Ewen M. Harrison

Discontinuation and non-publication of surgical randomised controlled trials: observational study

Objective To determine the rate of early discontinuation and non-publication of randomised controlled trials involving patients undergoing surgery. Design Cross sectional observational study of registered and published trials. Setting Randomised controlled trials of interventions in patients undergoing a surgical procedure. Data sources The ClinicalTrials.gov database was searched for interventional trials registered between January 2008 and December 2009 using the keyword “surgery”. Recruitment status was extracted from the ClinicalTrials.gov database. A systematic search for studies published in peer reviewed journals was performed; if they were not found, results posted on the ClinicalTrials.gov results database were sought. Email queries were sent to trial investigators of discontinued and unpublished completed trials if no reason for the respective status was disclosed. Main outcome measures Trial discontinuation before completion and non-publication after completion. Logistic regression was used to determine the effect of funding source on publication status, with adjustment for intervention type and trial size. Results Of 818 registered trials found using the keyword “surgery”, 395 met the inclusion criteria. Of these, 21% (81/395) were discontinued early, most commonly owing to poor recruitment (44%, 36/81). The remaining 314 (79%) trials proceeded to completion, with a publication rate of 66% (208/314) at a median time of 4.9 (interquartile range 4.0-6.0) years from study completion to publication search. A further 6% (20/314) of studies presented results on ClinicalTrials.gov without a corresponding peer reviewed publication. Industry funding did not affect the rate of discontinuation (adjusted odds ratio 0.91, 95% confidence interval 0.54 to 1.55) but was associated with a lower odds of publication for completed trials (0.43, 0.26 to 0.72). Investigators’ email addresses for trials with an uncertain fate were identified for 71.4% (10/14) of discontinued trials and 83% (101/122) of unpublished studies. Only 43% (6/14) and 20% (25/122) replies were received. Email responses for completed trials indicated 11 trials in press, five published studies (four in non-indexed peer reviewed journals), and nine trials remaining unpublished. Conclusions One in five surgical randomised controlled trials are discontinued early, one in three completed trials remain unpublished, and investigators of unpublished studies are frequently not contactable. This represents a waste of research resources and raises ethical concerns regarding hidden clinical data and futile participation by patients with its attendant risks. To promote future efficiency and transparency, changes are proposed to research governance frameworks to overcome these concerns.

Early stress protein gene expression in a human model of ischemic preconditioning.

Intermittent clamping of the porta hepatis (PHC) is commonly performed during liver surgery to reduce blood loss and has been reported to precondition livers resulting in improved outcome after liver surgery (humans) and transplantation (animals). This study investigated the early expression of cytoprotective stress proteins during ischemia-reperfusion induced by PHC. Liver samples were taken before and after each event in a two-cycle ischemia-reperfusion protocol using 15 minutes of PHC followed by 5 minutes of reperfusion. Liver tissue was analyzed by real-time polymerase chain reaction for heme oxygenase (HO)-1 and heat shock protein (HSP)-70 mRNA expression. Extracted protein was analyzed by Western blot for HO-1, and HSP-70 and nuclear extracts were analyzed by DNA mobility shift assay for hypoxia inducible factor (HIF)-1&agr; and heat shock factor (HSF)-1. Within minutes of PHC, significant increases in HO-1 mRNA expression were detected, and these were maintained throughout the protocol (P<0.01). Protein expression of HO-1 (P<0.03) and HO-1 activity (P<0.05) were similarly increased between the start and end of ischemia- reperfusion (40 minutes). Binding of active HIF-1&agr; to its consensus sequence was increased within 15 minutes of the start of the ischemia-reperfusion cycle. Although evidence of the transcriptionally active form of HSF-1 was detected at the same time point, this was not reflected in measurable changes in HSP-70 mRNA or protein. In conclusion, expression of the cytoprotective protein HO-1 is significantly up-regulated in the liver within minutes of PHC. It is likely that HO-1 contributes to the early protective effects of ischemic preconditioning.

Curcumin induces heme oxygenase-1 in hepatocytes and is protective in simulated cold preservation and warm reperfusion injury.

Preconditioning treatments hold significant potential for improving outcomes in solid organ transplantation. Protective phenotypes can be induced using certain drugs. Curcumin is a biologically active component of turmeric and has been reported to induce stress proteins in certain cell lines, leading to cell protection. This study investigates in detail the effect of curcumin on the stress-response in human hepatocytes, in particular its effect on heme oxygenase 1 (HO-1) and its cytoprotective effect. Pretreatment with curcumin protected hepatocytes in a model of oxidative injury and this protection was mediated through HO-1. In a model of cold preservation injury, curcumin pretreatment resulted in elevation of HO-1 throughout the cold storage and rewarming period, and was cytoprotective against oxidative injury. This is the first study to demonstrate that curcumin induces HO-1 in human hepatocytes, and that the protective effects of curcumin pretreatment may have clinical potential in hepatic transplantation.

Heat shock protein 90-binding agents protect renal cells from oxidative stress and reduce kidney ischemia-reperfusion injury.

Heat shock proteins (Hsps) are protective in models of transplantation, yet practical strategies to upregulate them remain elusive. The heat shock protein 90-binding agent (HBA) geldanamycin and its analogs (17-AAG and 17-DMAG) are known to upregulate Hsps and confer cellular protection but have not been investigated in a model relevant to transplantation. We examined the ability of HBAs to upregulate Hsp expression and confer protection in renal adenocarcinoma (ACHN) cells in vitro and in a mouse model of kidney ischemia-reperfusion (I/R) injury. Hsp70 gene expression was increased 30-40 times in ACHN cells treated with HBAs, and trimerization and DNA binding of heat shock transcription factor-1 (HSF1) were demonstrated. A three- and twofold increase in Hsp70 and Hsp27 protein expression, respectively, was found in ACHN cells treated with HBAs. HBAs protected ACHN cells from an H2O2-mediated oxidative stress, and HSF1 short interfering RNA was found to abrogate HBA-mediated Hsp induction and protection. In vivo, Hsp70 was upregulated in the kidneys, liver, lungs, and heart of HBA-treated mice. This was associated with a functional and morphological renal protection from I/R injury. Therefore, HBAs mediate upregulation of protective Hsps in mouse kidneys which are associated with reduced I/R injury and may be useful in reducing transplant-associated kidney injury.

Analgesia after open abdominal surgery in the setting of enhanced recovery surgery: a systematic review and meta-analysis.

IMPORTANCE The optimal analgesic technique following open abdominal surgery within an enhanced recovery protocol remains controversial. Thoracic epidural is often recommended; however, its role is increasingly being challenged and alternative techniques are being suggested as suitable replacements. OBJECTIVE To determine by meta-analysis whether epidurals are superior to alternative analgesic techniques following open abdominal surgery within an enhanced recovery setting in terms of postoperative morbidity and other markers of recovery. DATA SOURCES A literature search was performed of EMBASE, Medline, PubMed, and the Cochrane databases from 1966 through May 2013. STUDY SELECTION All randomized clinical trials comparing epidurals with an alternative analgesic technique following open abdominal surgery within an enhanced recovery protocol were included. DATA EXTRACTION AND SYNTHESIS All studies were assessed by 2 independent reviewers. Study quality was assessed using the Cochrane bias assessment tool and the Jadad and Chalmers modified bias risk assessment tools. Dichotomous data were analyzed by random or fixed-effects odds ratios. Qualitative analysis was performed where appropriate. RESULTS Seven trials with a total of 378 patients were identified. No significant difference in complication rate was detected between epidurals and alternative analgesic methods (odds ratio, 1.14; 95% CI, 0.49-2.64; P = .76). Subgroup analysis showed fewer complications in the patient-controlled analgesia group compared with epidural analgesia (odds ratio, 1.97; 95% CI, 1.10-3.53; P = .02). Following qualitative assessment, epidural analgesia was associated with faster return of gut function and reduced pain scores; however, no difference was observed in length of stay. CONCLUSIONS AND RELEVANCE Epidurals may be associated with superior pain control but this does not translate into improved recovery or reduced morbidity when compared with alternative analgesic techniques when used within an enhanced recovery protocol.

Hospital volume and patient outcomes after cholecystectomy in Scotland: retrospective, national population based study

Objectives To define associations between hospital volume and outcomes following cholecystectomy, after adjustment for case mix using a national database. Design Retrospective, national population based study using multilevel modelling and simulation. Setting Locally validated administrative dataset covering all NHS hospitals in Scotland. Participants All patients undergoing cholecystectomy between 1 January 1998 and 31 December 2007. Main outcome measures Mortality, 30 day reoperation rate, 30 day readmission rate, and length of stay. Results We identified 59 918 patients who had a cholecystectomy in one of 37 hospitals: five hospitals had high volumes (>244 cholecystectomies/year), 10 had medium volumes (173-244), and 22 had low volumes (<173). Compared with low and medium volume hospitals, high volume hospitals performed more procedures non-electively (17.1% and 19.5% v 32.8%), completed more procedures laparoscopically (64.7% and 73.8% v 80.9%), and used more operative cholangiography (11.2% and 6.3% v 21.2%; χ2 test, all P<0.001). In a well performing multivariable analysis with bias correction for a low event rate, the odds ratio for death was greater in both the low volume (odds ratio 1.45, 95% confidence interval 1.06 to 2.00, P=0.022) and medium volume (1.52, 1.11 to 2.08, P=0.010) groups than in the high volume group. However, in simulation studies, absolute risk differences between volume groups were clinically negligible for patients with average risk (number needed to treat to harm, low v high volume, 3871, 1963 to 17 118), but were significant in patients with higher risk. In models accounting for the hierarchical structure of patients in hospitals, those in medium volume hospitals were more likely to undergo reoperation (odds ratio 1.74, 1.31 to 2.30, P<0.001) or be readmitted (1.17, 1.04 to 1.31, P=0.008) after cholecystectomy than those in high volume hospitals. Length of stay was shorter in high volume hospitals than in low (hazard ratio for discharge 0.78, 0.76 to 0.79, P<0.001) or medium volume hospitals (0.75, 0.74 to 0.77, P<0.001). These differences were also only of clinical significance in patients at higher risk. Conclusions There is wide variation among hospitals in the management of gallstone disease and an association between higher hospital volume and better outcome after a cholecystectomy. The relative risk of death is lower in high volume centres, and although absolute risk differences between volume groups are significant for elderly patients and patients with comorbidity, they are clinically negligible for those at average risk.

Insulin induces heme oxygenase-1 through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in renal cells.

Heme oxygenase‐1 catalyzes the breakdown of heme and is protective in models of kidney transplantation. In this study we describe the induction of heme oxygenase‐1 mRNA and protein by insulin. Following treatment with insulin, a five‐fold increase in heme oxygenase‐1 mRNA and a four‐fold increase in protein expression were observed in renal adenocarcinoma cells; insulin‐induced heme oxygenase‐1 expression was also demonstrated in mouse primary tubular epithelial cells. The induction of heme oxygenase‐1 in renal adenocarcinoma cells was blocked by actinomycin D and cycloheximide and was abolished by the phosphatidylinositol 3‐kinase inhibitor, LY294002, but not by the inactive analog LY303511. Overexpressing a dominant‐negative form of Akt abrogated the heme oxygenase‐1‐inducing effects of insulin, whereas cells transfected with a constitutively active Akt construct demonstrated an increase in heme oxygenase‐1 promoter activity and protein expression. The transcription factor NF‐E2‐related factor‐2 was found to translocate to the nucleus following insulin treatment in a phosphatidylinositol 3‐kinase‐dependent manner. Pretreatment with NF‐E2‐related factor‐2 small‐interfering RNA abolished insulin‐induced heme oxygenase‐1 induction. Insulin was also found to activate the mitogen‐activated protein kinase cascades p38 and extracellular signal‐related kinase; however, inhibition of these pathways with SB202190 and PD98059 did not alter insulin‐induced heme oxygenase‐1 expression. Thus, insulin induces heme oxygenase‐1 mRNA and protein expression in renal cells in a phosphatidylinositol 3‐kinase/Akt and NF‐E2‐related factor‐2‐dependent manner.

Perforated peptic ulcer

Summary Perforated peptic ulcer (PPU) is a frequent emergency condition worldwide with associated mortality up to 30%. A paucity of studies on PPU limits the knowledge base for clinical decision-making, but a few randomised trials are available. While Helicobacter pylori and use of non-steroidal anti-inflammatory drugs are frequent causes of PPU, demographic differences in age, gender, perforation location and aetiology exist between countries, as do mortality rates. Clinical prediction rules are used, but accuracy varies with study population. Early surgery, either by laparoscopic or open repair, and proper sepsis management are essential for good outcome. Selected patients can perhaps be managed non-operatively or with novel endoscopic approaches, but validation in trials is needed. Quality of care, sepsis care-bundles and postoperative monitoring need further evaluation. Adequate trials with low risk of bias are urgently needed for better evidence. Here we summarize the evidence for PPU management and identify directions for future clinical research.

A meta-analysis and meta-regression of outcomes including biliary complications in donation after cardiac death liver transplantation

Donation after cardiac death (DCD) liver transplantation is increasingly common but concerns exist over the development of biliary complications and ischemic cholangiopathy (IC). This study aimed to compare outcomes between DCD and donation after brain death (DBD) liver grafts. Studies reporting on post‐transplantation outcomes after Maastricht category III DCD liver transplantation were screened for inclusion. Odds ratios (OR) with 95% confidence intervals were produced using random‐effects models for the incidence of biliary complications, IC, graft and recipient survival. Meta‐regression was undertaken to identify between‐study predictors of effect size for biliary complications and IC. PROSPERO Record: CRD42012002113. Twenty‐five studies with 62 184 liver transplant recipients (DCD = 2478 and DBD = 59 706) were included. In comparison with DBD, there was a significant increase in biliary complications [OR = 2.4 (1.9, 3.1); P < 0.00001] and IC [OR = 10.5 (5.7, 19.5); P < 0.00001] following DCD liver transplantation. In comparison with DBD, at 1 year [OR = 0.7 (0.5, 0.8); P = 0.0002] and 3 years [OR = 0.6 (0.5, 0.8); P = 0.001], there was a significant decrease in graft survival following DCD liver transplantation. At 1 year, there was also a nonsignificant decrease [OR = 0.8 (0.6, 1.0); P = 0.08] and by 3 years a significant decrease [OR = 0.7 (0.5, 1.0); P = 0.04] found in recipient survival following DCD liver transplantation. Eleven factors were entered into meta‐regression models, but none explained the variability in effect size between studies. DCD liver transplantation is associated with an increase in biliary complications, IC, graft loss and mortality. Significant unexplained differences in effect size exist between centers.

Heat-Shock Proteins and Acute Ischaemic Kidney Injury

The incidence of acute kidney injury due to ischaemia-reperfusion injury (IRI) is rising but effective treatments and preventative approaches are currently lacking. IRI is also an inevitable consequence of kidney transplantation and significantly contributes to delayed graft function. Heat-shock proteins (Hsps) are highly conserved and ubiquitously expressed molecular chaperones that help maintain and restore normal cellular function in the kidney following IRI. Hsp70 is one of the most frequently studied Hsps because of potential cytoprotective properties and attractiveness as a therapeutic target. However, the protective properties of Hsp70 in renal IRI are not fully understood and putative modes of protection include correction of protein conformation, cytoskeletal stabilisation, anti-inflammatory effects, requirement in autophagy, anti-apoptotic properties, influence over macrophage phenotype and stimulation of regulatory T cells. Significant clinical interest has been generated about the possibility of applying pharmacological agents to induce Hsp70 and prevent renal IRI, but prior to this, an increased mechanistic understanding of the protective nature of Hsp70 is needed. In particular, further investigation of Hsp expression on inflammatory cell behaviour is required as this could lead to the development of new therapeutic strategies for enhancing recovery following renal IRI and broaden the range of these therapies to a wider group of patients.