Title: A feasibility study of Cardiac Output optimisation following Liver Transplantation (COLT trial).
Funder: Department of Health and Social Care

Abstract: Background More than 800 liver transplants operations are performed each year in UK. It is the only effective treatment for advanced liver failure. Liver transplantation is a high risk operation with nearly two thirds of patients developing serious complications postoperatively. Complications after transplantation can lead to failure of the transplanted organ, decreased quality and length of a patient s life, and death. In addition to this, each postoperative complication represents a significant and avoidable increase to the cost of liver transplantation. The reasons for such a high rate of complications include the complexity of the operation and subsequent physiological impact this has on patients, the severity of underlying liver disease and the concomitant co-morbidities in this group of patients. Goal directed fluid therapy (GDFT) is a perioperative treatment strategy in which intravenous (IV) fluid is administered according to a protocol and guided by measurements from a device called a cardiac output monitor. GDFT has been shown to be beneficial in patients undergoing other forms of major high-risk surgery, reducing postoperative complications and hospital length of stay (2-4). A reduction in immediate postoperative complications leads to increased long-term survival and improved quality of life. However, it is not known whether GDFT will be beneficial or harmful in patients with liver cirrhosis who have undergone liver transplantation. Aggressive fluid replacement therapy in some circumstances has been widely followed in clinical practice but subsequently shown in clinical trials to be extremely dangerous. Currently GDFT is not used in patients following liver transplantation, firstly because of theoretical concerns about the possibility of harm and secondly because no trials have been conducted to demonstrate benefit. Hypotheses and objectives We propose that managing IV fluid requirements using a cardiac output monitor according to a GDFT protocol following transplantation for liver cirrhosis will be both feasible and safe. We believe that surgical outcomes can be improved in this patient group through the use of GDFT, however, the feasibility of this approach must be thoroughly explored prior to a definitive large-scale trial. We therefore propose to conduct the first ever feasibility study and safety assessment of GDFT versus current best practice in patients who have undergone liver transplantation. Methodology We shall undertake a single-centre randomised controlled trial of GDFT versus standard care post liver transplantation for patients with liver cirrhosis. Participants will be randomised into one of two study groups that will determine the mode of IV fluid management used in the first 12 hours postoperatively: GDFT. IV fluid prescribed according to a trial protocol, with measurements taken to guide treatment using a cardiac output monitor. Standard care. IV fluid will be prescribed in the standard manner according to the clinical team responsible for the patient. All other aspects of patient care will remain the same between the two groups. A number of outcome measures will also be collected in order to assess safety and determine the optimum primary outcome for a subsequent trial: Quality-of-life at pre-transplant, 3 and 6 months (EQ5D) Postoperative complications (Clavien Dindo) for 6 months Hospital length of stay ICU length of stay Graft (liver) function and survival for 6 months Patient survival for 6 months We intend to recruit 50 patients and our primary goals are to determine feasibility and demonstrate a lack of harm using GDFT. Innovation and impact If GDFT proves to be an effective way of reducing perioperative complications it could offer a cost effective way of improving quality of life and increasing patient survival following liver transplantation. The intervention could be rapidly and cheaply implimented throughout the NHS.

Lay abstract: Liver transplantation is currently the mainstay of treatment for liver failure and more than 800 liver transplants are performed each year in UK. Liver transplantation is associated with a high risk of postoperative complications; nearly two thirds of patients develop serious complications such as failure of the heart and lungs, loss of kidney function, infection, blood clots, or bleeding. Complications such as these can increase a patient s length of hospital stay, decrease their quality and length of life and result in failure of the transplanted organ, or even death. Following other types of major surgery a machine and protocol has been used to determine the amount of intravenous (IV) fluid required (goal directed fluid therapy &ndash; GDFT). GDFT has been shown to markedly reduce the incidence of postoperative complications. It is not known whether this method of treating patients is beneficial or harmful following liver transplantation because these patients differ enormously by having liver cirrhosis. Results on GDFT from other types of surgery may not be applicable. The proposed feasibility study will be the first trial to assess the practicability and safety of GDFT following liver transplantation. Participants will be randomised to receive either GDFT or standard current management of IV fluids for the first 12 hours postoperatively. We shall assess how many patients are willing to join the study and how many can tolerate the machine guided fluid therapy. We will also obtain preliminary information on whether GDFT is harmful or beneficial and determine which outcomes should be measured if a larger trial is required to prove benefit. The study will be conducted at the Royal Free Hospital, a national liver transplantation centre that performs approximately 100 liver transplants per year. We aim to recruit 50 patients into this study and follow patients up for six months post transplant.

Research activity codes: 6.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL