Introduction

Qualitative anesthetic management and surgical techniques resulted safe cardiac surgery and mortality after coronary artery bypass grafting (CABG) in expert centers ≤ 2—3% [1]. At the same time, incidence of intraoperative and postoperative complications in cardiac surgery is still high. K. Moazzami et al. [1] reported blood loss and hemodynamic disorders as the most common causes of complications. Perioperative stress, surgical trauma and excessive sympathetic activation increase the risk of cardiovascular and respiratory complications, slow down activation of patients, increase the likelihood of wound infection and impair clinical outcomes [2, 3]. High thoracic epidural anesthesia (HTEA) is one of the methods for prevention of these disorders.

Despite certain positive effects of neuraxial blockade in cardiac surgery [4, 5], there are still questions about safety and effectiveness of these procedures. Indeed, hemodynamic effects of HTEA associated with sympathetic blockade can affect perioperative infusion therapy. The benchmarks for this therapy are not always obvious.

It is confirmed that targeted perioperative infusion therapy can reduce severity of postoperative complications and length of hospital-stay [6]. Nevertheless, static hemodynamic parameters, in particular central venous pressure (CVP) and pulmonary artery occluded pressure (PAOP), do not always adequately predict the response to infusion [7, 8]. In recent years, dynamic tests (passive leg raising (PLR), infusion bolus, etc.) and dynamic parameters (variability of stroke volume, pulse pressure, plethysmography) have been actively used to assess the patient's susceptibility to infusion [9, 10]. At the same time, dynamic parameters and tests for assessing the volume status during HTEA-assisted cardiac surgery are not sufficiently studied and have certain limitations. In addition, the effect of epidural anesthesia during CABG and postoperative analgesia on patient responsiveness to infusion therapy is unclear.

Hypothesis and purpose of the study

We hypothesized that HTEA can change patient responsiveness to infusion therapy in coronary artery bypass surgery.

The purpose of the study was to evaluate the effect of HTEA on patient sensitivity to infusion therapy after off-pump CABG.

Material and methods

The Local ethics committee approved the study (protocol No. 09/12—18 dated 12/18/2018). A single-center prospective randomized controlled trial was conducted at the intensive care unit of the Volosevich First Municipal Clinical Hospital. We examined 70 patients who underwent elective off-pump CABG for the period from February 2019 to March 2020. Inclusion criteria: signed informed consent, age 18 — 70 years, elective cardiac surgery for coronary artery disease (isolated off-pump CABG), preoperative left ventricular ejection fraction (EF) > 40%, sinus rhythm. Exclusion criteria: refusal to participate in the study, refusal of epidural anesthesia, acute myocardial infarction within previous 30 days, severe course of chronic obstructive pulmonary disease, chronic kidney disease stage IV-V, uncontrolled course of diabetes mellitus, obesity with body mass index > 40 kg/m2. We also excluded the patients who required intraoperative conversion to on-pump CABG.

Randomization into the main and control groups (1:1) was carried out using envelopes.

Main group. All patients underwent general anesthesia with sevoflurane in combination with HTEA. At the operating theatre, we catheterized peripheral vein, initiated intravenous infusion of balanced solutions and catheterized epidural space within Th2-Th5. At the next stage, induction of anesthesia (propofol 1–2 mg/kg, fentanyl 2 µg/kg, pipecuronium bromide 0.08 mg/kg) was followed by tracheal intubation. Inhalation anesthesia was intraoperatively maintained by sevoflurane (1—2 MAC). Epidural analgesia was achieved by fractional administration of ropivacaine 0.5% up to total dose of 1 mg/kg. After surgery, we performed epidural infusion of ropivacaine 0.2% at a rate of 3—6 ml/h for 24 hours. Effective blockade was determined by NRS (numerical rating scale) score of pain < 3 at rest and < 4 in coughing.

Control group. Induction of anesthesia and tracheal intubation were performed in similar fashion. Inhalation anesthesia was intraoperatively maintained by sevoflurane (1—2 MAC).

Prior to surgery, we catheterized radial artery (Arteriofix, "B. Braun", Germany), internal jugular vein (Intradyn F8, "B. Braun", Germany) and pulmonary artery (Corodyn TD F7, "B. Braun", Germany) in both groups. Volume-controlled mechanical ventilation (Datex Ohmeda Aespire View, GE Healthcare Technologies, USA; Draeger Primus, Draeger, Germany) was performed with a tidal volume of 6—8 ml/kg predicted body weight. Positive end-expiratory pressure was 5 cm H₂O. Respiratory rate and respiratory minute volume were established at the level required to maintain normocapnia (EtCO2 35–40 mm Hg), fraction of inspired oxygen — to maintain SpO₂ > 96%. Mean blood pressure (BP) was maintained within 65—75 mm Hg, heart rate (HR) – 50 — 90 min–1.

Survey stages and monitoring. Hemodynamic parameters were assessed after induction of general anesthesia, at the end of surgery, after passive leg raising and infusion bolus tests. At all these stages, we analyzed mean BP, HR, CVP, cardiac index (CI), systemic vascular resistance index (SVRI), stroke volume index (SVI), PAOP, mean pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) (monitors "Nihon Kohden", Japan). In addition to hemodynamic assessment, we measured central venous blood saturation (ScvO₂), venoarterial carbon dioxide gradient (Pv-aCO₂) and lactate at the beginning and at the end of surgery, after dynamic tests and before transferring to cardiac surgery department.

Assessment of volume status. At admission of patients to the intensive care unit (ICU) under sedation with propofol 1 mg/kg/hour, we performed passive leg raising test and infusion bolus test with balanced solutions of crystalloids (Sterofundin isotonic "B. Braun Melsungen", Germany). Volume of infusion was 7 ml/kg (fluid challenge — FC). In addition to invasive hemodynamic monitoring, we analyzed plethysmogram variability index (PVI) on the index finger of a hand free from radial artery catheterization (Radical-7 monitor, Masimo, USA). Patients with CI increment > 10% and PVI decrement > 6% after dynamic tests were recognized as responders to infusion therapy [11].

Primary endpoint in our study was the number of responders to infusion therapy in all groups.

Secondary endpoints were intra- and postoperative changes of hemodynamic parameters, as well as lactate, ScvO₂ and Pv-aCO₂.

Sample size. In the pilot study, response rate was 60% in the control group. We assumed that 50% increase in the number of responders would be clinically significant. Accordingly, each group should comprise 31 patients to demonstrate outcome rate increase by 50% with a type I error set at 0.05 and statistical power 80%. Considering possible loss of data during formation of groups, we decided to enlarge the group up to 70 patients (35 patients for each group).

Statistical analysis was performed using the SPSS version 21.0 (SPSS Inc., USA) and the R version 4.0.3 software packages. Data distribution normality was tested using the Shapiro-Wilk test and graphical methods. In case of normal distribution and equal variances, we used the Student's t-test. Welch’s test was applied for unequal variances (Levene’s test). In case of skewed distribution, the Mann-Whitney test was used. Within-group analysis was performed using the paired t-test for normal distribution and Wilcoxon test for skewed distribution. In case of multiple pairwise comparisons, the Bonferroni correction was applied. Categorical variables were assessed using the Pearson χ² test. Continuous data are presented as median and interquartile range (IQR) for skewed distribution or mean ± standard deviation (M ± SD) for normal distribution. Categorical variables are presented as frequencies. Differences were considered significant at p-value <0.05.

Results

We excluded 1 patient in each group due to intraoperative conversion to on-pump CABG. Thus, we analyzed 68 patients (34 per a group). Both groups were comparable by age, gender, anthropometric indicators, EuroScore II, therapy and comorbidities (Table 1). Mean surgery time was 162 ± 31 min in the main group and 173 ± 47 min in the control group (p = 0.26).

Table 1. Demographic characteristics of patients

Note. ACE — angiotensin converting enzyme; CHF — chronic heart failure; HTEA — high thoracic epidural anesthesia.

Intraoperative period. We observed intraoperative increase in heart rate, CI and PVI without changes in mean BP, CVP, SVI, mean PAP and PAOP and decrease of SVRI. Transient between-group differences were detected before functional tests (CVP and PVI at the beginning of surgery and mean BP at the end of surgery) (Table 2). Intraoperative vasopressor therapy was required in 16 (47.1%) patients in the control group and 15 (44.1%) patients in the main group. Duration of therapy was 100 (IQR 125) and 180 (IQR 240) min, respectively (p = 0.28).

Table 2. Hemodynamic parameters at various stages

Note. HTEA — high thoracic epidural anesthesia; PLR — passive leg raising test; IB — infusion bolus test; BP — blood pressure; CVP — central venous pressure; CI — cardiac index; SVRI — systemic vascular resistance index; SVI — stroke volume index; PAOP — pulmonary artery occluded pressure; PAP — pulmonary artery pressure; PVR — pulmonary vascular resistance; PVI — plethysmography variability index; * — within-group difference when comparing the beginning and end of surgery; ** — within-group difference compared to the end of surgery; † — between-group difference.

Dynamic tests and parameters for assessing intravascular volume status. Both tests revealed significant within-group increment of mean BP, heart rate, CI, SVI and PVR (Table 2). CVP and PAOP decreased after tests as compared with the end of surgery. Mean PAP increased transiently only after passive leg raising test. Moreover, we obtained within-group decrease of PVI by 1.5 times in the main group (p = 0.02) and by 1.8 times in the control group (p = 0.02). Functional tests revealed no between-group differences.

CI and PVI changes in responders and non-responders to dynamic tests are shown in the Figure. After passive leg raising test, we obtained 65.7% of responders for CI and 68.6% for PVI in the HTEA group. In the control group, we observed 71.4% of responders for CI and 80.0% for PVI. The number of responders in both groups was similar (χ² = 0.28, p = 0.6 for CI and χ² = 0.6, p = 0.4 for PVI). In case of infusion bolus, the numbers of responders were similar (77.1% and 60.0% for CI, 62.9% and 71.4% for PVI in both groups, respectively). There were no between-group differences in distribution of responders and non-responders depending on the use of HTEA (χ² = 2.55, p = 0.11 for CI and χ² = 0.4, p = 0.5 for PVI). Postoperative vasopressor therapy was required in 8 (25.7%) patients of the control group and 5 (17.1%) patients of the main group throughout 130 (IQR 165) and 140 (IQR 720) min, respectively (p = 0.8).

Fig. Distribution of responders and non-responders to infusion therapy based on cardiac index increment and plethysmography variability index decrement.

PLRT — passive leg raising test; PVI — plethysmogram variability index; CI — cardiac index; BIT — bolus infusion test.

Oxygen transport. In both groups, lactate concentration increment was observed by the end of surgery. Moderate increase of lactate level persisted at the stage of transferring to the ICU and during dynamic tests. ScvO₂ at the beginning of surgery was higher in the VTEA group and significantly decreased at discharge from the ICU in both groups. Pv-aCO₂ was similar at all stages (Table 3).

Table 3. Oxygen transport parameters in study patients

Note. HTEA — high thoracic epidural anesthesia; Pv-aCO₂ — venoarterial carbon dioxide gradient; ScvO₂ — central venous oxygen saturation; ICU — intensive care unit; † — between-group difference; * — within-group for the end of surgery and stage after tests; ** — within-group difference between the stage after tests and discharge from ICU.

Volume balance by the end of surgery was + 876 ± 267 and + 838 ± 379 ml in the control and main groups, respectively (p = 0.63). After the first postoperative day, these values were +420 (IQR 462) and +275 (IQR 615) ml (p = 0.12).

Discussion

According to our data, epidural anesthesia did not affect patient sensitivity to infusion therapy in early postoperative period after off-pump CABG.

The latest Cochrane systematic review of epidural anesthesia in cardiac surgery showed that HTEA results less incidence of intra- and postoperative complications (myocardial infarction, acute respiratory distress syndrome, atrial fibrillation, etc.) [4]. Considering less severity of surgical stress [2], effective pain control and reduced time to tracheal extubation [4], HTEA can be used as a component of early surgical rehabilitation in cardiac surgery [6]. At the same time, HTEA combined with targeted fluid therapy is still discussable.

HTEA can variously influence the cardiovascular system [12, 13]. Nevertheless, we found similar hemodynamic changes in both groups that can indirectly indicate insignificant circulatory effect of HTEA.

Within-group changes in hemodynamics and oxygen transport by the end of surgery (heart rate and cardiac index increase, moderate vasodilation, PVI and lactate level increase) can be explained by the effect of surgery and anesthesia, as well as reperfusion after myocardial revascularization. These findings are similar to the results of previous studies devoted to HTEA in coronary artery bypass surgery [2, 14—16].

One of the main goals of fluid therapy is correction of hypovolemia and increase of cardiac output. However, hypervolemia may be no less dangerous, especially in cardiac patients [17]. In this regard, dynamic tests of patient susceptibility to infusion therapy can be used to form a personal infusion program [10, 11, 18–20]. In our study, we observed increment of CI, SVI and mean BP and decrease of PVI after passive leg raising and infusion bolus in both groups. Concomitant reduction of CVP and PAOP after tests can be explained by higher myocardial performance and cardiac output. These data also confirm the limited value of static preload indicators in patients on mechanical ventilation [7, 8, 14]. HTEA had no effect on distribution of responders to infusion therapy during passive leg raising test and infusion bolus. Other authors obtained similar results using dynamic tests after cardiac surgery [21—23]. However, HTEA was not used in these studies.

Dynamic tests have certain limitations. In particular, they are discrete that requires direct monitoring of cardiac output. In this regard, dynamic parameters for real-time assessment of patient sensitivity to infusion therapy are of particular relevance. PVI is one of these parameters. According to a recent systematic review, PVI accuracy is comparable with stroke volume variability [10]. Nevertheless, most studies devoted to dynamic parameters were performed in cardiac patients without epidural anesthesia. In our study, PVI-based assessment of intravascular volume status found no increase in the number of responders among patients with HTEA. At the same time, the role of PVI can be less in comparison with invasive dynamic parameters and tests due to dependence on the quality of pulse oximeter signal and peripheral tissue perfusion [24]. Theoretically, HTEA can influence patient sensitivity to fluid therapy through venous return modulation or improving the myocardial performance accompanied by rightward shift of the Frank-Starling curve. Vasoplegia following epidural anesthesia can reduce peripheral vascular resistance [25]. The last one is followed by decrease of mean systemic pressure of cardiac chamber filling [26]. Nevertheless, we found no significant between-group difference in SVRI. This is because compensatory vasoconstriction can neutralize this effect of HTEA [27]. Some authors observed better coronary perfusion under HTEA and subsequent increase in myocardial productivity, modulation of its inotropic and lusitropic properties [27–31].

These data can indirectly confirm HTEA-related increase of sensitivity to infusion therapy under optimizing coronary blood flow. However, perioperative volume balance was not considered or significantly differed in certain studies. For example, Jakobsen C.J. et al. [14] reported CI increase in the HTEA group while the volume of infusion therapy was higher in the main group. In our study, we found no between-group differences in CI, SVI and parameters of oxygen transport and tissue perfusion. These findings may be explained by similar infusion and vasopressor therapy in both groups, as well as low doses of ropivacaine. Interestingly, ropivacaine is characterized by higher cardiovascular safety compared to bupivacaine that induces cardiodepressive effects and more significant muscular blockade [4].

Limitations. We used only 2 tests for assessing the intravascular volume status (passive leg raising and infusion bolus). Moreover, we also applied only one dynamic parameter for assessing the patient's susceptibility to infusion load (non-invasive PVI). Perhaps, stroke volume and pulse pressure variability will show other results.

Conclusion

Passive leg raising and infusion bolus revealed no effect of high thoracic epidural anesthesia on sensitivity to infusion load in early postoperative period after off-pump coronary artery bypass grafting. Further study of the effect of high thoracic epidural anesthesia on dynamic parameters of preload is required.

Author contribution:

Concept and design of the study — Volkov D.A., Paromov K.V., Kirov M.Yu.

Collection and analysis of data — Volkov D.A., Paromov K.V.

Statistical analysis — Volkov D.A., Paromov K.V., Kirov M.Yu.

Writing the text — Volkov D.A., Paromov K.V., Kirov M.Yu.

Editing — Paromov K.V., Kirov M.Yu.

The authors declare no conflicts of interest.