Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial.

BackgroundThe dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio.Methods and findingsWe undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: NCT03532594). Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78-1.14] vs. 0.75 [IQR 0.57-0.99]; p 120 kg, and patients requiring therapeutic hypothermia to ConclusionsUsing a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients.Trial registrationClinicalTrials.gov Unique identifier NCT03532594

Optimal Timing of External Ventricular Drainage after Severe Traumatic Brain Injury: A Systematic Review

External ventricular drainage (EVD) may be used for therapeutic cerebrospinal fluid (CSF) drainage to control intracranial pressure (ICP) after traumatic brain injury (TBI). However, there is currently uncertainty regarding the optimal timing for EVD insertion. This study aims to compare patient outcomes for patients with early and late EVD insertion. Following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, MEDLINE/EMBASE/Scopus/Web of Science/Cochrane Central Register of Controlled Trials were searched for published literature involving at least 10 severe TBI (sTBI) patients from their inception date to December 2019. Outcomes assessed were mortality, functional outcome, ICP control, length of stay, therapy intensity level, and complications. Twenty-one studies comprising 4542 sTBI patients with an EVD were included; 19 of the studies included patients with an early EVD, and two studies had late EVD placements. The limited number of studies, small sample sizes, imbalance in baseline characteristics between the groups and poor methodological quality have limited the scope of our analysis. We present the descriptive statistics highlighting the current conflicting data and the overall lack of reliable research into the optimal timing of EVD. There is a clear need for high quality comparisons of early vs. late EVD insertion on patient outcomes in sTBI

Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration.

Following severe or chronic liver injury, adult ductal cells (cholangiocytes) contribute to regeneration by restoring both hepatocytes and cholangiocytes. We recently showed that ductal cells clonally expand as self-renewing liver organoids that retain their differentiation capacity into both hepatocytes and ductal cells. However, the molecular mechanisms by which adult ductal-committed cells acquire cellular plasticity, initiate organoids and regenerate the damaged tissue remain largely unknown. Here, we describe that ductal cells undergo a transient, genome-wide, remodelling of their transcriptome and epigenome during organoid initiation and in vivo following tissue damage. TET1-mediated hydroxymethylation licences differentiated ductal cells to initiate organoids and activate the regenerative programme through the transcriptional regulation of stem-cell genes and regenerative pathways including the YAP-Hippo signalling. Our results argue in favour of the remodelling of genomic methylome/hydroxymethylome landscapes as a general mechanism by which differentiated cells exit a committed state in response to tissue damage.RCUK Cancer Research UK ERC H2020 Wellcome Trus

Effect of hypoxemia on outcome in respiratory failure supported with extracorporeal membrane oxygenation: a cardinality matched cohort study.

Venovenous extracorporeal membrane oxygenation (ECMO) is recommended in adult patients with refractory acute respiratory failure (ARF), but there is limited evidence for its use in patients with less severe hypoxemia. Prior research has suggested a lower PaO2/FiO2 at cannulation is associated with a higher short-term mortality, but it is unclear whether this is due to less severe illness or a potential benefit of earlier ECMO support. In this exploratory cardinality-matched observational cohort study, we matched 668 patients who received venovenous ECMO as part of a national severe respiratory failure service into cohorts of ‘less severe’ and ‘very severe’ hypoxemia based on the median PaO2/FiO2 at ECMO institution of 68mmHg. Prior to matching, ICU mortality was 19% in the ‘less severe’ hypoxemia group and 28% in the ‘very severe’ hypoxemia group (RR for mortality = 0.69, 95% CI 0.54—0.88). After matching on key prognostic variables including underlying diagnosis, this difference remained statistically present but smaller: (23% vs. 30%, RR = 0.76, 95% CI 0.59—0.99). This may suggest the observed survival benefit of venovenous ECMO is not solely due to reduced disease severity. Further research is warranted to examine the potential role of ECMO in ARF patients with less severe hypoxemiaMedical Research Council UK (Grant Number MC_UU_00002/15

Predictors of health-related quality of life in patients undergoing extracorporeal membrane oxygenation for acute severe respiratory failure.

BACKGROUND: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a form of life support used in severe respiratory failure. While the short-term complications of VV-ECMO are well described, impacts on health-related quality of life (HRQOL) are less well characterised. This study aims to assess the HRQOL of patients who underwent VV-ECMO for acute severe respiratory failure and explore predictors of poor HRQOL. METHODS: We performed a retrospective, observational study of a large cohort of adults who underwent VV-ECMO for acute severe respiratory failure in a single tertiary centre (June 2013-March 2019). Patients surviving critical care discharge were invited to a six-month clinic, where they completed an EQ-5D-5L questionnaire assessing HRQOL. Multivariate analysis was performed to assess prognostic factors for HRQOL. RESULTS: Among the 245 consecutive patients included in this study (median age 45 years), 187 (76.3%) survived until ECMO decannulation and 172 (70.2%) until hospital discharge. Of those, 98 (57.3%) attended a follow-up clinic at a mean (±SD) of 204 (±45) days post-discharge. Patients reported problems with pain/discomfort (56%), usual daily activities (53%), anxiety/depression (49%), mobility (46%), and personal care (21%). Multivariate analysis identified limb ischaemia (-0.266, 95% C.I. [-0.116; -0.415], p = 0.0005), renal replacement therapy (-0.149, [-0.046; -0.252], p = 0.0044), and having received more than four platelet units (-0.157, [-0.031; -0.283], p = 0.0146) as predictors of poor HRQOL. CONCLUSION: We report that survivors of VV-ECMO have reduced HRQOL in multiple domains at 6 months, with pain reported most frequently. Patients who had limb ischaemia, renal replacement therapy or were transfused more than four units of platelets are particularly at risk of poor HRQOL and may benefit from added support measures

Acute kidney injury after thoracic surgery: a proposal for a multicentre evaluation (MERITS).

OBJECTIVES: Because the mortality rate is very low in thoracic surgery, its use as a quality discriminator is limited. Acute kidney injury (AKI) is a candidate measure because it is associated with increased rates of morbidity and mortality and is partly preventable. The incidence of AKI after thoracic surgery is not well documented. We conducted an audit to determine the incidence and outcomes of AKI. This audit became a pilot project, and the results indicate the feasibility of a larger study. METHODS: Retrospective data on renal function post-thoracic surgery were collected at a tertiary cardiothoracic unit over 12 months. Renal impairment was classified according to the Kidney Disease Improving Global Outcomes criteria. RESULTS: Of 568 patients (mean = 59  ±  SD 18; 38% women), AKI was diagnosed in 86 (15.1%) within 72 h post-thoracic surgery based on the Kidney Disease Improving Global Outcomes staging system (stage 1, n = 55; stage 2, n = 25; stage 3, n = 6). Significant differences were found in postoperative length of stay (3 vs 5 days; P < 0.001) of patients with and without AKI. There was a significant difference between the age groups of patients with and without AKI (P < 0.05) in the open surgical group but not in the group having video-assisted thoracoscopic surgery (VATS). There was no significant difference in the mortality rates between patients with and without AKI. CONCLUSIONS: The incidence of AKI after thoracic surgery was 15.1%. AKI was associated with longer hospital stays and was more likely in ≥60-year-old patients after open surgery than after VATS. Reducing AKI could improve patient outcomes. We propose that AKI may be a useful quality measure in thoracic surgery. We are developing a multicentre audit based on this approach

Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial

Funder: Jon Moulton Charity TrustBackground: The dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio. Methods and findings: We undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: NCT03532594). Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78–1.14] vs. 0.75 [IQR 0.57–0.99]; p 120 kg, and patients requiring therapeutic hypothermia to <28°C). Conclusions: Using a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients. Trial registration: ClinicalTrials.gov Unique identifier NCT03532594

Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm efficacy.

Pulmonary arterial hypertension is an unmet clinical need. Imatinib, a tyrosine kinase inhibitor, 200 to 400 mg daily reduces pulmonary artery pressure and increases functional capacity in this patient group, but is generally poorly tolerated at the higher dose. We have designed an open-label, single-arm clinical study to investigate whether there is a tolerated dose of imatinib that can be better targeted to patients who will benefit. The study consists of two parts. Part 1 seeks to identify the best tolerated dose of Imatinib in the range from 100 and up to 400 mg using a Bayesian Continuous Reassessment Method. Part 2 will measure efficacy after 24 weeks treatment with the best tolerated dose using a Simon's two-stage design. The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes · s · cm-5, success is defined by an absolute reduction in PVR of ≥300 dynes · s · cm-5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes · s · cm-5, success is a 30% reduction in PVR at 24 weeks. PVR will also be evaluated as a continuous variable by genotype as an exploratory analysis. Evaluating the response to that dose by genotype may inform a prospective biomarker-driven study