Comparison of regional with general anaesthesia on postoperative delirium (RAGA-delirium) in the older patients undergoing hip fracture surgery: study protocol for a multicentre randomised controlled trial

Introduction Postoperative delirium (POD) is a common serious postoperative complication especially in older people and is associated with increased mortality, morbidity and healthcare costs. There is no clear consensus which anaesthesia is associated with less incidence of POD for older patients. We aim to assess whether regional anaesthesia results in lower incidence of POD comparing with general anaesthesia (GA) among older patients undergoing hip fracture surgery. Methods and analysis RAGA-delirium is a pragmatic, multicentre, prospective, parallel grouped, randomised controlled clinical trial comparing RA or GA for hip fracture surgery. A total of 1000 patients who are 65 years or over and who are having planned hip fracture surgery in nine clinical trial centres of China will be randomised in a 1:1 ratio to receive either anaesthesia for the surgery. The primary endpoint will be the incidence of POD at day 7. The secondary endpoints will be the subtype, severity and duration of delirium, postoperative acute pain score, incidence of other postoperative non-delirium complications, quality of life and cost-effective outcomes. Randomisation will be performed at the patient level using computer-generated assignment. Outcome assessors will be blinded from intervention assignment. Assessments will be conducted before surgery, intraoperatively, postoperatively, during the hospital stay, at 30-day, 6-month and 1-year postoperative intervals. Potential impact of study This study will provide clinical evidence with a more robust methodology to help anaesthetists in selecting appropriate anaesthesia for older patients with high risk for POD. At the era of increasing emphasis on delirium prevention, this trial has the potential to inform the future national guideline to reduce POD. Ethics and dissemination Ethical approved by the local institutional review board. Trial results will be presented at national and international academic conferences, and published in peer-reviewed journals. Trial registration number ClinicalTrials.gov (NCT02213380); pre-results.


GENERAL COMMENTS
Li Ting and co-workers submitted a study protocol "Comparison of regional with general anaesthesia on post -operative delirium (RAGA-delirium) in the older patients undergoing hip fracture surgery: study protocol for a multicentre randomized controlled trial". Indeed there is a need for large scale rct assessing effectivenss of regional vs general anesthesia in regard to postoperative delirium. However there are several major concerns about the study protocol. This is of importance as the study has already recruited more than 400 patients and recruitment is estimated to be finished by September 2017. I do not see the benefit of the study protocol being published at this stage of the study. Response: Thanks for the reviewer's kind suggestion. The sentence has been rewritten to "At the era of aging and increasing emphasis on delirium prevention in China, this trial has the potential to inform the future national guideline to reduce POD."(please see the text in the manuscript).
METHODS AND DESIGN 2. Comment: pp6 Line 20-37. Would the contraindication to neuraxial blockade include severe valvular heart disease or other heart disease?
Response: Thank you for the comment. Patients with severe systemic disease such as Severe valvular heart disease or other heart disease, though are not absolute contraindication to neuraxial blockade. The anaesthetist will decide before randomization according to the guideline of the site.
3. Comment: pp9 Line 24-37: Please could the authors explain the rationale to allow premedication as these drugs could alter the incidence of delirium. If premedication was permitted could or should it be standardised?
Response: Thank you for the comment. Premedication for anaesthesia will not be encouraged in the protocol. Any medication impairing cognitive function, like midazolam or dexmedetomidine， will be avoided. If there is any premedication administered when deemed clinically necessary, it must be recorded in detail.

Comment: pp14
Line 30-32 It would read better if the sentences, "Recruitment of patients..." and " So the recruitment..." were joined with a comma.
Response: Thank you for the kind reminder. We have revised it in the manuscript text.
DISCUSSION 5. Comment: pp14 Line 44 : Add "as to" between the words "controversial" and "whether" Response: Thank you for the kind reminder. We have revised it in the manuscript text.
6. Comment: pp14 Line 56 : "was" instead of "were" Response: Thank you for the kind reminder. We have revised it in the manuscript text.
Reviewer: 2 7. Comment: Li Ting and co-workers submitted a study protocol "Comparison of regional with general anaesthesia on post -operative delirium (RAGA-delirium) in the older patients undergoing hip fracture surgery: study protocol for a multicentre randomized controlled trial". Indeed there is a need for large scale rct assessing effectivenss of regional vs general anesthesia in regard to postoperative delirium. However there are several major concerns about the study protocol. This is of importance as the study has already recruited more than 400 patients and recruitment is estimated to be finished by September 2017. I do not see the benefit of the study protocol being published at this stage of the study.
Response: Thank you for the comment. We are trying to publish our study protocol because we are doing our best to verify that the future research report will adhere to the original plan for trial conduct and analysis. Currently the trial is in the middle of recruitment. The estimated recruitment will be finished on July 2018.
Introduction: 8. Comment: Postoperative delirium is a clearly defined and established term. There is no need to try to rewrite delirium.
Response: Thank you for your comment. The sentence "Delirium, sometimes called "acute confusional state", is a common clinical syndrome characterised by disturbed consciousness and a change in cognitive function or perception which develops over a short period of time (usually 1-2 days)." have been deleted. 12. Comment: In this pragmatic approach authors are combining nerve blocks with GA and compare that with SA or Epidural anesthesia. This is not described, see comment above. Further it is not clear if patients are able to receive sedation with "regional anestehsia" and how this can be provided. 14. Comment: The authors are calculating a drop-out rate of 10% for the primary outcome parameter after randomization. This is critical, what are the reasons why you expect a drop-out after randomization? A PP and ITT analysis should be performed.
Response: Thank you for the comments.
A. The sample size calculation has been taken into account of available data. The dropout rate of follow-up among patients undergoing hip fracture surgery was less than 4% based on pilot data from one study site, that is why we made an estimate of 10% of dropout and a total of 1000 patients will be recruited during the trial.