This investigator-initiated, prospective, randomised trial was conducted at the Department for Anaesthesia, Intensive Care Medicine and Pain Medicine at the Medical University of Vienna, Austria. It was approved as part of a large multicentre outcome study evaluating the effect of goal-directed administration of crystalloids or colloids on a composite of postoperative complications.(19) The main trial was approved by the local ethics committee of the Medical University of Vienna in 2005 (Chairman Prof. Singer) (EK 431/2005) and was registered at ClinicalTrials.gov (NCT01195883) and EudraCT (2005-004602-86). Written informed consent was obtained from all participants. Patients scheduled for elective moderate to high-risk open abdominal surgery with an expected duration of at least 2 hours were included. Inclusion criteria were as follows: 18-80 years, American Society of Anesthesiologists physical status I-III and a body mass index of < 35kg/m2. Patients with compromised kidney function (estimated creatinine clearance less than 30 mL/min), estimated left ventricular ejection fraction < 35%, severe chronic obstructive pulmonary disease, coagulopathies and oesophageal or aortic abnormalities were excluded.
Before induction of anaesthesia patients were randomised 1:1 to Doppler-guided crystalloid (lactated Ringers´s solution) or colloid (hydroxyethyl starch 6% 130/0.4, Voluven, Fresenius-Kabi, Germany) bolus administration. The randomisation sequence was generated by the study statistician using the PLAN procedure in SAS statistical software (SAS Institute, USA) using randomly sized blocks. A trained study coordinator evaluated eligibility, obtained informed consent, and enrolled the participants by using a web-based system shortly before induction of anaesthesia. Intraoperative investigator and clinicians were not blinded to treatment. Research personal obtaining postoperative measurements were blinded to the treatment.
All patients received 5-7 mL/kg of lactated Ringer´s solution during induction of anaesthesia and thereafter 3-5 mL kg-1 h-1 for maintenance, normalized to ideal body weight, throughout surgery. Ideal body weight was calculated according to the Robinson formula.(20)
We used 1-3µg/kg fentanyl and 2-3mg/kg Propofol for induction of anaesthesia and 0.6mg/kg rocuronium for muscle relaxation. Anaesthesia was maintained with sevoflurane (up to 1.5 MAC) in a carrier of oxygen and air. We controlled mechanical ventilation to maintain an end-tidal CO2 at approximately 35mmHg. We administered additional bolus doses of fentanyl when heart rate or arterial blood pressure raised more than 20% of pre-induction values. All patients were actively warmed intra-operatively. We maintained a haematocrit level > 30% in patients with known cardiovascular disease and age > 65 years, 28% in patients with one or the other, and 26% in the remaining.
We intravenously administered oesophageal Doppler-guided fluid boluses of 250mL lactated Ringer´s solution and hydroxyethyl starch 140/0.4, respectively, according to a previous published algorithm. (6) (see online supplemental, eAppendix 1)
We administered 2 mL kg-1 h-1 lactated Ringer´s solution in the recovery room and intensive care unit, respectively, for two hours postoperatively. Subsequently, additional fluid was administered according to the attending physicians during the remaining study period.
Demographic data, such as age, BMI, gender, American Society of Anaesthesiologists (ASA) physical status, Revised Cardiac Risk Index (RCRI), comorbidities, long term medication, type of surgery and preoperative laboratory values were recorded. Intraoperative measurements included duration of anaesthesia and surgery, fluid and anaesthetic management, haemodynamic parameters and arterial blood gas analysis.
Fluid balance (total fluid input minus total fluid output) in the recovery room and on postoperative day 1 (POD 1) and 2 (POD 2) was recorded.
We took blood samples for NT-proBNP and troponin T measurements shortly after induction of anaesthesia for baseline measurements, within 2 hours after the end of surgery, on POD 1 and POD 2. Maximum NT-proBNP (maxNT-proBNP) and maximum troponin T respectively, was defined as the maximum concentration measured within 2 hours after surgery, on POD 1 or POD 2. Patients with MINS were identified using the following peri-operative high-sensitive troponin T thresholds: a) troponin T of 20 to < 65ng/L with an absolute change of at least 5ng/L or b) troponin T level > 65ng/L.(18,21) Maximum troponin T equal or greater than 0.03 pg/L (4th generation) were classified as MINS.(22)
All study specific blood samples were handled by study personnel, who was blinded to randomization. The laboratory measurements were performed at the department for laboratory medicine at the Medical University of Vienna. Our laboratory department used the 4th generation and 5th generation high-sensitivity troponin T immunoassays (Roche, Diagnostics), respectively. According to the change of the troponin T measurements technique in our department for laboratory medicine, we provided 4th and 5th generation troponin T values. In 22 patients, troponin T was measured using a 4th generation immunoassay and in 34 patient’s troponin T was measured using a 5th high-sensitive immunoassay.
Groups were compared for balance in patient characteristics demographic data, type of surgery and preoperative laboratory values. Normal distribution of data was tested using a Kolmogorov-Smirnov test. Normally distributed data were presented as mean ± standard deviation, not normally distributed data were given as median and percentile. Chi-square test was used to compare categorical variables.
Differences in intraoperative data, postoperative fluid balance data and outcome parameters between both study groups were tested using an unpaired t-test or Mann-Whitney-U test as appropriate according to data distribution.
MaxNT-proBNP concentrations were compared between the two groups using a Mann-Whitney-U test. The incidence of MINS between both groups was compared using a chi-square test.
We compared the increase of postoperative maxNT-proBNP concentrations to baseline values using a paired t-test or Wilcoxon signed rank test within each group. Postoperative maximum troponin T values were compared between the two groups using a Mann-Withney-U test. (eAppendix 2)
Spearman’s correlation coefficient was used to test associations between maxNT-proBNP values and overall fluid balance.