Prospective, randomised, double-blind, single-centre study, with two parallel group, was conducted at the University Medical Centre Ljubljana, Department of Anaesthesiology and Surgical Intensive Care and Department of Neurosurgery in years 2016- 2018 (trial registry: NCT03249298 at www.clinicaltrials.gov). The study was approved by the National Medical Ethics Committee of the Republic of Slovenia. All the procedures were performed in accordance with the declaration of Helsinki. The CONSORT recommendations for reporting randomized trials were followed. Written informed consent was obtained from all subjects participating in the trial.
80 patients, aged 18-80 years, ASA (American Society of Anaesthesiologists) Class 1-3 and GCS (Glasgow coma score) of 15, scheduled for elective craniotomy, were included in the study.
Exclusion criteria were (a) unwillingness to give a written informed consent, (b) cardiac arrhythmia (c) hemodynamic unstablity or shock (d) and coagulation disorder.
All patients were visited by a member of our team a day prior to surgery to seek an informed consent and to answer any question. Patients were able to freely withdraw from the trial.
Using a computer-generated list, the patients were randomised into two groups by the fourth author, not involved in patient care. The first author enrolled the patients and informed them about the participation in the study. The surgeon and the anaesthesiologist were blinded to the type of fluids used.
In the operating room standard monitoring was instituted. An arterial catheter was placed in the radial artery for continuous blood pressure monitoring. Advanced pulse contour cardiac output monitoring using the EVA 1000/FloTrac device (Edwards Lifescience, CA, USA) and near infrared spectroscopy oximetry (NIRS) monitoring (Medtronic, MN, USA) were applied.
Patients were premedicated (midazolam 7,5 mg po). Antibiotic prophylaxis with intravenous cefazolin 2g in 100 ml of 0.9% NaCl was invariably used in all patients.
Anaesthesia was induced with propofol 1-2 mgkg−1 (Propoven, Fresenius Kabi AG, Bad Homburg, Germany). Before intubation all patients received remifentanil 0.5-1 µgkg−1 (Ultiva, GlaxoSmithKline) and rocuronium 0.6 mgkg−1 (Esmeron, MSD, NY, USA).
Patients were intubated and mechanically ventilated (oxygen-air mixtures, I/E ratio 1:2, tidal volume 8 mlkg−1, peak inspiratory pressure 35 cm H2O). The goal was to reach normal values of partial pressure of carbon dioxide in arterial blood (paCO2) and normal values of partial pressure of oxygen in arterial blood. Anaesthesia was maintained by continuous infusion of propofol 4–6 mg kg−1h−1. Remifentanil was adjusted according to the degree of surgical manipulation (0.1–2 µg kg−1min−1) and was increased when mean arterial pressure and heart rate increased over 30% from baseline. The depth of anaesthesia was measured with bispectral index (BIS) and maintained from 40 to 60. This is according to hospital policy, since total intravenous infusion was used in order to prevent intraoperative awareness.
Haemodynamic management was followed by study protocol. Intraoperative basal fluid replacement was realized with continuous infusion 2-4 ml−1kg−1h−1 of balanced crystalloid regimes (Sterofundin, B. Braun Melsungen AG). Additional boluses of 250 ml fluid were given when stroke volume variation (SVV) measured by EVA 1000/FloTrac system rose above 10% (a sustained change during the previous 5 minutes) or in the case of a positive response to previous fluid challenge until normal SVV value (13 or less). Colloid group (CO) received colloid solution (Voluven 130/0.4 6%; Fresenius Kabi AG, Bad Homburg, Germany) and crystalloid group (CR) balanced crystalloid (Sterofundin). If mean arterial pressure (MAP) or cerebral oxygenation (ScO2) after fluid boluses were still < 20% from the baseline values with normal SVV values, vasoactive drugs were given (ephedrine 5-10 mg (0.5% Ephedrine, UMC Ljubljana Pharmacy, Slovenia) or phenylephrine 50 µg (0.01%, UMC Ljubljana Pharmacy, Slovenia)) to maintain MAP and/or ScO2 ± 20% from the baseline values. Bradycardia (heart rate (HR) < 40min−1) was treated with atropine 0.5 mg. If MAP and/or HR increased over 30% from baseline, the infusion of remifentanil was increased by 0.1 µg kg−1min−1. Any adverse haemodynamic events (increase of MAP and/or HR over 30% from baseline) that did not respond to higher remifentanil infusion rate, were managed with urapidil or metoprolol, as appropriate. Blood loss was replaced with colloids (CO group) or crystalloids (CR group) until a reduced PRBC transfusion trigger (haemoglobin level < 90 gl−1) was reached. Haemodynamic parameters were recorded continuously in 5-min intervals (from induction to discharge from the postanaesthesia care unit (PACU)). If needed, rotational tromboelastometry (ROTEM) was performed to detect early coagulopathy and to predict blood transfusion requirements (15). During dura closing piritramide 0.1 mg/kg−1 (Dipidolor, Janssen-Cillag GmbH, Neuss, Germany), metamizole 2,5 g (Analgin, Stada AG, Bad Vilbel, Germany) and ondansetron 4 mg were given to the patients.
Propofol infusion was stopped at the last skin suture. Remifentanil infusion was stopped after the removal of the Mayfield head holder.
Postoperatively intravenous infusion of piritramide was started as patient-controlled analgesia (PCA). The definition of operation duration was the time from the application of the Mayfield head holder to its removal. Duration of anaesthesia was measured from induction to extubation. The time from anaesthetics cessation to tracheal extubation was also recorded. All the patients were extubated in the operating theatre and then transferred to the PACU, where they stayed for not more than 2 hours. Afterwards they were admitted to the Department of Neurosurgery intensive care unit (ICU).
Standard postoperative monitoring generally used in these procedures was implemented. Oxygen was administered via a Venturi mask and titrated to the lowest level needed to achieve arterial oxygen saturation greater than 96%. During the hospital stay the main investigator (JMB) visited the patients daily to check the postoperative complications and the fluid loading.
The following data were collected: demographics, duration of surgery and anaesthesia, the consumption of intraoperative drugs, fluid balance and haemodynamic parameters, the length of hospital stay and postoperative complications during 15 days after surgery.
Postoperative complications were defined as any unintended changes in body function or well-being, such as hypertension (systolic blood pressure 30% higher than the baseline level), postoperative nausea with vomiting, pain (visual analogue scale (VAS) > 3), infection, pulmonary, cardiovascular and neurological events, reoperation and death.
The primary outcome measure was the difference in the consumption of the fluid used for haemodynamic optimization.
The secondary outcome measures included the incidence of postoperative complications, the length of hospital stay, perioperative haemodynamic variables, fluid balance, and serum safety control markers (lactate, haemoglobin, coagulation status).
The appropriate sample size was calculated from our previous pilot study of two independent groups (20 patients optimised with colloids and 20 patients treated with standard non-optimised approach) using a priori two-tailed t-test power analysis. The difference in the mean colloid consumption between the groups was used for the effect size calculation and the sample size determination. For a significance level of 5% (α = 0.05) and a power of 90% (β = 0.1), the calculated minimum sample size was 36. To compensate for possible withdrawals, 40 patients were included in each group. Two patients from each group were excluded for further analysis because of technical reasons (Figure 1).
The two-tailed t-test with unequal variances or the Chi-square test were used to test the differences in demographic data, duration of the procedure and anaesthesia, drug consumption, fluid balance, haemodynamic parameters, postoperative complications and hospital stay.
The means of continuous variables are presented, and categorical data are summarized as counts. A p-value of less than 0.05 was considered statistically significant. Data were analysed by SPSS 13.0 software package (IBM Corp., Armonk, NY, USA).