Abstract
The objectives of this research were to investigate (a) what was the most effective infusion rate of remifentanil and (b) the degree to which sympathomimetic effects were involved with cardiovascular stimulation by using a power spectral analysis of heart rate variability (HRV). A total of 63 healthy individuals scheduled for sagittal split ramus osteotomy were enrolled and randomly allocated to 1 of 3 groups: remifentanil infusion rate of 0.1, 0.2, or 0.4 μg/kg/min. Anesthesia was maintained with remifentanil and propofol. Before the surgical procedure, 2% lidocaine containing 12.5 μg/mL epinephrine was administered in the surgical field for local anesthesia. Systolic blood pressure (SBP), heart rate (HR), low-frequency (LF) and high-frequency (HF) components in HRV power spectral analysis, and the LF/HF ratio were analyzed. Increases in SBP and HR were observed after local anesthesia in all 3 groups, but no significant differences were observed between the groups. Remifentanil infusion at 0.1 μg/kg/min may be appropriate to minimize cardiovascular stimulation caused by exogenous epinephrine from local anesthesia. Although a rise in the LF/HF ratio was observed after local anesthesia in all groups, no relationship was observed between the cardiovascular changes and the increase in LF/HF ratio. This suggests that sympathomimetic effects are involved to a lesser extent with the cardiovascular stimulation caused by exogenous epinephrine.
Keywords: General anesthesia, Local anesthesia, Power spectral analysis, Heart rate variability, Remifentanil
During oral surgery under general anesthesia, local anesthetics containing epinephrine are frequently used to reduce general anesthetic requirements and bleeding from the surgical field.1 Epinephrine is a sympathomimetic catecholamine that directly stimulates both postsynaptic alpha and beta adrenoreceptors, generally leading to cardiovascular stimulation manifested as increases in heart rate (HR) and blood pressure. Additionally, exogenous epinephrine has been reported to stimulate the sympathetic nervous system by enhancing the secretion of endogenous norepinephrine through presynaptic beta-adrenoceptor–mediated positive feedback mechanisms.2,3 Therefore, the cardiovascular stimulation noted following epinephrine administration may be attributable in part to this feedback loop. Excessive cardiovascular stimulation can have deleterious effects in some patients, particularly those with hypertension and other underlying cardiovascular diseases.4
Remifentanil is an ultrashort-acting full opioid agonist that is widely used in general anesthesia and can exhibit sympatholytic effects.5,6 If cardiovascular stimulation due to exogenous epinephrine is mostly caused by its direct actions on postsynaptic adrenergic receptors, remifentanil might have little effects on these actions. In contrast, if cardiovascular stimulation due to exogenous epinephrine is to some extent caused by its indirect sympathomimetic effects, remifentanil could reduce these actions. Although current literature includes various studies on the cardiovascular effects of epinephrine or remifentanil alone,7–10 there is no study about the interactions between epinephrine and remifentanil at the dosages commonly used during anesthesia. A better understanding of the most effective infusion rate for remifentanil could help to reduce the risk of complications caused by exogenous epinephrine during surgery and avoid administration of excessive amounts of remifentanil.
This study therefore used a power spectral analysis of HR variability (HRV) to investigate (a) what is the most effective infusion rate of remifentanil and (b) the degree to which sympathomimetic effects are involved in cardiovascular stimulation after epinephrine administration. In this study, we used power spectral analysis of HRV to evaluate autonomic nervous activity. HRV is widely used as an indicator of autonomic nervous system function, and by assessing HRV it is possible to perform continuous and quantitative analysis of sympathetic and parasympathetic nervous system activity by analyzing the RR interval variability of the electrocardiogram.11,12 The low-frequency component (LF; 0.04–0.15 Hz) was used as an indicator of sympathetic and parasympathetic nervous system activity, and the high-frequency component (HF; 0.15–0.4 Hz) was used as an indicator of parasympathetic nervous system activity; the LF/HF ratio was calculated and used as an indicator of sympathetic nervous system activity.
METHODS
This study was approved by the Ethics Committee of Tokyo Dental College (Approval No. 804). Patients scheduled for a bilateral sagittal split ramus osteotomy under general anesthesia at Tokyo Dental College Suidobashi Hospital between September 2017 and August 2018 were enrolled in the study. Of the patients classified as American Society of Anesthesiologists physical status 1 or 2, 63 patients and/or their parents provided written informed consent to participate in this study. Exclusion criteria included patients with hypotension or bradycardia >20% of baseline values (as obtained prior to induction) after induction of general anesthesia and administration of local anesthetic. Patients taking medications that directly impact the cardiovascular system (ie, beta-blockers) were also excluded. Figure 1 shows the study protocol. Before general anesthesia was induced, standard anesthetic monitors (noninvasive automated sphygmomanometer, pulse oximetry, electrocardiogram, capnograph, and bispectral index [BIS]) were applied. Electrodes for HRV power spectral analysis were placed on the skin located at the thyroid cartilage and at the fourth intercostal space bilaterally. The electrocardiogram waveforms obtained were imported into a real-time HRV analysis program (MemCalc/Tarawa, GMN Company, Japan).13,14
Figure 1.
Schema of experimental protocol.
General anesthesia was induced without any preoperative sedative medications using a remifentanil continuous infusion at 0.2 μg/kg/min after preoxygenating the patients with oxygen (6 L/min) via face mask. After 5 min, a 2 mg/kg bolus dose of propofol (1% Diprivan Injection-kit, Aspen Japan Company, Japan) was administered, followed by a continuous infusion of propofol at 8.0 mg/kg/h (133mcg/kg/min) for anesthesia maintenance. The propofol infusion was adjusted to maintain BIS values between 40 and 60. The patients were intubated following muscle relaxation with a 0.6–0.8 mg/kg bolus of rocuronium (Rocuronium Bromide Intravenous Solution, Maruishi Pharmaceutical Company). The remifentanil infusion rates were adjusted to 0.1, 0.2 or 0.4 μg/kg/min based on randomly allocated group assignment that was performed using a random number table. Pressure-controlled ventilation was used with a tidal volume of 6–8 mL/kg, a respiratory rate of 12 breaths per min, and a positive end expiratory pressure of 3 cm H2O to maintain an end-tidal CO2 (ETCO2) of 40 ± 5 mmHg during general anesthesia. Thirty minutes after tracheal intubation and confirming BIS values were maintained at 40–60 and blood pressure and HR were stable, 2% lidocaine with 1:80,000 epinephrine was administered around the mandibular ramus via infiltration anesthesia and inferior alveolar nerve blocks. The following measurements were taken before local anesthesia (baseline), immediately after local anesthesia, and at 1, 3, and 5 min after local anesthesia: systolic blood pressure (SBP), HR, SpO2, BIS value, ETCO2, LF and HF components in HRV power spectral analysis, and the LF/HF ratio. The mean values of the LF and HF components and the LF/HF ratio over the 30-second period before and after the 5 measurement points described above were used for HRV power spectral analysis. The change at each measurement point compared with its baseline value was calculated as the value at each measurement point divided by the baseline value. SBP and HR after local anesthesia were observed at 4 measurement points, and we adopted their maximum values for statistical analysis. LF and HF values at that time were also used for the analysis.
Data are expressed as mean ± SD. The SPSS software (version 20) was used for statistical analyses. Student's t test was used to compare blood pressure and HR changes caused by epinephrine as compared to baseline. One-way analysis of variance was used to compare the circulatory changes among 3 groups. Single regression analysis was used to investigate whether sympathetic nervous system activity was involved in increases in HR and blood pressure. A p value <.05 was considered statistically significant.
An a priori power analysis was performed using G*Power version 3.1.9.2. The sample size for SBP change at 0.1 μg/kg/min remifentanil was calculated, using an α error = .05, a β error = .2, and an estimated effect size of 0.5 established by data from our pilot study, producing a minimum requirement of 34 patients per group.
RESULTS
Sixty-three patients were included in this study. Because 15 patients demonstrated hypotension or bradycardia more than 20% of blood pressure or HR before local anesthesia administration, these patients were excluded from the study. Of these 15 patients, 6 required additional treatment, including vasoactive agents.
Demographic data from the remaining 48 patients as grouped by their assigned study cohort were included in the analysis (Table 1). Mean age was 28.9 ± 11.2 years, and there were 14 males and 34 females. No significant differences were observed between the 3 groups for any of the demographic or local anesthetic variables, including epinephrine total dose and epinephrine dose per body weight.
Table 1.
Demographic and Local Anesthetic/Epinephrine Data*
|
0.1 μg/kg/min Group |
0.2 μg/kg/min Group |
0.4 μg/kg/min Group |
|
| No. of patients (No. male/No. female) | 17 (6/11) | 16 (3/13) | 15 (5/10) |
| Age, y | 30.6 ± 12.0 | 29.8 ± 11.7 | 26.1 ± 9.1 |
| Body weight, kg | 63.0 ± 16.0 | 57.3 ± 10.8 | 54.9 ± 10.4 |
| Local anesthetic volume, mL | 9.1 ± 2.0 | 9.3 ± 1.2 | 8.9 ± 1.0 |
| Epinephrine total dose, μg | 113.75 ± 25 | 116.25 ± 15 | 111.25 ± 12.5 |
| Epinephrine dose/body weight, μg/kg | 2.0 ± 0.5 | 2.1 ± 0.4 | 2.1 ± 0.5 |
| Administration time, s | 104.6 ± 47.0 | 102.7 ± 29.5 | 99.5 ± 39.8 |
| ETCO2 just before local anesthesia, mm Hg | 36.1 ± 2.1 | 36.7 ± 2.9 | 37.3 ± 2.8 |
Data showed no differences between the 3 groups. ETCO2, end-tidal CO2.
Cardiovascular data (SBP and HR) were analyzed for the 3 groups (Tables 2 and 3). The baseline values in SBP and HR demonstrated no significant difference between the 3 groups. After local anesthetic administration, an increase in SBP and HR was observed in all 3 groups. However, the maximal increases and percentage changes in SBP and HR showed no significant differences between the 3 groups (Tables 2 and 3). No adverse events occurred during the course of the study.
Table 2.
Systolic Blood Pressure (SBP) Data Before and After Local Anesthetic*
|
Group |
Baseline SBP Value, mm Hg |
Highest SBP Value, mm Hg |
Increase in SBP, mm Hg |
Increase in SBP, % |
| 0.1 μg/kg/min | 94.8 ± 8.4 | 104.9 ± 25.1 | 10.1 ± 23.5 | 10.7 ± 2.6 |
| 0.2 μg/kg/min | 88.7 ± 12.1 | 101.6 ± 15.5 | 12.9 ± 11.9 | 15.2 ± 1.5 |
| 0.4 μg/kg/min | 90.7 ± 6.7 | 108.1 ± 15.4 | 17.4 ± 18.1 | 20.0 ± 2.1 |
The baseline values, highest values, maximal increases, and percentage changes in SBP showed no differences between the 3 groups.
Table 3.
Heart Rate (HR) Data Before and After Local Anesthetic*
|
Group |
Baseline HR Value, beats/min |
Highest HR Value, beats/min |
Increase in HR, beats/min |
Increase in HR, % |
| 0.1 μg/kg/min | 63.5 ± 13.9 | 76.1 ± 14.8 | 12.5 ± 9.3 | 12.1 ± 1.8 |
| 0.2 μg/kg/min | 58.9 ± 8.2 | 70.4 ± 10.8 | 11.5 ± 6.6 | 11.9 ± 1.0 |
| 0.4 μg/kg/min | 60.9 ± 11.5 | 69.4 ± 9.8 | 8.6 ± 8.8 | 11.5 ± 1.2 |
The baseline values, highest values, maximal increases, and percentage changes in SBP showed no differences between the 3 groups.
Similar results were obtained in HF and LF. Increases in the highest LF/HF ratio (indicator of sympathetic activity) compared to baseline were observed in all patients after local anesthetic administration in all 3 groups. However, no relationship was observed between increases in the LF/HF ratio and increases in SBP or HR (Figures 2 and 3). Increases in the highest HF value (indicator of parasympathetic activity) compared to baseline were observed in all patients after local anesthetic administration in all 3 groups. However, no relationship was observed between increases in HF value and increases in SBP or HR (Figures 4 and 5). Increases in the highest LF value (indicator of sympathetic and parasympathetic activity) compared to baseline were observed in all patients after local anesthetic administration in all 3 groups. However, no relationship was observed between increases in LF value and increases in SBP or HR (Figures 6 and 7).
Figure 2.
Relationship between percentage changes in low-frequency/high-frequency (LF/HF) ratio and percentage changes in systolic blood pressure (SBP). The LF/HF ratio rose after local anesthetic administration in all 3 groups, but no relationship between these values and percentage changes in SBP was observed. X axis: percentage changes in highest LF/HF ratio compared to baseline value. Y axis: percentage changes in highest SBP compared to baseline value.
Figure 3.
Relationship between percentage changes in low-frequency/high-frequency (LF/HF) ratio and percentage changes in heart rate (HR). The LF/HF ratio rose after local anesthetic administration in all 3 groups, but no relationship between these values and percentage changes in HR was observed. X axis: percentage changes in highest LF/HF ratio compared to baseline value. Y axis: percentage changes in highest HR compared to baseline value.
Figure 4.
Relationship between percentage changes in high-frequency (HF) values and percentage changes in systolic blood pressure (SBP). HF rose after local anesthetic administration in all 3 groups. No correlation was observed between these values and percentage changes in SBP. X axis: percentage changes in highest HF compared to baseline value. Y axis: percentage changes in highest SBP compared to baseline value.
Figure 5.
Relationship between percentage changes in high-frequency (HF) values and percentage changes in heart rate (HR). HF rose after local anesthetic administration in all 3 groups. No correlation was observed between these values and percentage changes in HR. X axis: percentage changes in highest HF compared to baseline value. Y axis: percentage changes in highest HR compared to baseline value.
Figure 6.
Relationship between percentage changes in low-frequency (LF) values and percentage changes in systolic blood pressure (SBP). LF rose after local anesthetic administration in all 3 groups, but no correlation was observed between these values and percentage changes in SBP. X axis: percentage changes in highest LF compared to baseline value. Y axis: percentage changes in highest SBP compared to baseline value.
Figure 7.
Relationship between percentage changes in low-frequency (LF) values and percentage changes in heart rate (HR). LF rose after local anesthetic administration in all 3 groups, but no correlation was observed between these values and percentage changes in HR. X axis: percentage changes in highest LF compared to baseline value. Y axis: percentage changes in highest HR compared to baseline value.
DISCUSSION
We investigated (a) what was the most effective infusion rate of remifentanil and (b) the degree to which sympathomimetic effects were involved in cardiovascular stimulation after exogenous epinephrine administration. The results show that all 3 infusion rates of remifentanil tested (0.1, 0.2, and 0.4 μg/kg/min) revealed similar effects on the increases in HR and blood pressure attributed to exogenous epinephrine. Moreover, no relationship was found between the increases in SBP and HR and the increase in LF/HF ratio. These results suggest that cardiovascular stimulation caused by exogenous epinephrine may be mostly due to direct cardiovascular effects rather than a response mediated by autonomic nervous system activation.2,3,7 This may be why the administration of remifentanil, which has sympatholytic effects, was unable to suppress the cardiovascular stimulation caused by epinephrine. We also observed an increase in parasympathetic nervous system activity as evident by the increase in HF values after local anesthetic administration. This increase in parasympathetic activity may be a response of the body's homeostatic mechanisms to normalize the increased circulatory effects of exogenous epinephrine. This suggests that the cardiovascular stimulation following administration of local anesthesia with epinephrine may not be simply due to the action of epinephrine on the sympathetic nerves.
HRV is not only determined by HR, but is also influenced by concomitant diseases like coronary artery disease, drugs that act directly on the cardiovascular system, respiratory rate, and the depth of anesthesia and the level of analgesia.15 With the HF component, the involvement of effects from respiratory variability on cardiovagal activity means that the HF component is affected by the respiratory rate and tidal volume.14 Furthermore, CO2 directly dilates peripheral capillary arteries and simultaneously stimulates the sympathetic nerves in the central nervous system.16 In this study, no differences in ETCO2 were observed between the 3 groups, as ventilation was kept constant during local anesthetic administration and therefore should have had little effect on the results. BIS values were used to help standardize anesthetic depth between patients prior to local anesthesia administration, so the depth of anesthesia likely had little impact on HRV. Finally, patients taking other medications that directly affect the cardiovascular system were excluded from this study, so this likely did not impact the study results.
In this study, there were no differences in suppression of cardiovascular stimulation caused by exogenous epinephrine with the range of remifentanil infusion rates tested (0.1–0.4 μg/kg/min). Ideally, the study would have included a control group of patients who were not given remifentanil to clarify the degree to which sympathomimetic effects are involved in cardiovascular stimulation following epinephrine administration. However, the study design involved a total intravenous anesthesia technique using propofol and remifentanil for the maintenance of anesthesia, so the ethics committee would not have approved research on a group where remifentanil was not given. For this reason, it was not possible to truly determine if remifentanil could control cardiovascular stimulation because of the administration of epinephrine. However, at the range of remifentanil infusion rates used in this study, the degree of cardiovascular stimulation remained within +20% of baseline values for SBP and HR and is likely of little clinical importance.17,18 Therefore, it is possible that an infusion rate of remifentanil at 0.1 μg/kg/min may be appropriate for minimizing cardiovascular stimulation caused by exogenous epinephrine as routinely used in oral and maxillofacial surgery. Moreover, the results suggest that use of the high remifentanil infusion rate of 0.4 μg/kg/min for the purpose of suppressing cardiovascular stimulation due to exogenous epinephrine is unnecessary. However, increased infusion rates of remifentanil may be necessary to counter nociceptive surgical stimuli. Accordingly, infusion rates should be adjusted to suit the specific perioperative conditions.
This study was initially designed with a sample size of n = 34 in each group (α = 0.05, β = 0.8), based on data from our preliminary study. However, once we had collected data from 48 patients total, it became clear that any relationship between autonomic nervous activities, as evaluated from HRV power spectral analysis, and increases in HR and blood pressure was unlikely to be found. Thus, we concluded that obtaining any beneficial results would be unlikely even with a higher number of patients, so data collection was discontinued at that point.
There are a number of limitations with our research. First, propofol exhibits parasympathomimetic effects as well as sympatholytic effects,19 and we cannot rule out the possibility that propofol had an effect on the increase in HF values after epinephrine administration. However, in this study, propofol was continuously infused at a constant rate during the research period, and if there were any effects, they were probably minor. Because propofol would antagonize the sympathomimetic effects of epinephrine both directly through its sympatholytic action and indirectly through its parasympathomimetic action, the interactions between epinephrine and propofol are complex and additional animal studies and other research are needed for a more detailed analysis. Second, blood flow in the oral mucosa can be affected by the general anesthetics used.20 Based on the results from this study, it remains unclear whether the effects of local anesthetics containing epinephrine on autonomic function administered under propofol-remifentanil anesthesia are applicable to situations in which inhalation anesthesia is used. Third, because the patients enrolled in this study were all healthy adults, it is unclear whether similar outcomes would be obtained for autonomic activity in response to local anesthetics containing epinephrine administered in other situations, such as in the elderly, diabetics, patients taking beta-blocking or parasympatholytic agents, or those with hypovolemia and/or hypothermia. We have not investigated whether similar results would be obtained with different methods of anesthesia or in patients with different backgrounds, which illustrates potential areas for further investigation.
CONCLUSION
In conclusion, there was no difference in the degree of cardiovascular stimulation caused by exogenous epinephrine administration with the infusion rates of remifentanil used in this study. Remifentanil infusion at 0.1 μg/kg/min may be appropriate to minimize cardiovascular stimulation caused by exogenous epinephrine, as is common in oral and maxillofacial surgery. No relationship was observed between the hemodynamic changes and the increase in LF/HF ratio. These results suggest that the sympathomimetic effects are involved to a lesser extent for the cardiovascular stimulation caused by exogenous epinephrine.
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