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Xenon as an Adjuvant to Propofol Anesthesia in Patients Undergoing Off-Pump Coronary Artery Bypass Graft Surgery: A Pragmatic Randomized Controlled Clinical Trial

Al tmimi, Layth MD*; Devroe, Sarah MD*; Dewinter, Geertrui MD*; Van de Velde, Marc MD, PhD*†; Poortmans, Gert MD*; Meyns, Bart MD, PhD†‡; Meuris, Bart MD, PhD†‡; Coburn, Mark MD, PhD§; Rex, Steffen MD, PhD*†

doi: 10.1213/ANE.0000000000002179
Cardiovascular Anesthesiology: Original Clinical Research Report
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BACKGROUND: Xenon was shown to cause less hemodynamic instability and reduce vasopressor needs during off-pump coronary artery bypass (OPCAB) surgery when compared with conventionally used anesthetics. As xenon exerts its organ protective properties even in subanesthetic concentrations, we hypothesized that in patients undergoing OPCAB surgery, 30% xenon added to general anesthesia with propofol results in superior hemodynamic stability when compared to anesthesia with propofol alone.

METHODS: Fifty patients undergoing elective OPCAB surgery were randomized to receive general anesthesia with 30% xenon adjuvant to a target-controlled infusion of propofol or with propofol alone. The primary end point was the total intraoperative dose of norepinephrine required to maintain an intraoperative mean arterial pressure >70 mm Hg. Secondary outcomes included the perioperative cardiorespiratory profile and the incidence of adverse and serious adverse events.

RESULTS: Adding xenon to propofol anesthesia resulted in a significant reduction of norepinephrine required to attain the predefined hemodynamic goals (cumulative intraoperative dose: median [interquartile range]: 370 [116–570] vs 840 [335–1710] µg, P = .001). In the xenon-propofol group, significantly less propofol was required to obtain a similar depth of anesthesia as judged by clinical signs and the bispectral index (propofol effect site concentration [mean ± SD]: 1.8 ± 0.5 vs 2.8 ± 0.3 mg, P≤ .0001). Moreover, the xenon-propofol group required significantly less norepinephrine during the first 24 hours on the intensive care unit (median [interquartile range]: 1.5 [0.1–7] vs 5 [2–8] mg, P = .048). Other outcomes and safety parameters were similar in both groups.

CONCLUSIONS: Thirty percent xenon added to propofol anesthesia improves hemodynamic stability by decreasing norepinephrine requirements in patients undergoing OPCAB surgery.

Published ahead of print June 8, 2017.

From the Departments of *Anesthesiology, Cardiovascular Sciences, and Cardiac Surgery, KU Leuven–University of Leuven, University Hospitals Leuven, Leuven, Belgium; and §Department of Anesthesiology, University Hospital of the RWTH Aachen, Aachen, Germany.

Accepted for publication March 30, 2017.

Published ahead of print June 8, 2017.

Funding: Drs Rex and Al tmimi received a research grant from the European Association of Cardiothoracic Anaesthesiologists (EACTA) 2013–2014. Dr Rex has been supported by an unrestricted research grant from Air Liquide Belgium, by a research grant from Air Liquide France, by the Foundation Annie Planckaert-Dewaele (Biomedical Sciences Group, KU Leuven) and also by a clinical research fund of University Hospitals Leuven. Dr Coburn received lecture and consultant fees from Air Liquide France. Dr Van de Velde is financed by an unrestricted grant from Baxter Belgium. None of the funding institutions had any influence on the design, analysis, or publication of the study.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Initial results of the current study were presented as an abstract at the annual congress of the European Association of Cardiothoracic Anesthesiology in Gothenburg, Sweden, June 24–26, 2015.

Clinical trial number and registry: ClinicalTrials.gov (NCT01948765) URL https://clinicaltrials.gov/ct2/show/NCT01948765) and EudraCT (2013-000485-11).

Reprints will not be available from the authors.

Address correspondence to Layth Al tmimi, MD, Department of Anesthesiology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Address e-mail to layth.altmimi@uzleuven.be.

Off-pump coronary artery bypass (OPCAB) surgery is associated with a particular risk for perioperative hemodynamic instability and hypotension resulting from cardiac manipulations during surgical exposure.1

Xenon is known to affect hemodynamics much less than traditionally used anesthetics.2,3 Because of the scarcity of xenon, xenon anesthesia is expensive.4 Hence, strategies by which xenon consumption can be reduced without jeopardizing its favorable effects might significantly improve the cost-effectiveness of xenon. A possible approach is to administer lower concentrations of xenon together with another anesthetic agent. In rats, xenon exerted organ protective properties even in subanesthetic doses (approximately 0.5 minimum alveolar concentration [MAC]),5 implying that organ protection can be obtained independently from anesthetic effects.6 Also in humans, 0.5 MAC of xenon increased the levels of proteins implicated in organ protection during ischemia-reperfusion injury.7 Furthermore, the addition of subanesthetic concentrations of xenon to another anesthetic agent has been shown to permit a major reduction of the dose of the anesthetics to which xenon was added8 and to ameliorate hemodynamic effects associated with that agent.9 To the best of our knowledge, however, no data are available describing the consequences of a xenon-propofol combination in cardiac surgery.

We, therefore, hypothesized that in patients undergoing OPCAB surgery, adding 30% (0.5 MAC) of xenon to a target-controlled infusion (TCI) of propofol results in superior hemodynamic stability when compared to an equipotent general anesthesia with propofol alone. Moreover, we aimed to assess the safety, organ protective properties, and feasibility of a xenon-propofol combination during OPCAB surgery.

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METHODS

Study Subjects and Design

The current trial was performed in accordance with the principles of the International Declaration of Helsinki and the principles of good clinical practice. The local ethics committee (SR022013, Commissie Medische Ethiek van de Universitaire Ziekenhuizen KU Leuven, April 24, 2013) and the Federal Agency for Medicines and Health Products, Brussels, Belgium (reference FAGG/R&D/WHH/mm 445642) approved it. The trial was also registered at the European Medicines Agency (2013-000485-11, January 29, 2013), the ClinicalTrials.gov, and is reported as stated by the CONSORT (Consolidated Standards of Reporting Trials) guidelines (see Supplemental Digital Content, Checklist, http://links.lww.com/AA/B786).

Part of the results of the present study was recently published in an article aggregating data from 2 clinical trials and evaluating the predictive value of serum protein S100 for the occurrence of postoperative delirium.10

After having obtained written informed consent, 50 patients planned for elective OPCAB surgery were enrolled in this monocenter, randomized, single-blinded, controlled clinical trial. Patients were randomized to undergo general anesthesia either with xenon 30% in addition to propofol TCI or with propofol TCI alone.

Randomization was performed using a software-generated allocation sequence (QuickCalcs; GraphPad Software, La Jolla, CA). To avoid selection bias, we used a masked randomization process in which group assignments were hidden in closed, consecutively numbered envelopes that were only opened on arrival of the participant into the operation room. Two separate and independent investigators performed the study. Investigator I performed enrollment and the assessment of postoperative outcomes and was, together with the patient, unaware of the study allocation. Investigator II was the attending anesthetist and could, therefore, not be blinded to the treatment group because of the type of intervention (administration of the anesthetic agents through either a vapor or a syringe pump, monitoring of xenon concentrations).11

Inclusion criteria were as follows: age >18 years, elective OPCAB surgery, and ability to read and sign the informed consent document. Exclusion criteria comprise hypersensitivity to any study medication; chronic obstructive pulmonary disease with a global initiative for chronic obstructive lung disease status >II; risk for malignant hyperthermia; single-vessel grafting; preoperative renal dysfunction with serum creatinine >1.5 mg/dL; critical preoperative state (defined as the preoperative need for controlled mechanical ventilation, vasopressors, inotropic support or an intra-aortic balloon pump, preoperative cardiac massage, presence of life-threatening arrhythmias such as ventricular tachycardia or ventricular fibrillation, preoperative acute renal failure [defined as anuria or oliguria of <10 mL/h])12; disabling neuropsychiatric illness (such as schizophrenia, epilepsy, history of stroke with residuals, mental retardation, dementia, and severe depression as judged by the Geriatric Depression Scale).13 Patients with limited preoperative cognitive status (as defined by a Mini-Mental State Examination [MMSE] <25)14 or preoperative delirium (as screened with the Confusion Assessment Method [CAM])15 were also excluded.

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Anesthesia and Surgical Intervention

A day before surgery, all patients underwent baseline cognitive and neuropsychiatric examination by qualified research personnel using the MMSE, CAM, and the Geriatric Depression Scale. For premedication, lorazepam 0.03 mg/kg was sublingually administered to all patients an hour before surgery. In the operating room, cardiorespiratory monitoring was established according to our institutional standards, including 5-lead electrocardiogram, pulse oximetry, capnography, and intra-arterial measurement of the blood pressure (IntelliVue MX800 patient monitor; Philips, Boeblingen, Germany). Besides, regional cerebral oxygen saturation (INVOS; Covidien, Mansfield, MA) and the bispectral index (BIS; Covidien, Dublin, Ireland) were monitored continuously. General anesthesia was started with sufentanil (0.25–0.5 µg/kg) and propofol (1 mg/kg). For tracheal intubation, rocuronium (1 mg/kg) was administered. After the opening of the randomized envelope, general anesthesia was performed either with 30% xenon added to propofol TCI or with propofol TCI alone. TCI was based on the Marsh model16 that was applied using a commercially available syringe pump (Alaris PK Syringe Pump; CareFusion UK 305 Ltd, Hampshire, United Kingdom). To achieve an equipotent depth of anesthesia, predicted propofol plasma target concentrations were titrated in both groups based on clinical signs that possibly reflect an inadequate depth of anesthesia (such as sweating, heart rate, and blood pressure) and to obtain BIS values between 40 and 60. Patients were ventilated with a closed-circuit respirator (Felix Dual; Air Liquide Medical Systems, Paris, France).4 The fraction of inspired oxygen was maintained between 0.3 and 0.4 in both groups. During surgery, analgesia was ensured with a continuous infusion of sufentanil (0.5 µg/kg/h). All patients received total arterial revascularization in the off-pump technique without aortic cross-clamp.17

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Advanced Hemodynamic Monitoring

A central venous and pulmonary artery catheterization was performed after the induction of anesthesia to monitor the right atrial pressure and pulmonary artery pressure, mixed venous oxygen saturation, and cardiac output, respectively. In addition, arterial, mixed venous blood gas analyses and the determination of pulmonary capillary wedge pressure were performed at the following time points: T1: after start of anesthesia; T2: poststernotomy; T3: after stabilization of the ramus interventricularis anterior; T4: after dislocating the heart (for performing the anastomoses to the circumflex artery and/or coronary arteries of the posterior wall); T5: after infusion of protamine; T6: at the end of the surgical procedure.3

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Fluid Management and Hemodynamic Targets

Fluid replacement was accomplished with 1 mL/kg/h balanced crystalloid solution. In both groups, a treatment algorithm had to be followed to achieve hemodynamic stability that was a priori defined as a cardiac index >2.4 L/min/m2, mean arterial blood pressure >70 mm Hg, and mixed venous oxygen saturation >70%. The various therapeutic measures are illustrated in Figure 1.

Figure 1.

Figure 1.

The administration of inotropes, fresh frozen plasma, and other blood products remained at the preference of the attending anesthesiologist. A continuous autotransfusion system (Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany) was used in all cases.

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Postoperative Management and Monitoring

At the end of the operation, investigational treatment was discontinued. All patients were admitted to the intensive care unit (ICU) where patients were sedated with an infusion of piritramide (0.05–0.1 mg/kg/h) and propofol (1 mg/kg/h). An hour after ICU admission and at the first postoperative day, hemodynamic, respiratory, laboratory parameters, and a 12-lead electrocardiogram were recorded. Likewise, the Simplified Acute Physiology Score II18 and the Sequential Organ Failure Assessment score19 were determined once within the first 24 hours of ICU admission. Patients were weaned from mechanical ventilation and discharged to the ward once standard criteria were met.

Until postoperative day 5, patients were visited daily for the evaluation of vital parameters and screening for the presence of postoperative delirium using the ICU version of the CAM (CAM-ICU) or the CAM (on the ward). Subsequently, on postoperative day 3, the history of intraoperative awareness and postoperative cognitive dysfunction were evaluated using the modified Brice questionnaire20 and the MMSE. Likewise, adverse events (AEs) and serious adverse events (SAEs), as illustrated by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use21 guidelines, were documented. Six months after surgery, patients’ family practitioners were contacted to assess long-term outcomes such as hospital readmission due to cardiac-related reasons or mortality.

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Primary and Secondary Study Outcomes

The primary outcome was intraoperative hemodynamic stability, which was quantified with the doses of norepinephrine required intraoperatively to accomplish the predefined hemodynamic targets (Figure 1).

Norepinephrine was administered exclusively by continuous infusion using a dedicated syringe pump and a preprogrammed infusion scheme (taking into account the weight of the patient and the concentration of the particular norepinephrine solution; Alaris PK Syringe Pump, CareFusion). Cumulative norepinephrine requirements were obtained, for the individual patient, by multiplying the total infused norepinephrine solution (as displayed by the infusion pump at the end of surgery) with the concentration of norepinephrine solution (standard: 100 µg/mL).

Secondary outcomes comprised:

  • Safety parameters and data on organ protection
    • ○ The occurrence rate of major adverse cardiac and cerebral events up to 6 months after surgery (as defined previously),3 ie, all causes of mortality, perioperative myocardial infarction (occurring until hospital discharge), requirement for repeat coronary surgery, postoperative coronary angioplasty, and stroke.
    • ○ Any cerebrovascular accident not included in the definition of major adverse cardiac and cerebral events such as transient ischemic attacks and reversible ischemic neurologic deficit.
    • ○ Incidence of SAEs and suspected unexpected serious adverse reactions not mentioned above (defined according to the International Conference on Harmonization guidelines).21
    • ○ Intraoperative transfusion requirements.
    • ○ Use of vasoactive medications and inotropes.
    • ○ The development of postoperative delirium during the first 5 postoperative days as evaluated with the CAM-ICU or CAM.
    • ○ The postoperative incidence of renal dysfunction (as estimated by the risk, injury, failure, loss, and end-stage kidney disease [RIFLE] criteria).22
    • ○ Furthermore, arterial blood samples were collected from all patients at baseline (before the start of anesthesia), after completion of surgery (T6), and on postoperative day 1. These samples were required to determine the plasma level of creatine kinase-MB and high-sensitive cardiac troponin T (markers of myocardial ischemia) and the serum protein S100β (a marker of blood-brain barrier dysfunction; Roche Diagnostics, Vilvoorde, Belgium).
    • ○ Duration of postoperative mechanical ventilation, length of stay on ICU, and in the hospital.
    • ○ The severity of postoperative critical illness as quantified with the Simplified Acute Physiology score II and the Sequential Organ Failure Assessment score.
  • Feasibility data
    • ○ Depth of anesthesia (propofol consumption, opioid consumption, clinical signs, and intraoperative BIS values).
    • ○ Occurrence of intraoperative awareness and recall assessed on postoperative day 3 using the modified Brice questionnaire.20
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Sample Size Calculation and Statistical Analysis

This trial was designed to demonstrate that the application of 30% xenon in addition to general anesthesia with a TCI of propofol results in superior hemodynamics when compared to an equipotent general anesthesia with propofol alone. This end point was quantified using the norepinephrine doses required to achieve predefined hemodynamic goals. The sample size was calculated to show a superiority of xenon-propofol versus propofol alone regarding intraoperative norepinephrine requirements. We assumed, for the control group, a coefficient of variation (ie, the ratio of the standard deviation to the mean) of 0.5 and mean norepinephrine requirements of 0.077 µg/kg/min (based on data from patients previously undergoing OPCAB surgery at our institution). A minimal sample size of 24 patients per group was determined to detect a 33% reduction (corresponding to an effect size for the differences in means of 0.83) in the norepinephrine requirements in the xenon-propofol compared to the propofol-only group to have at least 80% power based on a 2-sided t test for independent groups with the level of significance set at 0.05 (G*Power version 3.1.9.2 for Mac with OS X 10.7 to 10.11).23 To account for possible dropouts, 25 patients were included in each group. The study results were analyzed using SPSS version 23.0.0 for Mac OS (IBM, Armonk, NY). All figures were made using Prism 6 for Mac OS X, version 6.0g (GraphPad Software).

Continuous variables were reported using mean and standard deviations and compared using an independent samples t test. In case of serious deviations from the normal distribution, as assessed by visual inspection of histograms, the data were described using median and interquartile range (IQR) and compared using the Mann-Whitney U test.

Categorical data were summarized by observed frequencies and percentages and compared using a χ2 test or Fisher exact test, as appropriate.

The primary end point showed serious deviations from normality, which were largely alleviated when applying a natural log-transformation to the data. Of note, for 3 patients in the xenon-propofol group who did not require noradrenaline intraoperatively, consumption of 100 µg was assumed to allow the necessary log-transformation. This 100 µg was the minimal consumption observed in the other xenon-propofol patients. These log-transformed data were compared using a t test. The estimated difference in means (and 95% confidence interval) was back-transformed to obtain the estimated treatment ratio.

The relationship between cumulative phenylephrine and norepinephrine doses was analyzed using the Spearman correlation test. Furthermore, longitudinal data were analyzed using a linear mixed model. For the analysis of predicted propofol plasma concentrations, the model included fixed effects for treatment group, time (as a linear variable), and their interaction. A random intercept per patient was included to account for correlations within patient. For norepinephrine data, the model was similar to the one described above but time was included as a third-degree polynomial. Within-patient correlations were accounted for by including a random intercept and slope per patient. The analyses of longitudinal data were performed using SAS software, version 9.4 (64-bit), SAS/STAT 14.1 of the SAS System for Windows (SAS Institute, Cary, NC).

Repeated data were analyzed using a multivariate linear model that included a factor for treatment and the baseline value as a covariate. Only if the factor for treatment was found to be significant, comparisons between the 2 groups were to be made at all postbaseline time points, using a Mann-Whitney U test and including a Bonferroni correction to control the familywise type I error when comparing multiple end points.

Freedom from postoperative delirium was analyzed with the Kaplan-Meier method and compared between the 2 groups using the log-rank (Mantel-Cox) test.24

All data were analyzed based on the intention-to-treat principle. All tests were 2 sided, and a P value of <.05 was considered to be statistically significant.

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RESULTS

Study Flow, Baseline, and Intraoperative Data

Eighty-six patients planned for elective coronary artery surgery in off-pump technique were screened from June 2013 to February 2014. A total of 50 patients were allocated randomly to receive either propofol-TCI alone (n = 25) or xenon 30% plus propofol-TCI (n = 25). All patients received the allocated intervention, and no patient was lost to follow-up (Figure 2).

Figure 2.

Figure 2.

Baseline characteristics and demographics data did not differ between the groups (Table 1).

Table 1.

Table 1.

Table 2.

Table 2.

Procedure and surgery-related data were comparable in both groups (Table 2). No patient had to be converted to on-pump surgery. Groups were similar regarding the intraoperative hemodynamic management as reflected by the use of a pacemaker, inotropes, total intraoperative fluid input (median and IQR: xenon-propofol 4720 [4000–5947] mL vs 4286 [3790–5571] mL in the propofol-only group, P = .167), and fluid balance (2780 [2218–3520] mL in the xenon-propofol group versus 2405 [2036–3065] mL in the propofol-only group, P = .377; Table 2).

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Primary End Point and Hemodynamic Stability

The use of xenon in combination with propofol allowed for a statistically significant reduction in intraoperative norepinephrine requirements as could be observed for both the cumulative norepinephrine doses (Figure 3A) and the weight- and time-corrected doses in microgram per kilogram per minute (Table 2; Supplemental Digital Content, Figure 1, http://links.lww.com/AA/B786). Likewise, the analysis of the log-transformed norepinephrine doses showed a statistically significant decrease in norepinephrine requirements with an estimated ratio of the means for propofol alone versus xenon-propofol of 2.4 (95% confidence interval, 1.7–3.7; P = .0001). Concerning intraoperative phenylephrine doses, both groups were similar (Table 2). In both groups, there was a positive correlation between cumulative phenylephrine doses and the subsequent intraoperative administration of norepinephrine (Spearman correlation coefficient = 0.683, P < .0001).

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Safety Parameters and Data on Organ Protection

In general, intraoperative hemodynamic parameters did not differ between both groups (Supplemental Digital Content, Figure 2, http://links.lww.com/AA/B786). Freedom from postoperative delirium during the observational period was comparable between the groups, log-rank (Mantel-Cox), df = 1, P = .081. Besides, both groups were similar regarding the incidence of other intra- and postoperative (S)AEs (Tables 3 and 4). In both groups, postoperative blood loss and transfusion requirements were comparable (Table 3). Likewise, groups did not differ regarding the duration of mechanical ventilation and length of stay in the ICU and the hospital (Table 3). However, the xenon-propofol group required significantly less norepinephrine than the propofol-only group during the first 24 postoperative hours (median [IQR]: 1.5 [0.1–7] vs 5 [2–8] mg, P = .048; Table 3).

Table 3.

Table 3.

Table 4.

Table 4.

Furthermore, the perioperative time course of myocardial injury markers (high-sensitive cardiac troponin T and creatine kinase-MB) was comparable between groups (Table 3; Supplemental Digital Content, Figure 3A and 3B, http://links.lww.com/AA/B786). Besides, both groups showed a similar elevation of postoperative serum protein S100β in comparison with the baseline (Supplemental Digital Content, Figure 3C, http://links.lww.com/AA/B786).

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Feasibility Data

Figure 3.

Figure 3.

Both groups had a comparable depth of anesthesia as judged by both clinical signs and continuous monitoring of the BIS (xenon-propofol mean BIS ± SD: 36 ± 5 versus propofol alone: 35 ± 6, df = 48, P = .417; Table 2; Figure 2B). Groups differed in intraoperative total propofol requirements; in the xenon-propofol group, mean intraoperative predicted plasma and effect site concentrations of propofol were significantly lower than in the propofol-only group (Table 2). The latter resulted in a significant reduction of the cumulative intraoperative propofol doses in the xenon-propofol group (mean ± SD: 1710 ± 740 vs 2472 ± 734 mg, df = 46, P = .002; Table 2; Supplemental Digital Content, Figure 4, http://links.lww.com/AA/B786). Furthermore, a comparison of predicted propofol plasma concentrations over time between both groups using a mixed linear model revealed a statistically significant difference (P < .0001). Intraoperative opioid consumption, cumulative doses of postoperative analgesics, and sedatives were also comparable in both groups (Table 3). When postoperatively examined with the modified Brice questionnaire, patients did not report any incidents of awareness or recall.

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DISCUSSION

In the current trial, we observed that in patients undergoing OPCAB surgery, the adjuvant use of 30% xenon in combination with a TCI of propofol anesthesia improved hemodynamic stability as demonstrated by decreased requirements. Besides, we found xenon to reduce significantly the propofol doses that were needed to achieve a sufficient depth of anesthesia during surgery. Moreover, the xenon-propofol group had significantly less demand for vasopressors during the first 24 hours on ICU. Other outcomes and safety parameters were not affected by the supplementation of xenon to propofol.

Patients undergoing off-pump cardiac surgery are prone to intraoperative hypotension owing to frequent manipulations and transitory dislocation of the heart.17 Intraoperative hypotension is a significant predictor of postoperative morbidity and mortality.25,26 Moreover, fluctuations of intraoperative arterial blood pressure were shown to affect outcome significantly.27,28

Hence, one of the essential goals in anesthesia for OPCAB surgery is to safeguard hemodynamic stability by avoiding and immediately treating arterial hypotension. The observations made in our study suggest that the adjuvant use of xenon may ease anesthesia for OPCAB surgery and probably other similar procedures that are associated with a particular risk of intraoperative hemodynamic instability and arterial hypotension. Our results are in line with other trials demonstrating that xenon better preserves arterial blood pressure and causes less hemodynamic instability when compared to conventionally used anesthetics, even in cardiac surgery.2,3,29

What renders our study novel, however, is that we used xenon not as a monoanesthetic but as a supplement to intravenous anesthesia with propofol in a cardiac surgical setting.

The more favorable hemodynamic profile observed with xenon supplementation can be either attributed to indirect or direct effects of low-dose xenon anesthesia. Patients with xenon supplementation received significantly less propofol. Propofol is well known to cause arterial hypotension in a dose-dependent manner, mainly by reducing catecholamine release and hence inhibiting the sympathetic nervous system.30 Xenon has been recently shown to preserve sympathetic tone by decreasing the norepinephrine reuptake into sympathetic nerves.31 It is, therefore, tempting to speculate that xenon counteracted propofol-mediated sympatholysis.

Surprisingly, norepinephrine consumption was also significantly increased in the propofol-only group during the first 24 postoperative hours of the ICU stay (despite stopping xenon administration at the end of the surgical procedure and although postoperative requirements of neither opioids nor propofol differed between groups). We are unable to explain this finding as xenon is nearly completely washed out of the body within several minutes.32 Nevertheless, also nitrous oxide as an adjunct to isoflurane has been recently demonstrated to enhance vascular reactivity to vasopressors even after nitrous oxide washout.33 Whether a comparable effect could clarify our observation regarding postoperative norepinephrine consumption needs yet to be confirmed in an adequately powered trial.

Supplementation of xenon allowed reducing propofol target concentrations by nearly 40%. This result indicates that xenon decreases the effective concentration of the anesthetics to which it is added. This conclusion is in line with a previous report of Barakat et al34 who found the effective concentration (EC95) of propofol to be reduced by 72% when 70% xenon instead of 70% N2O were added (this group also demonstrated that the accuracy of propofol-TCI using the Marsh model is not affected by the adjuvant administration of xenon). Likewise, an additive effect for the combination of xenon and halothane has been described already in 1969.35 Comparably, xenon has been demonstrated to reduce the MAC and the MAC-BAR (blockade of adrenergic responses) of sevoflurane in a dose-dependent manner.36 Unfortunately, the number of included patients did not allow us to perform a formal analysis whether xenon and propofol interacted additively or synergistically.5

It has to be acknowledged that our study is subject to several limitations. First, instead of measuring, eg, cumulative times under a predefined blood pressure threshold, hemodynamic (in)stability was only indirectly quantified by using vasopressor requirements as a quantitative and surrogate indicator for arterial hypotension,3,37 assuming that a greater need for vasopressors reflects a higher degree of hemodynamic instability. This approach was dictated by good clinical practice as hypotensive episodes in the intraoperative time course have to be strictly avoided or immediately treated during such high-risk surgeries. As a consequence of this hemodynamic therapy, intraoperative hemodynamic parameters did not differ between groups. Second, it appears perhaps questionable whether the reduced need for vasopressors represents a true improvement in outcome apart from facilitating hemodynamic management. However, vasopressor dependency has been found to be an independent predictor of postoperative morbidity and mortality in cardiac surgery.38–40 Third, it could be argued that the bolus administration of phenylephrine after induction of anesthesia (when a central venous line was not yet available) could have affected the subsequent need for norepinephrine. In fact, we found cumulative phenylephrine doses to directly correlate with norepinephrine requirements, most probably indicating that a higher vasopressor need immediately after induction of anesthesia preceded a higher need for norepinephrine later during the procedure (administered via the central venous catheter). Most importantly, both groups did not differ with respect to cumulative phenylephrine doses so that the observed intergroup differences in total norepinephrine requirements should not be attributed to the administration of phenylephrine. Fourth, it was not possible to blind the attending anesthesiologist for the group allocation owing to the administration of xenon by a dedicated anesthesia machine and the mandatory need to monitor the anesthetic concentrations. However, the investigators had to follow a strict hemodynamic management protocol, which resulted in an equal treatment of both groups. Thus, the observed decrease in intraoperative norepinephrine requirements in patients receiving a combination of xenon with propofol is most probably not due to disparities in perioperative management. Furthermore, the investigators who performed the postoperative follow-up visits were blinded to the treatment allocation. Nevertheless, we acknowledge the failure to blind the attending anesthesiologist by indicating our study as a “pragmatic” randomized controlled trial as it reflects the clinical routine. Fifth, we could not detect any effects of the adjunct administration of xenon to propofol concerning the occurrence rate of (S)AEs and the incidence of postoperative organ dysfunction. The latter may be owing to the small sample size or, in fact, to an absence of an effect of adjuvant xenon to propofol on the incidence of SAEs or postoperative organ (dys)function. Sixth, for the administration of propofol, we used the pharmacokinetic model originally described by Marsh et al16 in children. Although this model is widely used in clinical practice for adult anesthesia,41 it has to be acknowledged that data on validation of this model in cardiac surgery are sparse.42,43 In patients undergoing OPCAB surgery and experiencing major blood loss, the precision/accuracy of this model has never been investigated and is, therefore, uncertain. Serial measurements of propofol plasma concentrations would have overcome this limitation. Seventh, the utility of the BIS during xenon anesthesia has been demonstrated by several groups.44,45 It has not yet been formally studied if a BIS value for the combination of xenon with propofol represents the same depth of anesthesia as when the value is achieved with propofol alone. However, xenon has been described to induce changes in the raw electroencephalogram that are similar to those observed during propofol anesthesia.46 We therefore suggest that the combination of xenon with propofol most probably does not affect the response of the electroencephalogram and BIS to either agent alone. In our study, also vegetative signs, lack of movement, and absence of intraoperative awareness indicate that the patients had the same depth of anesthesia. Last, as the present trial was powered only for the primary outcome parameter and because of the relatively few included patients, all other secondary outcome measures including the lack of any impact (neither beneficial nor adverse) on postoperative organ function should, therefore, be interpreted with caution.

In summary, the adjuvant use of 30% xenon in combination with propofol facilitates hemodynamic management by decreasing norepinephrine requirements in patients undergoing elective OPCAB surgery. Hemodynamic advantages of xenon anesthesia can, therefore, be achieved with subanesthetic concentrations of xenon that are added to another anesthetic. A further trial should specifically investigate the efficacy and cost-efficiency of xenon supplementation versus monoanesthesia with xenon.

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ACKNOWLEDGMENTS

All authors express their appreciation to Mrs Christel Huygens and her team (research nurses), Mrs Ann Belmans (Department of Biostatistics and Statistical Bioinformatics Centre, Catholic University of Leuven, Belgium), and Professor K. Poesen, who supervised the laboratory analysis and the nursing staff of the cardiac surgical unit at the University Hospital of Leuven.

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DISCLOSURES

Name: Layth Al tmimi, MD.

Contribution: This author helped perform the study design, write the study protocol, carry out the clinical study, perform the data achievement and statistical analysis, draft the manuscript, critically revise the manuscript draft, and read and approve the final version.

Name: Sarah Devroe, MD.

Contribution: This author helped perform the study design, write the study protocol, critically revise the manuscript draft, and read and approve the final version.

Name: Geertrui Dewinter, MD.

Contribution: This author helped perform the study design, write the study protocol, critically revise the manuscript draft, and read and approve the final version.

Name: Marc Van de Velde, MD, PhD.

Contribution: This author helped perform the study design, write the study protocol, critically revise the manuscript draft, and read and approve the final version.

Name: Gert Poortmans, MD.

Contribution: This author helped perform the study design, write the study protocol, critically revise the manuscript draft, and read and approve the final version.

Name: Bart Meyns, MD, PhD.

Contribution: This author helped perform the study design, write the study protocol, critically revise the manuscript draft, and read and approve the final version.

Name: Bart Meuris, MD, PhD.

Contribution: This author helped perform the study design, write the study protocol, critically revise the manuscript draft, and read and approve the final version.

Name: Mark Coburn, MD, PhD.

Contribution: This author helped perform the study design, write the study protocol, critically revise the manuscript draft, and read and approve the final version.

Name: Steffen Rex, MD, PhD.

Contribution: This author is the principle investigator of the current study and helped perform the study design, write the study protocol, carry out the clinical study, perform the data achievement and statistical analysis, draft the manuscript, critically revise the manuscript draft, and read and approve the final version.

This manuscript was handled by: W. Scott Beattie, PhD, MD, FRCPC.

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REFERENCES

1. Chassot PG, van der Linden P, Zaugg M, Mueller XM, Spahn DR. Off-pump coronary artery bypass surgery: physiology and anaesthetic management. Br J Anaesth. 2004;92:400–413.
2. Law LS-C, Lo EA-G, Gan TJ. Xenon anesthesia: a systematic review and meta-analysis of randomized controlled trials. Anesth Analg. 2016;122:678–697.
3. Al Tmimi L, Van Hemelrijck J, Van de Velde M, et al. Xenon anaesthesia for patients undergoing off-pump coronary artery bypass graft surgery: a prospective randomized controlled pilot trial. Br J Anaesth. 2015;115:550–559.
4. Stoppe C, Rimek A, Rossaint R, et al. Xenon consumption during general surgery: a retrospective observational study. Med Gas Res. 2013;3:12.
5. Nakata Y, Goto T, Ishiguro Y, et al. Minimum alveolar concentration (MAC) of xenon with sevoflurane in humans. Anesthesiology. 2001;94:611–614.
6. David HN, Haelewyn B, Rouillon C, et al. Neuroprotective effects of xenon: a therapeutic window of opportunity in rats subjected to transient cerebral ischemia. FASEB J. 2008;22:1275–1286.
7. Stoppe C, Ney J, Brenke M, et al. Sub-anesthetic xenon increases erythropoietin levels in humans: a randomized controlled trial. Sports Med. 2016;46:1753–1766.
8. Goto T, Nakata Y, Ishiguro Y, Niimi Y, Suwa K, Morita S. Minimum alveolar concentration-awake of Xenon alone and in combination with isoflurane or sevoflurane. Anesthesiology. 2000;93:1188–1193.
9. Kobayashi S, Katoh T, Bito H, Sato S. Effect of xenon on catecholamine and hemodynamic responses to surgical noxious stimulation in humans. J Clin Anesth. 2006;18:343–348.
10. Al Tmimi L, Van de Velde M, Meyns B, et al. Serum protein S100 as marker of postoperative delirium after off-pump coronary artery bypass surgery: secondary analysis of two prospective randomized controlled trials. Clin Chem Lab Med. 2016;54:1671–1680.
11. Coburn M, Sanders RD, Maze M, Rossaint R; HIPELD Investigators. The Hip Fracture Surgery in Elderly Patients (HIPELD) study: protocol for a randomized, multicenter controlled trial evaluating the effect of xenon on postoperative delirium in older patients undergoing hip fracture surgery. Trials. 2012;13:180.
12. Nashef SA, Roques F, Sharples LD, et al. EuroSCORE II. Eur J Cardiothorac Surg. 2012;41:734–744.
13. Yesavage JA, Sheikh JI. 9/Geriatric Depression Scale (GDS). Clin Gerontol. 1986;5:165–173.
14. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–198.
15. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990;113:941–948.
16. Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth. 1991;67:41–48.
17. De Raet JM, Desimone JP, Sergeant PT. Off-pump coronary artery bypass grafting: Anno 2011. Multimed Man Cardiothorac Surg. 2011;2011:mmcts.2004.000539.
18. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA. 1993;270:2957–2963.
19. Vincent JL, de Mendonça A, Cantraine F, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med. 1998;26:1793–1800.
20. Avidan MS, Palanca BJ, Glick D, et al.; BAG-RECALL Study Group. Protocol for the BAG-RECALL clinical trial: a prospective, multi-center, randomized, controlled trial to determine whether a bispectral index-guided protocol is superior to an anesthesia gas-guided protocol in reducing intraoperative awareness with explicit recall in high risk surgical patients. BMC Anesthesiol. 2009;9:8.
21. Dixon JR. The international conference on harmonization good clinical practice guideline. Qual Assur. 1999;6:65–74.
22. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis Quality Initiative Workgroup. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–R212.
23. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175–191.
24. Machin D, Cheung YB, Parmar M. Survival Analysis: A Practical Approach. 2006.2nd ed. Hoboken, NJ: John Wiley & Sons Ltd.
25. Walsh M, Devereaux PJ, Garg AX, et al. Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension. Anesthesiology. 2013;119:507–515.
26. Sun LY, Wijeysundera DN, Tait GA, Beattie WS. Association of intraoperative hypotension with acute kidney injury after elective noncardiac surgery. Anesthesiology. 2015;123:515–523.
27. Hirsch J, DePalma G, Tsai TT, Sands LP, Leung JM. Impact of intraoperative hypotension and blood pressure fluctuations on early postoperative delirium after non-cardiac surgery. Br J Anaesth. 2015;115:418–426.
28. Aronson S, Stafford-Smith M, Phillips-Bute B, Shaw A, Gaca J, Newman M; Cardiothoracic Anesthesiology Research Endeavors. Intraoperative systolic blood pressure variability predicts 30-day mortality in aortocoronary bypass surgery patients. Anesthesiology. 2010;113:305–312.
29. Stoppe C, Fahlenkamp AV, Rex S, et al. Feasibility and safety of xenon compared with sevoflurane anaesthesia in coronary surgical patients: a randomized controlled pilot study. Br J Anaesth. 2013;111:406–416.
30. Minami K, Yanagihara N, Segawa K, Tsutsui M, Shigematsu A, Izumi F. Inhibitory effects of propofol on catecholamine secretion and uptake in cultured bovine adrenal medullary cells. Naunyn Schmiedebergs Arch Pharmacol. 1996;353:572–578.
31. Neukirchen M, Hipp J, Schaefer MS, et al. Cardiovascular stability and unchanged muscle sympathetic activity during xenon anaesthesia: role of norepinephrine uptake inhibition. Br J Anaesth. 2012;109:887–896.
32. Katz I, Murdock J, Palgen M, Pype J, Caillibotte G. Pharmacokinetic analysis of the chronic administration of the inert gases Xe and Ar using a physiological based model. Med Gas Res. 2015;5:8.
33. Samarska IV, van Meurs M, Buikema H, et al. Adjunct nitrous oxide normalizes vascular reactivity changes after hemorrhagic shock in mice under isoflurane anesthesia. Anesthesiology. 2009;111:600–608.
34. Barakat AR, Schreiber MN, Flaschar J, Georgieff M, Schraag S. The effective concentration 50 (EC50) for propofol with 70% xenon versus 70% nitrous oxide. Anesth Analg. 2008;106:823–829.
35. Cullen SC, Eger EI II, Cullen BF, Gregory P. Observations on the anesthetic effect of the combination of xenon and halothane. Anesthesiology. 1969;31:305–309.
36. Nakata Y, Goto T, Morita S. Effects of xenon on hemodynamic responses to skin incision in humans. Anesthesiology. 1999;90:406–410.
37. Frey UH, Karlik J, Herbstreit F, Peters J. β2-Adrenoceptor gene variants affect vasopressor requirements in patients after thoracic epidural anaesthesia. Br J Anaesth. 2014;112:477–484.
38. Weis F, Kilger E, Beiras-Fernandez A, et al. Association between vasopressor dependence and early outcome in patients after cardiac surgery. Anaesthesia. 2006;61:938–942.
39. Sastry P, Hardman G, Page A, et al. Mesenteric ischaemia following cardiac surgery: the influence of intraoperative perfusion parameters. Interact Cardiovasc Thorac Surg. 2014;19:419–424.
40. Hennessy SA, LaPar DJ, Stukenborg GJ, et al. Cardiac catheterization within 24 hours of valve surgery is significantly associated with acute renal failure. J Thorac Cardiovasc Surg. 2010;140:1011–1017.
41. Absalom AR, Glen JI, Zwart GJ, Schnider TW, Struys MM. Target-controlled infusion: a mature technology. Anesth Analg. 2016;122:70–78.
42. Barvais L, Rausin I, Glen JB, et al. Administration of propofol by target-controlled infusion in patients undergoing coronary artery surgery. J Cardiothorac Vasc Anesth. 1996;10:877–883.
43. Mathew PJ, Sailam S, Sivasailam R, Thingnum SK, Puri GD. Performance of target-controlled infusion of propofol using two different pharmacokinetic models in open heart surgery—a randomised controlled study. Perfusion. 2016;31:45–53.
44. Fahlenkamp AV, Krebber F, Rex S, et al. Bispectral index monitoring during balanced xenon or sevoflurane anaesthesia in elderly patients. Eur J Anaesthesiol. 2010;27:906–911.
45. Stoppe C, Peters D, Fahlenkamp AV, et al. aepEX monitor for the measurement of hypnotic depth in patients undergoing balanced xenon anaesthesia. Br J Anaesth. 2012;108:80–88.
46. Laitio RM, Kaskinoro K, Särkelä MO, et al. Bispectral index, entropy, and quantitative electroencephalogram during single-agent xenon anesthesia. Anesthesiology. 2008;108:63–70.

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