Effect of intraoperative goal-directed balanced crystalloid versus colloid administration on postoperative maximum NT-proBNP concentration in patients undergoing noncardiac surgery

Background: N-terminal pro brain natriuretic peptide (NT-proBNP) and troponin T are released during myocardial wall stress and/or ischemia and are strong predictors for postoperative cardiovascular complications. However, the effect of goal-directed crystalloid versus colloid administration on NT-proBNP and troponin T, especially in relatively healthy patients undergoing moderate- to high risk abdominal surgery, still remains unclear. Thus, we evaluated in this sub-study the effect of a goal-directed crystalloid versus a goal-directed colloid uid regimen on postoperative maximum NT-proBNP concentration. We further evaluated the incidence of MINS between both study groups. Methods: 30 patients were randomly assigned to receive additional intravenous uid boluses of 6% hydroxyethyl starch 130/0.4 and 30 patients to receive lactated Ringer´s solution. Intraoperative uid management was guided by oesophageal Doppler-according to a previously published algorithm. The primary outcome were differences in postoperative maximum NT-proBNP (maxNT-proBNP) between both groups. As our secondary outcome we evaluated the incidence of MINS between both study groups. We dened maxNT-proBNP as the maximum value measured within 2 hours after surgery and on the rst and second postoperative day. Results: In total 56 patients were analysed. There was no signicant difference in postoperative maximum NT-proBNP between the colloid group (258.7 ng/L (IQR 199.4 to 782.1)) and the crystalloid group (440.3 ng/L (IQR 177.9 to 691.2)) during the rst 2 postoperative days (P = 0.29). 5 patients in the colloid group and 7 patients in the crystalloid group developed MINS (P = 0.75). Conclusions: Based on this relatively small study goal-directed colloid administration did not decrease postoperative maxNT-proBNP concentration as compared to goal-directed crystalloid administration.


Background
Major cardiovascular complications occur in approximately 8% of patients undergoing noncardiac surgery.(1) Goal-directed perioperative uid strategies are used to improve haemodynamic stability and optimize cardiac performance (2) with the aim to reduce postoperative morbidity and mortality. (3)(4)(5) So far, most of previous published algorithm were colloid based. (6,7) Due to favourable plasma expanding effects of colloid solutions they are considered to be superior for intraoperative volume therapy compared to crystalloid solutions. (8) Goal-directed colloid administration reduces the amount of uid for maintaining haemodynamic stability during surgery. (9) It also allows to distinguish whether patients need uids or vasopressors at any given point in time. Intraoperative haemodynamic stability, especially the maintenance of a mean arterial blood pressure greater than 65 mmHg may be associated with a reduced risk of myocardial injury. (10) B-type natriuretic peptide (BNP) or N-terminal fragment of proBNP (NT-proBNP) and troponin T are strong predictors of myocardial infarction and mortality in patients undergoing noncardiac surgery. (11)(12)(13) NT-proBNP is released from overstretched myocytes and is therefore a potential indicator for overhydration and pressure overload. (14)(15)(16) Elevated troponin T concentration in noncardiac surgery is the diagnostic criterion for myocardial injury after non-cardiac surgery (MINS). (17) MINS is a common and clinically relevant diagnosis and approximately 1 in 10 patients suffering from MINS will die within 30 days after surgery. (17,18) We recently published a large multicentre trial, comparing goal-directed colloid versus crystalloid administration, which did not show an improvement of a composite outcome that consisted of cardiac, pulmonary, gastrointestinal, renal, infections and coagulation complications. (19) However, we detected a smaller number of major and minor cardiac events in patients receiving goal-directed colloids. (19) Nevertheless, the number of events was too small to draw de nitive conclusions.
Thus, in this sub-study of the fore mentioned randomized controlled trial, we tested the hypothesis that intraoperative goal-directed therapy with IV colloid compared to crystalloid solutions will lead to less myocardial injury. The primary aim was the effect on maximum NT-proBNP concentration, and our secondary outcome was the effect on MINS, in patients undergoing elective moderate-to high-risk open abdominal surgery, who received IV lactated Ringer´s or hydroxyethyl starch 6% solution.

Methods
This investigator-initiated, prospective, randomised trial was conducted at the Department for

Randomisation
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 webbased 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)

Protocol
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 sevo urane (up to 1.5 MAC) in a carrier of oxygen and air. We controlled mechanical ventilation to maintain an end-tidal CO 2 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 intraoperatively. 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 uid 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 uid was administered according to the attending physicians during the remaining study period.

Measurements
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, uid and anaesthetic management, haemodynamic parameters and arterial blood gas analysis.
Fluid balance (total uid input minus total uid 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 de ned as the maximum concentration measured within 2 hours after surgery, on POD 1 or POD 2. Patients with MINS were identi ed 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 (4 th generation) were classi ed as MINS. (22) All study speci c 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 4 th generation and 5 th generation highsensitivity troponin T immunoassays (Roche, Diagnostics), respectively. According to the change of the troponin T measurements technique in our department for laboratory medicine, we provided 4 th and 5 th generation troponin T values. In 22 patients, troponin T was measured using a 4 th generation immunoassay and in 34 patient's troponin T was measured using a 5 th high-sensitive immunoassay.

Statistical Analysis
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 uid 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 coe cient was used to test associations between maxNT-proBNP values and overall uid balance.

Results
A total of 60 patients (30 in each group) were enrolled between February 2015 and October 2016. In one patient in the crystalloid group surgery was cancelled after randomisation; thus 29 patients received the allocated intervention. In the colloid group 3 patients were lost to follow up; thus, data from 27 patients were analysed (Figure 1).
Patient characteristics such as age, BMI, gender, ASA classi cation, RCRI, comorbidities, long-term medication, type of surgery and preoperative laboratory values were comparable in both groups (Table 1).
Intraoperative data including duration of anaesthesia and surgery, uid, haemodynamic-and anaesthetic data are summarized in volume was signi cantly higher in the colloid group (P = 0.04). Further, haemodynamic data such as cardiac output (P = 0.13), heart rate (P = 0.86) and mean arterial pressure (P = 0.12) were similar between the groups. Postoperative uid balances on POD 1 and 2 were also similar between both groups (Table   3).

Discussion
In this sub-study we showed that goal-directed colloid administration might not decrease postoperative maximum NT-proBNP as compared to goal-directed crystalloid administration. This study was part of a large multicentre prospective, randomised trial showing that goal-directed colloid administration did not decrease a composite of major postoperative complications as compared to goal-directed crystalloid administration. (19) We performed this sub-study because in the original trial fewer patients in the colloid group developed major cardiac complications as compared to the crystalloid group. (19) Moreover, there were also fewer colloid patients developing minor cardiac complications. (19) Nevertheless, the actual number of major cardiac events (one in the colloid group versus eight in the crystalloid group) was too small to draw de nitive conclusions.
All patients received a baseline balanced crystalloid solution and additional Doppler-guided colloid-or crystalloid uid boluses to optimize corrected aortic ow time and stroke volume. Goal-directed uid administration allows to administer uids tailored to the individual needs of our patients. It has been shown in many studies that colloid-based uid optimization based on oesophageal Doppler variables improves postoperative outcome. (6,23) In our fore-mentioned main trial there was no difference in surgical outcomes between goal-directed colloid and crystalloid administration, which suggests that the actual type of uid might not matter, as long as we administer it in a goal-directed way. (24) This might also explain the fact that we did not see a difference in maxNT proBNP in patients receiving either colloid or crystalloid uids. Our results lead us to the assumption that goal-directed uid administration decreased uid overload and consequently minimized the risk of strain on myocardial tissues during the intraoperative period.
NT-proBNP concentration measured immediately after surgery were similar as compared to preoperative baseline values. Interestingly, there was a signi cant increase of NT-proBNP concentration on the rst and second day after surgery. Therefore, we tested, in a post-hoc analysis, the effect of postoperative uid administration on NT-proBNP concentration. Postoperative uid management was performed at the discretion of the attending physician. Again, there was no correlation between the volume of administered uid and the NT-proBNP concentration. Nevertheless, as NT-proBNP was elevated in all patients on the rst and second postoperative day it might play an important role in the diagnosis and management of patients with subclinical postoperative cardiac failure.(25) Moreover, it seems likely, that postoperative NT-proBNP concentration might be affected by several perioperative factors such as surgical stress, hemodynamic perturbations, or in ammation rather than by uid management alone. (26)(27)(28) We further evaluated the effect of colloids versus crystalloids on the incidence of MINS. We hypothesized that patients receiving colloids had a better hemodynamic stability, which might result in an improved myocardial perfusion and consequently in lower postoperative troponin T concentrations. In our study 5 (19%) patients in the colloid and 7 (24%) patients in the crystalloid group had MINS (P = 0.75). We found no difference in MINS between the two groups. Blood pressure was tightly controlled and managed with a time-weighted average mean arterial pressure of approximately 80 mmHg in both groups. Recent data indicates that intraoperative mean arterial blood pressure greater than 65 mmHg reduces the incidence of MINS. (29,30) However, despite good intraoperative blood pressure control, we observed a fairly high rate of MINS in our relatively healthy study population. This emphasizes that even patients with a low estimated cardiac risk having moderate-to high-risk surgery are at risk of myocardial ischemia. (31) The results of our trial have to be interpreted with caution. The major limitation of our study was the small sample size. Unfortunately, we added cardiac biomarker measurements late during the course of the main trial. The clinical importance of cardiac biomarkers as predictors of cardiovascular outcomes and mortality became evident during the past ve to eight years. We thus added cardiac biomarker assessment in 2015 when the main trail already arrived at an advanced state. The small sample size makes our study prone to a type II error. Thus, it is likely that our study is underpowered. In fact, based on our current results, we performed a posteriori sample size calculation, which indicates that a sample size of 196 patients is needed to detect a difference of 20% between both groups at a 95% signi cance level.
We included relatively healthy patients having moderate-to high-risk open abdominal surgery. Thus, we do not know whether and how our results would apply to patients with pre-existing cardiovascular risk factors. It is be possible, that patients with cardiac comorbidities might bene t from colloid administration due to the smaller volume and the fact that colloids remain in the vascular system longer than crystalloids. Last but not least we did not have access to blood pressure after surgery on the wards.
It is now well known that postoperative hypotension is common and that it is as an important risk factor for MINS (28,29). Thus, it is likely that postoperative hypotension was associated with MINS.
Nevertheless, our results in these relatively healthy patient population emphasize the clinical importance to assess cardiac biomarkers in the perioperative period in patients undergoing noncardiac surgery, especially in patients without pre-existing cardiac morbidity. (17) Moreover, the fact that NT-proBNP increased signi cantly even in our relatively healthy patient population, leads to the conclusion, that adequately powered studies are worthwhile to identify substantial factors affecting perioperative myocardial performance, and more importantly to evaluate possible treatment options.

Conclusions
Based on this relatively small study goal-directed colloid administration did not decrease postoperative maxNT-proBNP concentration as compared to goal-directed crystalloid administration. We are aware that the present study is underpowered. However, this emphasizes the need for future adequately powered studies to answer the question, if and how different types of uid might affect myocardial outcome after noncardiac surgery. The sponsors were not involved in protocol development, data acquisition, or data analysis.

Authors' contributions
All authors have read and approved the manuscript.  Consort 2010 ow diagram of patient enrolment