Title: Sugammadex for preventIoN oF pOst-operative pulmoNary complIcAtions (SINFONIA)
Funder: Public Health Agency, NI

Abstract: AIM:_x000D_ To conduct a large clinical trial comparing two drugs used to improve recovery from general anaesthesia and prevent lung complications in patients undergoing major surgery. _x000D_ _x000D_ BACKGROUND:_x000D_ General anaesthesia for major surgery requires specialised drugs which temporarily paralyse patients’ muscles. This allows the anaesthetist to insert a breathing tube into the airway and artificially ventilate the patient, whilst also making it easier for surgeons to perform the operation. These drugs, called neuromuscular blocking agents (NMBAs), can only be given by trained anaesthetists using careful monitoring. At the end of surgery and anaesthesia, the NMBA-induced muscle paralysis is reversed with another drug. Despite precautions, incomplete reversal is common, leaving patients with short-term residual muscle weakness which affects breathing, coughing and swallowing and leading to lung complications such as pneumonia. These complications delay patient recovery, prolong hospital stays, and increase the chance of dying. More than 1.5 million patients receive a general anaesthetic requiring an NMBA each year, but the group most at risk of lung complications are those aged 50 years or over undergoing major chest or abdominal surgery._x000D_ Anaesthetists choose between two drugs to reverse muscle paralysis, neostigmine or a newer drug, sugammadex, which reverses paralysis faster, and may help to prevent lung complications after surgery. However, this benefit has not yet been proven and must be weighed against two problems with the drug. Firstly, sugammadex can, very rarely, cause allergic reactions which will become more common with widespread use. Secondly, it is much more expensive than neostigmine, doubling the drug costs of a general anaesthetic. A survey of NHS anaesthetists has shown a 50:50 balance of opinion regarding which drug to use. We must provide robust evidence to guide anaesthetists in choosing which NMBA reversal drug to use in patients undergoing major chest and abdominal surgery at high risk for lung complications._x000D_ _x000D_ METHODS:_x000D_ We plan a clinical trial of 2500 patients aged 50 years and over who are having major chest or abdominal surgery. Our team includes two experienced patient researchers, one of whom has had anaesthesia for major surgery. They helped us design the trial and will continue to work with us throughout. Anaesthetists from our UK-wide Peri-Operative Medicine Clinical Trials Network will help us recruit patients. Each patient who agrees to take part will be randomly allocated to receive either sugammadex or neostigmine for NMBA reversal at the end of surgery. We will follow up patients for six months to find out whether they develop lung complications, how quickly they leave hospital after surgery, and whether any patients die within this period. We will then compare the two groups to confirm which drug is most effective and to work out the value for money from each drug. In a subgroup of 250 patients, we will test to find whether allergy to sugammadex has developed. This will help us understand the risks and benefits for each drug. _x000D_ _x000D_ DISSEMINATION:_x000D_ This trial will define best anaesthesia care for 250,000 NHS patients having major surgery every year. We will share our findings widely through published journal articles and to anaesthetic doctors through medical societies and the Royal College of Anaesthetists, and make accessible lay summaries available to patients, public and health policy makers.

Lay abstract: RESEARCH QUESTION_x000D_ In patients aged >=50 years undergoing major abdominal or thoracic surgery, does the use of sugammadex for reversal of neuromuscular blockade increase the number of Days Alive and out of Hospital within 30 days after surgery (DAH30), compared to neostigmine?_x000D_ _x000D_ BACKGROUND_x000D_ General anaesthesia often involves neuromuscular blocking agents (NMBAs), drugs which temporarily paralyse skeletal muscles, including those involved in airway reflexes and breathing, to facilitate invasive ventilation and surgical access. Incomplete reversal of paralysis is hard to detect. Despite careful monitoring, and administration of a reversal agent at the end of anaesthesia, one in three patients experience residual paralysis which leaves them with weak airway and respiratory muscles, predisposing to post-operative pulmonary complications (PPCs) such as atelectasis and pneumonia. Of more than 1.5 million NHS patients who receive an NMBA each year, the 250,000 patients aged >=50 years undergoing major abdominal and thoracic surgery are at particular risk of PPCs which lead to longer hospital stay and higher mortality, reflected in the patient-centred outcome measure of DAH30._x000D_ _x000D_ Two NMBA antagonist drugs are available to reverse paralysis. Neostigmine has been used since the 1950s, but can itself cause muscle weakness. A newer drug, sugammadex, reverses NMBAs more rapidly than neostigmine, reducing post-operative residual paralysis. Observational data suggest sugammadex may reduce PPCs by a third compared with neostigmine, but it is only used in a minority of NHS patients because the patient benefit remains unproven, and because of concerns about cost and drug allergy. In Japan, routine sugammadex use has led to a dramatic increase in allergic reactions. We must define the risks and benefits of sugammadex use before we consider this the NMBA reversal drug of choice in the NHS._x000D_ _x000D_ OBJECTIVES_x000D_ 1. To investigate whether sugammadex is superior to neostigmine for reversal of neuromuscular blockade after major abdominal or thoracic surgery._x000D_ 2. To investigate the cost effectiveness of sugammadex compared to neostigmine for reversal of neuromuscular blockade after major abdominal or thoracic surgery._x000D_ _x000D_ METHODS_x000D_ SINFONIA is a pragmatic multi-centre randomised trial with an efficient trial design. Patients aged >=50 years undergoing major thoracic or abdominal surgery in one of 40 participating NHS hospitals will be eligible. Patients will be randomly assigned to sugammadex or neostigmine for NMBA reversal at the end of surgery. The primary outcome is Days Alive and out of Hospital within 30 days after surgery (DAH30). Secondary outcomes are PPCs, mortality, health-related quality of life and cost effectiveness._x000D_ _x000D_ DELIVERY TIMELINES_x000D_ SINFONIA will run for 54 months from 1st March 2022. Month 0-6: trial setup. Month 7-18: internal pilot. Month 19-42: patient recruitment. Month 43-48: follow-up, data cleaning and analysis. Months 49-54: Analysis and dissemination._x000D_ _x000D_ IMPACT AND DISSEMINATION_x000D_ SINFONIA will define the standard of care for NMBA reversal for patients having major surgery. Findings will be disseminated to doctors through journal articles and conference presentations, and to patients, policy makers and public through lay summaries, infographics, and a dissemination workshop.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE