Impact of Inhalational Versus Intravenous Anaesthesia on Early

Downloaded from http://bmjopen.bmj.com/ on December 12, 2017 - Published by group.bmj.com Open Access Protocol Impact of inhalational versus intravenous anaesthesia on early delirium and long-term survival in elderly patients after cancer surgery: study protocol of a multicentre, open- label, and randomised controlled trial

Yue Zhang,1 Hui-Juan Li,2 Dong-Xin Wang,1 Hui-Qun Jia,3 Xu-De Sun,4 Ling-Hui Pan,5 Qing-Shan Ye,6 Wen Ouyang,7 Zhen Jia,8 Fang-Xiang Zhang,9 Yong-Qing Guo,10 Yan-Qiu Ai,11 Bin-Jiang Zhao,12 Xu-Dong Yang,13 Qin-Gong Zhang,14 Ning Yin,15 Hong-Yu Tan,16 Zhi-Heng Liu,17 Jian-Bo Yu,18 Daqing Ma19

To cite: Zhang Y, Li H-J, Abstract Strengths and limitations of this study Wang D-X, et al. Impact of Introduction Elderly patients who have solid organ cancer inhalational versus intravenous often receive surgery. Some of them may develop delirium ►► The trial design is prospective, multicentre and anaesthesia on early delirium after surgery and delirium development is associated with and long-term survival in elderly randomised controlled, with a relative large sample worse outcomes. Furthermore, despite all of the advances patients after cancer surgery: size. in medical care, the long-term survival in cancer patients study protocol of a multicentre, ►► The study will investigate the impact of two general is far from optimal. Evidences suggest that choice of open-label, and randomised anaesthesia techniques, that is, propofol-based anaesthetics during surgery, that is, either inhalational or controlled trial. BMJ Open intravenous anaesthesia versus sevoflurane-based intravenous anaesthetics, may influence outcomes. However, 2017;7:e018607. doi:10.1136/ inhalational anaesthesia, on the outcomes of elderly bmjopen-2017-018607 the impact of general anaesthesia type on the occurrence of patients after cancer surgery. postoperative delirium is inconclusive. Although retrospective ►► Prepublication history and ►► Both early (incidence of 7-day delirium as primary studies suggest that propofol-based intravenous anaesthesia additional material for this endpoint) and long-term (3-year survival as primary was associated with longer survival after cancer surgery paper are available online. To endpoint) outcomes will be explored. These two when compared with inhalational anaesthesia, prospective view these files, please visit the endpoints are both timely and important. journal (http://dx.doi. org/10. studies as such are still lacking. The purposes of this ►► All study personnel will be trained to follow a 1136/bmjopen- 2017-018607). randomised controlled trial are to test the hypotheses standard procedure for the preoperative visit as well that when compared with sevoflurane-based inhalational as postoperative follow-up assessment. Hence, data Received 9 July 2017 anaesthesia, propofol-based intravenous anaesthesia may will be robust. Revised 25 August 2017 reduce the incidence of early delirium and prolong long-term Accepted 4 September 2017 ►► A limitation is that the study design is not double- survival in elderly patients after major cancer surgery. blinded because the differences of anaesthesia Methods and analysis This is a multicentre, open- management cannot be masked. To decrease the label, randomised controlled trial with two parallel arms. potential bias produced by the open-label design, 1200 elderly patients (≥65 years but <90 years) who investigators performing postoperative follow-up are scheduled to undergo major cancer surgery (with are not involved in both anaesthesia implementation predicted duration ≥2 hours) are randomised to receive and postoperative care. either sevoflurane-based inhalational anaesthesia or propofol-based intravenous anaesthesia. Other anaesthetics and supplemental drugs including sedatives, Trial registration number ChiCTR-IPR-15006209; opioids and muscle relaxants are administered in both NCT02662257; NCT02660411. arms according to routine practice. The primary early outcome is the incidence of 7-day delirium after surgery and the primary long-term outcome is the duration of 3-year survival after surgery. Introduction For numbered affiliations see Ethics and dissemination The study protocol has been With ageing population together with end of article. approved by the Clinical Research Ethics Committees increasing risk factors, cancer occurrence 1 2 Correspondence to of Peking University First Hospital (2015[869]) and all is increasing both in China and globally. Dr Dong-Xin Wang; participating centres. The results of early and long-term Surgical resection is the first-line treatment wangdongxin@ hotmail.com outcomes will be analysed and reported separately. for solid organ cancer and indeed, it is

Zhang Y, et al. BMJ Open 2017;7:e018607. doi:10.1136/bmjopen-2017-018607 1 Downloaded from http://bmjopen.bmj.com/ on December 12, 2017 - Published by group.bmj.com Open Access estimated that >234 million major surgical procedures optimal. For example, the 5-year survival rate of Chinese are performed every year worldwide3; of which neoplasm cancer patients is only 36.9%.1 For patients after surgery, is one of the major reasons of surgery in a global survey.4 cancer recurrence and metastasis are the main factors Recently, evidences emerge that choice of anaesthetics, that worsen the quality of life and shorten the duration that is, either inhalational or intravenous anaesthetics, of survival. The balance between immune function and may influence the outcomes of elderly patients after cancer invasiveness is a key element that influences the cancer surgery. occurrence of cancer recurrence and metastasis after surgery. Choice of anaesthetics and early postoperative delirium The choice of general anaesthetics may influence Delirium, a state of acute and fluctuating disturbance of patient’s immune function. An international multicentre consciousness, attention, cognition and perception,5 is a team investigated the effects of propofol–paravertebral common complication in elderly after surgery. Systematic anaesthesia versus sevoflurane–opioid anaesthesia on the reviews showed that up to 54% patients develop delirium immune function in patients undergoing breast cancer after non-cardiac surgery, and its occurrence increases surgery (NCT00418457). The preliminary data published with age.6–8 The occurrence of delirium is associated with by this team so far indicated that propofol anaesthesia worse early outcomes, including prolonged hospital stay may be better than sevoflurane anaesthesia in preserving and increased complications and in-hospital mortality; it is immune function after surgery.24–26 Similar findings were also associated with worse long-term outcomes, including also reported in patients undergoing surgery for non-small- declined cognitive function, decreased quality of life and cell lung cancer27 and tongue cancer.28 Taken together, it increased postdischarge mortality.9–15 seems that propofol anaesthesia may have favourable effects Underlying mechanisms of delirium development on postoperative immune function when compared with are unknown but it is certainly related to multiple risk inhalational anaesthesia. However, conclusions cannot be factors.16–18 Evidence suggests that choice of anaesthetics made because (1) the sample sizes of those studies are small may also have an influence. In a study of 2000 patients and (2) the casual relationship between immune function undergoing general anaesthesia, those carrying ApoE4 and long-term outcomes has not been established yet. epsilon 4 allele were more likely to develop early post- The effects of general anaesthetics on cancer invasive- operative cognitive decline after inhalational anaesthesia ness are mainly tested in cultured cancer cells. Propofol but not after intravenous anaesthesia.19 In a small trial decreases cancer cell invasion and migration.29–31 On of 44 patients undergoing carotid endarterectomy, the the other hand, inhalational anaesthetics in this regard mini-mental state examination (MMSE) score was higher, is controversial. Isoflurane was found to increase cancer whereas blood S100B concentration was lower in the cell proliferation and migration,32 33 whereas sevoflurane propofol group than in the sevoflurane group at 24 hours and desflurane were found to decrease proliferation after surgery.20 In the study of Tang et al,21 200 elderly (≥60 and migration.34–37 The reasons for this discrepancy are years) patients with mild cognitive impairment randomly unknown but the duration and concentration of expo- received either sevoflurane or propofol anaesthesia for sure used in those studies are likely responsible. radical rectal resection. The negative cognitive effects Clinical studies in this aspect are very limited. In a were more severe after sevoflurane anaesthesia than after retrospective study of 2838 patients who underwent propofol anaesthesia. Conversely, in a randomised trial of breast or colorectal cancer surgery, 1935 received sevo- 50 elderly (≥65 years) patients undergoing long-duration flurane anaesthesia and 903 propofol anaesthesia. The laparoscopic surgery, the score of delirium rating scale 1- and 5 year survival rates were higher in propofol-an- was lower in the sevoflurane group than in the propofol aesthesised patients. However, the differences were not group on the postoperative days 2 and 3.22 In another statistically significant after adjustment with confounding trial of 128 patients undergoing on-pump cardiac surgery, factors.38 In another study, 11 395 patients after cancer postoperative cognitive function was better in the sevoflu- surgery were retrospectively analysed. After exclusions rane group than in the propofol group in patients who and propensity matching, 2607 patients remained in experienced intraoperative cerebral desaturation.23 each of the inhalational anaesthesia group or total intra- Caution must be taken when interpreting these find- venous anaesthesia group. The results showed that, after ings because: (1) target patient populations are different, a median follow-up duration of 2.66 years, volatile inha- (2) the diagnostic criteria of cognitive complications are lational anaesthesia was associated with a higher risk of inconsistent and (3) conclusions of large sample size death.39 studies are drawn from exploratory analyses rather than We hypothesise that, when compared with sevoflu- primary endpoints. Therefore, current data are inconclu- rane-based inhalational anaesthesia, propofol-based sive and further studies are warranted. intravenous anaesthesia may be beneficial on long-term survival in elderly after cancer surgery. However, due to Choice of anaesthetics and long-term outcomes after cancer the retrospective natures of previous publications, prop- surgery erly designed randomised controlled trials are urgently Despite all of the advances in oncological science, the needed to figure out the better anaesthetic regimen for long-term outcomes of cancer patients are far from cancer patients.

2 Zhang Y, et al. BMJ Open 2017;7:e018607. doi:10.1136/bmjopen-2017-018607 Downloaded from http://bmjopen.bmj.com/ on December 12, 2017 - Published by group.bmj.com Open Access

Study objectives Trial design and setting The objectives are to investigate the impact of inhala- This multicentre, open-label, randomised controlled tional versus intravenous anaesthesia on the occurrence trial with two parallel-arms is designed to compare the of delirium and long-term survival in elderly after major difference of two interventions. Eligible patients will be cancer surgery. enrolled and randomly assigned to receive either sevoflurane-based inhalational anaesthesia or propofol-based intravenous anaesthesia (figure 1). The study will be coor- Methods and analysis dinated by the Department of Anesthesiology and Critical The protocol is developed in accordance with the Care Medicine of Peking University First Hospital, and Recommendations for Interventional Trials (SPIRIT).40 will be conducted in the Departments of Anesthesiology The SPIRIT Checklist for this protocol is available as of 17 tertiary hospitals in China. ‘supplement’. The trial is registered at Chinese Clinical Trial Registry (www.chictr.org. cn) with identifier ChiC- Participant selection TR-IPR-15006209; and at clinicaltrials. gov with iden- Inclusion criteria tifier NCT02662257 for early outcomes and identifier Participants will be included if they meet all of the NCT02660411 for long-term outcomes. The latest V.3.5 following criteria: (1) age ≥65 years and <90 years; (2) of the trial protocol was approved on 19 April 2017. diagnosed as primary cancer, do not receive radiotherapy

Figure 1 Flowchart of the study.

Zhang Y, et al. BMJ Open 2017;7:e018607. doi:10.1136/bmjopen-2017-018607 3 Downloaded from http://bmjopen.bmj.com/ on December 12, 2017 - Published by group.bmj.com Open Access or chemotherapy before surgery; (3) scheduled to Patient recruitment and baseline data collection undergo surgery for cancer, with an expected duration of The day before surgery (or Friday for patients who will 2 hours or more, under general anaesthesia; (4) agree to undergo surgery the next Monday), investigators who participate, and give signed written informed consents. have been trained for the study conduct process and delirium assessment and are authorised by the principal Exclusion criteria investigator will screen potential participants according Patients will be excluded if they meet any of the following to the inclusion and exclusion criteria. Written informed criteria: (1) preoperative history of schizophrenia, consents (see online Supplementary file 1) will be epilepsy, parkinsonism or myasthenia gravis; (2) inability obtained from eligible patients, their next of kin or their to communicate in the preoperative period because of legal representatives. To promote participant retention coma, profound dementia, language barrier or end-stage and complete follow-up, the addresses and telephone disease; (3) critical illness (preoperative American Society numbers of both patients and their relatives are collected of Anesthesiologists physical status classification ≥IV), after obtaining consents. severe hepatic dysfunction (Child-Pugh class C) or severe For recruited patients, baseline data will be collected. renal dysfunction (undergoing dialysis before surgery); These include demographic data (age, gender, education (4) neurosurgery; (5) refuse to participate in the study level and body mass index), current and previous histo- or (6) other reasons that are considered to be unsuitable ries of diseases (surgical diagnosis, comorbidity, medical for study participation by the responsible surgeons or treatment and surgical history), as well as main results investigators (reasons must be recorded in the case report of physical, laboratory and instrumental examinations. form). Severity of comorbid disorders (assessed with Charlson comorbidity index and New York Heart Association Sample size calculation cardiac function classification) and evaluation of physical For the purpose of delirium reduction status (assessed with American Society of Anesthesiolo- In our recent study, the incidence of postoperative gists physical status classification and Barthel Index) will delirium in a comparable patient population was 8%. In be recorded. Cognitive function (assessed with MMSE), a small sample size study comparing the effects of propo- delirium status (assessed with confusion assessment fol-based versus sevoflurane-based anaesthesia, the inci- method (CAM)) and pain severity (assessed with numer- dence of delirium during the first three postoperative ical rating scale (NRS), an 11-point scale where 0=no pain days was 16% (4/25) versus 0% (0/25).22 In another and 10=the most severe pain) will also be collected. study, comparing the effect of sevoflurane versus propofol general anaesthesia, the incidence of severe cognitive Randomisation dysfunction at 7 days after surgery was 16.1% (16/99) 21 A biostatistician who does not participate in data manage- versus 5.9% (6/101). We propose that the incidence ment and statistical analysis generate random numbers of delirium will be reduced from 8% in the sevoflurane in a 1:1 ratio, with a block size of 4, using the SAS V.9.2 group to 4% in the propofol group (ie, a 50% reduction). software package (SAS Institute, Cary, North Carolina, With significance and power set at 0.05% and 80%, respec- USA). Randomisation is stratified by centres. The results tively, the sample size required to detect difference was of randomisation are sealed in the envelopes and stored 1106 patients. Taking into account a loss-to-follow-up rate at the site of investigation until the end of the study. of about 6%, we need to enrol 1177 patients. For each study centre, a study coordinator is assigned to preserve and distribute randomisation results according For the purpose of long-term survival improvement to the sequence of recruited patients, and to coordinate In our previous study, the 3-year mortality rate of elderly between investigators. For each recruited patient, group patients after cancer surgery was 30%. In a retrospective 39 assignment will be clarified in the operating room on the study of Wigmore et al, the mortality rate at a median day of surgery; an anaesthesiologist will be assigned for 2.66 years after cancer surgery was 13.6% in patients after anaesthesia management and intraoperative data collec- total intravenous anaesthesia and 24% in those after inha- tion. Postoperative follow-up will be performed by inves- lational anaesthesia (ie, a 43.3% decrease with total intra- tigators who do not participate in patient care and have venous anaesthesia). We propose that the 3-year mortality been trained to follow-up patients prior to the study. Both rate will be reduced from 30% in the sevoflurane group anaesthesiologist(s) and investigator(s) do not communi- to 20% in the propofol group (ie, a 33% reduction). With cate with each other while collecting data. significance and power set at 0.05% and 80%, respec- tively, the sample size required to detect difference was Anaesthesia management and study intervention 588 patients. Taking into account a loss-to-follow-up rate No preanaesthesia medication will be given. Intraoper- of about 20%, we need to enrol 735 patients. ative monitoring include ECG, non-invasive blood pressure, pulse oxygen saturation, bispectral index (BIS), Final sample size of the study end-tidal partial pressure of carbon dioxide, end-tidal After considering the two calculated sample size, we plan concentration of inhalational anaesthetics, nasopharyn- to enrol 1200 patients in the present study. geal temperature and urine output. Intra-arterial blood

4 Zhang Y, et al. BMJ Open 2017;7:e018607. doi:10.1136/bmjopen-2017-018607 Downloaded from http://bmjopen.bmj.com/ on December 12, 2017 - Published by group.bmj.com Open Access pressure (including parameters derived from arterial these patients will be included in the intention-to-treat pressure waveform, such as stroke volume variation analysis. (SVV) from a FloTrac system), central venous pressure and thermodilution cardiac output (measured through Patient follow-up and outcome assessment a pulmonary artery catheter or a PiCCO system) may be Early postoperative outcomes monitored when necessary. Patients will be followed up two times per day during Anaesthesia will be induced intravenously with midaz- the first 7 days after surgery, and then weekly until the olam, opiates (remifentanil, sufentanil and/or fentanyl), 30th day after surgery (by telephone for those who are propofol and muscle relaxants (rocuronium or cisatra- discharged from the hospital) by the investigators. curium). For patients with predicted difficult airway, Delirium will be assessed two times per day, that is, succinylcholine may be used for rapid sequence intuba- between 8–10 am and 6–8 pm, during postoperative days tion or awake intubation may be performed. Dexameth- 1–7. Intubated patients will be assessed with the Confusion asone (4–5 mg) may be administered before anaesthesia Assessment Method for the Intensive Care Unit (CAM- induction for the prevention of postoperative nausea and ICU), and non-intubated patients will be assessed with vomiting. the CAM. For patients who are discharged from hospital, For patients in the sevoflurane group, anaesthesia will withdraw consents or die within 7 days after surgery, the be maintained with sevoflurane inhalation, of which the last follow-up results will be regarded as the final results. concentration will be adjusted to maintain the BIS value Pain severity, both at rest and with movement (such between 40 and 60. For patients in the propofol group, as during coughing), will be evaluated with the NRS two anaesthesia will be maintained with propofol infusion, of times per day during postoperative days 1–3. Subjective which the infusion rate will be adjusted to maintain the sleep quality will be evaluated with the NRS (an 11-point BIS value between 40 and 60. For patients of both groups, scale where 0=the worst sleep, and 10=the best sleep) once analgesia will be maintained with remifentanil, sufentanil daily, that is, between 8 and 10 am, during postoperative and/or fentanyl; muscle relaxation will be maintained days 1–7. Medications (including sedatives, analgesics, with rocuronium or cisatracurium. anticholinergics and glucocorticoids) used during post- Intraoperative mechanical ventilation will be estab- operative days 1–7 will be recorded. lished with a tidal volume between 6 and 8 mL/kg, a The occurrence of non-delirium complications, which positive end-expiratory pressure of 5 cm H2O, a plateau are defined as newly occur medical conditions that are pressure of <30 cm H2O, a frequency between 12 and harmful for patients’ recovery and require therapeutic 16 per minute and a 1:1 air–oxygen mixture. Intraoper- intervention, will be monitored during postoperative ative fluid therapy will be managed according to routine days 1–30. Other postoperative data including admission practice. Packed red blood cells will be transfused when to the intensive care unit (ICU), the lengths of both ICU necessary in order to maintain haemoglobin levels and hospital stay after surgery, and readmissions after within the target range of 7–10 g/dL. Vasopressors and/ hospital discharge within 30 days will be recorded. For or inotropics will be administered when necessary in patients who die within 30 days after surgery, the exact order to maintain systolic blood pressure within 20% of date of death will be recorded. For 30-day survivors, cogni- baseline. tive function will be assessed with Telephone Interview for Postoperative analgesia during the first 3 days will be Cognitive Status-Modified (TICS-m, Chinese version). provided by a patient-controlled analgesia pump, which For early postoperative outcomes, the primary is established with morphine (0.5 mg/mL) or sufentanil endpoint is the incidence of delirium during the first (1–2 µg/mL), programmed to deliver a 2 mL bolus with a 7 days after surgery. Secondary endpoints include lockout interval of 6–10 min and a background infusion ICU admission after surgery, length of stay in hospital of 1 mL/h. The pump setting may be adjusted according after surgery, the incidence of non-delirium complica- to patients’ condition. Other opiates and non-steroid tions (including readmission after hospital discharge) anti-inflammatory drugs can also be used for postoper- during the first 30 days after surgery, cognitive function ative analgesia. Postoperative analgesia after that period of 30-day survivors and all-cause 30 day mortality. Other will be provided by intravenous injection or oral intake. endpoints include pain severity during postoperative Intraoperative data including the type of surgery, dura- days 1–3 and subjective sleep quality during postoper- tions of anaesthesia and surgery, doses of anaesthetics, ative days 1–7. analgesics and other drugs used during anaesthesia, fluid balance and transfusion of blood products, as well as fluc- Long-term postoperative outcomes tuation of monitoring variables will be collected by the Patients will be followed up (by telephone) one time anaesthesiologists. For all enrolled patients, dexmedeto- yearly until the third year after surgery by the investiga- midine is not allowed; scopolamine and penehyclidine tors. The results of pathological diagnosis and the final are prohibited; atropine is used only for the purpose of cancer stage at hospital discharge will be documented. reversing bradycardia. For patients who deviate from the The performance of postoperative re-examinations and study protocol, deviations will be corrected whenever therapies for the primary cancer will be recorded. The possible and follow-up will be completed. The results of results of re-examination will be judged by surgeons (and

Zhang Y, et al. BMJ Open 2017;7:e018607. doi:10.1136/bmjopen-2017-018607 5 Downloaded from http://bmjopen.bmj.com/ on December 12, 2017 - Published by group.bmj.com Open Access radiologists when necessary) for cancer recurrence and database system. A data manager will perform database metastasis; the date of confirmed recurrence and/or check out using SAS V.9.2 software. Data queries will be metastasis will be documented. Postoperative therapies answered by investigators. After data entry and database including radiotherapy, chemotherapy, reoperation and check out are completed and all problems encountered other therapies will be collected. Other data including during the procedure solved, the database will be locked. newly diagnosed tumour (ie, tumour that is definitely The decision to lock database will be made by the prin- different from the primary one) and disease (ie, disease ciple investigator, the database manager and a statistician that is different from the recorded preoperative comor- who is responsible for statistical analysis. Investigators and bidity) will be recorded. a statistician who are authorised by the principal investi- For patients who die within 3 years after surgery, the gator have access to the final trial dataset. exact date of death will be recorded. For 3- year survivors, Considering the fact that both inhalational and intra- quality of life will be assessed with the European Organ- venous general anaesthesia are routinely performed isation for Research and Treatment of Cancer Quality of in daily practice and no additional risk is produced Life Questionnaire (EORTC QLQ-C30); cognitive func- to participants, no interim analysis will be performed tion will be assessed with the TICS-m (Chinese version). and the trial will continue until the target sample size For long-term postoperative outcomes, the primary is achieved. endpoint is the duration of 3-year survival after surgery. The conduct of the study will be monitored by study Secondary endpoints include rates of survival at different coordinator(s) and supervisor(s) in each centre. Auditing time points after surgery, duration of recurrence-free for the trial conduct will be carried out eight times by survival after surgery, rates of recurrence-free survival at an independent auditor (MRW) from Peking University different time points after surgery, as well as quality of life Clinical Research Institute. Data management and statis- and cognitive function in 3-year survivors after surgery. tical analysis will be performed by the Peking University Clinical Research Institute. Safety consideration In the present study, the intervention measures adminis- Statistical analysis tered for patients of both groups are anaesthesia methods Analyses will be performed on an intention-to-treat basis, currently being used during daily practice. Therefore, that all subjects will be analysed in the group which our study will not produce additional risk on participants. they are assigned to. Per-protocol analyses will also be However, adverse events may occur even during a normal performed for the primary endpoints. All statistical anal- anaesthesia. In such case, anaesthesiologists will manage yses will be performed with SAS V.9.2 software (SAS Insti- patients according to routine practice. The occurrence of tute, Cary, North Carolina, USA). adverse events will be monitored from the beginning of Numeric variables will be presented as mean (SD) or anaesthesia until 24 hours after surgery. median (minimum, maximum; or IQR) and analysed An adverse event means any unpredictable, unfavour- with independent sample t test or Wilcoxon rank sum able medical event that is associated with any medical test. Categorical variables (including the incidence of intervention and occurs during the study period. It can 7 day delirium after surgery) will be presented as number be related to the study intervention or otherwise. It can of cases (percentage) and analysed with Χ2 test, conti- manifest as any uncomfortable signs (including abnormal nuity correction Χ2 test or Fisher exact test. Time-to- laboratory findings), symptoms or transient morbidity. A event variables (including the duration of 3-year survival severe adverse event indicates any unpredictable medical after surgery) will be analysed with Kaplan-Meier survival events that lead to death, threat of life, prolonged length analysis, with difference between groups assessed with of hospital stay, persistent disability or dysfunction, or log-rank test. A Cox proportional hazard model will be other severe event. used to calculated hazard ratio (HR) and the 95% CI to Any adverse events will be treated promptly according estimate the between group difference. Subgroup anal- to routine practice, followed up until it is completely yses will be performed according to the locations and the resolved or therapy is terminated, and documented. final pathological diagnoses of cancers. Documentation of adverse events include the following, Two-tailed tests will be used in all statistical analyses, that is, time of occurrence, diagnosis, time of diagnosis, and p values of <0.05 will be considered to be of statistical management, duration of persistence, sequelae and significance (unless otherwise specified). severity. The occurrence of severe adverse events will be reported to the local ethics committee as soon as possible. Participant timeline Participant recruitment and data collection were started Data management and monitoring in April 2015. The recruitment will continue until suffi- All original data will be recorded in the Case Report cient participants (1200 patients) are enrolled, which Forms accordingly. The completed Case Report Forms, is scheduled at the end of September 2017. Early post- after signed by the supervisors, will be sent to the Clinical operative follow-up will be completed in October 2017. Research Institute of Peking University. Data entry will be Long-term postoperative follow-up will be completed doubly performed by two persons using the EpiData3.10 in October 2020. Data analysis and evaluation for early

6 Zhang Y, et al. BMJ Open 2017;7:e018607. doi:10.1136/bmjopen-2017-018607 Downloaded from http://bmjopen.bmj.com/ on December 12, 2017 - Published by group.bmj.com Open Access and long-term outcomes will be performed separately for 11Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou publications. University, Zhengzhou, Henan, China 12Department of Anesthesiology, Beijing Shijitan Hospital, Beijing, China 13Department of Anesthesiology, Peking University Hospital of Stomatology, Beijing, China 14Department of Anesthesiology, Shanxi Provincial Cancer Hospital, Taiyuan, Shanxi, Ethics and dissemination China The study protocol has been approved by the Clinical 15Department of Anesthesiology, Southeast University Zhongda Hospital, Nanjing, Research Ethics Committee of the Peking University Jiangsu, China 16 First Hospital (first version protocol approved on 13 Department of Anesthesiology, Peking University Cancer Hospital&Institute, Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education), April 2015 with number 2015[869]) and the Ethics Beijing, Beijing, China Committees of all participating centres. Any revision 17Department of Anesthesiology, Shenzhen Second People’s Hospital, Shenzhen, of the study protocol must be approved by the Ethics Guangzhou, China Committee before it can be executed in the study. 18Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin, China 19 During the study period, Declaration of Helsinki Department of Surgery and Cancer, Anaesthetics, Pain Medicine and Intensive Care Section, Faculty of Medicine, Imperial College London, Chelsea and and Chinese guidelines of Good Clinical Practice are Westminster Hospital, London, UK strictly followed in order to guarantee the right of the participants. The principle investigator (DXW) will Acknowledgements The authors thank Professor Xin-Yu Sun (Department submit report of the study progress to the local Ethics of Psychiatry, Peking University Sixth Hospital, Beijing, China) for her help in Committee regularly. psychiatric consultation and investigator training, and Drs Dong-Liang Mu, Xian Su, Ya-Wei Li and nurses Cui Yuan, Xiao-Jing Liu and Bin Wei (Department of For every potential participant, the investigators will Anesthesiology and Critical Care Medicine) for their help in investigator training. explain in detail the study purposes, procedures, as well Contributors D-XW: conceived the study and is the principal investigator and as potential benefits and risks from the study in a written has overall responsibility for the trial. YZ and D-XW: drafted the protocol. H-JL: informed manner. The investigators must let every poten- revised the parts of data management and statistical analysis. H-QJ, Q-SY, L-HP, tial participant know that he/she has the right to withdraw WO, ZJ, X-DS, F-XZ, Y-QG, Q-GZ, X-DY, H-YT, B-JZ, Y-QA, NY, Z-HL, J-BY and DM: consent at any time during the study period. Every poten- participated in the study design and coordination of the study. All authors: read and approved the final manuscript. tial participant must be given sufficient time for careful Funding This study is supported by grants from the Wu Jieping Medical consideration before making decision. Every participant Foundation, Beijing, China (320.6750.15175) and the Chinese Society of or the authorised surrogate of the participant must sign Cardiothoracic and Vascular Anesthesiology, Beijing, China. The study sponsors the consent before he/she can be enrolled in the study. have no role in study design, in the collection, analysis, and interpretation of data, Written informed consents will be kept as a part of the in the writing of the report, or in the decision to submit the report for publication. The contents of this article are solely the responsibility of the authors and do not clinical trial documents. necessarily represent the official views of the Wu Jieping Medical Foundation or the Personal information of all participants will be confi- Chinese Society of Cardiothoracic and Vascular Anesthesiology. dentially kept. All related documents will be locked up Competing interests DXW is supported by grants from the Wu Jieping Medical and preserved according to the Chinese guidelines of Foundation(320.6750.15175), China and the Chinese Society of Cardiothoracic Good Clinical Practice. For each participant, all data and Vascular Anesthesiology, China; he reports lecture fees and travel expenses collected during the study period will be identified for lectures from Jiangsu Hengrui Medicine Co Ltd, China, Yichang Humanwell Pharmaceutical Co Ltd, China, and Jiangsu Nhwa Pharmaceutical Co Ltd, China. by a serial number and a name acronym in the Case DM is supported by grants from the British Oxygen Chair, and British Journal of Report Forms. Results of the study will be presented at Anaesthesia Fellowship, London, UK. academic conferences and submitted to peer-reviewed Patient consent Obtained. journals. Ethics approval The study protocol has been approved by the Clinical Research Ethics Committee of the Peking University First Hospital (first version protocol Author affiliations approved on 13 April 2015 with number 2015[869]) and the Ethics Committees of 1Department of Anesthesiology and Critical Care Medicine, Peking University First all participating centers. Any revision of the study protocol must be approved by the Hospital, Beijing, China Ethics Committee before it can be executed in the study. 2Project Development and Project Management Department, Peking University Clinical Research Institute, Beijing, China Provenance and peer review Not commissioned; externally peer reviewed. 3 Department of Anesthesiology, Fourth Hospital of Hebei Medical University, Open Access This is an Open Access article distributed in accordance with the Shijiazhuang, Hebei, China Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which 4Department of Anesthesiology, Tang-Du Hospital Fourth Military Medical University, permits others to distribute, remix, adapt, build upon this work non-commercially, Xi'an, Shaanxi, China and license their derivative works on different terms, provided the original work is 5Department of Anesthesiology, Affiliated Tumor Hospital of Guangxi Medical properly cited and the use is non-commercial. 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8 Zhang Y, et al. BMJ Open 2017;7:e018607. doi:10.1136/bmjopen-2017-018607 Downloaded from http://bmjopen.bmj.com/ on December 12, 2017 - Published by group.bmj.com

Impact of inhalational versus intravenous anaesthesia on early delirium and long-term survival in elderly patients after cancer surgery: study protocol of a multicentre, open-label, and randomised controlled trial Yue Zhang, Hui-Juan Li, Dong-Xin Wang, Hui-Qun Jia, Xu-De Sun, Ling-Hui Pan, Qing-Shan Ye, Wen Ouyang, Zhen Jia, Fang-Xiang Zhang, Yong-Qing Guo, Yan-Qiu Ai, Bin-Jiang Zhao, Xu-Dong Yang, Qin-Gong Zhang, Ning Yin, Hong-Yu Tan, Zhi-Heng Liu, Jian-Bo Yu and Daqing Ma

BMJ Open 2017 7: doi: 10.1136/bmjopen-2017-018607

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