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The TARGIT-A trial compared risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (TARGIT) versus fractionated external beam radiotherapy (EBRT) for breast cancer. We report 5-year results for local recurrence and the first analysis of overall survival. TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684. Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of 1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median follow-up of 2 years and 5 months (IQR 12–52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local recurrence in the conserved breast was 3·3% (95% CI 2·1–5·1) for TARGIT versus 1·3% (0·7–2·5) for EBRT (p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT: 2·1% (1·1–4·2) versus 1·1% (0·5–2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group difference was larger than 2·5% (TARGIT 5·4% [3·0–9·7] vs EBRT 1·7% [0·6–4·9]; p=0·069). Overall, breast cancer mortality was much the same between groups (2·6% [1·5–4·3] for TARGIT vs 1·9% [1·1–3·2] for EBRT; p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8–2·5] vs 3·5% [2·3–5·2]; p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3·9% (2·7–5·8) for TARGIT versus 5·3% (3·9–7·3) for EBRT (p=0·099). Wound-related complications were much the same between groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731, p=0·029). TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative EBRT. University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research.

Patients undergoing cardiac surgery often receive red-cell transfusions, along with the associated risks and costs. Early intraoperative normovolemic hemodilution (i.e., acute normovolemic hemodilution [ANH]) is a blood-conservation technique that entails autologous blood collection before initiation of cardiopulmonary bypass and reinfusion of the collected blood after bypass weaning. More data are needed on whether ANH reduces the number of patients receiving allogeneic red-cell transfusion. In a multinational, single-blind trial, we randomly assigned adults from 32 centers and 11 countries who were undergoing cardiac surgery with cardiopulmonary bypass to receive ANH (withdrawal of ≥650 ml of whole blood with crystalloids replacement if needed) or usual care. The primary outcome was the transfusion of at least one unit of allogeneic red cells during the hospital stay. Secondary outcomes were death from any cause within 30 days after surgery or during the hospitalization for surgery, bleeding complications, ischemic complications, and acute kidney injury. A total of 2010 patients underwent randomization; 1010 were assigned to ANH and 1000 to usual care. Among patients with available data, 274 of 1005 (27.3%) in the ANH group and 291 of 997 (29.2%) in the usual-care group received at least one allogeneic red-cell transfusion (relative risk, 0.93; 95% confidence interval, 0.81 to 1.07; P = 0.34). Surgery for postoperative bleeding was performed in 38 of 1004 patients (3.8%) in the ANH group and 26 of 995 patients (2.6%) in the usual-care group. Death within 30 days or during hospitalization occurred in 14 of 1008 patients (1.4%) in the ANH group and 16 of 997 patients (1.6%) in the usual-care group. Safety outcomes were similar in the two groups. Among adults undergoing cardiac surgery, ANH did not reduce the number of patients receiving allogeneic red-cell transfusion. (Funded by the Italian Ministry of Health; ANH ClinicalTrials.gov number, NCT03913481.).

The optimal level of positive end–expiratory pressure (PEEP) during minimally invasive abdominal surgery is uncertain. Intraoperative ventilation with individualized high PEEP and recruitment maneuvers can be used to keep the driving pressure (ΔP) low, but can also lead to hypotension. In addition, the resulting ΔP and feasibility of individualized high PEEP in minimally invasive abdominal surgery is unclear. Planned interim analysis on safety and feasibility of ‘Driving Pressure During General Anesthesia for Minimally Invasive Abdominal Surgery’ (GENERATOR), an ongoing randomized clinical trial that compares individualized high PEEP, titrated to the lowest ΔP, with a standard low PEEP ventilation strategy with respect to postoperative pulmonary complications. The primary endpoint for this analysis was the proportion of patients with intraoperative hypotension. Secondary endpoints were other intraoperative complications, ventilation variables and feasibility parameters. From December 2023 to July 2024, 181 patients were enrolled. Data for analysis were available for 177 patients, of which 87 patients were randomized to individualized high PEEP and 90 to standard low PEEP. Intraoperative hypotension was similar between the individualized high PEEP vs standard low PEEP group (11.5 vs 11.1 %, relative risk ratio 1.0 [95 % CI 0.5–2.4], p = 1.00), while vasopressor use was higher in the intervention group. The median difference in ΔP between both groups was 6 cm H2O. Protocol compliance was 81.6 % in the individualized high PEEP group vs 97.8 % in the standard low PEEP group; most instances of non–compliance in the individualized high PEEP group concerned a level of PEEP that was too high. In minimally invasive abdominal surgery, a ventilation strategy using individualized high PEEP was not associated with a higher incidence of hypotension, but did show an increased use of vasopressors. The intervention was highly feasible, and led to a lower ΔP. These interim findings warrant confirmation in the main analysis of GENERATOR. This research was funded by ZonMW, grant number 10390012110091. •Individualized high PEEP ventilation is feasible in minimally invasive abdominal surgery.•Intraoperative hypotension is similar between individualized high PEEP and standard low PEEP.•Vasopressors were used in higher doses with individualized high PEEP compared to standard low PEEP.•Driving pressure was lower with individualized high PEEP compared to standard low PEEP.

Postoperative ileus is common after abdominal surgery, and small clinical studies have reported that intraoperative administration of dexmedetomidine may be associated with improvements in postoperative gastrointestinal function. However, findings have been inconsistent and study samples have been small. Further examination of the effects of intraoperative dexmedetomidine on postoperative gastrointestinal function is needed. To evaluate the effects of intraoperative intravenous dexmedetomidine vs placebo on postoperative gastrointestinal function among older patients undergoing abdominal surgery. This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at the First Affiliated Hospital of Anhui Medical University in Hefei, China (lead site), and 12 other tertiary hospitals in Anhui Province, China. A total of 808 participants aged 60 years or older who were scheduled to receive abdominal surgery with an expected surgical duration of 1 to 6 hours were enrolled. The study was conducted from August 21, 2018, to December 9, 2019. Dexmedetomidine infusion (a loading dose of 0.5 μg/kg over 15 minutes followed by a maintenance dose of 0.2 μg/kg per hour) or placebo infusion (normal saline) during surgery. The primary outcome was time to first flatus. Secondary outcomes were postoperative gastrointestinal function measured by the I-FEED (intake, feeling nauseated, emesis, physical examination, and duration of symptoms) scoring system, time to first feces, time to first oral feeding, incidence of delirium, pain scores, sleep quality, postoperative nausea and vomiting, hospital costs, and hospital length of stay. Among 808 patients enrolled, 404 were randomized to receive intraoperative dexmedetomidine, and 404 were randomized to receive placebo. In total, 133 patients (60 in the dexmedetomidine group and 73 in the placebo group) were excluded because of protocol deviations, and 675 patients (344 in the dexmedetomidine group and 331 in the placebo group; mean [SD] age, 70.2 [6.1] years; 445 men [65.9%]) were included in the per-protocol analysis. The dexmedetomidine group had a significantly shorter time to first flatus (median, 65 hours [IQR, 48-78 hours] vs 78 hours [62-93 hours], respectively; P < .001), time to first feces (median, 85 hours [IQR, 68-115 hours] vs 98 hours [IQR, 74-121 hours]; P = .001), and hospital length of stay (median, 13 days [IQR, 10-17 days] vs 15 days [IQR, 11-18 days]; P = .005) than the control group. Postoperative gastrointestinal function (as measured by the I-FEED score) and delirium incidence were similar in the dexmedetomidine and control groups (eg, 248 patients [72.1%] vs 254 patients [76.7%], respectively, had I-FEED scores indicating normal postoperative gastrointestinal function; 18 patients [5.2%] vs 12 patients [3.6%] had delirium on postoperative day 3). In this randomized clinical trial, the administration of intraoperative dexmedetomidine reduced the time to first flatus, time to first feces, and length of stay after abdominal surgery. These results suggest that this therapy may be a viable strategy to enhance postoperative recovery of gastrointestinal function among older adults. Chinese Clinical Trial Registry Identifier: ChiCTR1800017232.

Delirium is a common and serious postoperative complication. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia, and some evidence suggests that ketamine prevents delirium. The primary purpose of this trial was to assess the effectiveness of ketamine for prevention of postoperative delirium in older adults. The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] study is a multicentre, international randomised trial that enrolled adults older than 60 years undergoing major cardiac and non-cardiac surgery under general anaesthesia. Using a computer-generated randomisation sequence we randomly assigned patients to one of three groups in blocks of 15 to receive placebo (normal saline), low-dose ketamine (0·5 mg/kg), or high dose ketamine (1·0 mg/kg) after induction of anaesthesia, before surgical incision. Participants, clinicians, and investigators were blinded to group assignment. Delirium was assessed twice daily in the first 3 postoperative days using the Confusion Assessment Method. We did analyses by intention-to-treat and assessed adverse events. This trial is registered with clinicaltrials.gov, number NCT01690988. Between Feb 6, 2014, and June 26, 2016, 1360 patients were assessed, and 672 were randomly assigned, with 222 in the placebo group, 227 in the 0·5 mg/kg ketamine group, and 223 in the 1·0 mg/kg ketamine group. There was no difference in delirium incidence between patients in the combined ketamine groups and the placebo group (19·45% vs 19·82%, respectively; absolute difference 0·36%, 95% CI −6·07 to 7·38, p=0·92). There were more postoperative hallucinations (p=0·01) and nightmares (p=0·03) with increasing ketamine doses compared with placebo. Adverse events (cardiovascular, renal, infectious, gastrointestinal, and bleeding), whether viewed individually (p value for each >0·40) or collectively (36·9% in placebo, 39·6% in 0·5 mg/kg ketamine, and 40·8% in 1·0 mg/kg ketamine groups, p=0·69), did not differ significantly across groups. A single subanaesthetic dose of ketamine did not decrease delirium in older adults after major surgery, and might cause harm by inducing negative experiences. National Institutes of Health and Cancer Center Support.

Background The case has been made for more and better theory-informed process evaluations within trials in an effort to facilitate insightful understandings of how interventions work. In this paper, we provide an explanation of implementation processes from one of the first national implementation research randomized controlled trials with embedded process evaluation conducted within acute care, and a proposed extension to the Promoting Action on Research Implementation in Health Services (PARIHS) framework. Methods The PARIHS framework was prospectively applied to guide decisions about intervention design, data collection, and analysis processes in a trial focussed on reducing peri-operative fasting times. In order to capture a holistic picture of implementation processes, the same data were collected across 19 participating hospitals irrespective of allocation to intervention. This paper reports on findings from data collected from a purposive sample of 151 staff and patients pre- and post-intervention. Data were analysed using content analysis within, and then across data sets. Results A robust and uncontested evidence base was a necessary, but not sufficient condition for practice change, in that individual staff and patient responses such as caution influenced decision making. The implementation context was challenging, in which individuals and teams were bounded by professional issues, communication challenges, power and a lack of clarity for the authority and responsibility for practice change. Progress was made in sites where processes were aligned with existing initiatives. Additionally, facilitators reported engaging in many intervention implementation activities, some of which result in practice changes, but not significant improvements to outcomes. Conclusions This study provided an opportunity for reflection on the comprehensiveness of the PARIHS framework. Consistent with the underlying tenant of PARIHS, a multi-faceted and dynamic story of implementation was evident. However, the prominent role that individuals played as part of the interaction between evidence and context is not currently explicit within the framework. We propose that successful implementation of evidence into practice is a planned facilitated process involving an interplay between individuals, evidence, and context to promote evidence-informed practice. This proposal will enhance the potential of the PARIHS framework for explanation, and ensure theoretical development both informs and responds to the evidence base for implementation. Trial registration ISRCTN18046709 - Peri-operative Implementation Study Evaluation (PoISE).

BackgroundInsufficient vascular supply is one of the main causes of anastomotic leak in colorectal surgery. Intraoperative indocyanine-green (ICG) angiography has been shown to provide information on tissue perfusion, identifying a well-perfused location for colonic and rectal transections, and thus possibly reducing the leak rate. Aim of this study was to evaluate the usefulness of intraoperative assessment of anastomotic perfusion using ICG angiography in patients undergoing left-sided colon or rectal resection with colorectal anastomosis.MethodsThis randomized trial involved 252 patients undergoing laparoscopic left-sided colon and rectal resection randomized 1:1 to intraoperative ICG or to subjective visual evaluation of the bowel perfusion without ICG. The primary aim was to assess whether ICG angiography could lead to a reduction in anastomotic leak rate. Secondary outcomes were possible changes in the surgical strategy and postoperative morbidity.ResultsAfter randomization, 12 patients were excluded. Accordingly, 240 patients were included in the analysis; 118 were in the study group, and 122 in the control group. ICG angiography showed insufficient perfusion of the colic stump, which led to extended bowel resection in 13 cases (11%). An anastomotic leak developed in 11 patients (9%) in the control group and in 6 patients (5%) in the study group (p = n.s.).ConclusionsIntraoperative ICG fluorescent angiography can effectively assess vascularization of the colic stump and anastomosis in patients undergoing colorectal resection. This method led to further proximal bowel resection in 13 cases, however, there was no statistically significant reduction of anastomotic leak rate in the ICG arm.Clinical trialClinicalTrials.gov NCT02662946.

Postoperative acute kidney injury (AKI) is common after non-cardiac surgery. Normal saline and lactated Ringer's solution are both used for volume replacement during surgery. Normal saline decreases renal blood flow and causes hyperchloremic acidosis whereas lactated Ringer's does not. The incidence of AKI is similar with modest volumes of each fluid. But it remains unclear whether larger volumes of normal saline provoke AKI. Evaluate whether intraoperative crystalloid volume modifies the relationship between the AKI risk and treatment group. Secondary analysis of a single-center multiple cross-over cluster trial. Intraoperative care. We enrolled 8616 adults who had colorectal or orthopedic surgery at a large academic institution. Clusters of patients were alternately assigned to intraoperative normal saline or lactated Ringer's solution. The primary outcome was the incidence of acute kidney injury (AKI) as a function of intraoperative crystalloid volume (0–1, 1–2, 3–4, or 4+ liters) and the type of crystalloid. Our secondary outcome was the change in postoperative serum chloride concentration during the first 24 h. The risk of AKI did not differ significantly in patients given 0–1, 1–2, or 3–4 L saline or lactated Ringers solutions. In contrast, patients given 2–3 or > 4 L of lactated Ringer's solution had a higher risk of AKI than those given saline. Patients assigned to normal saline had progressively greater plasma chloride concentrations than those given lactated Ringer's across all volume categories. While saline administration clearly causes volume-dependent hyperchloremia, we found no evidence to support the theory that large volumes of saline provoke AKI. Therefore, either fluid seems reasonable for intraoperative use. •The incidence of AKI is similar with modest volumes of normal saline and lactated Ringer's solutions, but it remains unclear whether larger volumes of normal saline provoke AKI.•In a multiple cross-over cluster trial, 8616 patients were assigned to normal saline and lactated Ringer's solutions. Patients given 2–3 or > 4 L of lactated Ringer's solution had a higher risk of AKI than those given saline.•Normal saline and lactated Ringer's solutions both seem reasonable for intraoperative use.

Objectives To compare the clinical effectiveness of Kirschner wire fixation with locking plate fixation for patients with a dorsally displaced fracture of the distal radius.Design A multicentre two arm parallel group assessor blind randomised controlled trial with 1:1 treatment allocation.Setting 18 trauma centres in the United Kingdom.Participants 461 adults with a dorsally displaced fracture of the distal radius within 3 cm of the radiocarpal joint that required surgical fixation. Patients were excluded if the surgeon thought that the surface of the wrist joint was so badly displaced it required open reduction.Interventions Kirschner wire fixation: wires are passed through the skin over the dorsal aspect of the distal radius and into the bone to hold the fracture in the correct anatomical position. Locking plate fixation: a locking plate is applied through an incision over the volar (palm) aspect of the wrist and secured to the bone with fixed angle locking screws.Main outcome measures Primary outcome measure: validated patient rated wrist evaluation (PRWE). This rates wrist function in two (equally weighted) sections concerning the patient’s experience of pain and disability to give a score out of 100. Secondary outcomes: disabilities of arm, shoulder, and hand (DASH) score, the EuroQol (EQ-5D), and complications related to the surgery.Results The baseline characteristics of the two groups were well balanced, and over 90% of patients completed follow-up. The wrist function of both groups of patients improved by 12 months. There was no clinically relevant difference in the patient rated wrist score at three, six, or 12 months (difference in favour of the plate group was −1.3, 95% confidence interval −4.5 to 1.8; P=0.40). Nor was there a clinically relevant difference in health related quality of life or the number of complications in each group.Conclusions Contrary to the existing literature, and against the rapidly increasing use of locking plate fixation, this trial found no difference in functional outcome in patients with dorsally displaced fractures of the distal radius treated with Kirschner wires or volar locking plates. Kirschner wire fixation, however, is cheaper and quicker to perform.Trial registration Current Controlled Trials ISCRTN 31379280. UKCRN 8956.

Background Inadvertent intraoperative hypothermia (core temperature < 36 °C) is a common but preventable adverse event. This study aimed to determine whether active intraoperative warming reduced bleeding in patients undergoing major operations: open thoracic surgery and hip replacement surgery. Methods / Design The study was a pilot, prospective, parallel two-arm randomized controlled trial. Eligible patients were randomly allocated to two groups: passive warming (PW), with application of a cotton blanket (thermal insulation), or active warming (AW), with a forced-air warming system. The primary endpoint was intraoperative blood loss, and secondary endpoints were surgical-site infection, cardiovascular events, and length of stay in the post-anesthesia care unit, intensive care unit, and hospital. Results Sixty-two patients were enrolled. Forced-air active warming maintained intraoperative normothermia in all AW subjects, whereas intraoperative hypothermia occurred in 21/32 (71.8%) of PW patients ( p  = 0.000). The volume of blood loss was more in the PW group (682 ± 426 ml) than in the AW group (464 ± 324 ml) ( p  < 0.021), and the perioperative hemoglobin value declined more in the PW group (28.6 ± 17.5 g/L) than in the AW group (21.0 ± 9.9 g/L) ( p  = 0.045). However, there were no difference in other clinical outcomes between two groups. Conclusion Intraoperative active warming is associated with less blood loss than passive warming in open thoracic and hip replacement operations in this pilot study. Trial registration This trial was registered with Clinicaltrials.gov (Identifier: NCT02214524 ) on 27 August 2014.