Role of Hypothermia in Adult Cardiac Surgery Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: To review studies that assessed systemic hypothermia as an organ protection strategy in adults undergoing cardiac surgery with cardiopulmonary bypass. DESIGN: A systematic review and meta-analysis. SETTING AND PARTICIPANTS: Randomized controlled trials, irrespective of blinding, language, publication status, and date of publication, were identified by searching the Cochrane Central register of Controlled Trials, MEDLINE, and Embase until November 2020. Risk of bias assessment was performed according to Cochrane methodology. Treatment effects were expressed as risk ratios and 95% confidence intervals. Heterogeneity was expressed as I2. INTERVENTIONS: Systemic hypothermia. MEASUREMENTS AND MAIN RESULTS: Forty-eight trials enrolling 6,690 patients were included in the analysis. Methodologic quality of the studies included was low, mostly due to insufficient allocation concealment or blinding. Random-effects meta-analysis did not resolve uncertainty as to the risks and benefits for hypothermia versus normothermia for key primary and secondary outcomes, including mortality (1.21, 0.94 to 1.56, I2 = 0%) and brain injury (0.87, 0.67 to 1.14, I2 = 0%). Sensitivity analyses restricted to trials at low risk of important bias demonstrated higher mortality with hypothermia (1.70, 1.05 to 2.75, I2 = 0%), with little or no treatment effect on brain injury (1.01, 0.69 to 1.49, I2 = 0%). There was no interaction between cardioplegia temperature and the effects of cardiopulmonary bypass temperature on outcomes. There was insufficient evidence to assess the effects of hypothermia in noncoronary artery bypass graft surgery. CONCLUSION: The existing evidence for an organ-protective effect of hypothermia in adult cardiac surgery is of low quality and inconsistent.

Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): an open-label, single-arm, phase 2a clinical trial.

BACKGROUND: Malignant mesothelioma remains an incurable cancer, with no effective treatments in the setting of relapsed disease. Homologous recombination deficiency predicts sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. In mesothelioma, BRCA1-associated protein 1 carboxy-terminal hydrolase (BAP1), which regulates DNA repair, is frequently mutated. We aimed to test the hypothesis that BAP1-deficient or BRCA1-deficient mesotheliomas would be sensitive to PARP inhibition by rucaparib. METHODS: We did a single-centre, open-label, single-arm, phase 2a trial in Leicester, UK, with prospective molecular stratification (Mesothelioma-Stratified Therapy 1 [MiST1]). Patients aged 18 years or older who had radiologically progressing, histologically confirmed, malignant mesothelioma after at least one course of systemic treatment; with cytoplasmic-BAP1-deficient or BRCA1-deficient mesothelioma (pleural or peritoneal or other primary localisation), and who met the other inclusion criteria, were deemed eligible. All eligible patients who consented to take part were given rucaparib 600 mg twice a day orally, for six cycles of 28 days, or until disease progression, unacceptable toxicity, withdrawal of consent, or death. Response was measured by CT scan every 6 weeks. The primary outcome was disease control (complete response, partial response, or stable disease) at 12 weeks in all patients who received study drug; secondary outcomes were the safety and toxicity profile, objective response rate (proportion of complete or partial responses), and disease control rate at 24 weeks. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03654833. FINDINGS: Between Feb 9 and June 10, 2019, we enrolled 26 molecularly and clinically eligible patients. Ten (38%) of 26 patients were BAP1 negative and BRCA1 negative, 23 patients (89%) were BAP1 negative, and 13 patients (50%) were BRCA1 negative. Disease control rate at 12 weeks was 58% (95% CI 37-77; 15 of 26 patients), and at 24 weeks was 23% (9-44; six of 26 patients). Rucaparib was well tolerated, with 15 (9%) of 166 adverse events being grade 3 or 4, which were seen in nine (35%) of 26 patients, and there were no deaths. The most common grade 1-2 adverse events were nausea (18 [69%] of 26 patients), fatigue (14 patients [54%]), and decreased appetite (ten patients [38%]). The most common grade 3-4 adverse events were upper respiratory tract infection (three patients [12%]) and anaemia (three patients [12%]). All six cycles of rucaparib were received by eight (31%) of 26 patients. One or more dose reductions occurred in nine patients (35%). INTERPRETATION: Rucaparib in patients with BAP1-negative or BRCA1-negative mesothelioma met the prespecified criteria for success, showing promising activity with manageable toxicity. Further investigation of homologous recombination deficiency mutations is planned to refine the identification of predictive biomarkers for PARP inhibition in mesothelioma. FUNDING: University of Leicester (Leicester, UK), Asthma UK and British Lung Foundation Partnership, and the Victor Dahdaleh Foundation (Toronto, ON, Canada).

Blood Transfusion Threshold in Patients Receiving Extracorporeal Membrane Oxygenation Support for Cardiac and Respiratory Failure-A Systematic Review and Meta-Analysis.

OBJECTIVE: To review studies that have evaluated the effects of liberal or restrictive red cell transfusion thresholds on clinical outcomes in patients requiring extracorporeal membrane oxygenation (ECMO) support for cardiac or respiratory failure. DESIGN: A systematic review and meta-analysis. SETTING AND PARTICIPANTS: The study comprised 1,070 patients from observational studies and randomized controlled trials analyzing transfusion policies in venoarterial (VA) and venovenous (VV) ECMO adult populations. MEASUREMENTS AND MAIN RESULTS: Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials, Medline, and EMBASE until March 4, 2020, using a combination of subject headings and text words. Risk of bias assessment was performed to assess study quality according to the ROBINS-I tool and the case series studies appraisal checklist. There was high risk of bias in the studies analyzed, and none had methodologic adequacy. Three studies analyzed VA ECMO and VV ECMO patients separately. Five datasets were related exclusively or mostly to VA ECMO. Four were retrospective analyses, and one was conducted as a prospective observational study; the median transfusion threshold reported was 8 g/dL, with a mean mortality of 52%. Eight datasets were related either exclusively or mostly to VV ECMO. Six were retrospective and two were prospective observational studies; the median transfusion threshold was 8 g/dL, and the mean mortality rate was 33%. CONCLUSIONS: The present study did not resolve uncertainty as to transfusion management in ECMO, although several studies (most of them in VV ECMO) demonstrated that a restrictive threshold has acceptable outcomes in single-center cohorts.

Effect of sildenafil (Revatio) on postcardiac surgery acute kidney injury: a randomised, placebo-controlled clinical trial: the REVAKI-2 trial protocol.

Introduction: Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. The administration of pharmacological renoprotective agents during the perioperative period could prevent or reduce the severity of AKI and improve clinical outcomes. Experimental studies suggest that sildenafil may have therapeutic potential for the prevention of AKI. This trial will test the hypothesis that postoperative AKI will be reduced in cardiac surgery patients if they receive sildenafil compared with placebo. Methods and analysis: Adult cardiac surgery patients 18 years of age or above undergoing cardiac surgery with cardiopulmonary bypass and cardioplegic arrest at a single tertiary cardiac centre in the UK will be randomised in a 1:1 ratio to receive either sildenafil or placebo. The primary outcome is serum creatinine concentration measured at preoperation and daily for up to 7 days postoperatively. Secondary outcomes will include measures of inflammation, organ injury, volumes of blood transfused and resource use. Allocation concealment, internet-based randomisation stratified by operation type, and blinding of outcome assessors will reduce the risk of bias. A sample size of 112 patients will have a 90% power to detect a mean difference of 10 µmol/L for serum creatinine values between treatment and placebo control groups with an alpha value of 0.05. Ethics and dissemination: The trial protocol was approved by a UK ethics committee (reference 15/YH/0489). The trial findings will be disseminated in scientific journals and meetings. Trial registration number: ISRCTN18386427.