Efficiency of probiotics in elderly patients undergoing orthopedic surgery for postoperative cognitive dysfunction: a study protocol for a multicenter, randomized controlled trial

Postoperative cognitive dysfunction (POCD) refers to cognitive function changes, such as decreased learning and memory ability and inability to concentrate, after anesthesia and surgery. In severe cases, personality changes and decreased social behavior ability are observed [1]. Some patients even develop irreversible cognitive impairment [2]. POCD increases the hospitalization time of patients, prolongs their stay in intensive care units, increases their medical expenses, and increases the mortality of patients 1 year postoperatively [3]. POCD have become a widespread concern of clinicians and patients. Clinical studies showed that its incidence after a major surgery is relatively high, and major surgeries are often accompanied by blood redistribution caused by factors, such as bleeding and hypotension, resulting in intestinal mucosal ischemia [4, 5]. Intestinal mucosal ischemia is an important cause of intestinal flora imbalance [6, 7]. Patients with severe diseases (including sepsis, acute respiratory distress syndrome, and multiorgan failure) and those undergoing intestinal surgery are prone to changes in the intestinal flora. They are more likely to have intestinal flora disorders due to long-term applications of antibiotics, unstable hemodynamics, long-term parenteral nutrition, and other factors [8]. Such patients are more prone to POCD [9]. Its incidence in patients undergoing intestinal surgery is also relatively high. Tan et al. [10]. found that its incidence after an endoscopic or open colectomy is approximately 47%.

Studies in our laboratory proved that [11] giving probiotics to mice before operation can prevent POCD. However, at present, there is a lack of clinical evidence. In this study, probiotics will be used to intervene with the intestinal flora imbalance perioperatively in order to reduce the incidence of POCD and provide new ideas and methods for its clinical prevention and treatment.

In this study, we will recruit 220 participants from Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Guanghua Integrated Traditional Chinese and Western Medicine Hospital, and Shanxi Jincheng Hospital. The clinical trial was approved by the Ethics Committee of Renji Hospital (2018–232) and registered at ClinicalTrials.gov on August 15, 2019 (No. NCT04017403). The trial was conducted according to the recommendations of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (supplemental file, SPIRIT checklist). We presented the trial registration data in the form of supplemental data.

This is a multicenter, double-blind, randomized, placebo-controlled, interventional superiority clinical study. We will observe the effect of perioperative probiotics on the postoperative cognitive function of elderly patients undergoing orthopedic surgery.

The purpose of this study is to determine whether the perioperative intervention with probiotics on intestinal flora can reduce the occurrence of POCD and to provide new ideas for its clinical prevention and treatment. Our primary objective is to assess the incidence of POCD 7 days after surgery. Our secondary objective is to assess the incidence of POCD and postoperative delirium (POD) 1 month and 7 days after surgery, respectively. We predict that probiotic intervention will reduce its incidence in elderly patients undergoing orthopedic surgery.

The schedule of the major study events for each visit is shown in Fig. 1. Patients who are scheduled to undergo orthopedic surgery will be included in this study. The entire process of recruitment and consenting of study participants by members of the research team will be consistent with good clinical practice (GCP) recommendations. Patients will be recruited mainly from the three centers.

The inclusion/exclusion criteria are summarized in Table 1.

After assessing the patient’s eligibility for inclusion, his/her informed consent will be obtained. A designated doctor will explain the experiment in detail to interested participants and provide them with informed consent. Participants will have at least 24 h to decide whether they want to participate in the trial. An informed consent form will be signed by the participants or their trustee or guardian; it can be withdrawn at any time during the trial. A written informed consent and patient baseline data will be obtained before randomization. Moreover, participants will be encouraged to contact the research team if they have any health concerns during the trial.

We will collect baseline data from patients and randomize allocation using Statistical Analysis Set (SAS) software. Furthermore, participants can contact our team if they have any health concerns during the trial. The recruitment and consenting of study participants by the research team are in line with the GCP guidelines. During the clinical trial, the researchers will immediately report any serious adverse events, whether related to the probiotics under study or not, to the director in charge of the clinical trial of the research institution and contact Professor Diansan Su or Dr. Xiaoyi Zhang.

No ancillary study is planned, and we have no plans to collect additional participant data or biological specimens outside of what is mentioned in this protocol.

Participant information will be confidential and managed according to the Data Protection Act, NHS Caldecott Principles, The Research Governance Framework for Health and Social Care, and the conditions of Research Ethics Committee approval.

Figure 1 shows the schedule of major study events for each visit. Elderly patients planning to undergo orthopedic surgery will be included in this study. The surgery will be performed within 2 days after screening. The drug will be used a day before operation until 6 days postoperatively. The probiotic group will be treated with Peifeikang (Bifidobacterium triple viable powder, 210 mg per capsule), while the control group will be treated with placebo in the same package. The drug will be taken orally, four capsules at a time, twice a day, and the postoperative cognitive function will be evaluated using a neuropsychological test. If participants request to withdraw from the trial, we will discontinue the allocated intervention for the given trial participants. Adherence to interventions primarily refers to patient self-management adherence. No concomitant care or interventions will be permitted during this trial.

Figure 1 presents the schedule for enrollment, interventions, assessments, and visits of participants.

Cognitive function assessment: 1 day before operation: Mini-Mental State Examination (MMSE) screening, digit span test, digit symbol test, Wechsler Memory Scale (WMS), visual regeneration, and digital connection test will be performed. 7 days after operation or before discharge: digit span test, digit symbol test, WMS, visual regeneration, and digital connection tests will be performed again. 7 days after operation: POD will be assessed using the CAM, which includes acute onset, inattention, disorganized thinking, and abnormal consciousness. The diagnosis of delirium by CAM requires the presence of features 1 and 2 and either 3 or 4. Table 2 presents the specific content.

We will also assess the long-term cognitive status using a modified cognitive state telephone interview (TICS-m) 1 month after surgery. TICS-m has been used to screen for dementia and mild cognitive impairment. The TICS-m score ranges from 0 to 48. The higher the score, the better the function. An evaluator will comprehensively evaluate the patient’s condition according to the patient’s medical history, clinical observation, current scale evaluation, and information provided by family members or nursing staff.

According to previous studies, the incidence rate of POCD after a major surgery was 25% [12], and the estimated application of probiotics could reduce it to 10%. According to alpha = 0.05, Power = 0.80, PASS 11 will be applied. The calculated sample size is n = 100 cases, with a shedding rate of 10%. The sample size of each group is n = 110 cases.

This study is a multicenter clinical trial. All data collection physicians will be specially trained by assessors. We will conduct online meetings regularly to share the progress of the trial and discuss the problems that we encounter during the project. Moreover, we will conduct field visits to subcenters for quality control. We shall also organize the trial data regularly to check for any missing data. Furthermore, to promote data quality, we intend to apply other methods and call the participants for follow-up.

Before surgery, the doctor will conduct medical visits for up to 40 min and complete the scale for each patient; furthermore, they will inform the patients that they will be followed up and observed for several consecutive days after surgery. If necessary, the doctor will communicate with the patient through WeChat to understand their latest situation in addition to communicating through phone calls. One day before surgery, the anesthesiologist will record each patient’s general information, including sex, years of education, BMI, dietary habits, history of disease, medication, and surgery. During surgery, blood pressure fluctuations are maintained within 20% of the baseline blood pressure level. Anesthesiologists will record the volume of infusion, estimated blood loss, and urine output and assess the need for a blood transfusion. Similarly, the duration of surgery, anesthesia, and hospital stay after surgery are recorded. After surgery, an analgesia pump will be used for intravenous self-analgesia (uniformly prepared by the pharmacy). Patient-controlled analgesia and or nerve block would be used for postoperative analgesia in all patients to maintain a VAS score of less than 3. The PCIA pump includes the following analgesics: sufentanil citrate 100 μg and flurbiprofen axetil 100 mg which are prepared into 0.9% sodium chloride, in a total volume of 100 ml. All patients receive a 1.5 ml on-demand bolus with a lockout interval of 15 min. The infusion was started immediately after suturing the skin incision and lasted 48 h. We use morphine as rescue drug, which is given according to the patient’s pain situation. At the same time, the drug dosage of the patient’s analgesia pump used and morphine dosage are recorded. Three months after operation, the same doctor will call the patient again for follow-up. All data collected during this clinical study will be entered and/or filed in the patients’ CRFs. The patients’ study participation must be documented appropriately in the CRF with their study number, subject number, date of subject information, informed consent, and date of each visit. Source data will be filed according to the GCP guidelines. The data manager will be responsible for data processing, following the sponsor’s standard operating procedures.

Regular monitoring will be conducted to ensure that the data are adequate, accurate, and complete. The database will be locked only after the completion of quality assurance procedures.

All statistical tests are conducted by two-sided test, and the difference tested will be considered to be statistically significant if P ≤ 0.05(unless otherwise specified). The primary outcome measure will be statistically analyzed by chi-square or Fisher exact probability. Secondary outcome measures will be tested by group t-test. The description of quantitative indicators will calculate the mean, standard deviation, median, minimum, and maximum. The number and percentage of patients are used to statistically describe the demographic information, medical history, combined diseases and symptoms, physical examination, operation time, etc. According to the numerical characteristics of variables, t-test/Wilcoxon rank sum test is used to compare the quantitative data of age, height, and weight between the two groups; chi-square test/exact probability method is used to compare the categorical variables such as gender, medical history, combined diseases and symptoms, physical examination and so on.

The methods used for statistical analyses will also be used for additional analyses of primary and secondary outcomes. Intention-to-treat basis will be used to conduct statistical analysis. The analyses of the outcomes will be analyzed as randomized, regardless of protocol adherence. All variables will be screened for frequency and type of missingness. If missingness is > 5% for any variable, the mean normal value of the patient group will be used for imputation.

No formal interim analysis of primary and secondary outcomes is planned.

Secondary outcomes comprise the following:

Postoperative delirium will be assessed 7 days after surgery using the Confusion Assessment Method (CAM), which includes acute onset, inattention, disorganized thinking, and abnormal consciousness. The diagnosis of delirium by CAM requires the presence of features 1 and 2 and either 3 or 4 (Table 2).

The cognitive status will be determined based on a telephone interview and will be evaluated via TICS-m in 1 month after surgery.

General safety evaluations will be based on the incidence and type of adverse events (AEs). Safety variables will be tabulated and presented for all patients in the safety set. Adverse events will be coded using World SIVA adverse sedation event reporting tool. The number (%) of subjects with any AEs will be summarized. Probiotics, as beneficial bacteria in the human body, are generally well-tolerated. To date, there has been no evidence that this study may cause any risk or discomfort to participants. However, any harm from the intervention will still be evaluated. Any adverse events, including those voluntarily provided by subjects or obtained through physical examination, laboratory examination, or other examination methods, will be recorded on CRFs and actively handled. We will record any adverse events that occur during the clinical trial, regardless of whether these events were associated with the intervention. Furthermore, all these expected and unexpected trial-related adverse events will be reported in trial publications. A close follow-up will be done until remission or stable condition.

If a participant suffers harm from this trial, he/she will receive free treatment.

The study results will be disseminated via articles published in peer-reviewed journals.

This section is not applicable as we have no plans to provide access to the full protocol, participant-level data, and statistical code.

We have no plans to collect or store biological specimens in this trial.