Abstract

Background: This study aims to compare the effects of fentanyl and remifentanil on hemodynamic stability, release of troponin-I and early extubation during off-pump coronary artery bypass graft (CABG) surgery.

Methods: Forty patients who were scheduled for elective offpump CABG surgery were randomly assigned to two groups. The remifentanil group received 1 μg/kg^-1 remifentanil over one minute for induction, followed by 0.1-1 μg/kg^-1 min^-1 continuous infusion plus midazolam 0.1-0.15 mg/kg^-1 for maintenance dose. The fentanyl group received 10-15 μg/kg^-1 fentanyl over one minute for induction and 0.1-1 μg/kg^-1 min^-1 continuous infusion plus midazolam 0.1-0.15 mg/kg-1 for maintenance dose. Rocuronium bromide at 0.6-0.8 mg/kg^-1 was administered to facilitate tracheal intubation. Midazolam infusion at 0.4-1 μg/kg^-1 min^-1 was initiated for maintenance therapy.

Results: The depth of anesthesia was adjusted to maintain a BIS value between 40-60. Following skin incision and sternotomy, systolic arterial pressure was lower in the remifentanil group compared to the fentanyl group (115±14 mmHg vs. 130±22 mmHg p<0.05; 125±14 mmHg vs. 135±19 mmHg, p<0.05). Total dose of midazolam was significantly higher in the remifentanil group compared to the fentanyl group (13.9±3.7 mg vs. 11.6±3.7 mg, p<0.05). Intraoperative use of beta blockers, nitroglycerine and sodium nitroprusside was similar in both groups. The median time to extubation and the length of stay in the intensive care unit were shorter in the remifentanil group (6.5±3 h vs. 10±3 h, p<0.05; 14±6 h vs. 20±6 h, p<0.05). The incidence of postoperative electrocardiographic changes and troponin I measurements were similar in both groups.

Conclusion: Although remifentanil infusion offers a better intraoperative hemodynamic stability and postoperative recovery, both agents have similar effects on myocardial injury during offpump CABG surgery.

Off-pump coronary artery bypass graft (CABG) surgery is increasingly being performed, especially for high-risk patients,[1] and vasopressors or beta blockers used during the displacement and stabilization of the heart, monitorization and management of myocardial ischemia during coronary occlusion, and management of hypothermia are important modalities for patients during this surgical procedure.[2] The findings of elevated inflammatory markers and the release of cardiospecific enzymes in individual patients imply an ongoing need to develop more effective strategies for myocardial protection during off-pump CABG.[3]

The coronary blood flow during anastomosis can be compromised due to hemodynamic disturbances even in the presence of intracoronary shunts this procedure. There is also evidence that the level of intraoperative analgesia may influence the risk of postoperative myocardial infarction (MI) in all patients undergoing cardiac surgery.[4,5] Therefore, choosing the appropriate opioid and prescribing the proper dosage in order to maintain a stable heart rate and blood pressure by using the least possible vasoactive medication during surgery is a great challenge for every cardiac anesthesiologist.

Remifentanil is a potent, synthetic opioid with an ultra-short duration of action. It has a stable, contextsensitive half-time compared with other opioids, and its rapid elimination allows for the depth of analgesia to be adjusted according to the phase of the operation, thus successfully blocking the stress response.[6]

The goal of this prospective randomized study was to compare the effects of fentanyl and remifentanil as they related to hemodynamic stability, troponin I release, and early extubation in off-pump CABG surgery.

Methods

This clinical study was performed at Türkiye Yüksek İhtisas Education and Research Hospital with the approval of the ethics committee and the informed consent of the participants. Forty patients, aged 40 to 75 years, with the American Society of Anesthesiologists (ASA) physical status II and III who were to undergo off-pump CABG surgery were enrolled in the study. The exclusion criteria were the following: an ejection fraction (EF) of less than 40%, the preoperative use of inotropic agents and/or an intraaortic balloon pump, major organ failure [creatinine >1.5 mg/kg^-1, serum glutamic oxalacetic transaminase (SGOT) >40 IUL^-1, serum glutamic pyruvic transaminase (SGPT) >40 IUL^-1, hematocrit (Htc) <30%], opioid intolerance, a history of neurological diseases, or a cerebrovascular event.

The patients were premedicated with 10 mg diazepam (Diazem, DEVA Holding, Istanbul, Turkey) orally the day before surgery and with 0.1-0.15 mg/kg^-1 morphine hydrochloride (HCL) (Biosel İlaç Sanayi ve Ticaret A.Ş., Istanbul, Turkey) intramuscularly on the day of surgery. Monitorization of all patients was done via electrocardiogram (ECG), arterial oxygen saturation, and nasopharengeal and rectal temperature. The patients’ blood pressure was also monitored via a left arterial line, and a catheter was inserted in the right internal jugular vein to observe the central vein pressure. The depth of anesthesia was measured using the Bispectral Index™ (BIS™) brain function monitoring system (Covidien, Mansfield, MA, USA). The baseline blood pressure was recorded before instrumentation, and a baseline blood sample was collected for cardiac enzyme analysis.

Before the induction of anesthesia, each of the 40 patients scheduled for elective off-pump CABG was given 100% oxygen for at least three minutes and randomly assigned to either the remifentanil group (group R), which received 1 μg/kg^-1 remifentanil (Ultiva™, GlaxoSmithKline, Istanbul, Turkey) over one minute for induction and 0.1-1 μg/kg^-1 min^-1 continuous infusion for maintenance, or the fentanyl group (group F), which received 10-15 μg/kg^-1 fentanyl (Abbott Laboratories, Istanbul, Turkey) over one minute for induction and 0.1-1 μg/kg^-1 min^-1 continuous infusion for maintenance. Rocuronium bromide 0.6-0.8 mg/kg^-1 and 0.1-0.15 mg/kg^-1 midazolam (Zolamid, Defarma, Ankara, Turkey) were administered to facilitate tracheal intubation and continued as 0.3 mg/kg^-1 every 30-45 minutes. Midazolam maintenance infusion 0.4-1 μg/kg^-1 min^-1 was also started, and the depth of anesthesia was adjusted to maintain a BIS™ value of between 40-60.

In addition, the patients were ventilated with oxygen and air, with the ventilation being adjusted to maintain an end-tidal carbon dioxide (CO₂) of between 30-35 mmHg. Adjustments were also made with regard to the hypnotic (midazolam), analgesic, and antihypertensive treatments as they related to the intraoperative response (Tables 1 and 2).

Table 1: Bispectral index^TM guided anesthetic management

Table 2: Procedure times

The mean arterial pressure, heart rate and BIS™ index were recorded before induction, after induction, five minutes after intubation, after the skin incision and sternotomy, during the left internal mammary artery (LIMA) dissection, and at coronary anastomosis and skin closure.

All patients underwent coronary revascularization using the LIMA. For additional grafts, a saphaneus vein was used. All patients received a single dose of intravenous heparin (Vasparin, Defarma, Ankara, Turkey), 75-150 IU/kg^-1 after the LIMA dissection, and the activated coagulation time was measured to ensure the appropriate heparin effect and reversal.

The anastomosis, anesthesia, and surgery durations were recorded, and blood samples for troponin I analysis were obtained at the baseline and six hours after the surgery.

Postoperatively, the patients were followed up until discharge from the intensive care unit (ICU). Intramuscular diclofenac sodium and intravenous paracetamol (Parol, Atabay, İstanbul, Turkey) were used for postoperative pain control, and the duration of tracheal extubation and ICU discharge times along with any postoperative complications (nausea, vomiting, arrythmias, reintubation, awareness, bleeding, and myocardial ischemia), and the use of inotropics and antihypertensive drugs were recorded.

Data analysis was performed via the SPSS version 11.5 for Windows software program (SPSS Inc., Chicago, IL, USA). Student’s t-test was used to determine whether or not there was a statistically meaningful difference between the two groups regarding the commonly distributed variables with continual measurement. If there was a difference, the Mann-Whitney U test was then employed to determine if there was any connection with the abnormally distributed variables. The Friedman test was used to evaluate whether there was a statistically meaningful difference between more than two concurrent measurements within the groups If there was, then the Wilcoxon signedrank test for multicomparison was performed and the measurement times that caused the difference were determined. In cases in which there was a second concurrent measurement, the significance in the difference between the measurements was evaluated via a dependent t test or Wilcoxon signedrank test. Nominal variables were compared using Pearson’s chi-square or Fisher’s probability tests with complete results, and a p value of <0.05 was considered to be significant. During all possible in-group or multiple comparisons, the Bonferroni correction was applied so as to take into account the type I fault.

Results

Of the original 40 patients enrolled in this study, one was excluded because of the need to switch to on-pump coronary artery bypass grafting (CABG). The patients in group F and group R were comparable with respect to age, gender, weight, additional diseases, preoperative use of beta (ß) blockers, and left ventricular ejection fraction (LVEF). Thirteen patients in group R and 15 patients in group F had additional diseases [hypertension, diabetes mellitus (DM), hyperlipidemia, malignancy, epilepsy, and rheumatoid arthritis (RA)]. Furthermore, 27 patients were on preoperative ß blocker therapy, (Table 3). The mean BIS™ values of the patients during the surgery are shown in Figure 1.

Table 3: Demographic data

Figure 1: 1. Before induction; 2. After induction; 3.5. Five minutes later after intubation; 4. After skin incision; 5. After sternotomy; 6. During left internal mammary artery dissection; 7. At coronary anastomosis; 8. At chest closure; and 9. At skin closure. BIS™: Bispectral Index™.

The heart rate measurements were significantly lower in group R than in group F after sternotomy (67±8 vs. 79±12; p<0.05) (Figure 2). After the skin incision and sternotomy, the mean arterial blood pressures was also lower in group R than in group F (80±14 mmHg vs. 92±22 mmHg; p<0.05; 86±14 mmHg vs. 94±19 mmHg, respectively; p<0.05) (Figure 3).

Figure 2: 1. Before induction; 2. After induction; 3. Five minutes later after intubation; 4. After skin incision; 5. After sternotomy; 6. During left internal mammary artery dissection; 7. At coronary anastomosis; 8. At chest closure; and 9. At skin closure. HR: Heart rate.

Figure 3: 1. Before induction; 2. After induction; 3. Five minutes later after entubation; 4. After skin incision; 5. After sternotomy; 6. During left internal mammary artery dissection; 7. At coronary anastomosis; 8. At chest closure; and 9. At skin closure. MAP: Mean arterial pressure.

A total of 4.6±1.2 mg fentanyl and 8.8±2.5 mg remifentanil were used in the groups during the surgery. The amount of midazolam was significantly higher in group R than group F (13.9±3.7 mg vs. 11.6±3.7 mg, respectively; p<0.05), but the intraoperative use of ß blockers, nitroglycerin, and sodium nitroprusside were similar between the two groups (Table 4).

Table 4: Use of opioids, midazolam, and other drugs during the surgery

The median durations of anesthesia, surgery, and bypass were also comparable. The median time to extubation and length of ICU stay were shorter in group R (6.5±3 hours and 10±3 hours, respectively; p<0.05) than in group F (14±6 hours and 20±6 hours, respectively; p<0.05) (Table 2).

The incidence of postoperative ECG changes [atrial fibrillation (AF) in one patient in group R and T-wave changes in the second-fifth vertebrae in another patient in group F) and troponin I measurements were similar between the groups (Figure 4).

Figure 4: Pre- and postoperative troponin-I values.

Nitroglycerin and sodium nitroprusside were needed in 18 patients in group R and 16 in group F postoperatively (p<0.05), and the postoperative side effects, such as nausea, vomiting, emphysema, arrhythmia, convulsions, and reintubation due to hypercarbia, are shown in Table 5.

Table 5: Postoperative complications

Discussion

In the last 20 years, interest in performing CABG without the use of CPB has emerged in order to reduce postoperative complications associated with CPB and aortic manipulation, including generalized systemic inflammation, cerebral injury, myocardial injury, hemodynamic instability, and renal dysfunction. However, the initial enthusiasm over off-pump CABG has decreased with concerns about the completeness of revascularization, the rate of perioperative MI, and long-term graft patency.

As with conventional CABG, the overall goal of off-pump CABG is to preserve hemodynamic stability throughout the surgery while also maintaining an adequate level of anesthesia.

In cardiac surgery, patient comorbidity and periods of hemodynamic instability make it difficult to avoid occasional instances of light anesthesia. Furthermore, unrecognized inadequencies in depth of anesthesia may occur during CPB, which can alter the pharmacokinetics and pharmacodynamics of prescribed medications, resulting in considerable changes in the drug concentrations. In addition, the oxygenator and tubing may bind large amounts of drugs. In addition, there is high risk involved with the rewarming process when restoration of brain normothermia coupled with decreased anesthetic concentrations could result in inadequate depth of anesthesia and potential for awareness.

There are potential limitations associated with processed electroencephalography (EEG) instruments such as the relative unresponsiveness to certain hypnotic agents like opioids, the proclivity of interference from other sources (which affects signal acquisition), the high cost of routine use, the inability to distinguish sleep from anesthetic-induced unconsciousness, and the unvarying nature of the indices (beyond loss of responsiveness) over a wide range of anesthetic drug concentrations. Although these limitations exist, the sensible use of a processed EEG tool like BIS™ to assess depth of anesthesia may help reduce the chances of intraoperative awareness. Vigilance is required, especially during intubation or intense surgical stimulation, instances of hemodynamic instability, and the rewarming phase of CPB.[7]

In our study, the efficacy of remifentanil and fentanyl regarding intraoperative hemodynamic changes, the use of ß-blockers, nitroglycerin, and sodium nitroprusside, extubation time, ICU length of stay, and the impact on perioperative troponin I release was evaluated.

One way to suppress the sympathetic response to a direct laryngoscope and orotracheal intubation is the use of high doses of opioids, but this may cause respiratory depression, indicating the need for long, postoperative ventilatory support. It is understood that remifentanil, with its rapid elimination, is responsible for the depth of analgesia. This leads to the successful prevention of the stress response that forms during procedures such as orotracheal intubation, skin incision, and sternotomy.[8]

Möllhoff et al.,[9] in their study that compared the effectiveness of remifentanil and fentanyl during on-pump CABG found a higher response to tracheal intubation in the group fentanil. Additionally, Mekis et al.[8] reported h igher stability during i ntubation a nd sternotomy with 0.5 mg/kg^-1 remifentanil and propofol compared with 5 μg/kg^-1 fentanyl and propofol.

In adult anesthesia, remifentanil has a reputation for causing cardiovascular instability. Although the administration of a crystalloid solution or a vagolytic drug may minimize the incidence of bradycardia and hypotension, it appears to be more appropriate to use smaller doses of remifentanil.[10] In children, in particular neonates, remifentanil is known to cause bradycardia, but there is not much evidence of this in the pediatric literature. Some authors have suggested parasympathetic activation as a mechanism for bradycardia, but direct negative chronotropic effect and pretreatment with atropine or glycopyrrolate may also play a role in this condition.[11] Shinohara et al.[12] attempted to elucidate the cause of the hemodynamic effects of remifentanil in two groups of anesthetized rabbits using single doses of 1, 2, 5 mg/kg and found that it had a central vagotonic action which caused bradycardia and hypotension; however, it also was responsible for a corresponding increase in sympathetic activity.

In our study, no significant differences were found between the two groups regarding the heart rate and mean arterial pressures related to intubation (p>0.05). We believe this is related to the nitroglycerin added to the induction and the difference in the drug doses and combinations. The mean artery pressure values after the skin incision and sternotomy were lower in group R, but changes in both groups remained within the clinically acceptable rate of 20%. Asystole and serious bradycardia were reported after remifetanil induction during cardiac surgery and simultaneously administered sevoflurane and propofol, but the lack of the use of anticholinergic agents was found to be responsible.[13,14] However, others have proposed that remifentanil has a direct negative chronotropic effect.[15]

The reason for the different results in our study might be that we administered midazolam instead of propofol along with the fact that nitroglycerin increases the heart rate.

Off-pump CABG surgery is associated with hemodynamic changes that result from positioning and stabilizing the heart during distal anastomosis. [16] In addition, vessel occlusion associated with the distal anastomosis may cause ischemia, which may add to the hemodynamic changes. Several possible treatment methods can be used to counteract the hemodynamic changes during off-pump CABG surgery. Volume loading is helpful for increasing the preload. Additionally, placing the patient in the Trendelenburg position with the feet raised by 20-30° is also beneficial, both for increasing the preload and for assisting in cardiac displacement. The use of inotropes, vasopressors during grafting, and nitroglicerin for ischemia are other potential treatment options.

Kessler et al.,[17] compared three different anesthesia techniques used in off-pump CABG surgery in connection with the significant increase in heart rate during coronary anastomoses and discovered that n the general anesthesia group, intravenous esmolol administration was required for seven patients. In our study, no statistically significant difference was found between the two groups in connection with the intraoperatively administered ß-blocker, nitroglycerin, and sodium nitroprusside doses. We did observe that there were more hypnotic (midazolam) drugs needed in the group R from the induction of anesthesia until the completion of the operation in order to maintain the same BIS™ values. This may be because the remifentanil had less of an effect on the change in the BIS™ than the fentanyl. Similarly, there were no significant differences noted between the two groups of patients regarding the need for antihypertensive treatment in the postoperative ICU.

Although anesthesia affects cardiac surgery patients postoperatively, the therapeutic strategies used during this period are the primary factors that determine the extubation time and length of ICU stay. A significant difference was observed between the duration in ICU in both groups in connection with the mean extubation periods, and shorter ICU stays were seen in the group R. There were no significant differences between the groups with regard to gender and age, and no patient needed intraoperative or postoperative inotropic agents. Both anesthetic regimes were well tolerated in our study, and similar postoperative complications were seen in the two groups (35% in group R and 30% in group F).

The hemodynamic changes that occur with displacement and stabilization of the heart often happen within seconds and end within five minutes; however, progressive decreases in systemic pressure may occur from ischemia during distal anastomosis. Typically, some degree of new-onset ST-segment elevation or depression can be found. Bein et al.[18] reported echocardiographic evidence of preserved myocardial function with sevoflurane in patients undergoing minimal invasive bypass surgery. Furthermore, Hemmerling et al.[19] recently compared isoflurane and sevoflurane and concluded that both the agents provided similar myocardial protection during off-pump CABG. In one study.[20] sevoflurane or propofol was administered to maintain the BIS™ between 40 and 60, but a cardioprotective effect could not be demonstrated since the cardiac troponin I levels and hemodynamics were comparable in both groups. Similar to the results of the Law-Koune et al.[21] study in which they compared the myocardial protective effects of the sevoflurane/remifentanil and propofol/ remifentanil anesthesia techniques associated with BIS™ in off-pump CABG surgery, we did not find any differences related to the troponin I levels between the remifentanil and fentanyl groups.

As suggested by Glass et al.[22] we a djusted the hypnotic and analgesic doses according to the BIS™. In this way, we administered the analgesics and anesthetics with equipotent doses in both groups. Due to the small sample size of our groups, the negative cardiac results are open to debate, and wider series and multi-central evaluations are necessary to confirm our findings.

In conclusion, although remifentanil infusion provides better intraoperative hemodynamic stability and postoperative weaning than fentanyl, both agents appear to have similar effects on myocardial injury during off-pump CABG bypass surgery. Therefore, either can be used during off-pump CABG surgery.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

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