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Background Colorectal cancer (CRC) is the second most prevalent type of cancer in the world. Surgery is the only curative option. However, postoperative complications occur in up to 50% of patients and are associated with higher morbidity and mortality rates, lower health related quality of life (HRQoL) and increased expenditure in health care. The number and severity of complications are closely related to preoperative functional capacity, nutritional state, psychological state, and smoking behavior. Traditional approaches have targeted the postoperative period for rehabilitation and lifestyle changes. However, recent evidence shows that the preoperative period might be the optimal moment for intervention. This study will determine the impact of multimodal prehabilitation on patients’ functional capacity and postoperative complications. Methods/design This international multicenter, prospective, randomized controlled trial will include 714 patients undergoing colorectal surgery for cancer. Patients will be allocated to the intervention group, which will receive 4 weeks of prehabilitation (group 1, prehab), or the control group, which will receive no prehabilitation (group 2, no prehab). Both groups will receive perioperative care in accordance with the enhanced recovery after surgery (ERAS) guidelines. The primary outcomes for measurement will be functional capacity (as assessed using the six-minute walk test (6MWT)) and postoperative status determined with the Comprehensive Complication Index (CCI). Secondary outcomes will include HRQoL, length of hospital stay (LOS) and a cost-effectiveness analysis. Discussion Multimodal prehabilitation is expected to enhance patients’ functional capacity and to reduce postoperative complications. It may therefore result in increased survival and improved HRQoL. This is the first international multicenter study investigating multimodal prehabilitation for patients undergoing colorectal surgery for cancer. Trial registration Trial Registry: NTR5947 – date of registration: 1 August 2016.

Rapid reversal of vitamin K antagonist (VKA)-induced anticoagulation is often necessary for patients needing urgent surgical or invasive procedures. The optimum means of VKA reversal has not been established in comparative clinical trials. We compared the efficacy and safety of four-factor prothrombin complex concentrate (4F-PCC) with that of plasma in VKA-treated patients needing urgent surgical or invasive procedures. In a multicentre, open-label, phase 3b randomised trial we enrolled patients aged 18 years or older needing rapid VKA reversal before an urgent surgical or invasive procedure. We randomly assigned patients in a 1:1 ratio to receive vitamin K concomitant with a single dose of either 4F-PCC (Beriplex/Kcentra/Confidex; CSL Behring, Marburg, Germany) or plasma, with dosing based on international normalised ratio (INR) and weight. The primary endpoint was effective haemostasis, and the co-primary endpoint was rapid INR reduction (≤1·3 at 0·5 h after infusion end). The analyses were intended to evaluate, in a hierarchical fashion, first non-inferiority (lower limit 95% CI greater than −10% for group difference) for both endpoints, then superiority (lower limit 95% CI >0%) if non-inferiority was achieved. Adverse events and serious adverse events were reported to days 10 and 45, respectively. This trial is registered at ClinicalTrials.gov, number NCT00803101. 181 patients were randomised (4F-PCC n=90; plasma n=91). The intention-to-treat efficacy population comprised 168 patients (4F-PCC, n=87; plasma, n=81). Effective haemostasis was achieved in 78 (90%) patients in the 4F-PCC group compared with 61 (75%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 14·3%, 95% CI 2·8–25·8). Rapid INR reduction was achieved in 48 (55%) patients in the 4F-PCC group compared with eight (10%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 45·3%, 95% CI 31·9–56·4). The safety profile of 4F-PCC was generally similar to that of plasma; 49 (56%) patients receiving 4F-PCC had adverse events compared with 53 (60%) patients receiving plasma. Adverse events of interest were thromboembolic adverse events (six [7%] patients receiving 4F-PCC vs seven [8%] patients receiving plasma), fluid overload or similar cardiac events (three [3%] patients vs 11 [13%] patients), and late bleeding events (three [3%] patients vs four [5%] patients). 4F-PCC is non-inferior and superior to plasma for rapid INR reversal and effective haemostasis in patients needing VKA reversal for urgent surgical or invasive procedures. CSL Behring.

Among 550 patients with stroke due to large-vessel occlusion who had presented within 4.5 hours after onset, 90-day functional outcomes were better with intravenous tenecteplase before thrombectomy than with thrombectomy alone.

Anaemia and iron deficiency are frequent in patients scheduled for cardiac surgery. This study assessed whether immediate preoperative treatment could result in reduced perioperative red blood cell (RBC) transfusions and improved outcome. In this single-centre, randomised, double-blind, parallel-group controlled study, patients undergoing elective cardiac surgery with anaemia (n=253; haemoglobin concentration (Hb) <120 g/L in women and Hb <130 g/L in men) or isolated iron deficiency (n=252; ferritin <100 mcg/L, no anaemia) were enrolled. Participants were randomly assigned (1:1) with the use of a computer-generated range minimisation (allocation probability 0·8) to receive either placebo or combination treatment consisting of a slow infusion of 20 mg/kg ferric carboxymaltose, 40 000 U subcutaneous erythropoietin alpha, 1 mg subcutaneous vitamin B12, and 5 mg oral folic acid or placebo on the day before surgery. Primary outcome was the number of RBC transfusions during the first 7 days. This trial is registered with ClinicalTrials.gov, number NCT02031289. Between Jan 9, 2014, and July 19, 2017, 1006 patients were enrolled; 505 with anaemia or isolated iron deficiency and 501 in the registry. The combination treatment significantly reduced RBC transfusions from a median of one unit in the placebo group (IQR 0–3) to zero units in the treatment group (0–2, during the first 7 days (odds ratio 0·70 [95% CI 0·50–0·98] for each threshold of number of RBC transfusions, p=0·036) and until postoperative day 90 (p=0·018). Despite fewer RBC units transfused, patients in the treatment group had a higher haemoglobin concentration, higher reticulocyte count, and a higher reticulocyte haemoglobin content during the first 7 days (p≤0·001). Combined allogeneic transfusions were less in the treatment group (0 [IQR 0–2]) versus the placebo group (1 [0–3]) during the first 7 days (p=0·038) and until postoperative day 90 (p=0·019). 73 (30%) serious adverse events were reported in the treatment group group versus 79 (33%) in the placebo group. An ultra-short-term combination treatment with intravenous iron, subcutaneous erythropoietin alpha, vitamin B12, and oral folic acid reduced RBC and total allogeneic blood product transfusions in patients with preoperative anaemia or isolated iron deficiency undergoing elective cardiac surgery. Vifor Pharma and Swiss Foundation for Anaesthesia Research.

Decreased surgical site infections (SSIs) and morbidity have been reported with mechanical and oral antibiotic bowel preparation (MOABP) compared with no bowel preparation (NBP) in colonic surgery. Several societies have recommended routine use of MOABP in patients undergoing colon resection on the basis of these data. Our aim was to investigate this recommendation in a prospective randomised context. In this multicentre, parallel, single-blinded trial, patients undergoing colon resection were randomly assigned (1:1) to either MOABP or NBP in four hospitals in Finland, using a web-based randomisation technique. Randomly varying block sizes (four, six, and eight) were used for randomisation, and stratification was done according to centre. The recruiters, treating physicians, operating surgeons, data collectors, and analysts were masked to the allocated treatment. Key exclusion criteria were need for emergency surgery; bowel obstruction; colonoscopy planned during surgery; allergy to polyethylene glycol, neomycin, or metronidazole; and age younger than 18 years or older than 95 years. Study nurses opened numbered opaque envelopes containing the patient allocated group, and instructed the patients according to the allocation group to either prepare the bowel, or not prepare the bowel. Patients allocated to MOABP prepared their bowel by drinking 2 L of polyethylene glycol and 1 L of clear fluid before 6 pm on the day before surgery and took 2 g of neomycin orally at 7 pm and 2 g of metronidazole orally at 11 pm the day before surgery. The primary outcome was SSI within 30 days after surgery, analysed in the modified intention-to-treat population (all patients who were randomly allocated to and underwent elective colon resection with an anastomosis) along with safety analyses. The trial is registered with ClinicalTrials.gov, NCT02652637, and EudraCT, 2015–004559–38, and is closed to new participants. Between March 17, 2016, and Aug 20, 2018, 738 patients were assessed for eligibility. Of the 417 patients who were randomised (209 to MOABP and 208 to NBP), 13 in the MOABP group and eight in the NBP were excluded before undergoing colonic resection; therefore, the modified intention-to-treat analysis included 396 patients (196 for MOABP and 200 for NBP). SSI was detected in 13 (7%) of 196 patients randomised to MOABP, and in 21 (11%) of 200 patients randomised to NBP (odds ratio 1·65, 95% CI 0·80–3·40; p=0·17). Anastomotic dehiscence was reported in 7 (4%) of 196 patients in the MOABP group and in 8 (4%) of 200 in the NBP group, and reoperations were necessary in 16 (8%) of 196 compared with 13 (7%) of 200 patients. Two patients died in the NBP group and none in the MOABP group within 30 days. MOABP does not reduce SSIs or the overall morbidity of colon surgery compared with NBP. We therefore propose that the current recommendations of using MOABP for colectomies to reduce SSIs or morbidity should be reconsidered. Vatsatautien Tutkimussäätiö Foundation, Mary and Georg Ehrnrooth's Foundation, and Helsinki University Hospital research funds.

Skin antisepsis with iodine povacrylex resulted in fewer surgical-site infections than antisepsis with chlorhexidine gluconate in patients with closed limb fractures but not in those with open fractures.

Rectal indometacin decreases the occurrence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). However, the population most at risk and the optimal timing of administration require further investigation. We aimed to assess whether pre-procedural administration of rectal indometacin in all patients is more effective than post-procedural use in only high-risk patients to prevent post-ERCP pancreatitis. We did a multicentre, single-blinded, randomised controlled trial at six centres in China. Eligible patients with native papilla undergoing ERCP were randomly assigned in a 1:1 ratio (with a computer-generated list) to universal pre-procedural indometacin or post-procedural indometacin in only high-risk patients, with stratification by trial centres and block size of ten. In the universal indometacin group, all patients received a single dose (100 mg) of rectal indometacin within 30 min before ERCP. In the risk-stratified, post-procedural indometacin group, only patients at predicted high risk received rectal indometacin, immediately after ERCP. Investigators, but not patients, were masked to group allocation. The primary outcome was overall ocurrence of post-ERCP pancreatitis. The analysis followed the intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT02002650. Between Dec 15, 2013, and Sept 21, 2015, 2600 patients were randomly assigned to universal, pre-procedural indometacin (n=1297) or risk-stratified, post-procedural indometacin (n=1303). Overall, post-ERCP pancreatitis occurred in 47 (4%) of 1297 patients assigned to universal indometacin and 100 (8%) of 1303 patients assigned to risk-stratified indometacin (relative risk 0·47; 95% CI 0·34–0·66; p<0·0001). Post-ERCP pancreatitis occurred in 18 (6%) of 305 high-risk patients in the universal group and 35 (12%) of 281 high-risk patients in the risk-stratified group (p=0·0057). Post-ERCP pancreatitis was also less frequent in average-risk patients in the universal group (3% [29/992]), in which they received indometacin, than in the risk-stratified group (6% [65/1022]), in which they did not receive the drug (p=0·0003). Other than pancreatitis, adverse events occurred in 41 (3%; two severe) patients in the universal indometacin group and 48 (4%; one severe) patients in the risk-stratified group. The most common adverse events were biliary infection (22 [2%] patients vs 33 [3%] patients) and gastrointestinal bleeding (13 [1%] vs ten [1%]). Compared with a risk-stratified, post-procedural strategy, pre-procedural administration of rectal indometacin in unselected patients reduced the overall occurrence of post-ERCP pancreatitis without increasing risk of bleeding. Our results favour the routine use of rectal indometacin in patients without contraindications before ERCP. National Key Technology R&D Program, National Natural Science Foundation of China.

Pretreatment with anti-thymocyte globulin (ATG) decreases the occurrence of chronic graft-versus-host disease (CGVHD) after haemopoietic cell transplantation from an unrelated donor, but evidence of patient benefit is absent. We did a study to test whether ATG provides patient benefit, particularly in reducing the need for long-term immunosuppressive treatment after transplantation. We did a phase 3, multicentre, open-label, randomised controlled trial at ten transplant centres in Canada and one in Australia. Eligible patients were aged 16 to 70 years with any haematological malignancy and a Karnofsky score of at least 60 receiving either myeloablative or non-myeloablative (or reduced intensity) conditioning preparative regimens before haemopoietic cell transplantation from an unrelated donor. We allocated patients first by simple randomisation (1:1), then by a minimisation method, to either pretransplantation rabbit ATG plus standard GVHD prophylaxis (ATG group) or standard GVHD prophylaxis alone (no ATG group). We gave a total dose of ATG of 4·5 mg/kg intravenously over 3 days (0·5 mg/kg 2 days before transplantation, 2·0 mg/kg 1 day before, and 2·0 mg/kg 1 day after). The primary endpoint was freedom from all systemic immunosuppressive drugs without resumption up to 12 months after transplantation. Analysis was based on a modified intention-to-treat method. This trial was registered at ISRCTN, number 29899028. Between June 9, 2010, and July 8, 2013, we recruited and assigned 203 eligible patients to treatment (101 to ATG and 102 to no ATG). 37 (37%) of 99 patients who received ATG were free from immunosuppressive treatment at 12 months compared with 16 (16%) of 97 who received no ATG (adjusted odds ratio 4·25 [95% CI 1·87–9·67]; p=0·00060. The occurrence of serious adverse events (Common Terminology Criteria grades 4 or 5) did not differ between the treatment groups (34 [34%] of 99 patients in the ATG group vs 41 [42%] of 97 in the no ATG group). Epstein-Barr virus reactivation was substantially more common in patients who received ATG (20 [one of whom died—the only death due to an adverse event]) versus those who did not receive ATG (two [no deaths]). No deaths were attributable to ATG. ATG should be added to myeloblative and non-myeloblative preparative regimens for haemopoietic cell transplantation when using unrelated donors. The benefits of decreases in steroid use are clinically significant. Epstein-Barr virus reactivation is increased, but is manageable by prospective monitoring and the use of rituximab. Future trials could determine whether the doses of ATG used in this trial are optimum, and could also provide additional evidence of a low relapse rate after non-myeloablative regimens. The Canadian Institutes of Health Research and Sanofi.

Surgical site infection (SSI) is the most common postoperative complication worldwide. WHO guidelines to prevent SSI recommend alcoholic chlorhexidine skin preparation and fascial closure using triclosan-coated sutures, but called for assessment of both interventions in low-resource settings. This study aimed to test both interventions in low-income and middle-income countries. FALCON was a 2 × 2 factorial, randomised controlled trial stratified by whether surgery was clean-contaminated, or contaminated or dirty, including patients undergoing abdominal surgery with a skin incision of 5 cm or greater. This trial was undertaken in 54 hospitals in seven countries (Benin, Ghana, India, Mexico, Nigeria, Rwanda, and South Africa). Patients were computer randomised 1:1:1:1 to: (1) 2% alcoholic chlorhexidine and non-coated suture, (2) 2% alcoholic chlorhexidine and triclosan-coated suture, (3) 10% aqueous povidone–iodine and non-coated suture, or (4) 10% aqueous povidone–iodine and triclosan-coated suture. Patients and outcome assessors were masked to intervention allocation. The primary outcome was SSI, reported by trained outcome assessors, and presented using adjusted relative risks and 95% CIs. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03700749. Between Dec 10, 2018, and Sept 7, 2020, 5788 patients (3091 in clean-contaminated stratum, 2697 in contaminated or dirty stratum) were randomised (1446 to alcoholic chlorhexidine and non-coated suture, 1446 to alcoholic chlorhexidine and triclosan-coated suture, 1447 to aqueous povidone–iodine and non-coated suture, and 1449 to aqueous povidone–iodine and triclosan-coated suture). 14·0% (810/5788) of patients were children and 66·9% (3873/5788) had emergency surgery. The overall SSI rate was 22·0% (1163/5284; clean-contaminated stratum 15·5% [454/2923], contaminated or dirty stratum 30·0% [709/2361]). For both strata, there was no evidence of a difference in the risk of SSI with alcoholic chlorhexidine versus povidone–iodine (clean-contaminated stratum 15·3% [223/1455] vs 15·7% [231/1468], relative risk 0·97 [95% CI 0·82–1·14]; contaminated or dirty stratum 28·3% [338/1194] vs 31·8% [371/1167], relative risk 0·91 [95% CI 0·81–1·02]), or with triclosan-coated sutures versus non-coated sutures (clean-contaminated stratum 14·7% [215/1459] vs 16·3% [239/1464], relative risk 0·90 [95% CI 0·77–1·06]; contaminated or dirty stratum 29·4% [347/1181] vs 30·7% [362/1180], relative risk 0·98 [95% CI 0·87–1·10]). With both strata combined, there were no differences using alcoholic chlorhexidine or triclosan-coated sutures. This trial did not show benefit from 2% alcoholic chlorhexidine skin preparation compared with povidone–iodine, or with triclosan-coated sutures compared with non-coated sutures, in preventing SSI in clean-contaminated or contaminated or dirty surgical wounds. Both interventions are more expensive than alternatives, and these findings do not support recommendations for routine use. National Institute for Health Research (NIHR) Global Health Research Unit Grant, BD.

Preoperative physical exercise is emerging as a growing field of research globally. There are still challenges in recruiting vulnerable older people, and time constraints in preoperative cancer care to consider. We therefore evaluated the feasibility of short-term supervised home-based exercise in older people prior to colorectal cancer surgery. This feasibility study was conducted between September 2016 and June 2018. People ≥70 years scheduled for colorectal cancer surgery were recruited and randomized to an intervention group receiving supervised home-based physical exercise at a high level of estimated exertion or a standard care group following the standard preoperative path. The exercise (respiratory, strength, and aerobic) consisted of 2-3 supervised sessions a week in the participants' homes, for at least 2-3 weeks or until surgery, and a self-administered exercise program in between. The primary outcome was process feasibility, including aspects specifically related to recruitment rate, compliance to the intervention, and acceptability. The secondary outcome was scientific feasibility including treatment safety, description of dose level and response, and estimation of treatment results. Twenty-three participants were included (recruitment rate 35%). A median of 6 supervised sessions was conducted over a 17-day exercise period. Compliance with the supervised sessions was 97%, and participants found the intervention acceptable. Concerning the self-administered exercise, a median of 19 inspiratory muscle training, 6 functional strength, and 8.5 aerobic sessions were reported. Challenges reported by program instructors were time constraints and difficulties in achieving high exercise intensities on the Borg CR-10 scale. A statistically significant between-group difference was only found in inspiratory muscle strength, favoring the intervention group (p<0.01). A short-term preoperative supervised home-based physical exercise intervention can be conducted, with respect to compliance and acceptability, in older people with similar physical status as in this study prior to colorectal cancer surgery. However, modifications are warranted with respect to improving recruitment rates and achieving planned intensity levels prior to conducting a definitive trial.