Effect of Intraoperative Goal-directed Balanced Crystalloid versus Colloid Administration on Postoperative Cardiac Outcome CURRENT STATUS: UNDER REVIEW

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 subanalysis the effect of a goal-directed crystalloid versus a goal-directed colloid fluid regimen on postoperative cardiac outcome. Methods: 30 patients were randomly assigned to receive additional fluid boluses of 6% hydroxyethyl starch 130/0.4 and 30 patients to receive lactated Ringer´s solution. Intraoperative fluid management was guided by oesophageal Doppler according to a previously published algorithm. The primary outcome were differences of maximum NT-proBNP (maxNT-proBNP) and maximum troponin T (maxTnT) concentrations during the first two postoperative days between both study groups. We defined maxNT-proBNP and maxTnT as maximum values measured 2 hours after surgery and on the first and second postoperative day. Results: In total 56 patients were analysed. There was no significant 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 first 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: Postoperative cardiac outcome as defined by cardiac biomarkers was not significantly affected by goal-directed colloid administration; however, there was a tendency of lower maximum NT-proBNP concentrations in patients receiving colloids. Trial registration: ClinicalTrials.gov (NCT01195883) Morbidity.


Introduction
Major cardiovascular complications such as heart failure and myocardial ischemia occur in approximately 1.9% of patients undergoing noncardiac surgery. 1 Goal-directed fluid therapy helps to optimize intraoperative cardiac performance while preventing excessive fluid overload as well as hypovolaemia and its harmful consequences. [2][3][4][5][6] Fluid overload is associated with increased brain natriuretic peptide release. 7 8 On the other hand, hypotension, mediated by hypovolaemia might be a contributor to myocardial injury after noncardiac surgery (MINS). 9 B-type natriuretic peptide (BNP) or N-terminal fragment of proBNP (NT-proBNP) and troponin T are strong predictors of myocardial infarction (MI) and mortality in patients undergoing noncardiac surgery. [10][11][12] NT-proBNP is mainly released from overstretched myocytes during elevated myocardial wall stress and is therefore a potential indicator for overhydration and pressure overload. 7 13 14 Elevated troponin T in patients undergoing noncardiac surgery is the diagnostic criterion for MINS. 1 MINS is a common and clinically relevant diagnosis and approximately 1 in 10 patients suffering MINS will die within 30 days after surgery. 1 15 Goal-directed perioperative fluid strategies are used to improve haemodynamic stability and to optimize cardiac performance 16 with the aim to reduce postoperative morbidity and mortality. [17][18][19] Due to favourable plasma expanding effects colloid solutions are considered to be superior for intraoperative volume therapy compared to crystalloid solutions. 20 21 Goal-directed colloid administration not only reduces the required amount of fluid for maintaining haemodynamic stability during surgery but also allows to distinguish whether patients need fluid or vasopressors at any given point in time. 22 Improved intraoperative haemodynamic stability, especially better preserved arterial blood pressure might positively effect myocardial perfusion and might therefore positively effect NT-proBNP and troponin T release in the immediate postoperative period. 23 However, there is scarce evidence regarding the effect of different used types of fluid used for surgery on myocardial strain and MINS during the first postoperative days. In this subanalysis of a randomized controlled trial, we hypothesize that intraoperative goal-directed therapy with colloids will lead to less postoperative cardiac complications determined by maximum NT-proBNP and maximum troponin T concentrations in patients undergoing elective moderate-to high-risk open abdominal surgery.

Material And Methods
This investigator initiated, prospective, randomised, controlled 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 goaldirected administration of crystalloids or colloids on a composite of postoperative complications. 24 The main trial was approved by the local ethics committee of the

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 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. 25 Protocol We used 1-3 µg/kg fentanyl and 2-3 mg/kg Propofol for induction of anaesthesia and 0.6 mg/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 CO 2 at approximately 35 mmHg. 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 administered oesophageal doppler guided fluid bolus of 250 mL lactated Ringer´s solution and hydroxyethyl starch 140/0.4, respectively, according to a previous published algorithm. 26 (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 fluid 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, fluid and anaesthetic management, haemodynamic parameters and arterial blood gas analysis.
Fluid balance 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 (maxTnT) respectively, is defined the maximum biomarker concentration measured within 2 hours after surgery, on POD 1 or POD 2.
According to the change of the troponin T measurements technique in our laboratory department, we provided 4th and 5th generation troponin T values.
Maximum NT-proBNP values > 300 ng/L were classified to predict myocardial events within 30 days after surgergy. 27 Identification of MINS was based on troponin T assessment. Maximum troponin T equal or greater than 0.03 pg/L (4th generation) or over 20 ng/dL (5th generation) were classified as

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 comparing 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. The proportions of patients with NT-proBNP values between 0-299 ng/L; 300-899 ng/L; and > 900 ng/L as well as the incidence of MINS between both groups were compared with Fisher´s exact test.
Within each group the increase of postoperative maxNT-proBNP and maxTnT concentrations compared to baseline values was analysed using a paired t-test or Wilcoxon signed rank test.
Spearman's correlation coefficient was used to test associations between maxNT-proBNP values and overall fluid balance.
As no data about the effect of goal-directed fluid therapy on cardiac biomarker has been available, thus we performed this subanalysis. Based on these 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% significance level.

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 (Fig. 1). Patient characteristics such as age, BMI, gender, ASA classification, RCRI, comorbidities, long-term medication, type of surgery and preoperative laboratory values were comparable in both groups (Table 1). 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 fluid balances on POD 1 and 2 were also similar between both groups (Table 3).    In 22 patients, troponin T was measured using a 4th generation immunoassay and in 34 patient's troponin T was measured using a 5th highsensitive immunoassay. There was a significant increase in postoperative maxTnT concentration in the 4th generation troponin T group (P < 0.01) and in the 5th generation troponin T group (P < 0.01) as compared to baseline. There was no significant difference

Discussion
This study is a subanalysis of a large multicenter prospective, randomised, trial showing that goaldirected colloid administration did not decrease a composite of major postoperative complications as compared to goal-directed crystalloid administration. 24 However, significantly fewer patients in the colloid group developed cardiac complications as compared to the crystalloid group. 24 Nevertheless, the actual numbers (one in the colloid group versus eight in the crystalloid group) were too small to draw any further conclusions. Similarly, in our subanalysis we did not find a statistically significant difference in NT-proBNP and troponin T concentrations between goal-directed colloid versus crystalloid fluid regimens.
Correspondingly recent studies have shown that serum BNP determination is a tool to indirectly monitor fluid status in surgical patients. 7 8 Blood volume expansion increases myocardial wall stress and thus contributes to increased BNP values in healthy volunteers. 29 We used a baseline crystalloid solution and additionally administered Doppler-guided colloid-or crystalloid fluid boluses to optimize cardiac performance. This provided individualized fluid and/or vasopressor therapy to maintain physiologically similar quantities of each fluid type throughout surgery 26 30 , which minimized the risk of a relevant intraoperative volume overload. Except for stroke volume, which was slightly higher in the colloid group, all other haemodynamic parameters including cardiac index and arterial blood pressure were comparable between both groups.
NT-proBNP values measured on the first two days after surgery were significantly higher compared to preoperative baseline values. In contrast, NT-proBNP concentrations within two hours after surgery were nearly unchanged as compared to preoperative baseline values. As previously shown 7 31 , we primarily assumed that the increase of postoperative NT-proBNP concentration was an effect of the intraoperative administered fluid volume. However, we found no correlation in our study between the intraoperative administered fluid volume and the postoperative increase of NT-proBNP within the first two days. It seems likely, that postoperative NT-proBNP concentration might be affected by several perioperative factors such as surgical stress, hemodynamic perturbations, myocardial strain, or inflammation rather than by fluid management alone. 32 33 Postoperative NT-proBNP values between 0 -299 ng/L, 300 -899 ng/L and greater than 900 ng/L are associated with a composite of 30-day mortality or nonfatal MI at a rate of 1.8%, 8.7%, and 27%, respectively. 10  The association between perioperative hypotension and postoperative myocardial injury, kidney function and death has been shown in several studies. 34 Even short episodes of intraoperative hypotension are associated with myocardial injury and kidney failure. 35 36 An intraoperative mean arterial blood pressure threshold of greater than 65 mmHg is associated with a reduced incidence of MINS. 23 37 Moreover, intraoperative individualized blood pressure control reduces postoperative organ dysfunction. 38 A recent trial demonstrated that perioperative hypotensive episodes, defined as systolic blood pressure less than 90 mmHg for more than 10 minutes, are major contributors to cardiovascular events, even in patients without coronary artery disease. 39 It seems likely, that intraoperative goal-directed 18 fluid management as well as individualized blood pressure control to avoid clinical important hypotension are effective methods to reduce postoperative cardiovascular complications.
We tightly controlled intraoperative blood pressure, which resulted in a time-weighted average mean arterial pressure of near 80 mmHg in both groups. However, during the first two postoperative days 5 (19%) patients in the colloid and 7 (24%) patients in the crystalloid group developed MINS. This is in accordance with the previous published rate of MINS of approximately 18% measured with highsensitive troponin immunoassay. 12 It has been recently shown that ward hypotension after surgery is common and is an independent predictor for myocardial infarction and death. 9 40 According to our study protocol, we did not record blood pressure during the postoperative study period. Thus, we are unable to make any statement concerning hypotensive episodes on the ward, which might have contributed to our results.
We observed high rates of MINS, which emphasizes that even patients with a low estimated cardiac risk 41 having moderate-to high-risk surgery are at risk to develop MINS in the postoperative period.
Implementation of perioperative fluid guidelines and optimization of perioperative blood pressure control will be crucial to reduce cardiovascular complications after moderate to high-risk noncardiac surgery. This includes the implementation of standardized perioperative BNP and troponin T measurements as well as continuous blood pressure monitoring on the ward.
Only recently the clinical importance of perioperative monitoring of cardiac biomarkers in patients undergoing noncardiac was proven, even in patients without any pre-existing cardiac morbidity. 1 Accordingly, we started our measurement late during the course of our main trial, which was stopped earlier per protocol after the futility boundary was crossed.
In summary, postoperative cardiac biomarkers were not significantly affected by goal-directed colloid administration. There was a markedly increase of postoperative maximum NT-proBNP concentration and a high incidence of MINS in both groups. The association between postoperative maximum NT-13 proBNP concentrations and outcome in patients with low cardiac risk is unclear and still needs further research.

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barbara.kabon@meduniwien.ac.at

Competing interests
The authors declare no competing interests.