Study design
This was a prospective single-center single-blind randomized controlled trial, the protocol of which was approved by the ethics committee of Northern Jiangsu People’s Hospital (2021ky178). The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100050474). Written informed consent was obtained from all the enrolled patients.The flow chart of this study is shown in Fig. 1.
Participants
Patients aged more than 18 years who were scheduled to undergo thoracoscopic lung resection (pulmonary resection or anatomic pulmonary segments) were eligible for enrollment in this trial. Sixty patients satisfied the following inclusion criteria and were enrolled in our study: American Society of Anesthesiologists physical (ASA) status I–Ⅲ, body mass index between 18.5 and 25 kg·m-2, ultrasound screening revealing a kidney depth (distance from the skin surface to kidney capsule) of <40 mm; and New York Heart Association (NYHA) classes Ⅰ–Ⅲ. The exclusion criteria were receipt of emergency procedures, ASA status Ⅳ or Ⅴ, cardiac failure (NYHA class IV), preoperative abnormal lung function (forced expiratory volume in 1 s < 50% of the predicted values), nervous system diseases, peripheral vascular disease, coagulation dysfunction, anemia (hemoglobin [Hb], <90 g/L), serum creatinine (sCr) level of ≥1.5 mg/dL, end-stage renal disease or receipt of renal transplant, frequent intraoperative cardiac arrhythmia, and OLV time of <60 min.
Randomization
The enrolled patients were allocated in a 1:1 ratio to undergo fluid management during OLV into the GDFT protocol group (GDFT group) or the restrictive fluid therapy group (group C). The randomization was stratified by sequential blocking based on a computerized random number generator. Allocation details were kept in sealed envelopes marked by serial numbers. Before the induction of anesthesia, the sealed, numbered, and opaque envelopes containing the treatment assignments were opened by an independent anesthesiologist. The data assessment or analysis was performed by an independent research staff supervised by an independent statistician. To ensure the reliability of data acquisition, the patients, clinical researchers involved in the collection of data and blood samples, and postoperative follow-up team were all blinded to group allocation. Group allocation was scarcely revealed when the final data analysis was completed.
Perioperative management
All participants performed respiratory functional exercises, were encouraged to quit smoking (patients who did not quit smoking were still allowed to complete the study), and improved their nutritional status before the surgery. No premedication was administered, and solid food and clear fluid intake were allowed until 12 and 3 h before surgery, respectively. General anesthesia was induced with propofol, midazolam, sufentanil, and atracurium cis-benzene sulfonate and maintained with sevoflurane, remifentanil, dexmedetomidine, and atracurium cis-benzene sulfonate. The depth of general anesthesia was controlled to maintain a bispectral index of 45–60. OLV was employed using a double-lumen tube during the operation, and the correctness of the position of the tube was confirmed by fiberoptic bronchoscopy. The trachea was intubated, and the participants were ventilated with a tidal volume (VT) of 7 ml·kg-1 (ideal body weight) during OLV. The inspiratory to expiratory time (I/E) ratio was 1:2, and positive end-expiratory pressure (PEEP) was 5 cmH2O. The frequency of ventilation was controlled such that the end-tidal carbon dioxide was 4.7~5.3 kPa, and adjustment the fraction of inspired oxygen (FiO2) to maintain saturation higher than 94% during two-lung ventilation and more than 90% during OLV. If FiO2 was more than 70% during OLV, the nondependent lung was insufflated with 100% oxygen at 1–5 cmH2O. The Vigileo-FloTrac system was used for hemodynamic monitoring in the GDFT group. Postoperative pain control was achieved with intravenous controlled analgesia.
Intraoperative fluid management
Hemodynamic parameters, including the arterial blood pressure (BP), SV, SVV, cardiac output, and cardiac index (CI), were measured using the Vigileo-FloTrac system. Baseline Ringer’s solution of sodium acetate was administered at a rate of 3 ml kg/kg·h in both groups. In the GDFT group, hemodynamic control was achieved using the Vigileo-FloTrac system according to a predetermined protocol based on a previous study that showed the beneficial effects of GDFT during high-risk abdominal surgery[30]. After the induction of anesthesia, the measured SV was set as the baseline volume for patients with an SVV of 12%. If the SVV was >12%, fluid with 250 ml of hydroxyethyl starch was administered over 20 min. This fluid challenge was repeated up to two times until an SVV of 12% was achieved. The SV measured at that time was then set as the baseline volume. During surgery, if the SVV exceeded 12% or remained at 8–12% and the percentage decrease in SV was >10% for at least 2 min, 250 ml of colloid was administered over 20 min. This was repeated until a stable hemodynamic condition (SVV < 13% and SV decrease < 10%) was achieved. The maximum amount of 6% hydroxyethyl starch that could be administered was 50 ml·kg-1. In addition, when the SVV remained <8%, norepinephrine was administered to maintain systolic BP (SBP) of >90 mmHg (Fig. 2).
In the restrictive fluid therapy group (group C), hydroxyethyl starch was infused to manage blood loss, and the ratio of hydroxyethyl starch to blood loss was 1:1 (ml). Norepinephrine was administered to maintain SBP of >90 mmHg. The infusion rate was adjusted by anesthesiologists according to their experience. If the urine volume was less than 0.5 ml·kg-1·h-1 for 2 h, 250 ml of Ringer’s solution of sodium acetate was administered until the target value is reached. The anesthesia care providers were blinded to the measurements obtained by the Vigileo-FloTrac system for the entire duration of the surgery.
Tissue oxygenation monitoring
Tissue oxygenation monitoring was performed non-invasively using a tissue oximeter based on near-infrared spectroscopy before the induction of anesthesia. A cerebral oximeter probe was placed at least 2 cm above the eyebrow on the left forehead, while a bispectral index (BIS) monitor was placed on the right forehead. An oximetry probe was placed on the brachioradialis muscle of the forearm (approximately two fingers below the anterior fold of the elbow) to monitor oxygen saturation of the muscle tissue of the forearm that was not used for cuff blood pressure monitoring. A third oximetry probe was placed on one side of the flank area that overlies the kidney to monitor renal regional tissue oxygen saturation under sonographic guidance. To visualize the kidney, an ultrasound probe was placed in the lower rib space in the posterior axillary line (below the 10th or 11th ribs). After obtaining a long-axis image of the kidney, the depth of the kidney (the distance from the skin surface to the renal capsule) was measured. The oximetry probe was placed on the probe placement point at a depth of <40 mm in the kidney. Patients were excluded from the study if the depth was ≥40 mm. Monitoring and data recording was started when the patient was awake breathing room air before anesthesia induction and stopped at the end of the surgery.
Data collection
Demographic data, including age, sex, weight, height, type of surgery, and ASA physical status score, were collected. Past medical history, including a diagnosis of hypertension and diabetes mellitus, was recorded. Intraoperative variables that were recorded included the surgical time, OLV time, sum of intraoperative bleeding, fluid infusion volume (crystalloid and colloid), urine output, and types and dosage of vasoactive drugs. Inoperative hemodynamic indicators (HR, MAP, CI, and SVV) and rSO2 were recorded before induction (T1), before OLV (T2), 30 min after OLV (T3), 60 min after OLV (T4), and at the end of surgery (T5). Arterial blood gas analysis data (pH and lactate) were recorded at T1, T4, and T5. Postoperative outcomes included (1) the quality of recovery over the first 24 h after surgery as measured by the 15-item quality-of-recovery scale; (2) the incidence of postoperative complications, including AKI, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary infection, atelectasis, and bronchial fistula; (3) creatinine and urea nitrogen levels at 1 day after operation; (4) incidence of postoperative nausea and vomiting; and (5) postoperative hospital stay.
Confidentiality
Private information about participants will not be collected. Only study codes will be collected. Collected data will be kept confidential until analysis is required. Collected data will be stored encrypted for 2 years after the study is completed.
Sample size calculation
The sample size calculation is based on the primary outcome “the effects of different fluid management methods on rSO2”. According to the results of our pre-experiments, μ1=79.1, μ2=74.1, δ=μ1-μ2≠0. The sample size for this study was calculated to achieve a statistical power of 0.9 and alpha error of 0.05 using a two-sided test. Considering a dropout rate of 20%, 30 patients are required in each group. PASS (version 15.0, NCSS, LLC, Kaysville, UT, USA) was used to estimate the sample size.
Statistical analysis
Data are presented as mean ± SD, median (interquartile range), or numbers of patients (%). Statistical analyses were performed using SPSS for Windows version 21.0 (IBM Corp., Armonk, NY, USA). The analysis of categorical variables was performed by Fisher's exact test or Chi-square test. Time-dependent data were compared using repeated-measures analysis of variance (between periods in each group and between groups). A preplanned subgroup analysis was conducted using an unpaired t-test if the data were normally distributed, while the Mann–Whitney U test was performed if the data were not normally distributed. All statistical tests were two-sided and a P-value lower than 0.05 was considered to be statistically significant.