This manuscript adheres to the applicable CONSORT guidelines. The supporting CONSORT checklist is available as Additional File 1. This prospective, randomized, parallel design, single-blind, single-center clinical trial was approved by the ethics committee of Kagoshima University Hospital and was conducted from May 2017 to November 2018 at Kagoshima University Hospital. This trial was prospectively registered on a publicly accessible database (UMIN Clinical Trials Registry ID: UMIN 000026957). Written informed consent was obtained from all participants.
The inclusion criteria were an American Society of Anesthesiologists physical status of I to III and performance of elective open gynecological surgery requiring a direct arterial line. The exclusion criteria were a history of uncompensated cardiac disease, stroke, arrhythmias, and severe liver/renal dysfunction.
Before induction of general anesthesia, a thoracic or lumbar epidural catheter (17G Tuohy needle, Hakko disposable epidural catheter; Hakko, Nagano, Japan) was placed at T10 to L1 according to the incision level, and 3 mL of 1% mepivacaine without epinephrine was administered. General anesthesia was induced with target-controlled infusion of propofol (1.0–2.0 mg kg−1), remifentanil (0.3–0.5 μg kg−1 min−1), and rocuronium (0.6–1.0 mg kg−1). Anesthesia was maintained with desflurane (0.6–0.7 age-adjusted minimum alveolar concentration) and remifentanil (0.05–0.5 μg kg−1 min−1) and intermittent bolus administration of rocuronium (10 mg) and fentanyl (2–10 μg kg−1). The rate of remifentanil infusion was tailored to control hemodynamic responses. Rocuronium was used to maintain a train-of-four ratio of ≤1 (TOF-Watch SX; Organon, Dublin, Ireland). The Life Scope J was used to continuously monitor the heart rate, direct arterial blood pressure, electrocardiogram, peripheral oxygen saturation, end-tidal carbon dioxide tension (ETCO2), PPV, PI derived from the pulse oximeter plethysmographic waveform, bladder temperature, and skin temperature of the hand. To assess the hemodynamic effects of the intervention, we continuously monitored the cardiac index (CI) and SV variation (SVV) with a high-fidelity dedicated pressure transducer (FloTrac sensor; Edwards Lifesciences, Irvine, CA, USA) and the Vigileo monitor, software version 3.01 (Edwards Lifesciences). The CI was calculated based on real-time analysis of the arterial waveform during a 20-second period. This calculation was performed at a sample rate of 100 Hz without the need for prior calibration using a proprietary algorithm based on the principle that the aortic pulse pressure is proportional to the SV. Dynamic arterial elastance (Eadyn), which represents the arterial load, was calculated as the ratio between the PPV and SVV.
The patients’ lungs were ventilated with an inspired oxygen fraction of 0.4 and tidal volume of 8 mL kg−1 of ideal body weight, and the respiratory rate was adjusted to maintain an ETCO2 of 35 to 45 mmHg and a positive end-expiratory pressure of 5 to 8 cmH2O. The patients were randomly allocated to one of two groups with an allocation ratio of 1:1 using Internet-based software in a complete randomization manner (Research Randomizer version 4.0, retrieved on October 13, 2016 from http://www.randomizer.org/). The patients were blinded to the allocation. In the intervention group, 250 mL of colloid (Voluven; Otsuka Pharmaceutical, Tokyo, Japan) was infused during induction, followed by continuous infusion of a balanced crystalloid (Bicanate; Otsuka Pharmaceutical) at a rate of 2 mL kg−1 h−1. In addition to the balanced crystalloid, 4.3% dextrose solution (Soldem 3A; Terumo, Tokyo, Japan) was administered at a rate of 20 mL h−1. If the MAP was <60 mmHg, the trend of the PI was evaluated (Figure 1). If the PI increased by >5% of previous value in 15 minutes, we considered that the hypotension was due to afterload reduction and administered a 0.1-mg bolus of phenylephrine followed by continuous infusion of phenylephrine at rate of 1.0 mg/h. The infusion rate of phenylephrine was adjusted every 10 minutes (0.1–2.0 mg h−1) to maintain the MAP within 60 to 90 mmHg. If the PI did not increase by >5% of previous value in 15 minutes, we evaluated the PPV. If the PPV was <13%, we considered that the hypotension was due to reduced contractility and administered a continuous infusion of dobutamine at a rate of 3 μg kg−1 min−1. The infusion rate of dobutamine was adjusted every 10 minutes (1–5 μg kg−1 min−1) to maintain the MAP within 60 to 90 mmHg. If the PPV was ≥13%, we considered that the hypotension was due to preload reduction and administered a 250-mL bolus of colloid (Voluven; Otsuka Pharmaceutical). In the control group, the hemodynamic management was performed at the discretion of the anesthesia care provider. Red blood cells were transfused when the hemoglobin level was <7 g dL−1. Arterial blood samples were taken at the time of skin incision, every 2 hours during surgery, and at the end of surgery. The lactate concentration was measured using an ABL 620 analyzer (Radiometer, Copenhagen, Denmark). Postoperative complications were recorded during the first 30 days after surgery; these included pulmonary infection and infection of other organs as well as leakage at the anastomosis site.
The primary outcome was the peak lactate level during surgery. The secondary outcomes were the duration of hypotension (MAP of <60 mmHg or 30% below the value measured the day before surgery while the patient was resting quietly for at least 15 minutes), intraoperative fluid balance, intraoperative urine output, and postoperative complication rate. To detect a 0.5-mmol L−1 difference in the peak lactate level with a two-sided approximation while accepting an a error of 5% and b error of 20%, the required study size was calculated as 34 patients based on the preliminary data using Power and Sample Size Calculation version 3.1.2 (Dupont WD and Plummer WD, Vanderbilt University, Nashville, TN). To account for patient dropout, 20% more patients were added, giving a final sample size of 40 patients. All data were expressed as mean with standard deviation or 95% confidence interval. The statistical analysis was performed using Student’s t-test and Fisher’s exact test (GraphPad Prism 5.0; GraphPad Software, La Jolla, CA, USA). A P value of <0.05 was considered statistically significant.