Title: A placebo controlled randomised trial of intravenous lidocaine in accelerating gastrointestinal recovery after colorectal surgery
Funder: Chief Scientist Office, Scotland

Abstract: Elective colorectal surgery is a common NHS hospital intervention (approx. 30,000 operations per year), following which delayed return of gut function is the most common cause of delayed discharge from hospital. A reduction in the current 20-40% prevalence would benefit a large number of patients with attendant reduction in health service costs related to reduced length of stay and reduced expenditure on management of the complication itself. Intravenous lidocaine is cheap, safe and easy to administer, and offers to reduce prevalence of delayed return of gut function and accelerate postoperative recovery. Study design: Multicentre double blind randomised placebo-controlled clinical trial. Treatment allocation 1:1. Stratification for laparoscopic and open colectomy using an adaptive trial design to monitor effect size and event rate in each subgroup. Intervention: iv lidocaine bolus at induction of anaesthesia (1.5mg/kg) followed by 1-2mg/kg/hr infusion for 6-12 hours. Placebo: 0.9% saline bolus/infusion Study population: patients scheduled for elective laparoscopic or open segmental colectomy. Exclusions: new stomas, rectal cancer, inability to give consent, pregnancy, age<18 years. Sample size calculation: Data from our pilot study in laparoscopic colectomy showed that 20 of 50 patients suffered gut dysfunction sufficient to prevent discharge on the third postoperative day. With a sample size of 562 randomised 1:1 to IV lidocaine or placebo the study will have 90% power at a 2-sided 5% level of significance to detect a relative reduction of 33% from 40% to 26.8% (absolute reduction of 13.2%) in gut dysfunction at 3 days post-op (or if the event rate is lower, the same power to detect a 40% relative reduction from 30% to 18% (a 12% absolute reduction)). Given the 3-day measure is in hospital there should be no appreciable loss to follow up (the perioperative death rate is ~1% for the whole duration of hospital stay and the very few discharged before 3 days can be assumed to have return of gut function). Setting: Minimising the variation generated by inconsistent perioperative care would be a key part of study design, therefore 10-12 high volume UK NHS colorectal surgery units able to implement a consistent study protocol would be invited to participate. Primary endpoint: Reduction in the proportion of participants with delayed return of gut function, defined by a validated composite endpoint (GI-3: the later of the following two events: time to tolerating solid food and time to first passage of flatus or stool. The assessment of the primary outcome on post-op day 3 will be blinded to treatment allocation. Secondary endpoints: PROMs for Quality of recovery, nausea and vomiting, pain scores; proportion of patients meeting medical criteria for discharge from hospital on postoperative day 3 (adequate oral intake without iv supplement, pain controlled with oral analgesia, no medical contraindication, willing to go home); quality of life scores; length of stay; measure of study protocol compliance; complications including iv lidocaine safety data; in-hospital, 30-day and 90-day mortality; 12 month mortality and hospital re-admission rates from record linkage into HES/eDRIS national routine data systems.

Lay abstract: Bowel surgery is very common in the UK. It happens every day, in every hospital. Although approximately half of these patients will recover without complications, 20-40% will get nausea and vomiting because their guts stop working for a short time after the operation. They can’t eat, they feel sick, their tummies swell up and their bowels don’t work. Delayed return of gut function can lead on to “prolonged postoperative ileus” (PPOI for short). These patients need intravenous fluids (more needles!) and sometimes a tube has to be pushed into the nose, down the gullet and into the stomach to empty the fluid that builds up in the gut (the dreaded nasogastric tube). We think PPOI is caused by lots of things together, including the operation, anaesthetic drugs, painkillers, stress etc. Almost always the gut starts working normally again in its own good time, but the problem can keep the patient in hospital for 2-7 days extra. There is no medicine to cure it. We don’t know why it happens in some patients and not others after exactly the same operation. However, intravenous lidocaine is a treatment that may help reduce this problem. It is a new use for a very well-known and commonly used medicine, so it is safe. It is also cheap. It is started at the beginning of the operation and continued for 6-12 hours. There is evidence from previous research studies that it may have a number of benefits. First, it reduces postoperative pain, so that patients need painkillers less often and for less time after surgery. Second, it may reduce the number of patients who get PPOI, and may reduce the severity of the condition in those who do get it. Thirdly, and this may be partly a thanks to the two reasons above, patients may recover to be fit for discharge from hospital more quickly. In order to assess the real world benefit of this treatment to NHS patients, and to the NHS as a whole, we are proposing a scientific study to compare two groups: one getting the intravenous lidocaine, the other a placebo (an inactive fluid). Neither patients nor hospital staff will know which treatment is being given, so that they cannot influence the results (of course the study team will know using a concealed code). In order to get the best chance of a clear result from a study such as this, we will aim to make every other aspect of treatment the same in both groups, therefore the operation and care after the operation will have to be the same (as far as possible) in all cases. We will include patients having laparoscopic (keyhole) or open (a normal big incision) segmental colectomy (removing part of the large bowel) and the aftercare will be based on the best current NHS practice. If the result of the study is positive, i.e. if intravenous lidocaine is effective, it could mean that a lot of patients benefit from a smoother recovery after this type of surgery, so that they are less likely to get PPOI, can eat and drink more quickly, won't need needles and intravenous fluids and nasogastric tubes, can go home more quickly and feel better sooner. If patients go home more quickly, a lot of money could be saved for the NHS too. And if it works, it is likely that the benefits could be applied to lots of other types of abdominal surgery as well.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL