We recruited 105 ESRF patients with SHPT who were scheduled for parathyroidectomy at our hospital between August and December 2018. Patients with primary hyperparathyroidism, severe pulmonary hypertension, arrhythmia, atherosclerosis, aortic stenosis, or chronic cardiac dysfunction were excluded. Patients with upper limb edema or malformation, or with blood pressure difference >10 mm Hg between the arms, were excluded. In total, three patients were excluded from this study. All patients were receiving hemodialysis thrice weekly or daily peritoneal dialysis. The patients had an American Society of Anesthesiologists physical status of III. Patients were randomized into two equal groups by a computerized random-number generator (managed by a third-party statistician): a control group, managed with a restricted-fluid regimen (restrictive group), and a PPV group (GDFT group) that was given normal saline infusion and monitored for change in PPV (Figure 1). The same operative team performed all operations.
Anesthesia and mechanical ventilation
No sedative or analgesic drugs were administered before the induction of anesthesia. Dialytic therapy was performed on the day before surgery. After their arrival in the operating room, patients received routine monitoring, including pulse oximetry (SPO2), electrocardiogram, bispectral index (MedTronic, Minneapolis, MN, USA), and end-tidal CO2. CNAP was established and calibrated to measure blood pressure and other hemodynamic variables. We used the CNAPTM system (CNSystem, Medizintechnik, Graz, Austria).
General anesthesia was induced in all patients with bolus infusion and a target-controlled infusion of propofol (Fresenius Kabi AB, Macclesfield, UK) for a plasma concentration of 3.0-3.5 μg/mL; bolus of remifentanil (Yichang Humanwell Pharmaceutical Co., Ltd., Yichang, China) 1.5 μg/kg infused over 30 s; and cisatracurium besylate 0.15 mg/kg (Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, China). After tracheal intubation, ventilation was established with 6-8 mL/kg tidal volume, and respiratory rate was adjusted to target end-tidal CO2 of 35-45 mmHg. Since the operation was performed and completed under endoscopy and in order to avoid excessive high airway pressure during the operation, we maintained the tidal volume at 8 ml/kg, which was lowered (but still >6 ml/kg) only when the airway pressure was too high. Since the patient's PaCO2 had to remain within 35-45 mmHg, it did not achieve the criteria of permissive hypercapnia. Anesthesia was maintained with target-controlled infusion propofol (target concentration: 2.5-3.5 µg/ml), IV remifentanil (0.2-0.3 μg/kg/min), and cisatracurium besylate (0.05 mg/kg/min, intermittent intravenous injection). The intermittent injection of cisatracurium was based on the patients' muscle tone during the operation. During the operation, bispectral index values (MedTronic, Minneapolis, MN, USA) were maintained within 45 ± 5 by regulating the infusion rate of propofol. Thirty minutes before the end of the surgery, the cisatracurium besylate infusion was stopped. Propofol and remifentanil were turned off in both groups after wound closure.
The endotracheal tube was removed when patients were able to follow verbal commands to open their eyes, after checking for spontaneous respiration, swallowing, fist boxing, and keeping the head up before extubation, and the T7/T4 ratio was 90%. Patients were kept in the post-anesthesia care unit for one hour.
In the restrictive group, only vasoactive agents were administered, without fluid infusion. In the GDFT group, intravenous fluid therapy and the use of vasoactive agents were determined according to the change of PPV and other hemodynamic variables. If PPV was >13%, 250 mL of normal saline was administered over 15 min. Fluid responsiveness was evaluated every 15 min.
In both patient groups, demographic data, dialysis history, preoperative complications, duration of operation, total volume of anesthetics (propofol, remifentanil, and cisatracurium besylate) used, and intraoperative fluid and vasoactive agents infused were recorded. Postoperative complications, including hypotension, hypertension, pulmonary edema, infection, incision disunion, and arteriovenous fistula occlusionwere recorded.
Vital signs and weight were recorded before and after the last dialysis and before the administration of anesthesia. Baseline SBP was the SBP measured after the last dialysis before surgery. The measurements were taken in the hemodialysis ward before transfer to the operating room. The SBP was measured in the supine position. Values were considered “maximum,” “minimum,” or “baseline.” Hemodynamic variables were continually recorded at baseline (T0); before induction (T1); after induction (T2); immediately after intubation (T3); beginning of mechanical ventilation (T4); before incision (T5); 30 min, 60 min, and 90 min during the operation (T6, T7, T8); and 120 min during the operation or at the end of the operation if the operative time was > 120 min (T9).
Blood samples were taken from the femoral artery before and 30 min after the operation and analyzed for brain natriuretic peptide, blood gases, hemoglobin/hematocrit, lactate, and electrolytes.
In order to preserve the integrity of the arteriovenous fistula, we avoided any blood pressure monitoring and puncture in the arm with the fistula. We used the lower extremity venous access, placed the arm with the arteriovenous fistula on the side of the body, and the nurse repeatedly confirmed that there was no compression of the venous fistula. Any abnormality of the arteriovenous fistula pulsation was assessed before and after the operation, in order to ensure functional integrity.
The primary endpoint of this study was hypotension after operation. The secondary endpoints were total volume of fluid administered, the doses of vasopressors used, the incidence of postoperative complications, abnormalities in blood gas values, and electrolyte concentrations.
Regarding complications, hypotension was considered when blood pressure is lower than the baseline blood pressure by 20%. Hypertension was considered when blood pressure is higher than basic blood pressure by 20%. Pulmonary edema was considered in the presence of hypoxemia, foamy sputum, auscultation of double lung wet rales, and confirmation by chest X-ray. Infections were confirmed by elevated C-reactive protein levels. Poor wound healing was defined as incision edema.
Data and statistical analysis
According to the records of the research center, postoperative hypotension rarely occurs in patients receiving dynamic fluid replacement, while postoperative hypotension is prone to occur with conventional surgery. Therefore, the difference in postoperative complications between the two groups was estimated at about 20%. Postoperative hypotension was also considered in the calculation process of the minimum sample size. A sample of 44 patients in each group was required to detect a 20% reduction in postoperative hypotension at a significance level of 0.05 and power of 80%. Considering a possible 20% dropout rate, a sample with a minimum of 53 per group was required.
Statistical analyses were performed with SPSS version 21.0 (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp). The data were tested for normal distribution with the Kolmogorov-Smirnov test and for homogeneity of variances with the Levene test . Normally distributed continuous data were presented as mean ± standard deviation, and those with abnormal distributions were expressed as median (25–75th percentile). Categorical variables were expressed as number (%). The independent-samples t-test was used to compare continuous variables between the two groups, and repeated-measures one-way ANOVA was used for within-group comparisons. All enumeration data were compared using the chi-squared test or Fisher's exact test. Comparisons between ranked data were made with the Kruskal-Wallis test or the Wilcoxon test.
The study was a single-blind randomized controlled trial, which was conducted at The Second Affiliated Hospital of Anhui Medical University, Hefei, China between August and December 2018. The protocol approved by the Ethics Committee for Clinical Trials of The Second Affiliated Hospital of Anhui Medical University (approval No. PJ-YX2018-008(F1)). Written informed consent was obtained from each patient. This trial was registered with the Chinese Clinical Trial Registry (ChiCTR1800017302). This manuscript adheres to the applicable Consolidated Standards of Reporting Trials (CONSORT) guidelines.