Tom Morris

Evaluation of Radiographic Lucency or Opaqueness of Gallstones as a Means of Identifying Cholesterol or Pigment Stones: Correlation of lucency or opaqueness with calcium and mineral

A major criterion for the selection of patients with gallstones for treatment with chenodeoxycholic acid is the radiographic demonstration of lucent gallstones. In this study, we sought to evaluate the degree of selectivity of that criterion for distinguishing patients with cholesterol stones from those with pigment stones and to define the determinants of stone lucency or opaqueness. Of 92 lucent stones, 14% were pigment stones; and of 18 of opaque stones, 33% were cholesterol. Thus, the criterion of stone lucency allows inclusion of a significant number of subjects (14%) with lucent pigment stones, which may account for about one-half of the reported 33% incidence of treatment failures with chenodeoxycholic acid. Conversely, of patients with opaque stones, the one-third with cholesterol stones would be excluded from chenodeoxycholic acid treatment. Calcium is the major metal of both types of stones. However, opaque stones contain 6 times more calcium than lucent stones, which accounts for the difference in radiographic appearance.

A randomised controlled trial of six weeks of home enteral nutrition versus standard care after oesophagectomy or total gastrectomy for cancer: report on a pilot and feasibility study

BackgroundPoor nutrition in the first months after oesophago-gastric resection is a contributing factor to the reduced quality of life seen in these patients. The aim of this pilot and feasibility study was to ascertain the feasibility of conducting a multi-centre randomised controlled trial to evaluate routine home enteral nutrition in these patients.MethodsPatients undergoing oesophagectomy or total gastrectomy were randomised to either six weeks of home feeding through a jejunostomy (intervention), or treatment as usual (control). Intervention comprised overnight feeding, providing 50 % of energy and protein requirements, in addition to usual oral intake. Primary outcome measures were recruitment and retention rates at six weeks and six months. Nutritional intake, nutritional parameters, quality of life and healthcare costs were also collected. Interviews were conducted with a sample of participants, to ascertain patient and carer experiences.ResultsFifty-four of 112 (48 %) eligible patients participated in the study over the 20 months. Study retention at six weeks was 41/54 patients (76 %) and at six months was 36/54 (67 %). At six weeks, participants in the control group had lost on average 3.9 kg more than participants in the intervention group (95 % confidence interval [CI] 1.6 to 6.2). These differences remained evident at three months (mean difference 2.5 kg, 95 % CI −0.5 to 5.6) and at six months (mean difference 2.5 kg, 95 % CI −1.2 to 6.1). The mean values observed in the intervention group for mid arm circumference, mid arm muscle circumference, triceps skin fold thickness and right hand grip strength were greater than for the control group at all post hospital discharge time points. The economic evaluation suggested that it was feasible to collect resource use and EQ-5D data for a full cost-effectiveness analysis. Thematic analysis of 15 interviews identified three main themes related to the intervention and the trial: 1) a positive experience, 2) the reasons for taking part, and 3) uncertainty of the study process.ConclusionsThis study demonstrated that home enteral feeding by jejunostomy was feasible, safe and acceptable to patients and their carers. Whether home enteral feeding as ’usual practice’ is a cost-effective therapy would require confirmation in an appropriately powered, multi-centre study.Trial registrationUK Clinical Research Network ID 12447 (main trial, first registered 30 May 2012); UK Clinical Research Network ID 13361 (qualitative substudy, first registered 30 May 2012); ClinicalTrials.gov NCT01870817 (first registered 28 May 2013)

Randomized trial of red cell washing for the prevention of transfusion-associated organ injury in cardiac surgery

Background. Experimental studies suggest that mechanical cell washing to remove pro‐inflammatory components that accumulate in the supernatant of stored donor red blood cells (RBCs) might reduce inflammation and organ injury in transfused patients. Methods. Cardiac surgery patients at increased risk of large‐volume RBC transfusion were eligible. Participants were randomized to receive either mechanically washed allogenic RBCs or standard care RBCs. The primary outcome was serum interleukin‐8 measured at baseline and at four postsurgery time points. A mechanism substudy evaluated the effects of washing on stored RBCs in vitro and on markers of platelet, leucocyte, and endothelial activation in trial subjects. Results. Sixty adult cardiac surgery patients at three UK cardiac centres were enrolled between September 2013 and March 2015. Subjects received a median of 3.5 (interquartile range 2‐5.5) RBC units, stored for a mean of 21 (SD 5.2) days, within 48 h of surgery. Mechanical washing reduced concentrations of RBC‐derived microvesicles but increased cell‐free haemoglobin concentrations in RBC supernatant relative to standard care RBC supernatant. There was no difference between groups with respect to perioperative serum interleukin‐8 values [adjusted mean difference 0.239 (95% confidence intervals ‐0.231, 0.709), P=0.318] or concentrations of plasma RBC microvesicles, platelet and leucocyte activation, plasma cell‐free haemoglobin, endothelial activation, or biomarkers of heart, lung, or kidney injury. Conclusions. These results do not support a hypothesis that allogenic red blood cell washing has clinical benefits in cardiac surgery. Clinical trial registration. ISRCTN 27076315.

A Phase I study to determine the pharmacokinetic profile, safety and tolerability of sildenafil (Revatio®) in cardiac surgery: the REVAKI-1 study

AIMS Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio®, Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre‐clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients. METHODS We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil. RESULTS Thirty‐six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC∞ 537 ng h ml−1, Cmax 189.4 ng ml−1 and t1/2 10.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post‐surgery nitric oxide bioavailability. CONCLUSIONS Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery.

Trial protocol for a randomised controlled trial of red cell washing for the attenuation of transfusion-associated organ injury in cardiac surgery: the REDWASH trial.

Introduction It has been suggested that removal of proinflammatory substances that accumulate in stored donor red cells by mechanical cell washing may attenuate inflammation and organ injury in transfused cardiac surgery patients. This trial will test the hypotheses that the severity of the postoperative inflammatory response will be less and postoperative recovery faster if patients undergoing cardiac surgery receive washed red cells compared with standard care (unwashed red cells). Methods and analysis Adult (≥16 years) cardiac surgery patients identified at being at increased risk for receiving large volume red cell transfusions at 1 of 3 UK cardiac centres will be randomly allocated in a 1:1 ratio to either red cell washing or standard care. The primary outcome is serum interleukin-8 measured at 5 postsurgery time points up to 96 h. Secondary outcomes will include measures of inflammation, organ injury and volumes of blood transfused and cost-effectiveness. Allocation concealment, internet-based randomisation stratified by operation type and recruiting centre, and blinding of outcome assessors will reduce the risk of bias. The trial will test the superiority of red cell washing versus standard care. A sample size of 170 patients was chosen in order to detect a small-to-moderate target difference, with 80% power and 5% significance (2-tailed). Ethics and dissemination The trial protocol was approved by a UK ethics committee (reference 12/EM/0475). The trial findings will be disseminated in scientific journals and meetings. Trial registration number ISRCTN 27076315.

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.

Unequal cluster sizes in stepped-wedge cluster randomised trials: a systematic review

Objectives To investigate the extent to which cluster sizes vary in stepped-wedge cluster randomised trials (SW-CRT) and whether any variability is accounted for during the sample size calculation and analysis of these trials. Setting Any, not limited to healthcare settings. Participants Any taking part in an SW-CRT published up to March 2016. Primary and secondary outcome measures The primary outcome is the variability in cluster sizes, measured by the coefficient of variation (CV) in cluster size. Secondary outcomes include the difference between the cluster sizes assumed during the sample size calculation and those observed during the trial, any reported variability in cluster sizes and whether the methods of sample size calculation and methods of analysis accounted for any variability in cluster sizes. Results Of the 101 included SW-CRTs, 48% mentioned that the included clusters were known to vary in size, yet only 13% of these accounted for this during the calculation of the sample size. However, 69% of the trials did use a method of analysis appropriate for when clusters vary in size. Full trial reports were available for 53 trials. The CV was calculated for 23 of these: the median CV was 0.41 (IQR: 0.22–0.52). Actual cluster sizes could be compared with those assumed during the sample size calculation for 14 (26%) of the trial reports; the cluster sizes were between 29% and 480% of that which had been assumed. Conclusions Cluster sizes often vary in SW-CRTs. Reporting of SW-CRTs also remains suboptimal. The effect of unequal cluster sizes on the statistical power of SW-CRTs needs further exploration and methods appropriate to studies with unequal cluster sizes need to be employed.

Tu1463 Failure of Oral Intake to Meet Nutritional Requirements in the Early Months After Esophagectomy

BackgroundNutritional intake is often compromised in themonths following esophagogastric resection. Enteral nutrition has been used as an adjunct to oral intake but studies evaluating the role of extended jejunostomy feeding (JEJ) following hospital discharge are lacking. Methods As part of a randomized controlled trial investigating the effect of six weeks of home jejunostomy feeding, nutritional intake was assessed at 4 time points: hospital discharge, 6 weeks after discharge, 3 and 6 months post surgery. Dietary intake was assessed using 3 day dietary records, analysed using Dietplan6®. Information on JEJ intake was collected for the same period. Ideal nutritional requirements for energy were calculated using the Henry equation adjusted for activity level. Oral intake was considered adequate if reported intake provided >75% of estimated energy needs. Results 54 participants were enrolled in the study. There were 13 early withdrawals leaving 41 participants for analysis. Surgery comprised esophagectomy in 32 participants and total gastrectomy in 9. Twenty participants were randomised to a planned program of home JEJ feeding providing 50% of energy and protein requirements, inaddition to usual dietary intake. Twenty-one participants in the control group received care as usual with jejunostomy feeding being stopped on discharge from hospital. 17/20 participants (85%) in the intervention group received treatment as allocated. Seven participants (35%) in the control group had to recommence home feeding due to clinical and/or nutritional need. At the time of hospital discharge, dietary intake was poor in both groups with JEJ feeding still meeting the energy requirements of most participants. By 6 weeks post hospital discharge, oral nutritional intake remained inadequate in 47% and 50% of the intervention and control group respectively. Total calorie intake was adequate in the intervention group because of the contribution from jejunostomy feeding (Table). Conclusions This study has shown that energy requirements are frequently inadequate in patients after esophagectomy and total gastrectomy in the months after surgery. It has also demonstrated that supplementary jejunostomy feeding may make an important contribution to nutritional requirements in these early months.

Tu1767 A Randomized Controlled Trial of Six Weeks of Home Enteral Nutrition Versus Standard Care After Esophagectomy or Total Gastrectomy for Cancer: Report on a Pilot and Feasibility Study

Background: Poor nutrition in the first months after oesophago-gastric resection is a contributing factor to the reduced quality of life seen in these patients. The aim of this pilot and feasibility study was to ascertain the feasibility of conducting a multi-centre randomised controlled trial to evaluate routine home enteral nutrition in these patients. Methods: Patients undergoing oesophagectomy or total gastrectomy were randomised to either six weeks of home feeding through a jejunostomy (intervention), or treatment as usual (control). Intervention comprised overnight feeding, providing 50 % of energy and protein requirements, in addition to usual oral intake. Primary outcome measures were recruitment and retention rates at six weeks and six months. Nutritional intake, nutritional parameters, quality of life and healthcare costs were also collected. Interviews were conducted with a sample of participants, to ascertain patient and carer experiences. Results: Fifty-four of 112 (48 %) eligible patients participated in the study over the 20 months. Study retention at six weeks was 41/54 patients (76 %) and at six months was 36/54 (67 %). At six weeks, participants in the control group had lost on average 3.9 kg more than participants in the intervention group (95 % confidence interval [CI] 1.6 to 6.2). These differences remained evident at three months (mean difference 2.5 kg, 95 % CI �0.5 to 5.6) and at six months (mean difference 2.5 kg, 95 % CI �1.2 to 6.1). The mean values observed in the intervention group for mid arm circumference, mid arm muscle circumference, triceps skin fold thickness and right hand grip strength were greater than for the control group at all post hospital discharge time points. The economic evaluation suggested that it was feasible to collect resource use and EQ-5D data for a full cost-effectiveness analysis. Thematic analysis of 15 interviews identified three main themes related to the intervention and the trial: 1) a positive experience, 2) the reasons for taking part, and 3) uncertainty of the study process.