Title: A cluster randomised trial of clinically-assisted hydration in patients in the last days of life (CHELsea II study)
Funder: Department of Health and Social Care

Abstract: Aim _x000D_ The aim is to assess whether giving patients in the last days of life fluids via a drip (“clinically-assisted hydration” / CAH) is effective at preventing them from developing delirium / “terminal agitation”. This problem often occurs at end-of-life, and causes distress to patients (e.g. confusion, restlessness), families, and healthcare professionals. Furthermore, it often means that the patient requires sedating in the last days of life. We will also explore if CAH affects other end-of-life problems (e.g. noisy breathing, shortness of breath), causes any side effects, and affects length of survival._x000D_ Background _x000D_ The use of CAH in the last days of life is very variable (and controversial), because there is no high-quality research to show whether it improves (or worsens) end-of-life care. In some patients there is a clear reason to start or to continue CAH, whilst in other patients there is a clear reason not to start or to discontinue CAH. However, in most patients there is no indication one way or another._x000D_ The research team has recently completed a feasibility (provisional) study, which included 200 cancer patients from hospices/hospitals in England and Wales. The results suggest that CAH may delay the onset of delirium, but that CAH can cause side effects in some patients (e.g. fluid retention). A larger study is, therefore, needed to rigorously evaluate the role of CAH at the end of life. _x000D_ Design & methods_x000D_ 80 hospices/hospitals in United Kingdom, and 1600 patients in the last week of life, will take part in the study_x000D_ The study will be a so-called cluster randomised trial, which means that hospices/hospitals (“clusters”) will be allocated at random to one of two standard (usual) interventions. Intervention A involves supporting the patient to drink, regular mouth care, and management of pain and other symptoms. Intervention B involves supporting the patient to drink, regular mouth care, management of pain and other symptoms, and CAH. All eligible patients within each hospice/hospital will receive the same intervention (if appropriate)._x000D_ Consent will be obtained whenever possible from the patient, but advice about study entry may be obtained from a “personal consultee” (family member, friend) or a “nominated consultee” (healthcare professional) if the patient is unable to provide consent. Patients will be given fluids either into a vein, or into the tissues under the skin. The amount of fluid given will be based on the patient’s weight, and the decision to continue/discontinue the fluids will be made by the patient’s usual doctors and nurses._x000D_ Patients will be assessed for end-of-life problems at least every 4 hours by the patient’s usual doctors and nurses, and data will be collected on the presence of these problems, use of medication (to treat these problems), and side effects of CAH._x000D_ Patient & public involvement_x000D_ The local cancer PPI group contributed to the feasibility study, and a cancer patient and carer for a cancer patient, were members of the Trial Monitoring Committee. In addition, the Marie Curie Research Voices Group provided (positive) feedback on the current proposal. The research team will continue to work with local PPI groups during the study, involving them in all aspects of the study._x000D_ Dissemination_x000D_ The results will be disseminated to healthcare professionals through presentations at scientific meetings, and publications in medical journals, and to the public by means of usual media sources.

Lay abstract: Research question_x000D_ Our hypothesis is clinically-assisted hydration (CAH) in the last days of life reduces the frequency of delirium (aka “terminal agitation”), as a result of preservation of renal function, and prevention of build-up of drugs/toxins. Furthermore, CAH will prevent death due to dehydration before death due to the underlying disease._x000D_ Background_x000D_ Provision of CAH at the end-of-life is one of the most contentious issues in medicine. The reasons include: a) lack of evidence; b) disparate opinions of healthcare professionals (HCPs); and c) generally positive opinions of patients and their carers (and negative opinions about withholding/withdrawing CAH). Unsurprisingly, the provision of CAH at the end-of-life is extremely variable in clinical practice (e.g. 12-88% cancer patients in the last week of life). This definitive study leads on from a RfPB-funded feasibility study, which achieved all of its predetermined criteria for success. _x000D_ Aim and objectives _x000D_ The aim is to evaluate CAH in the last days of life. The objectives are to assess: effect of CAH on hyperactive delirium; effect of CAH on audible upper airway secretions (“death rattle”); effect of CAH on pain and other symptoms; tolerability of CAH; effect of CAH on survival; and health economic impact of CAH._x000D_ Methodology _x000D_ The study is a cluster randomised trial, where the sites are randomised to an intervention: the intervention will become the standard of care at the site, and will be given to all patients unless there is a valid clinical reason. The study will recruit 1600 subjects from 80 sites (mainly hospices). The consent process follows the Mental Capacity Act: if the patient has capacity then consent will be sought in the normal way; if the patient does not have capacity, then a personal or nominated consultee will be approached for advice about the patient entering the study. Intervention “A” is: continuance of oral intake; regular mouth care; and usual management of symptoms. Intervention “B” is: continuance of oral intake; regular mouth care; usual management of symptoms; and CAH, i.e. parenteral fluids. The fluids may be given intravenously or subcutaneously. The fluid will be dextrose saline (4% dextrose, 0.18% sodium chloride), and the volume depends on the patient’s weight (as per NICE guidance). Participants will be reviewed every 4 hr, and an assessment made as to whether relevant problems are present. A study-specific clinical observation document will be completed by the clinical team. Indications for medication will also be recorded by the clinical team. The primary endpoint is the proportion of subjects that develop delirium using the Nursing Delirium Screening Scale._x000D_ Timelines _x000D_ The study will start in October 2021, and last for 42 months: the first 12 months will be to set up the study (including site training/initiation), the next 24 months to recruit participants, and the final 6 months to analyse data, write reports/publications, and close down the study. _x000D_ Anticipated impact and dissemination_x000D_ The study will provide much needed evidence on CAH, which will lead to more consistent management in the NHS, and reduce the distress/conflict around decision making. The results will be disseminated to HCPs via scientific meetings/journal articles, and to the public via usual media sources.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL