Stephen O'Neill

Clinical effectiveness of transversus abdominis plane (TAP) block in abdominal surgery: a systematic review and meta‐analysis

Aim  Reduced opioid use in the immediate postoperative period is associated with decreased complications. This study aimed to determine the effect of transversus abdominis plane (TAP) block on morphine requirements 24 h after abdominal surgery. Secondary outcomes included the effect of TAP block on morphine use 48 h after surgery, incidence of postoperative nausea and vomiting (PONV) and impact on reported pain scores (visual analogue scale).

Systematic review and meta-analysis of continuous local anaesthetic wound infiltration versus epidural analgesia for postoperative pain following abdominal surgery

Local anaesthetic wound infiltration techniques reduce opiate requirements and pain scores. Wound catheters have been introduced to increase the duration of action of local anaesthetic by continuous infusion. The aim was to compare these infiltration techniques with the current standard of epidural analgesia.

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.

Evaluation of novel local anesthetic wound infiltration techniques for postoperative pain following colorectal resection surgery: a meta-analysis

BACKGROUND: Novel local anesthetic blocks have become increasingly popular in the multimodal pain management following abdominal surgery, but have not been evaluated in a procedure-specific manner in colorectal surgery. OBJECTIVE: This study aims to evaluate the efficacy of novel local anesthetic techniques in colorectal surgery. DATA SOURCES: Electronic literature search of PubMed, EMBASE, and Cochrane databases (date range, January 1990 to February 2013) STUDY SELECTION: Randomized controlled trials comparing a novel local anesthetic technique with placebo/routine analgesia in adults undergoing open or laparoscopic colonic or rectal resection were selected. INTERVENTIONS: This is a meta-analysis of randomized controlled trials evaluating novel local anesthetic wound infiltration techniques such as wound catheter, transversus abdominis plane block, and intraperitoneal instillation in colorectal surgical procedures. The comparator group was defined as placebo/routine analgesia. OUTCOME MEASURES: The primary outcome was opiate requirement at 24 hours. Secondary outcomes included opiate requirements at 48 hours, pain numerical rating score at 24 and 48 hours at rest and on movement, recovery (length of stay, nausea and vomiting, time until bowel movement and diet resumption), and complications. Subgroup analysis was performed to evaluate specific local anesthetic techniques and open and laparoscopic surgery. RESULTS: Twelve randomized controlled trials compared local anesthetic techniques with placebo/routine analgesia. Local anesthetic techniques demonstrated a significant reduction in opiate requirement at 48 hours. Local anesthetic techniques were also associated with lower pain scores on movement at 24 and 48 hours, shorter length of stay, and earlier resumption of diet. LIMITATIONS: The diverse study design led to statistical heterogeneity in several analyses. CONCLUSIONS: Novel local anesthetic wound infiltration techniques in colorectal surgery appear to reduce opiate requirements, to reduce pain scores, and to improve recovery in comparison with placebo/routine analgesia.

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.

Meta-analysis of ischaemic preconditioning for liver resections.

Vascular clamping reduces blood loss during liver resection but leads to ischaemia–reperfusion injury. Ischaemic preconditioning (IP) may reduce this. This study aimed to evaluate IP in liver resection under clamping.

The role of heat shock protein 90 in modulating ischemia-reperfusion injury in the kidney

Introduction: Kidney transplantation is the gold standard treatment for end-stage renal disease. Ischemia–reperfusion injury (IRI) is an unavoidable consequence of the transplantation procedure and is responsible for delayed graft function and poorer long-term outcomes. Areas covered: Pharmacological induction of heat shock protein (Hsp) expression is an emerging pre-conditioning strategy aimed at reducing IRI following renal transplantation. Hsp90 inhibition up-regulates protective Hsps (especially Hsp70) and potentially down-regulates NF-κB by disruption of the IκB kinase (IKK) complex. However, the clinical application of Hsp90 inhibitors is currently limited by their toxicity profile and the exact mechanism of protection conferred is unknown. Toll-like receptor 4 (TLR4) is a further regulator of NF-κB and recent studies suggest TLR4 plays a dominant role in mediating kidney damage following IRI. The full interaction of Hsps with TLRs is yet to be delineated and whether TLR4 signalling can be targeted by Hsp90 inhibition in IRI remains uncertain. Expert opinion: Pharmacological pre-conditioning by Hsp90 inhibition involves direct treatment to the kidney donor and/or organ, which aims to reduce injury prior to the onset of ischemia. The major challenges going forward are to establish the exact mechanism of protection offered by these drugs and the investgiation of less toxic analogues that could be safely translated into human studies.

Heat shock protein 90 inhibition abrogates TLR4-mediated NF-κB activity and reduces renal ischemia-reperfusion injury

Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury. Toll-like receptor 4 (TLR4) mediates sterile inflammation following renal IRI. Heat shock protein 90 (Hsp90) inhibition is a potential strategy to reduce IRI, and AT13387 is a novel Hsp90 inhibitor with low toxicity. This study assessed if pre-treatment with AT13387 could reduce renal IRI and established if the mechanism of protection involved a reduction in inflammatory signalling. Mice were pre-treated with AT13387 prior to renal IRI. 24 h later, renal function was determined by serum creatinine, kidney damage by tubular necrosis score, renal TLR4 expression by PCR and inflammation by cytokine array. In vitro, human embryonic kidney cells were co-transfected to express TLR4 and a secreted alkaline phosphatase NF-κB reporter. Cells were pre-treated with AT13387 and exposed to endotoxin-free hyaluronan to stimulate sterile TLR4-specific NF-κB inflammatory activation. Following renal IRI, AT13387 significantly reduced serum creatinine, tubular necrosis, TLR4 expression and NF-κB-dependent chemokines. In vitro, AT13387-treatment resulted in breakdown of IκB kinase, which abolished TLR4-mediated NF-κB activation by hyaluronan. AT13387 is a new agent with translational potential that reduces renal IRI. The mechanism of protection may involve breakdown of IκB kinase and repression of TLR4-mediated NF-κB inflammatory activity.

Clinical involvement and transparency in medical apps; not all apps are equal.

theless, it is generally accepted that authorship disclosure, as well as conflict of interest disclosure, affects users‘ perceptions of interest, validity, reliability and usability. In conclusion, we agree with the authors that physicians should be aware of both the opportunities and risks caused by medical apps and should critically appraise them. More regulatory guidance is needed involving all stakeholders and a patient-centred approach to safeguard patient safety and improve quality of care [4].

Challenges in early clinical drug development for ischemia-reperfusion injury in kidney transplantation

Introduction: In an effort to expand the donor pool, kidneys from donation after cardiac death (DCD) donors are increasingly utilised in renal transplantation. These kidneys suffer greater ischemia-reperfusion injury (IRI) and have a higher incidence of delayed graft function. In the last 25 years, relatively few pharmacological therapies to reduce IRI have been tested in randomised controlled trials in renal transplantation and currently no pharmacological agents are routinely utilised for this purpose. Areas covered: The authors look at why promising treatments in pre-clinical studies have not translated to significant clinical benefit in human trials. This may reflect a translational disconnect between the pre-clinical models used and clinical problems that are encountered in the transplant population. They also discuss the issues in conducting clinical trials and its implication on drug development. Expert opinion: Translating pharmacological strategies for reducing IRI is highly challenging at every stage of development from pre-clinical studies to clinical trials. Scientific knowledge of the complexity of IRI is rapidly evolving and new treatments are expected to emerge. There are ethical barriers that prevent donor treatments, particularly in the DCD setting. However, new clinical techniques such as normothermic regional and ex-vivo perfusion represent exciting opportunities to utilise pharmacological agents earlier in the process of transplantation.