 (95%CI: 0.25, 4.02), p = 1.0000). SLMA was associated with reduced time to effective ventilation (Mean Difference--MD -22.96; 95%CI: - 23.71, - 22.21 s) compared to ETT group (p <  0.0001). Ventilation parameters, maternal and fetal outcomes were similar between the groups, and there was no aspiration. CONCLUSIONS: SLMA could be an alternative airway management technique for a carefully selected low-risk obstetric population, with similar insertion success rates, reduced time to ventilation and less hemodynamic changes compared with ETT. Our findings are consistent with the airway guidelines in recommending the second-line use of LMA in the management of the obstetric airway. TRIAL REGISTRATION: The study was registered at http://www.clinicaltrials.gov , identifier: NCT01858467 , retrospectively registered. Date of registration: May 21, 2013.

Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized, Double-blind, Parallel-group Study.

PURPOSE: The objective of this study was to assess pharmacokinetic (PK) and safety profiles of 2 fixed-dose combinations in development for the treatment of chronic obstructive pulmonary disease (COPD): budesonide/glycopyrronium/formoterol fumarate dihydrate metered-dose inhaler (BGF MDI; triple combination) and glycopyrronium/formoterol fumarate dihydrate (GFF MDI; dual combination). The PK and safety profiles of BGF MDI and GFF MDI were assessed for the first time in healthy Chinese adults after single and repeated (7-day) dosing. METHODS: This Phase I, randomized, double-blind, parallel-group study was conducted at a single site in Shanghai, China. Male or female Chinese subjects, 18-45 years of age and in good general health, were randomized 1:1:1 to receive BGF MDI 320/14.4/10 µg, BGF MDI 160/14.4/10 µg, or GFF MDI 14.4/10 µg. PK parameters were assessed after a single dose (day 1) and at steady state (day 8), and included AUC0-12, Cmax, and Tmax. Tolerability was assessed using physical examination findings, adverse events reporting, 12-lead ECG, vital signs, and clinical laboratory values. FINDINGS: Ninety-six subjects (mean age, 25.6 years; 83.3% male) were randomized and received treatment. All randomized subjects were included in the safety and PK populations. After single and repeated dosing, budesonide AUC0-12 and Cmax were increased dose proportionally from BGF MDI 160/14.4/10 µg to BGF MDI 320/14.4/10 µg, respectively (single dose: AUC0-12, 811.8 vs 1748 h · pg/mL; Cmax, 224.3 vs 459.3 pg/mL; repeated dosing: AUC0-12, 1250 vs 2510 h · pg/mL; Cmax, 315.4 vs 626.4 pg/mL). After single and repeated dosing, glycopyrronium AUC0-12 and Cmax were similar across all treatments (single dose: AUC0-12, 27.20-29.40 h · pg/mL; Cmax, 4.884-5.674 pg/mL; repeated dosing: AUC0-12, 69.49-77.08 h · pg/mL; Cmax, 11.30-13.12 pg/mL) and formoterol (single dose: AUC0-12, 46.49-53.58 h · pg/mL; Cmax 9.651-10.62 pg/mL; repeated dosing: AUC0-12, 81.94-85.32 h · pg/mL; Cmax, 16.13-17.71 pg/mL), suggesting that the addition of budesonide did not appreciably alter the PK properties of GFF MDI. All treatment-emergent adverse events were mild in severity and rates were similar across groups (range, 50.0%-56.3%). There were no new or unexpected findings on tolerability. IMPLICATIONS: Overall, all treatments were well tolerated and PK parameters were generally comparable to those previously reported in Western and Japanese healthy subjects, suggesting that the doses of BGF MDI and GFF MDI in development globally for COPD are also appropriate for Chinese patients with COPD. ClinicalTrials.gov identifier: NCT03075267.

Dermatological conditions seen in renal transplant recipients in a Singapore tertiary hospital.

INTRODUCTION: Lifelong immunosuppression after renal transplant exerts effects on the recipients' skin, including skin infections, skin cancers and drug-induced skin disorders. Our study aimed to determine the epidemiology of skin conditions among renal transplant recipients in the largest tertiary hospital in Singapore. METHODS: We reviewed the medical records of kidney transplant recipients at Singapore General Hospital, Singapore, between 1 January 2003 and 31 December 2013. Among these patients, the clinical data of patients who sought skin consultations with either dermatologists or plastic surgeons within the hospital was captured. RESULTS: A total of 178 patients were included in our study. There were 88 (45.6%) skin infections, 23 (11.9%) drug-induced skin conditions, 9 (4.7%) skin cancers and 73 (37.8%) other skin conditions. Skin infection was the predominant reason for consultation, with viral warts (15%, n = 29) being the most common. Of the nine cases in our cohort with skin cancer, there were three cases of basal cell carcinoma, three cases of Bowen's disease, two cases of extramammary Paget's disease and one case of squamous cell carcinoma. Drug-induced skin conditions, mainly attributable to long-term steroids and cyclosporin use, were represented by acne (9.3%, n = 18) and sebaceous hyperplasia (2.6%, n = 5). CONCLUSION: Our study demonstrated the spectrum of skin conditions that can be expected after renal transplantation. We wish to highlight the importance of careful dermatological screening and long-term follow-up for these patients, in order to reduce post-transplant skin complications.

Statistical analysis plan for the control of blood pressure and risk attenuation-rural Bangladesh, Pakistan, Sri Lanka (COBRA-BPS) trial: a cluster randomized trial for a multicomponent intervention versus usual care in hypertensive patients.

BACKGROUND: In rural south Asia, hypertension remains a significant public health issue with sub-optimal blood pressure (BP) control rates. The goal of the trial is to evaluate the effectiveness and cost-effectiveness of a multicomponent intervention (MCI) compared to usual care on lowering BP among adults with hypertension in rural south-Asian communities. This article describes the statistical analysis plan for the primary and secondary objectives related to intervention effectiveness based on clinical and patient-reported endpoints. METHODS/DESIGN: The study is a cluster randomized trial which will enroll 2550 participants aged ≥ 40 years with hypertension from rural communities in Bangladesh, Pakistan, and Sri Lanka. The unit of randomization is a cluster defined by 250-300 households. Thirty clusters, 10 from each country, are randomized in a 1:1 ratio to either MCI or usual care, stratified by country and their distance from the clinic. All participants will be assessed every six months over a two-year period after baseline with measurements of systolic and diastolic BP, antihypertensive and statin medication use, medication adherence, physical activity level, anthropometric parameters, smoking status, and dietary habits. The primary objective is to assess the effectiveness of MCI as compared with usual care in terms of mean change in systolic BP from baseline to final follow-up at two years. The primary outcome will be modelled using a generalized linear mixed-model for repeated measures based on a participant-level analysis. The model will include cluster random-effects and will use a non-independence residual correlation matrix to account for repeated measures on the same participant. Sensitivity analyses for the primary endpoint will be based on multiple imputation as well as pattern mixture model tipping point analyses. Secondary outcomes will be analyzed using the same modeling approach as for the primary outcome, with appropriate distributions within the exponential family and corresponding link functions. DISCUSSION: The a priori statistical analysis plan will avoid reporting bias and data-driven analysis for the primary and key secondary outcomes. The results of the study will provide evidence of the benefits and risks of the MCI for BP control in rural communities in south Asian countries with low-resourced public health infrastructure. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02657746 . Registered on 14 January 2016.

Lofexidine versus diazepam for the treatment of opioid withdrawal syndrome: A double-blind randomized clinical trial in Singapore.

BACKGROUND: Many individuals leave costly inpatient detoxification programs prematurely because of the severity of withdrawal symptoms experienced. In the absence of opioid-assisted detoxification in Singapore, diazepam is used to manage withdrawal. However since diazepam is addictive, there is a need to explore the effectiveness of alternative medications. DESIGN AND PROCEDURES: The study aimed to examine the safety and efficacy of lofexidine, a non-opiate, non-addictive, alpha 2-adrenergic agonist in assisting opioid detoxification in Singapore, using a randomized, double-blind, investigator-initiated placebo-controlled trial comparing lofexidine against diazepam. Opioid dependent patients (n = 111) were randomized to receive a 10-day course of lofexidine (n = 56) or diazepam (n = 55). The primary endpoint was the Objective Opioid Withdrawal Scale (OOWS) score on days 3 and 4 and secondary outcomes were the Short Opioid Withdrawal Scale (SOWS) score, program retention rate, and ratings of opiate craving. MAIN FINDINGS: The OOWS, SOWS and opiate craving scores were consistently lower in the lofexidine group relative to the diazepam group over the 14-day study period; however no statistically significant differences were found on days 3 and 4 (peak withdrawal). Changes in mean pupil size during peak withdrawal were significantly smaller in the lofexidine group and more participants in the lofexidine group remained in treatment and completed detoxification. CONCLUSIONS: Lofexidine was at least as effective as diazepam in reducing the opioid withdrawal syndrome and increased treatment retention. In addition to its non-addictive and non-abuse properties, lofexidine has several clinical advantages over diazepam. The use of lofexidine is recommended when opioid-assisted medications are not available.

Diabetes Control: Is Vinegar a Promising Candidate to Help Achieve Targets?

BACKGROUND: Renewed interest in vinegar as a glucose-lowering agent led to several small trials in the recent past. However, none of the trials could independently provide sufficient evidence. OBJECTIVES: Our review aimed to obtain reliable estimates of effects of vinegar on short-term and long-term blood glucose control. METHODS: Large bibliographic databases were searched from inception to date of search without language and publication date restrictions. All clinical trials evaluating effect of vinegar on diabetes mellitus patients were eligible. Two authors independently extracted data on fasting and 2-hour postprandial blood glucose, insulin, and HbA1c levels at the various time points. MS Excel, SAS® v9.3, and RevMan v5.3 were used for data analysis. RESULTS: Small significant reduction in mean HbA1c was observed after 8 to 12 weeks of vinegar administration: -0.39% (95% confidence interval = -0.59, -0.18; I2 = 0%). Other long-term outcomes favored vinegar but were not significant. Short-term outcomes showed significantly lower pooled mean difference in glucose levels at 30 minutes in the vinegar group. Readings at 60, 90, and 120 minutes were lower in the vinegar group but not statistically significant. Adverse effects profile also favored the vinegar group. CONCLUSIONS: It is worthwhile to carry out carefully planned large trails to determine the efficacy and effectiveness of vinegar as an adjunct treatment modality.

Automated mandatory bolus versus basal infusion for maintenance of epidural analgesia in labour.

BACKGROUND: Childbirth may cause the most severe pain some women experience in their lifetime. Epidural analgesia is an effective form of pain relief during labour and is considered to be the reference standard. Traditionally epidural analgesia has been delivered as a continuous infusion via a catheter in the epidural space, with or without the ability for the patient to supplement the analgesia received by activating a programmable pump to deliver additional top-up doses, known as patient-controlled epidural analgesia (PCEA). There has been interest in delivering maintenance analgesic medication via bolus dosing (automated mandatory bolus - AMB) instead of the traditional continuous basal infusion (BI); recent randomized controlled trials (RCTs) have shown that the AMB technique leads to improved analgesia and maternal satisfaction. OBJECTIVES: To assess the effects of automated mandatory bolus versus basal infusion for maintaining epidural analgesia in labour. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, the World Health Organization International Clinial Trials Registry Platform (WHO-ICTRP) and ClinicalTrials.gov on 16 January 2018. We screened the reference lists of all eligible trials and reviews. We also contacted authors of included studies in this field in order to identify unpublished research and trials still underway, and we screened the reference lists of the included articles for potentially relevant articles. SELECTION CRITERIA: We included all RCTs that compared the use of bolus dosing AMB with continuous BI for providing pain relief during epidural analgesia for labour in women. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were: risk of breakthrough pain with the need for anaesthetic intervention; risk of caesarean delivery; risk of instrumental delivery. Secondary outcomes included: duration of labour; local anaesthetic consumption. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included 12 studies with a total of 1121 women. Ten studies enrolled healthy nulliparous women only and two studies enrolled healthy parous women at term as well. All studies excluded women with complicated pregnancies. There were variations in the technique of initiation of epidural analgesia. Seven studies utilized the combined spinal epidural (CSE) technique, and the other five studies only placed an epidural catheter without any intrathecal injection. Seven studies utilized ropivacaine: six with fentanyl and one with sufentanil. Two studies used levobupivacaine: one with sufentanil and one with fentanyl. Three used bupivacaine with or without fentanyl. The overall risk of bias of the studies was low.AMB probably reduces the risk of breakthrough pain compared with BI for maintaining epidural analgesia for labour (from 33% to 20%; risk ratio (RR) 0.60; 95% confidence interval (CI) 0.39 to 0.92, 10 studies, 797 women, moderate-certainty evidence). AMB may make little or no difference to the risk of caesarean delivery compared to BI (15% and 16% respectively; RR 0.92; 95% CI 0.70 to 1.21, 11 studies, 1079 women, low-certainty evidence).AMB may make little or no difference in the risk of instrumental delivery compared to BI (12% and 9% respectively; RR 0.75; 95% CI 0.54 to 1.06, 11 studies, 1079 women, low-certainty evidence). There is probably little or no difference in the mean duration of labour with AMB compared to BI (mean difference (MD) -10.38 min; 95% CI -26.73 to 5.96, 11 studies, 1079 women, moderate-certainty evidence). There is probably a reduction in the hourly consumption of local anaesthetic with AMB compared to BI for maintaining epidural analgesia during labour (MD -1.08 mg/h; 95% CI -1.78 to -0.38, 12 studies, 1121 women, moderate-certainty evidence). Five out of seven studies reported an increase in maternal satisfaction with AMB compared to BI for maintaining epidural analgesia for labour; however, we did not pool these data due to their ordinal nature. Seven studies reported Apgar scores, though there was significant heterogeneity in reporting. None of the studies showed any significant difference between Apgar scores between groups. AUTHORS' CONCLUSIONS: There is predominantly moderate-certainty evidence that AMB is similar to BI for maintaining epidural analgesia for labour for all measured outcomes and may have the benefit of decreasing the risk of breakthrough pain and improving maternal satisfaction while decreasing the amount of local anaesthetic needed.

Incidence and association factors for the development of chronic post-hysterectomy pain at 4- and 6-month follow-up: a prospective cohort study.

Chronic pain has major adverse effects on health-related quality of life and contributes to significant socioeconomic burden. Hysterectomy is a very common gynecological surgery, resulting in chronic post-hysterectomy pain (CPHP), an important pain syndrome. We conducted a prospective cohort study in 216 Asian women who underwent abdominal or laparoscopic hysterectomy for benign conditions. Demographic, psychological, and perioperative data were recorded. Postoperative 4- and 6-month phone surveys were conducted to assess the presence of CPHP and functional impairment. The incidence rates of CPHP at 4 and 6 months were 32% (56/175) and 15.7% (25/159), respectively. Women with CPHP at 4 and 6 months had pain that interfered with their activities of daily living. Independent association factors for CPHP at 4 months were higher mechanical temporal summation score, higher intraoperative morphine consumption, higher pain score in the recovery room, higher pain score during coughing and itching at 24 hours postoperatively, and preoperative pain in the lower abdominal region. Independent association factors for CPHP at 6 months were preoperative pain during sexual intercourse, higher mechanical temporal summation score, and higher morphine consumption during postoperative 24 and 48 hours. In a majority of cases, CPHP resolved with time, but may have significant impact on activities of daily living.

Modifiable Factors Associated With Survival After Out-of-Hospital Cardiac Arrest in the Pan-Asian Resuscitation Outcomes Study.

STUDY OBJECTIVE: The study aims to identify modifiable factors associated with improved out-of-hospital cardiac arrest survival among communities in the Pan-Asian Resuscitation Outcomes Study (PAROS) Clinical Research Network: Japan, Singapore, South Korea, Malaysia, Taiwan, Thailand, and the United Arab Emirates (Dubai). METHODS: This was a prospective, international, multicenter cohort study of out-of-hospital cardiac arrest in the Asia-Pacific. Arrests caused by trauma, patients who were not transported by emergency medical services (EMS), and pediatric out-of-hospital cardiac arrest cases (<18 years) were excluded from the analysis. Modifiable out-of-hospital factors (bystander cardiopulmonary resuscitation [CPR] and defibrillation, out-of-hospital defibrillation, advanced airway, and drug administration) were compared for all out-of-hospital cardiac arrest patients presenting to EMS and participating hospitals. The primary outcome measure was survival to hospital discharge or 30 days of hospitalization (if not discharged). We used multilevel mixed-effects logistic regression models to identify factors independently associated with out-of-hospital cardiac arrest survival, accounting for clustering within each community. RESULTS: Of 66,780 out-of-hospital cardiac arrest cases reported between January 2009 and December 2012, we included 56,765 in the analysis. In the adjusted model, modifiable factors associated with improved out-of-hospital cardiac arrest outcomes included bystander CPR (odds ratio [OR] 1.43; 95% confidence interval [CI] 1.31 to 1.55), response time less than or equal to 8 minutes (OR 1.52; 95% CI 1.35 to 1.71), and out-of-hospital defibrillation (OR 2.31; 95% CI 1.96 to 2.72). Out-of-hospital advanced airway (OR 0.73; 95% CI 0.67 to 0.80) was negatively associated with out-of-hospital cardiac arrest survival. CONCLUSION: In the PAROS cohort, bystander CPR, out-of-hospital defibrillation, and response time less than or equal to 8 minutes were positively associated with increased out-of-hospital cardiac arrest survival, whereas out-of-hospital advanced airway was associated with decreased out-of-hospital cardiac arrest survival. Developing EMS systems should focus on basic life support interventions in out-of-hospital cardiac arrest resuscitation.

Supreme™ laryngeal mask airway use in general Anesthesia for category 2 and 3 Cesarean delivery: a prospective cohort study.

BACKGROUND: The Supreme™ laryngeal mask airway (SLMA) is a single-use LMA with double lumen design that allows separation of the respiratory and the alimentary tract, hence potentially reducing the gastric volume and risk of aspiration. The purpose of this prospective cohort study is to evaluate the the role of the SLMA as an airway technique for women undergoing category 2 and 3 Cesarean delivery under general anesthesia. METHODS: We recruited 584 parturients who underwent category 2 or 3 Cesarean delivery under general anesthesia, in which 193 parturients underwent category 2 and 391 parturients underwent category 3 Cesarean delivery. The primary outcome was insertion success rate at 1st attempt in SLMA insertion. The secondary outcomes included anaesthetic, obstetric outcomes and maternal side effects associated with airway device. RESULTS: The 1st attempt insertion success rate was 98.3%, while the overall insertion success rate was 100%. The mean (Standard deviation) time to effective ventilation was 15.6 (4.4) seconds. Orogastric tube insertion was successful at the 1st attempt in all parturients. There was no clinical evidence of aspiration or regurgitation. No episodes of hypoxemia, laryngospasm or bronchospasm were observed intra-operatively. The incidence of complications was low and with good maternal satisfaction reported. CONCLUSIONS: The SLMA could be an alternative effective airway in category 2 and 3 parturients emergency Cesarean Delivery under general anesthesia in a carefully-selected obstetric population. TRIAL REGISTRATION: Clinical Trials Registration: Clinicaltrials.gov Registration NCT02026882 . Registered on December 31, 2013.

Multicomponent intervention versus usual care for management of hypertension in rural Bangladesh, Pakistan and Sri Lanka: study protocol for a cluster randomized controlled trial.

BACKGROUND: High blood pressure (BP) is the leading attributable risk for cardiovascular disease (CVD). In rural South Asia, hypertension continues to be a significant public health issue with sub-optimal BP control rates. The goal of the trial is to compare a multicomponent intervention (MCI) to usual care to evaluate the effectiveness and cost-effectiveness of the MCI for lowering BP among adults with hypertension in rural communities in Bangladesh, Pakistan and Sri Lanka. METHODS/DESIGN: This study is a stratified, cluster randomized controlled trial with a qualitative component for evaluation of processes and stakeholder feedback. The MCI has five components: (1) home health education by government community health workers (CHWs), (2) BP monitoring and stepped-up referral to a trained general practitioner using a checklist, (3) training public and private providers in management of hypertension and using a checklist, (4) designating hypertension triage counter and hypertension care coordinators in government clinics and (5) a financing model to compensate for additional health services and provide subsidies to low income individuals with poorly controlled hypertension. Usual care will comprise existing services in the community without any additional training. The trial will be conducted on 2550 individuals aged ≥40 years with hypertension (with systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg, based on the mean of the last two of three measurements from two separate days, or on antihypertensive therapy) in 30 rural communities in Bangladesh, Pakistan and Sri Lanka. The primary outcome is change in systolic BP from baseline to follow-up at 24 months post-randomization. The incremental cost of MCI per CVD disability-adjusted life years averted will be computed. Stakeholders including policy makers, provincial- and district-level coordinators of relevant programmes, physicians, CHWs, key community leaders, hypertensive individuals and family members in the identified clusters will be interviewed. DISCUSSION: The study will provide evidence of the effectiveness and cost-effectiveness of MCI strategies for BP control compared to usual care in the rural public health infrastructure in South Asian countries. If shown to be successful, MCI may be a long-term sustainable strategy for tackling the rising rates of CVD in low resourced countries. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02657746 . Registered on 14 January 2016.

A randomised controlled trial investigating the analgesic efficacy of transversus abdominis plane block for adult laparoscopic appendicectomy.

INTRODUCTION: We conducted a single-centre, prospective randomised clinical trial to investigate the analgesic efficacy of transversus abdominis plane (TAP) block in adult patients undergoing laparoscopic appendicectomy. METHODS: Patients undergoing urgent laparoscopic appendicectomy under general anaesthesia alone (control group) and general anaesthesia supplemented by TAP block (TAP intervention group) were compared. All patients received a multimodal analgesia regime, which included postoperative morphine via a patient-controlled analgesia device. The primary endpoints were morphine consumption at 12 hours and 24 hours postoperatively. Secondary endpoints included pain scores, incidence of nausea and vomiting, and time to hospital discharge. A total of 58 patients were recruited, with 29 patients in each group. RESULTS: Mean postoperative morphine consumption at 12 hours (control group: 11.45 ± 7.64 mg, TAP intervention group: 9.79 ± 8.09 mg; p = 0.4264) and 24 hours (control group: 13.38 ± 8.72 mg, TAP intervention group: 11.31 ± 8.66 mg; p = 0.3686) for the control and TAP intervention groups were not statistically different. Secondary outcomes were also not different between the two groups. Length of stay in the post-anaesthesia care unit was significantly shorter for the TAP intervention group, with a trend toward faster hospital discharge being observed. CONCLUSION: TAP block, a regional anaesthetic procedure performed immediately prior to skin incision for laparoscopic appendicectomy, did not significantly improve postoperative analgesia outcomes.

Evaluation of timings and outcomes in category-one caesarean sections: A retrospective cohort study.

BACKGROUND AND AIMS: A decision-to-delivery interval (DDI) of 30 min for category-one caesarean section (CS) deliveries is the standard of practice recommended by clinical guidelines. Our institution established a protocol for category-one ('crash') CS to expedite deliveries. The aim of this study is to evaluate DDI, factors that affect DDI and the mode of anaesthesia for category-one CS. METHODS: This retrospective cohort study evaluated 390 women who underwent category-one CS in a tertiary obstetric centre. We analysed the factors associated with DDI, mode of anaesthesia and perinatal outcomes. Summary statistics were performed for the outcomes. The association factors were considered significant at P < 0.05. RESULTS: The mean (standard deviation) DDI was 9.4 (3.2) min with all deliveries achieved within 30 min. The longest factor in the DDI was time taken to transfer patients. A shorter DDI was not significantly associated with improved perinatal outcomes. The majority (88.9%) of women had general anaesthesia (GA) for category-one CS. Of those who had an epidural catheter already in situ (34.4%), 25.6% had successful epidural extension. GA was associated with shorter DDI, but worse perinatal outcomes than regional anaesthesia (RA). CONCLUSIONS: Our 'crash' CS protocol achieved 100% of deliveries within 30 min. The majority (88.9%) of the patients had GA for category-one CS. GA was found to be associated with shorter anaesthesia and operation times, but poorer perinatal outcomes compared to RA.

Hyperbaric versus isobaric bupivacaine for spinal anaesthesia for caesarean section.

BACKGROUND: Bupivacaine is an amide local anaesthetic used in hyperbaric and isobaric forms. These are administered intrathecally into the spine to provide regional anaesthesia for caesarean section. Several trials have compared hyperbaric and isobaric bupivacaine but none have conclusively shown the benefit of either. This review was first published in 2013 and updated in 2016. OBJECTIVES: Our objectives were to:1. Determine the effectiveness of hyperbaric bupivacaine compared to isobaric bupivacaine for spinal anaesthesia in women undergoing caesarean section;2. Determine the safety of hyperbaric bupivacaine compared to isobaric bupivacaine for spinal anaesthesia in women undergoing caesarean section. SEARCH METHODS: We originally searched the following databases to January 2011: CENTRAL, MEDLINE and Embase.For this update, we reran our search in the above databases from January 2011 to March 2016; two studies are awaiting a response from authors for assessment and will be dealt with when we next update the review.We imposed no language restriction. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) involving parturients undergoing spinal anaesthesia for elective caesarean section that compared the use of hyperbaric with isobaric bupivacaine. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data. The data that were extracted included the number of events and the sample sizes in both the intervention and control groups. For continuous outcomes, we extracted mean and standard deviation.We reported odds ratios (ORs) and risk ratios (RRs) for binary outcomes, and mean differences (MDs) for continuous outcomes. MAIN RESULTS: We included three new RCTs in this update, which now comprises 10 studies with a total of 614 participants. We judged most trials as having uncertain risk of bias regarding randomization. Other than this, the overall risk of bias was low. Most included trials had small sample sizes. All of the trials assessed the primary outcome of conversion to general anaesthesia. Ten trials comparing anaesthesia performed with hyperbaric and isobaric bupivacaine failed to show any difference in need for conversion to general anaesthesia (RR 0.33, 95% CI 0.09 to 1.17, 614 participants, very low quality of evidence). Nine trials also failed to show a difference in the need for supplemental analgesics (RR 0.61, 95% CI 0.26 to 1.41, 554 participants, very low quality of evidence). Four trials comparing requirement for ephedrine did not show any difference (RR 0.89, 95% CI 0.57 to 1.38, 256 participants, very low quality of evidence). Seven trials did not provide convincing evidence of difference in nausea and vomiting (RR 0.99, 95% CI 0.57 to 1.72, 433 participants, low quality of evidence). Three trials failed to show a difference in headache (OR 1.82, 95% CI 0.47 to 6.99, 234 participants, low quality of evidence). Two trials showed that the time until sensory block to the thoracic 4th (T4) spinal level was shorter with hyperbaric bupivacaine (MD -1.06 minutes, 95% CI -1.80 to -0.31, 128 participants, moderate quality of evidence). Six trials showed no difference in the amount of ephedrine used (RR 0.23, 95% CI -1.65 to 2.12, 386 participants, moderate quality of evidence). Three trials failed to show any difference in high block (RR 0.88, 95% CI 0.16 to 4.90, 205 participants). AUTHORS' CONCLUSIONS: Data are limited for some of the outcomes. Reporting of the included trials is less than optimal. For these reasons the overall quality of evidence is low or very low for most of the outcomes, based on the GRADE method of assessment. This review found that intrathecal hyperbaric bupivacaine had a more rapid onset of sensory blockade at the 4th thoracic vertebra (T4) level than isobaric bupivacaine. Hower, despite incorporating more data in the analysis, we found little evidence that the need for conversion to general anaesthesia and supplemental analgesia differed between the hyperbaric or isobaric bupivacaine groups. This is mainly due to the rarity of these outcomes, variability in the dose, use of adjuvant drugs and differences in the technique used for regional anaesthesia. There were no differences in the adverse effects studied. Any possible advantage of hyperbaric bupivacaine needs to be confirmed in larger randomized trials. In future research, criteria for conversion to general anaesthesia need to be defined objectively and applied uniformly.

Control of blood pressure and risk attenuation: a public health intervention in rural Bangladesh, Pakistan, and Sri Lanka: feasibility trial results.

BACKGROUND: High blood pressure (BP) is the leading attributable risk for cardiovascular disease globally. There is little information on effective and sustainable public health system strategies for managing hypertension in South Asian countries. We conducted a feasibility study to gather preliminary data to optimize BP-lowering strategies for a public health intervention in rural communities in Bangladesh, Pakistan, and Sri Lanka. METHODS: A mixed method feasibility study comprised a 3-month pre and postevaluation of a multicomponent intervention (MCI), including BP screening and home health education by trained government community health worker (CHW); providers trained in hypertension management, and compensation of CHW for additional services. Checklists were used to document care. Stakeholder interviews were also conducted. Individuals aged 40 years and above with high BP (systolic ≥140 mmHg or diastolic ≥90 mmHg based on two readings from 2 separate days, or receiving antihypertensive medications) were enrolled from rural communities in Bangladesh, Pakistan, and Sri Lanka. BP was measured at baseline and 3 months postintervention. RESULTS: A total of 412 (90%) of the 454 eligible individuals were recruited. Of those recruited, 90% received home health education session by trained CHWs, 80% were referred to trained providers, of whom 83% completed the management checklist. A follow-up rate of 95.6% was achieved. The mean SBP declined significantly by 4.5 mmHg 95% confidence interval (2.3, 6.7) mmHg (P < 0.001) in the overall pooled analysis in three countries; however, it varied among countries. BP decline was 10.5 mmHg (8.1, 13.0 mmHg) (P < 0.001) in the pooled analysis of individuals with uncontrolled hypertension at baseline, and was also significant each of the three countries. All 98 stakeholders strongly supported upscaling the proposed MCI strategies. CONCLUSION: The proposed MCI is feasible for implementation and requires long-term, large-scale evaluation in the rural public health infrastructure in South Asian countries to determine sustainability of health system changes and BP control. If these long-term effects are confirmed, MCI may be a long-term strategy for tackling rising rates of cardiovascular disease in low-resourced countries.Clintrial.gov NCT02341651.