Impact of propofol versus sevoflurane on the incidence of postoperative delirium in elderly patients after spine surgery: study protocol of a randomized controlled trial

Explanation for the choice of comparators

Propofol and sevoflurane are commonly used anesthetics, and the different effects of the two drugs on postoperative delirium are controversial. Thus, we want to compare the effect of the two drugs on the incidence of delirium.

Intervention description Anesthesia management and study intervention

Intraoperative monitoring includes an electrocardiogram (ECG), invasive blood pressure (IBP), pulse oxygen saturation (SPO2), bispectral index (BIS), end-tidal partial pressure of carbon dioxide (PetCO2), end-tidal concentration of inhalational anesthetics, cerebral oxygen saturation, and urine output.

Participants will be induced with midazolam (0.03–0.06mg/kg), etomidate (0.05–0.3mg/kg), sufentanil (0.2–0.5μg/kg), and atracurium (0.5mg/kg) intravenously. For patients in the sevoflurane group, anesthesia will be maintained with sevoflurane inhalation, of which the concentration will be adjusted to maintain the BIS value between 40 and 60. For patients in the propofol group, anesthesia will be maintained with propofol infusion (target-controlled infusion, TCI), of which the target concentration will be adjusted to maintain the BIS value between 40 and 60. For patients of both groups, intraoperative analgesia will be maintained with remifentanil (0.1–0.5μg kg min−1) and muscle relaxation will be maintained with continuous infusion of atracurium (10 μg kg min−1).

Intraoperative mechanical ventilation will be established with a tidal volume between 6 and 8 mL/kg, plateau pressure of <40 cm H2O, frequency between 12 and 16 per min, and FIO2: 60%. The PetCO2 will be maintained between 35 and 45 mmHg. Intraoperative fluid therapy will be managed according to routine practice. A blood cell saver will be used if it is estimated that the bleeding exceeds 500 mL during the operation. Packed red blood cells will be transfused if necessary in order to maintain hemoglobin levels within the target range of 7–10 g/dL. Vasoactive drugs (dopamine, norepinephrine, phenylephrine, urapidil, or nitroglycerin) will be administered if necessary in order to maintain the systolic blood pressure fluctuation range within 30% of baseline. After the operation, the patients will be transferred to the postanesthesia care unit (PACU).

When suturing the skin, sufentanil (10μg) will be given to analgesia and the atracurium will be stopped. Postoperative analgesia during the first 2 days will be provided by a patient-controlled analgesia pump, which is established with sufentanil (1.5–2 μg/mL) and ondansetron (0.16 mg/mL), programmed to deliver a 0.5-mL bolus with a lockout interval of 15min and a background infusion of 2mL/h. Other opiates and non-steroid anti-inflammatory drugs can also be used for postoperative analgesia. Postoperative rescue analgesia will be provided by intravenous injection or oral intake.

Intraoperative data included the type of surgery (categorized the complexity and invasiveness of the surgical procedure according to an established four-tier rating system [25]); durations of anesthesia and surgery; dosages of anesthetics, analgesics, and other drugs used during anesthesia; fluid balance and transfusion of blood products; and fluctuation of monitoring variables.

Criteria for discontinuing or modifying allocated interventions

Patients can refuse to continue the study at any time for any reason without any consequences. The patient’s participation in this study can also be ended by the investigator if the patient is allergic to propofol or sevoflurane during surgery, is uncooperative, or cannot be assessed (e.g., endotracheal intubation or coma) with a 3-min diagnostic interview for Confusion Assessment Method (3D-CAM) after surgery. The patient data that have been collected up to that moment will be included in the analysis.

Strategies to improve adherence to interventions

Not applicable. Interventions in this study will be completed during general anesthesia and without the patients’ cooperation.

Relevant concomitant care permitted or prohibited during the trial

No pre-anesthesia medication will be given before the patient arrived in the operation room. For all enrolled patients, scopolamine and penehyclidine are prohibited; atropine is used only for the purpose of reversing bradycardia, and the dosage will be recorded.

Provisions for post-trial care

Not applicable. In the present study, the intervention measures administered for patients of both groups are anesthesia methods currently being used during daily practice. Patients will be managed according to routine practice.

Outcomes Primary outcome

The incidence of postoperative delirium in two groups. Delirium will be assessed twice each day, that is, between 8–10 am and 6–8 pm, during postoperative days 1–7 with 3D-CAM. For patients who are discharged from the hospital, withdraw consents, or die within 7 days after surgery, the last follow-up results will be regarded as the final results. Because of the waxing and waning nature of delirium, researchers will review all progress notes and nursing documentation for delirium diagnoses, and a thorough medical record review process using the Chart-based Delirium Identification Instrument [26] will be performed.

Secondary outcome

If the patient develops postoperative delirium, the day of postoperative delirium onset, duration (time from first to last delirium-positive day), and total delirium-positive days among patients will be recorded. The tracheal intubation time, incidence of postoperative shivering, incidence of postoperative nausea and vomiting (PONV), incidence of emergence agitation (EA), and pain severity will be assessed during the recovery period in PACU. Postoperative shivering will be assessed with the Crossley and Mahajan Scale (0, no shivering; 1, one or more of the following: piloerection, peripheral vasoconstriction, and peripheralcyanosis with no other cause, but no muscle activity; 2, visible muscular activity confined to one muscle group; 3, visible muscular activity in more than one muscle; 4, gross muscular activity involving the whole body) [27]. Nausea is defined as a subjective, unpleasant sensation associated with awareness of the urge to vomit. Retching is defined as the labored, spastic, rhythmic contraction of the respiratory muscles without expulsion of the gastric contents. Vomiting is defined as the forceful expulsion of gastric contents from the mouth. Each episode is recorded as either presence or absence. If the patients had nausea, the severity will be recorded using the following scale: 1, mild nausea; 2, moderate nausea; and 3, severe nausea. If the patients had retching or vomiting, the severity of episodes will be recorded using the following scale: 1, one episode; 2, two episodes; and 3, three or more episodes [28]. PONV are also assessed during postoperative days 1–3. EA will be assessed immediately after extubation using the Richmond Agitation–Sedation Scale (RASS) and patients with RASS score > +1 are evaluated as EA [29]. RASS are also assessed in patients who developed delirium to define the types of delirium (patients with delirium are classified into three subtypes: hyperactive (RASS score consistently positive, from +1 to +4), hypoactive (RASS score consistently neutral or negative, from −3 to 0), and mixed) [30]. Pain severity will be assessed with the visual analogue scale (VAS), when the patients are transferred out of PACU and during postoperative days 1–3.

Postoperative recovery quality on the first day after operation will be assessed with QoR40. The occurrence of non-delirium complications, which are defined as newly occurring medical conditions that are harmful for patients’ recovery and require therapeutic intervention, will be monitored during postoperative days 1–30. For patients who die within 30 days after surgery, the exact date of death will be recorded.

Participant timeline

The participant timeline is presented in Fig. 1.

Fig. 1figure 1Sample size

The sample size was calculated for the primary outcome (the incidence of delirium after spine surgery) based on a retrospective study investigating the risk factors of delirium after spine surgery [31]. Calculations are performed using PASS 15.0 and the parameters used included the following: a two-sided, significance level of 0.05, 95% confidence interval, 80% power, and 1:1 allocation. The minimum number of subjects required to confirm statistical significance is determined to be 134 individuals per group. Accounting for a dropout rate of 10%, we aim to recruit a total of 298 people, with 149 for each group.

Recruitment

Patients will be recruited at the First Affiliated Hospital of Shandong First Medical University, China. More than 400 elderly patients undergo spine surgery in the center annually.

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