- Email: [email protected]
Small Bolus of Esmolol Effectively Prevents Sodium Nitroprusside-Induced Reflex Tachycardia Without Adversely Affecting Blood Pressure
ANESTHESIA/FACIAL PAIN J Oral Maxillofac Surg 70:1045-1051, 2012
Small Bolus of Esmolol Effectively Prevents Sodium Nitroprusside-Induced Reflex Tachycardia Without Adversely Affecting Blood Pressure Hiroshi Hanamoto, DDS, PhD,* Mitsutaka Sugimura, DDS, PhD,† Yoshinari Morimoto, DDS, PhD,‡ Chiho Kudo, DDS, PhD,§ Aiji Boku, DDS, PhD,储 and Hitoshi Niwa, DDS, PhD¶ Purpose: Hypotensive anesthesia with sodium nitroprusside (SNP) often is associated with reflex
tachycardia. The purpose of this study was to investigate whether a small bolus of esmolol could counteract SNP-induced reflex tachycardia and sympathetic activation without affecting blood pressure. Materials and Methods: Using a time-series study design, 27 healthy young patients scheduled for mandibular osteotomy were enrolled in this study. General anesthesia was maintained with 2% sevoflurane and 67% nitrous oxide in oxygen. SNP was administered to decrease the mean arterial pressure to 55 to 65 mm Hg. When heart rate (HR) increased reflexively to higher than 95 beats/min from SNP-induced hypotension, esmolol 0.5 mg/kg was given. Blood pressure and HR were measured, and the low-frequency component (0.04 to 0.15 Hz) of systolic blood pressure variability and high-frequency component (0.15 to 0.4 Hz) of HR variability were calculated to evaluate the autonomic condition. Data were analyzed using 1-way analysis of variance after multiple comparisons or t test. P ⬍ .05 was considered statistically significant. Results: Of the 27 patients analyzed, 19 patients (70%) required esmolol. In these patients, SNP caused an increase in the low-frequency component of systolic blood pressure variability and a decrease in the high-frequency component of HR variability, leading to tachycardia (HR range, 95.9 ⫾ 7.3 to 106.7 ⫾ 7.4 beats/min; P ⬍ .001). Esmolol suppressed the effects of SNP on the low-frequency component of systolic blood pressure variability and high-frequency component of HR variability, resulting in an immediate decrease in HR to 86.9 ⫾ 6.2 beats/min (P ⬍ .001), whereas mean arterial pressure remained unchanged. Conclusions: A small bolus of esmolol can suppress reflex tachycardia without significantly changing mean arterial pressure. Thus, esmolol restores the autonomic imbalance induced by SNP during hypotensive anesthesia. © 2012 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 70:1045-1051, 2012
During general anesthesia for orthognathic surgery, induced hypotension is often used to decrease bleeding and provide a satisfactory bloodless surgical field.1 For this purpose, various drugs, such as systemic vasodilators, ganglionic blockers, and -adrenergic Received from the Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Osaka, Japan. *Assistant Professor. †Associate Professor. ‡Associate Professor. §Assistant Professor. 储Clinical Fellow. ¶Professor.
blockers, are administered to achieve the desired hypotensive state. Sodium nitroprusside (SNP), an intense vasodilator, is one of the most widely used agents because of its rapid onset and short duration of depressor effect.2-4 Although other vasodilators or Address correspondence and reprint requests to Dr Hanamoto: Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, 1-8 Yamada-Oka, Suita, Osaka, 5650871 Japan; e-mail: [email protected] © 2012 American Association of Oral and Maxillofacial Surgeons
0278-2391/12/7005-0$36.00/0 doi:10.1016/j.joms.2011.12.036
1045
1046 remifentanil have been used to induce hypotension, SNP remains useful and effective. However, SNP-induced hypotension is often associated with reflex tachycardia. The rapid decrease in blood pressure (BP) because of SNP activates baroreceptor-mediated responses. Activation of the sympathetic nervous and renin-angiotensin systems could be involved in this reflex tachycardia and in tachyphylaxis and rebound hypertension.5 Previous studies have shown that SNP-induced hypotension causes an increase in plasma levels of catecholamines, renin, and vasopressin.6,7 Severe reflex tachycardia during induced hypotension can make control of BP more difficult, resulting in an increase in the SNP requirements to adequately maintain the desired hypotension. Furthermore, reflex tachycardia may adversely affect the myocardial oxygen supply and demand balance. Khambatta et al8,9 stated that premedication with oral propranolol is safe and effective in suppressing SNP-induced reflex tachycardia because it attenuates the release of catecholamines and renin induced by SNP-induced hypotension. Apipan et al10 also reported the efficacy of oral propranolol. However, a single oral dose of propranolol has a fixed onset and duration of action, which may limit the period of induced hypotension anesthesia. In contrast, propranolol may remain active even after the operation because of its prolonged duration of action. A residual -blockade in the postoperative period might mask the tachycardia that is indicative of hypovolemia or hypoxemia. Moreover, not all patients who have SNPinduced hypotension develop reflex tachycardia.11 Therefore, it is not a rational strategy to administer an oral premedication with propranolol to all patients scheduled for SNP-induced hypotension. Esmolol is an ultrashort-acting -adrenergic receptor blocking drug with rapid onset and a short duration of action.12 Many studies have reported the efficacy of continuous intravenous esmolol for reflex tachycardia during SNP-induced hypotension.5,13 According to those studies, esmolol infusion can counteract the reflex tachycardia and tachyphylaxis from SNP and decrease the SNP requirement during induced hypotension. A decrease in the dose requirements of SNP decreases the risk of adverse effects such as cyanide toxicity. However, the autonomic effects of esmolol during SNP-induced hypotension are still unclear. In this study, the autonomic effects of a small bolus dose of esmolol on reflex tachycardia were explored by analyzing BP and heart rate (HR) variability to assess the autonomic status. Although plasma catecholamine concentration is a useful index of sympathetic activity, it is not as sensitive to rapid changes in sympathetic activity. Hence, spectral analyses of BP and HR variability were used in the present study. The
ESMOLOL AND SNP-INDUCED REFLEX TACHYCARDIA
low-frequency component of systolic BP (SBP-LF) and high-frequency component of HR (HR-HF) are reliable indexes of sympathetic and parasympathetic activity, respectively. An increase in SBP-LF indicates an increase in sympathetic tone, whereas a decrease in HR-HF indicates a decrease in parasympathetic tone. The purpose of this study was to investigate the hemodynamic and autonomic nervous system effects of a small bolus of esmolol on SNP-induced reflex tachycardia by analyzing HR and BP variabilities. The investigators hypothesized that a small bolus of esmolol could counteract SNP-induced reflex tachycardia and excessive sympathetic activation without affecting BP. The specific aims of this study were to 1) investigate the incidence of reflex tachycardia resulting from SNP-induced hypotensive anesthesia; 2) identify predisposing factors for the development of tachycardia; and 3) estimate the effects of esmolol by measuring HR, mean arterial pressure (MAP), SBP-LF, and HR-HF.
Materials and Methods STUDY DESIGN
To address the research purpose, the investigators designed and implemented a study to evaluate the hemodynamic and autonomic nervous system effects of esmolol on reflex tachycardia resulting from SNPinduced hypotensive anesthesia. The study population was composed of all patients presenting to the authors’ hospital for the evaluation and management of jaw deformity and who were scheduled for elective mandibular osteotomy from January 2007 through April 2008. To be included in the study sample, patients had to be Class I on the American Society of Anesthesiologists’ Physical Status Scale and have no medical complications. Patients were excluded as study subjects if their BP was low and SNP was not required. This study was performed according to the Declaration of Helsinki and approved by the institutional review board and ethical committee of Osaka University Dental Hospital. Written informed consent was obtained from all patients. STUDY PROTOCOL
As preanesthetic medication, atropine sulfate 0.01 mg/kg and meperidine (pethidine) hydrochloride 1 mg/kg were intramuscularly injected 20 minutes before the induction of anesthesia. Anesthesia was induced with thiamylal sodium 5 mg/kg followed by vecuronium bromide 0.1 mg/kg to facilitate nasotracheal intubation. Anesthesia was maintained with 66% nitrous oxide and sevoflurane at an end-tidal concentration of 2% in oxygen. Ventilator settings were adjusted to maintain the end-tidal carbon diox-
1047
HANAMOTO ET AL
ide pressure from 30 to 35 mm Hg, with a respiratory rate of 12 breaths/min and an inspiratory/expiratory ratio of 1:2. After anesthetic induction, a 22-gauge indwelling catheter was placed in the dorsalis pedis artery for continuous monitoring of arterial blood pressure. Local anesthesia, in the form of 1% lidocaine 20 mL with 1:100,000 epinephrine, was administered by the surgeon 5 minutes before the start of the operation to decrease the primary afferent nociception owing to the surgical procedure. In the authors’ hospital, some trainee oral-maxillofacial surgeons take longer than usual to perform operations and sometimes there is unexpected blood loss. Hence, although mandibular osteotomies do not usually bleed as much as maxillary osteotomies, the authors routinely provide hypotensive anesthesia for mandibular and maxillary osteotomies. Induced hypotension was commenced 15 minutes before incision of the mandibular bone and was continued until closure of the mandibular mucosa. SNP infusion was initiated at a rate of 0.5 g/kg/min and titrated to maintain the MAP at 55 to 65 mm Hg. The adequacy of urine output was monitored during the hypotensive period, although the authors have no data of the exact amounts of urine output during the hypotensive period. When the HR exceeded 95 beats/ min, esmolol 0.5 mg/kg was administered and patients were included in the esmolol (ESM) group.14 If the HR did not decrease to below 95 beats/min after the initial administration of esmolol or it increased again to above 95 beats/min during hypotensive anesthesia, an additional dose of esmolol (0.5 mg/kg) was administered. The patients with an HR that did not exceed 95 beats/min after SNP administration were not given esmolol and were analyzed as the non-ESM group. DATA COLLECTION METHODS
Continuous arterial pressure and electrocardiographic waveforms were measured and digitalized at 1,000 Hz (IntelliVue MP50, Philips, the Amsterdam, Netherlands). Artifact-free digitalized signals were stored on a personal computer for later analysis. The fast peak of R waves on electrocardiograms was detected and RR intervals were measured. Peak values of SBP were analyzed with commercially available software (Fluclet, Dainippon Sumitomo Pharmaceutical Co Ltd, Suita, Japan), where 2 frequency bands were automatically separated: a low-frequency band (LF; 0.04 to 0.15 Hz) and a high-frequency band (HF; 0.15 to 0.4 Hz). During the previous 10 years, continuous attempts have been made to measure the activity of the autonomic nervous system using power spectral analysis of BP and beat-to-beat interval fluctuations.15 Recently, power spectral analysis of HR variability and
BP variability have been widely used as noninvasive methods for quantifying autonomic function. In this study, the wavelet method was used to analyze the spectral power of HR and SBP variability because of its high time resolution.16,17 The wavelet transform (WT) is considered to provide a markedly superior quantitative analysis of cardiovascular variability than the fast Fourier transform during autonomic nervous adaptations induced by external agents or some sort of stress, with 2 main advantages. First, the WT allows a temporally localized sliding analysis of signals using a known function that is called the mother wavelet. When the balance of the autonomic nervous equilibrium is instantaneously modified in clinical situations, such as by the administration of SNP or esmolol, the WT method can be used to assess the status of HR and BP variabilities at any given time point. Second, the shape of the WT analysis equation differs from the fixed sinusoidal shape of the fast Fourier transform and can be customized to fit the shape of the analyzed signal, allowing a better quantitative measurement.16,17 The SBP-LF is a good marker of sympathetic activity because it is sensitive to the sympathetic blockade and is associated with muscle sympathetic nerve activity.18 In contrast, the HR-HF coincides with the respiratory frequency and primarily reflects respiration-linked variations in the HR resulting from centrally mediated cardiac vagus control. STUDY VARIABLES
In this study, the primary predictor variable was esmolol exposure. The outcome variables measured were HR, MAP, SBP-LF, and HR-HF. These outcome variables were measured at 3 time points: baseline (5 min before SNP administration), 10 minutes after a stable level of SNP-induced hypotension (MAP, 55 to 65 mm Hg), and 1 minute after the administration of esmolol. All measurements were made before the osteotomy because it is a highly invasive surgical procedure that could influence the condition of the autonomic nervous system. The third category of variables studied were demographic and perioperative variables. Demographic variables included gender, age, height, weight, and body mass index; and perioperative measurements included anesthesia time, surgical time, blood loss volume, infusion volume, and SNP infusion rate. STATISTICAL ANALYSES
Data are expressed as mean ⫾ standard deviation. Statistical analysis was performed with the SPSS software package (SPSS Inc, Chicago, IL). Gender was analyzed statistically by the 2 test. Other demographic data were analyzed by the unpaired t test. The MAP, HR, SBP-LF, and HR-HF were analyzed statistically using 1-way analysis of variance for repeated
1048
ESMOLOL AND SNP-INDUCED REFLEX TACHYCARDIA
measures followed by the Tukey test to adjust for multiple comparisons or the paired t test. Statistical comparisons between groups were assessed using the unpaired t test. A P value less than .05 was considered statistically significant.
Results Of 30 patients initially included in the study, 3 patients were excluded because their MAP decreased to approximately 55 to 65 mm Hg with 2% sevoflurane and nitrous oxide alone. Hence, they did not require SNP-induced hypotension. Table 1 presents the clinical characteristics and procedural summary of the remaining 27 patients. They were given SNP and were divided into 2 groups based on their HR response to SNP. Nineteen patients whose HR increased to above 95 beats/min with SNP administration were given esmolol (ESM group). Eight patients whose HR was 95 beats/min or less were not given esmolol (non-ESM group). There were no differences in demographic data, surgical and anesthesia times, blood loss, and mean infusion rate of SNP between the 2 groups. Table 2 presents the hemodynamic and autonomic variables in the 2 groups. There were no significant differences in the baseline levels of MAP and SBP-LF between the 2 groups. However, the baseline values of HR and HR-HF were higher and lower, respectively, in the ESM group than in the non-ESM group. This finding suggests that the non-ESM group had a para-
Table 1. CLINICAL CHARACTERISTICS AND PROCEDURAL SUMMARY OF THE 27 PATIENTS
Esmolol Exposure Variable
Yes (ESM group)
No (non-ESM group)
Patients (n) 19 8 Male/female patients 6/13 3/5 Age (yrs) 21.9 ⫾ 3.3 24.9 ⫾ 7.6 Height (cm) 163.4 ⫾ 9.8 161.8 ⫾ 5.7 Weight (kg) 56.0 ⫾ 10.4 57.4 ⫾ 9.8 Body mass index 20.9 ⫾ 2.9 21.9 ⫾ 3.2 (kg/m2) Anesthesia time 246 ⫾ 77 270 ⫾ 62 (min) Surgical time (min) 174 ⫾ 83 186 ⫾ 55 Blood loss (mL) 363 ⫾ 254 426 ⫾ 328 Infusion volume (mL) 1997 ⫾ 577 2306 ⫾ 643 SNP infusion rate 0.72 ⫾ 0.29 0.61 ⫾ 0.31 (g/kg/min)
P Value
— .776 .319 .664 .751 .426 .452 .719 .595 .230 .417
Note: Data represent number of patients or mean ⫾ standard deviation. Abbreviation: SNP, sodium nitroprusside. Hanamoto et al. Esmolol and SNP-Induced Reflex Tachycardia. J Oral Maxillofac Surg 2012.
sympathetic predominance compared with the ESM group. SNP decreased the MAP to a similar extent in the 2 groups. However, SNP caused a greater increase in HR (106.7 ⫾ 7.4 beats/min) in the ESM group compared with that in the non-ESM group (87.7 ⫾ 5.7 beats/min). The tachycardia in the ESM group was associated with an increased SBP-LF and a decreased HR-HF, with the increase in SBP-LF indicating an increase in sympathetic tone and a decrease in HR-HF indicating a decrease in parasympathetic tone. There were significant differences in SBP-LF and HR-HF between the 2 groups. Esmolol was given to 19 of 27 patients (ESM group). The increased HR after SNP administration decreased to 86.9 ⫾ 6.2 beats/min with esmolol without a significant change in the MAP. Esmolol attenuated the increased SBP-LF and restored the decreased HR-HF to baseline values. Ten patients in the ESM group required additional doses of esmolol at intervals of 15 to 20 minutes.
Discussion The purpose of this study was to investigate the hemodynamic and autonomic nervous system effects of a small bolus of esmolol on SNP-induced reflex tachycardia, using HR and BP variability, and to confirm the hypothesis that a small bolus of esmolol could counteract SNP-induced reflex tachycardia and excessive sympathetic activation without affecting BP. The specific aims of this study were to 1) investigate the incidence of reflex tachycardia with SNPinduced hypotensive anesthesia; 2) compare the characteristics of patients with and without reflex tachycardia; and 3) estimate the effects of esmolol by measuring HR, MAP, SBP-LF, and HR-HF. The results of this study confirmed the authors’ hypothesis, suggesting that a small bolus of esmolol can be used effectively to counteract the tachycardia resulting from SNP-induced hypotensive anesthesia without causing any adverse hemodynamic effects. In the present study, reflex tachycardia was observed in about 70% of patients; this means that reflex tachycardia does not always develop with SNP-induced hypotension under sevoflurane anesthesia. Similar results have been reported under halothane anesthesia.11 An increase in SBP-LF indicates an increase in sympathetic tone, whereas a decrease in HR-HF indicates a decrease in parasympathetic tone. Patients with reflex tachycardia (ESM group) had a higher HR and a lower HR-HF than patients in the non-ESM group, even at baseline. This finding suggests that the ESM group might have had a sympathetic dominance under sevoflurane and nitrous oxide anesthesia. Because sevoflurane and nitrous oxide
1049
HANAMOTO ET AL
Table 2. MEAN ARTERIAL PRESSURE, HEART RATE, LOW-FREQUENCY POWER OF SYSTOLIC BLOOD PRESSURE, AND HIGH-FREQUENCY POWER OF RR INTERVAL CHANGES AT EACH TIME POINT
Outcome Variable
Baseline
TSNP
TESM
P Value
72.4 ⫾ 6.0
60.6 ⫾ 3.7
60.2 ⫾ 4.6
No (non-ESM group) Intergroup comparisons (P value) HR (beats/min) Esmolol exposure Yes (ESM group)
68.4 ⫾ 5.8 .118
57.6 ⫾ 3.9 .072
—
⬍.001* ⬍.001† 1‡ .003
95.9 ⫾ 7.3
106.7 ⫾ 7.4
86.9 ⫾ 6.2
No (non-ESM group) Intergroup comparisons (P value) SBP-LF (mm Hg/Hz½) Esmolol exposure Yes (ESM group)
83.7 ⫾ 5.3 .001
87.7 ⫾ 5.7 ⬍.001
—
0.14 ⫾ 0.10
0.42 ⫾ 0.17
0.25 ⫾ 0.12
No (non-ESM group) Intergroup comparisons (P value) HR-HF (ms/Hz½) Esmolol exposure Yes (ESM group)
0.15 ⫾ 0.14 .729
0.28 ⫾ 0.10 .038
—
1.22 ⫾ 1.53
0.48 ⫾ 0.39
1.08 ⫾ 1.13
No (non-ESM group) Intergroup comparisons (P value)
2.32 ⫾ 1.70 .034
1.62 ⫾ 1.45 .006
—
MAP (mm Hg) Esmolol exposure Yes (ESM group)
⬍.001* ⬍.001† ⬍.001‡ .014
⬍.001* .001† ⬍.001‡ .01
⬍.001* .959† ⬍.002‡ .338
Note: Data are presented as mean ⫾ standard deviation. Abbreviations: baseline, before sodium nitroprusside administration; HR, heart rate; HR-HF, high-frequency (0.15 to 0.4 Hz) component of RR interval; MAP, mean arterial pressure; SBP-LF, low-frequency (0.04 to 0.15 Hz) component of systolic blood pressure; SNP, sodium nitroprusside; TESM, 1 minute after esmolol administration; TSNP, 10 minutes after a stable level of hypotension (mean arterial pressure, 55 to 65 mm Hg). *TSNP versus baseline. †TESM versus baseline. ‡TSNP versus TESM. Hanamoto et al. Esmolol and SNP-Induced Reflex Tachycardia. J Oral Maxillofac Surg 2012.
anesthesia markedly decreases SBP-LF and HR-HF,19 parasympathetic activity, reflected by HR-HF, might have been suppressed to a greater extent in the ESM group. SNP increased SBP-LF in the 2 groups, with a greater increase in the ESM group. In addition, SNP caused a greater decrease in HR-HF in the ESM group. These results suggest that SNP increased sympathetic tone and decreased parasympathetic tone, leading to reflex tachycardia in the ESM group. In contrast, the non-ESM group showed a smaller increase in SBP-LF. The reason for this difference in the autonomic response between the 2 groups in the present study is not known. The autonomic effects of vasodilators have been explored previously. Although SNP has no direct effect on adrenergic receptors, its hypotensive effect causes a reflex increase in sympathetic tone20 and an
increase of SBP-LF21 in awake healthy volunteers. Cloarec et al22 also reported that the sympathetic nervous system is activated during nitroglycerin administration in the awake state. Inhalational anesthetics have an impact on the autonomic nervous system. Sevoflurane and nitrous oxide anesthesia markedly decreases sympathetic and parasympathetic activities.19 However, SNP causes an increase in plasma catecholamine levels during sevoflurane and nitrous oxide anesthesia.23 In the present study, SNP increased SBP-LF, which reflects an increased sympathetic activation. This finding corresponds with a previous study using blood catecholamine levels.23 However, previous studies have not been able to confirm the sympathomimetic effects of other vasodilators, such as nicardipine, nitroglycerin, and prostaglandin E1, during induced hypotension anesthesia.24,25
1050 Beta-adrenergic blockers are commonly used to control tachycardia during SNP-induced hypotension. Previous studies have reported the effectiveness of oral propranolol premedication on reflex tachycardia. However, this method has some disadvantages because of the slow onset and long duration of the action of oral propranolol. Esmolol is a cardioselective intravenous -adrenergic receptor blocking drug with a very rapid onset of action and an extremely short elimination half-life (9 min).12 Esmolol is effective in the management of perioperative hemodynamic responses caused by sympathetic stimulation. Although esmolol can be used alone for the induction of hypotension, its use is associated with marked myocardial depression. Dyson et al26 reported that esmolol 1.5 mg/kg produced an excessive decrease (⬎20%) in SBP. It has been suggested that esmolol may exacerbate the decrease in cardiac output and aggravate cardiac depression when combined with SNP in patients with hypovolemia or heart failure.27 In the present study, a small bolus of esmolol (0.5 mg/kg) was administered for the control of reflex tachycardia during SNP-induced hypotension. Esmolol was able to decrease reflex tachycardia without altering blood pressure during SNP-induced hypotension. The efficacy of esmolol is supported by the evidence from BP and HR variability analyses. Esmolol suppressed the increased SBP-LF and restored the decreased HR-HF. These results reflect the suppression of sympathetic overactivity and restoration of the decreased parasympathetic nervous activity, respectively. Edmondson et al13 stated that esmolol infusion augments induced hypotension by decreasing myocardial contractility, thus enabling a decrease of the SNP dose. In the present study, however, the small bolus dose of esmolol used did not result in a further decrease in the MAP. Hence, the SNP infusion rate could not be decreased. Therefore, the dose of esmolol administered in this study inhibited only reflex tachycardia without causing myocardial depression. A single bolus administration of esmolol is useful and controllable because of its rapid onset and short duration of action. In this study, however, repeated administration of esmolol at intervals of 15 to 20 minutes was required in some patients. This requirement was likely to be dependent on the surgical invasiveness. All patients enrolled in this study were administered atropine sulfate 0.01 mg/kg intramuscularly as preanesthetic medication for its antisialagogue effect. Atropine sulfate is an anticholinergic agent that suppresses parasympathetic activity. Therefore, the autonomic effects of atropine might have influenced the measurements of HR and BP variabilities; this is a
ESMOLOL AND SNP-INDUCED REFLEX TACHYCARDIA
limitation of the present study. For a strict assessment of autonomic parameters, premedication with anticholinergics is undesirable. However, atropine sulfate was used because the study patients were undergoing intraoral surgeries.28 Similarly, all patients were administered meperidine 1 mg/kg intramuscularly 20 minutes before anesthetic induction. Although meperidine has atropine-like effects, these effects would have been small at the time of hypotensive anesthesia, approximately 1 to 2 hours after premedication, because hypotensive anesthesia was commenced 15 minutes before incision of the mandibular bone. All patients were also administered 1% lidocaine 20 mL with 1:100,000 epinephrine as local anesthesia. Although epinephrine has effects on autonomic nervous activities and hemodynamics, the effects are temporary because epinephrine has a short duration of action. Further, the 2 groups of patients included in this study received equal doses of atropine, meperidine, and lidocaine with epinephrine. Hence, although these agents might have had some influence on the autonomic nervous system variables investigated in this study, the main results of this study suggest the beneficial effects of using a small bolus of esmolol in clinical practice. In conclusion, about 70% of patients exhibited reflex tachycardia in response to SNP-induced hypotension. A small dose of esmolol can improve the reflex tachycardia in these patients without changing BP. An increase in SBP-LF indicates an increase in sympathetic tone, whereas a decrease in HR-HF indicates a decrease in parasympathetic tone. Esmolol can suppress SNP-induced excessive sympathetic activation and restore the decreased parasympathetic activation to its original state. Hence, a small bolus of esmolol is useful to counteract the reflex tachycardia of SNPinduced hypotensive anesthesia. Further studies are needed to assess better methods of induced-hypotension anesthesia. Future studies on the efficacy of esmolol in decreasing the tachycardia associated with induced hypotension should be performed without preanesthetic anticholinergic administration to confirm these beneficial effects of esmolol.
References 1. Aken HV, Miller ED: Deliberate hypotension, in Miller RD (ed): Anesthesia (ed 5). New York, Churchill Livingstone, 2000, p 1470 2. Testa LD, Tobias JD: Pharmacologic drugs for controlled hypotension. J Clin Anesth 7:326, 1995 3. Degoute CS: Controlled hypotension: A guide to drug choice. Drugs 67:1053, 2007 4. Friederich JA, Butterworth JF: Sodium nitroprusside: Twenty years and counting. Anesth Analg 81:152, 1995 5. Shah N, Del Valle O, Edmondson R, et al: Esmolol infusion during nitroprusside-induced hypotension: Impact on hemodynamics, ventricular performance, and venous admixture. J Cardiothorac Vasc Anesth 6:196, 1992
HANAMOTO ET AL 6. Zubrow AB, Daniel SS, Stark RI, et al: Plasma renin, catecholamine, and vasopressin during nitroprusside-induced hypotension in ewes. Anesthesiology 58:245, 1983 7. Knight PR, Lane GA, Hensinger RN, et al: Catecholamine and renin-angiotensin response during hypotensive anesthesia induced by sodium nitroprusside or trimethaphan camsylate. Anesthesiology 59:248, 1983 8. Khambatta HJ, Stone JG, Khan E: Propranolol alters renin release during nitroprusside-induced hypotension and prevents hypertension on discontinuation of nitroprusside. Anesth Analg 60:569, 1981 9. Khambatta HJ, Stone JG, Matteo RS, et al: Propranolol premedication blunts stress response to nitroprusside hypotension. Anesth Analg 63:125, 1984 10. Apipan B, Rummasak D: Efficacy and safety of oral propranolol premedication to reduce reflex tachycardia during hypotensive anesthesia with sodium nitroprusside in orthognathic surgery: A double-blind randomized clinical trial. J Oral Maxillofac Surg 68:120, 2010 11. Abdulatif M: Sodium nitroprusside induced hypotension: Haemodynamic response and dose requirements during propofol or halothane anaesthesia. Anaesthesiol Intensive Care 22:155, 1994 12. Wiest D: Esmolol. A review of its therapeutic efficacy and pharmacokinetic characteristics. Clin Pharmacokinet 25:190, 1995 13. Edmondson R, Del Valle O, Shah N, et al: Esmolol for potentiation of nitroprusside-induced hypotension: Impact on the cardiovascular, adrenergic, and renin-angiotensin systems in man. Anesth Analg 69:202, 1989 14. Gold MI, Sacks DJ, Grosnoff DB, et al: Use of esmolol during anesthesia to treat tachycardia and hypertension. Anesth Analg 68:101, 1989 15. Akselrod S, Gordon D, Ubel FA, et al: Power spectrum analysis of heart rate fluctuation: A quantitative probe of beat-to-beat cardiovascular control. Science 13:220, 1981 16. Sugimura M, Hirose Y, Hanamoto H, et al: Influence of acute progressive hypoxia on cardiovascular variability in conscious spontaneously hypertensive rats. Auton Neurosci 141:94, 2008
1051 17. Sugimura M, Hanamoto H, Boku A, et al: Influence of acute hypoxia combined with nitrous oxide on cardiovascular variability in conscious hypertensive rats. Auton Neurosci 156:73, 2010 18. Brychta RJ, Shiavi R, Robertson D, et al: A simplified twocomponent model of blood pressure fluctuation. Am J Physiol Heart Circ Physiol 292:1193, 2007 19. Shin WJ, Kang SJ, Kim YK, et al: Link between heart rate and blood pressure Mayer wave during general anesthesia. Clin Auton Res 21:309, 2011 20. Sanders JS, Mark AL, Ferguson DW: Importance of aortic baroreflex in regulation of sympathetic responses during hypotension. Evidence from direct sympathetic nerve recordings in humans. Circulation 79:83, 1989 21. Schächinger H, Weinbacher M, Kiss A, et al: Cardiovascular indices of peripheral and central sympathetic activation. Psychosom Med 63:788, 2001 22. Cloarec-Blanchard L, Funck-Brentano C, Carayon A, et al: Rapid development of nitrate tolerance in healthy volunteers: Assessment using spectral analysis of short-term blood pressure and heart rate variability. J Cardiovasc Pharmacol 24:266, 1994 23. Yoshikawa F, Kohase H, Umino M, et al: Blood loss and endocrine responses in hypotensive anaesthesia with sodium nitroprusside and nitroglycerin for mandibular osteotomy. Int J Oral Maxillofac Surg 38:1159, 2009 24. Sato J, Saito S, Takahashi T, et al: Sevoflurane and nitrous oxide anaesthesia suppresses heart rate variabilities during deliberate hypotension. Eur J Anaesthesiol 18:805, 2001 25. Kimura T, Ito M, Komatsu T, et al: Heart rate and blood pressure power spectral analysis during calcium channel blocker induced hypotension. Can J Anaesth 46:1110, 1999 26. Dyson A, Isaac PA, Pennant JH, et al: Esmolol attenuates cardiovascular responses to extubation. Anesth Analg 71:675, 1990 27. Takeda S, Masuda R, Kanazawa T, et al: Esmolol attenuates hepatic blood flow responses during sodium nitroprussideinduced hypotension in dogs. Can J Anaesth 51:348, 2004 28. Stoelting RK, Miller RD: Preoperative Medication: Basics of Anesthesia (ed 4). New York, Churchill Livingstone 2000, p 124
Small Bolus of Esmolol Effectively Prevents Sodium Nitroprusside-Induced Reflex Tachycardia Without Adversely Affecting Blood Pressure Hiroshi Hanamoto, DDS, PhD,* Mitsutaka Sugimura, DDS, PhD,† Yoshinari Morimoto, DDS, PhD,‡ Chiho Kudo, DDS, PhD,§ Aiji Boku, DDS, PhD,储 and Hitoshi Niwa, DDS, PhD¶ Purpose: Hypotensive anesthesia with sodium nitroprusside (SNP) often is associated with reflex
tachycardia. The purpose of this study was to investigate whether a small bolus of esmolol could counteract SNP-induced reflex tachycardia and sympathetic activation without affecting blood pressure. Materials and Methods: Using a time-series study design, 27 healthy young patients scheduled for mandibular osteotomy were enrolled in this study. General anesthesia was maintained with 2% sevoflurane and 67% nitrous oxide in oxygen. SNP was administered to decrease the mean arterial pressure to 55 to 65 mm Hg. When heart rate (HR) increased reflexively to higher than 95 beats/min from SNP-induced hypotension, esmolol 0.5 mg/kg was given. Blood pressure and HR were measured, and the low-frequency component (0.04 to 0.15 Hz) of systolic blood pressure variability and high-frequency component (0.15 to 0.4 Hz) of HR variability were calculated to evaluate the autonomic condition. Data were analyzed using 1-way analysis of variance after multiple comparisons or t test. P ⬍ .05 was considered statistically significant. Results: Of the 27 patients analyzed, 19 patients (70%) required esmolol. In these patients, SNP caused an increase in the low-frequency component of systolic blood pressure variability and a decrease in the high-frequency component of HR variability, leading to tachycardia (HR range, 95.9 ⫾ 7.3 to 106.7 ⫾ 7.4 beats/min; P ⬍ .001). Esmolol suppressed the effects of SNP on the low-frequency component of systolic blood pressure variability and high-frequency component of HR variability, resulting in an immediate decrease in HR to 86.9 ⫾ 6.2 beats/min (P ⬍ .001), whereas mean arterial pressure remained unchanged. Conclusions: A small bolus of esmolol can suppress reflex tachycardia without significantly changing mean arterial pressure. Thus, esmolol restores the autonomic imbalance induced by SNP during hypotensive anesthesia. © 2012 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 70:1045-1051, 2012
During general anesthesia for orthognathic surgery, induced hypotension is often used to decrease bleeding and provide a satisfactory bloodless surgical field.1 For this purpose, various drugs, such as systemic vasodilators, ganglionic blockers, and -adrenergic Received from the Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Osaka, Japan. *Assistant Professor. †Associate Professor. ‡Associate Professor. §Assistant Professor. 储Clinical Fellow. ¶Professor.
blockers, are administered to achieve the desired hypotensive state. Sodium nitroprusside (SNP), an intense vasodilator, is one of the most widely used agents because of its rapid onset and short duration of depressor effect.2-4 Although other vasodilators or Address correspondence and reprint requests to Dr Hanamoto: Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, 1-8 Yamada-Oka, Suita, Osaka, 5650871 Japan; e-mail: [email protected] © 2012 American Association of Oral and Maxillofacial Surgeons
0278-2391/12/7005-0$36.00/0 doi:10.1016/j.joms.2011.12.036
1045
1046 remifentanil have been used to induce hypotension, SNP remains useful and effective. However, SNP-induced hypotension is often associated with reflex tachycardia. The rapid decrease in blood pressure (BP) because of SNP activates baroreceptor-mediated responses. Activation of the sympathetic nervous and renin-angiotensin systems could be involved in this reflex tachycardia and in tachyphylaxis and rebound hypertension.5 Previous studies have shown that SNP-induced hypotension causes an increase in plasma levels of catecholamines, renin, and vasopressin.6,7 Severe reflex tachycardia during induced hypotension can make control of BP more difficult, resulting in an increase in the SNP requirements to adequately maintain the desired hypotension. Furthermore, reflex tachycardia may adversely affect the myocardial oxygen supply and demand balance. Khambatta et al8,9 stated that premedication with oral propranolol is safe and effective in suppressing SNP-induced reflex tachycardia because it attenuates the release of catecholamines and renin induced by SNP-induced hypotension. Apipan et al10 also reported the efficacy of oral propranolol. However, a single oral dose of propranolol has a fixed onset and duration of action, which may limit the period of induced hypotension anesthesia. In contrast, propranolol may remain active even after the operation because of its prolonged duration of action. A residual -blockade in the postoperative period might mask the tachycardia that is indicative of hypovolemia or hypoxemia. Moreover, not all patients who have SNPinduced hypotension develop reflex tachycardia.11 Therefore, it is not a rational strategy to administer an oral premedication with propranolol to all patients scheduled for SNP-induced hypotension. Esmolol is an ultrashort-acting -adrenergic receptor blocking drug with rapid onset and a short duration of action.12 Many studies have reported the efficacy of continuous intravenous esmolol for reflex tachycardia during SNP-induced hypotension.5,13 According to those studies, esmolol infusion can counteract the reflex tachycardia and tachyphylaxis from SNP and decrease the SNP requirement during induced hypotension. A decrease in the dose requirements of SNP decreases the risk of adverse effects such as cyanide toxicity. However, the autonomic effects of esmolol during SNP-induced hypotension are still unclear. In this study, the autonomic effects of a small bolus dose of esmolol on reflex tachycardia were explored by analyzing BP and heart rate (HR) variability to assess the autonomic status. Although plasma catecholamine concentration is a useful index of sympathetic activity, it is not as sensitive to rapid changes in sympathetic activity. Hence, spectral analyses of BP and HR variability were used in the present study. The
ESMOLOL AND SNP-INDUCED REFLEX TACHYCARDIA
low-frequency component of systolic BP (SBP-LF) and high-frequency component of HR (HR-HF) are reliable indexes of sympathetic and parasympathetic activity, respectively. An increase in SBP-LF indicates an increase in sympathetic tone, whereas a decrease in HR-HF indicates a decrease in parasympathetic tone. The purpose of this study was to investigate the hemodynamic and autonomic nervous system effects of a small bolus of esmolol on SNP-induced reflex tachycardia by analyzing HR and BP variabilities. The investigators hypothesized that a small bolus of esmolol could counteract SNP-induced reflex tachycardia and excessive sympathetic activation without affecting BP. The specific aims of this study were to 1) investigate the incidence of reflex tachycardia resulting from SNP-induced hypotensive anesthesia; 2) identify predisposing factors for the development of tachycardia; and 3) estimate the effects of esmolol by measuring HR, mean arterial pressure (MAP), SBP-LF, and HR-HF.
Materials and Methods STUDY DESIGN
To address the research purpose, the investigators designed and implemented a study to evaluate the hemodynamic and autonomic nervous system effects of esmolol on reflex tachycardia resulting from SNPinduced hypotensive anesthesia. The study population was composed of all patients presenting to the authors’ hospital for the evaluation and management of jaw deformity and who were scheduled for elective mandibular osteotomy from January 2007 through April 2008. To be included in the study sample, patients had to be Class I on the American Society of Anesthesiologists’ Physical Status Scale and have no medical complications. Patients were excluded as study subjects if their BP was low and SNP was not required. This study was performed according to the Declaration of Helsinki and approved by the institutional review board and ethical committee of Osaka University Dental Hospital. Written informed consent was obtained from all patients. STUDY PROTOCOL
As preanesthetic medication, atropine sulfate 0.01 mg/kg and meperidine (pethidine) hydrochloride 1 mg/kg were intramuscularly injected 20 minutes before the induction of anesthesia. Anesthesia was induced with thiamylal sodium 5 mg/kg followed by vecuronium bromide 0.1 mg/kg to facilitate nasotracheal intubation. Anesthesia was maintained with 66% nitrous oxide and sevoflurane at an end-tidal concentration of 2% in oxygen. Ventilator settings were adjusted to maintain the end-tidal carbon diox-
1047
HANAMOTO ET AL
ide pressure from 30 to 35 mm Hg, with a respiratory rate of 12 breaths/min and an inspiratory/expiratory ratio of 1:2. After anesthetic induction, a 22-gauge indwelling catheter was placed in the dorsalis pedis artery for continuous monitoring of arterial blood pressure. Local anesthesia, in the form of 1% lidocaine 20 mL with 1:100,000 epinephrine, was administered by the surgeon 5 minutes before the start of the operation to decrease the primary afferent nociception owing to the surgical procedure. In the authors’ hospital, some trainee oral-maxillofacial surgeons take longer than usual to perform operations and sometimes there is unexpected blood loss. Hence, although mandibular osteotomies do not usually bleed as much as maxillary osteotomies, the authors routinely provide hypotensive anesthesia for mandibular and maxillary osteotomies. Induced hypotension was commenced 15 minutes before incision of the mandibular bone and was continued until closure of the mandibular mucosa. SNP infusion was initiated at a rate of 0.5 g/kg/min and titrated to maintain the MAP at 55 to 65 mm Hg. The adequacy of urine output was monitored during the hypotensive period, although the authors have no data of the exact amounts of urine output during the hypotensive period. When the HR exceeded 95 beats/ min, esmolol 0.5 mg/kg was administered and patients were included in the esmolol (ESM) group.14 If the HR did not decrease to below 95 beats/min after the initial administration of esmolol or it increased again to above 95 beats/min during hypotensive anesthesia, an additional dose of esmolol (0.5 mg/kg) was administered. The patients with an HR that did not exceed 95 beats/min after SNP administration were not given esmolol and were analyzed as the non-ESM group. DATA COLLECTION METHODS
Continuous arterial pressure and electrocardiographic waveforms were measured and digitalized at 1,000 Hz (IntelliVue MP50, Philips, the Amsterdam, Netherlands). Artifact-free digitalized signals were stored on a personal computer for later analysis. The fast peak of R waves on electrocardiograms was detected and RR intervals were measured. Peak values of SBP were analyzed with commercially available software (Fluclet, Dainippon Sumitomo Pharmaceutical Co Ltd, Suita, Japan), where 2 frequency bands were automatically separated: a low-frequency band (LF; 0.04 to 0.15 Hz) and a high-frequency band (HF; 0.15 to 0.4 Hz). During the previous 10 years, continuous attempts have been made to measure the activity of the autonomic nervous system using power spectral analysis of BP and beat-to-beat interval fluctuations.15 Recently, power spectral analysis of HR variability and
BP variability have been widely used as noninvasive methods for quantifying autonomic function. In this study, the wavelet method was used to analyze the spectral power of HR and SBP variability because of its high time resolution.16,17 The wavelet transform (WT) is considered to provide a markedly superior quantitative analysis of cardiovascular variability than the fast Fourier transform during autonomic nervous adaptations induced by external agents or some sort of stress, with 2 main advantages. First, the WT allows a temporally localized sliding analysis of signals using a known function that is called the mother wavelet. When the balance of the autonomic nervous equilibrium is instantaneously modified in clinical situations, such as by the administration of SNP or esmolol, the WT method can be used to assess the status of HR and BP variabilities at any given time point. Second, the shape of the WT analysis equation differs from the fixed sinusoidal shape of the fast Fourier transform and can be customized to fit the shape of the analyzed signal, allowing a better quantitative measurement.16,17 The SBP-LF is a good marker of sympathetic activity because it is sensitive to the sympathetic blockade and is associated with muscle sympathetic nerve activity.18 In contrast, the HR-HF coincides with the respiratory frequency and primarily reflects respiration-linked variations in the HR resulting from centrally mediated cardiac vagus control. STUDY VARIABLES
In this study, the primary predictor variable was esmolol exposure. The outcome variables measured were HR, MAP, SBP-LF, and HR-HF. These outcome variables were measured at 3 time points: baseline (5 min before SNP administration), 10 minutes after a stable level of SNP-induced hypotension (MAP, 55 to 65 mm Hg), and 1 minute after the administration of esmolol. All measurements were made before the osteotomy because it is a highly invasive surgical procedure that could influence the condition of the autonomic nervous system. The third category of variables studied were demographic and perioperative variables. Demographic variables included gender, age, height, weight, and body mass index; and perioperative measurements included anesthesia time, surgical time, blood loss volume, infusion volume, and SNP infusion rate. STATISTICAL ANALYSES
Data are expressed as mean ⫾ standard deviation. Statistical analysis was performed with the SPSS software package (SPSS Inc, Chicago, IL). Gender was analyzed statistically by the 2 test. Other demographic data were analyzed by the unpaired t test. The MAP, HR, SBP-LF, and HR-HF were analyzed statistically using 1-way analysis of variance for repeated
1048
ESMOLOL AND SNP-INDUCED REFLEX TACHYCARDIA
measures followed by the Tukey test to adjust for multiple comparisons or the paired t test. Statistical comparisons between groups were assessed using the unpaired t test. A P value less than .05 was considered statistically significant.
Results Of 30 patients initially included in the study, 3 patients were excluded because their MAP decreased to approximately 55 to 65 mm Hg with 2% sevoflurane and nitrous oxide alone. Hence, they did not require SNP-induced hypotension. Table 1 presents the clinical characteristics and procedural summary of the remaining 27 patients. They were given SNP and were divided into 2 groups based on their HR response to SNP. Nineteen patients whose HR increased to above 95 beats/min with SNP administration were given esmolol (ESM group). Eight patients whose HR was 95 beats/min or less were not given esmolol (non-ESM group). There were no differences in demographic data, surgical and anesthesia times, blood loss, and mean infusion rate of SNP between the 2 groups. Table 2 presents the hemodynamic and autonomic variables in the 2 groups. There were no significant differences in the baseline levels of MAP and SBP-LF between the 2 groups. However, the baseline values of HR and HR-HF were higher and lower, respectively, in the ESM group than in the non-ESM group. This finding suggests that the non-ESM group had a para-
Table 1. CLINICAL CHARACTERISTICS AND PROCEDURAL SUMMARY OF THE 27 PATIENTS
Esmolol Exposure Variable
Yes (ESM group)
No (non-ESM group)
Patients (n) 19 8 Male/female patients 6/13 3/5 Age (yrs) 21.9 ⫾ 3.3 24.9 ⫾ 7.6 Height (cm) 163.4 ⫾ 9.8 161.8 ⫾ 5.7 Weight (kg) 56.0 ⫾ 10.4 57.4 ⫾ 9.8 Body mass index 20.9 ⫾ 2.9 21.9 ⫾ 3.2 (kg/m2) Anesthesia time 246 ⫾ 77 270 ⫾ 62 (min) Surgical time (min) 174 ⫾ 83 186 ⫾ 55 Blood loss (mL) 363 ⫾ 254 426 ⫾ 328 Infusion volume (mL) 1997 ⫾ 577 2306 ⫾ 643 SNP infusion rate 0.72 ⫾ 0.29 0.61 ⫾ 0.31 (g/kg/min)
P Value
— .776 .319 .664 .751 .426 .452 .719 .595 .230 .417
Note: Data represent number of patients or mean ⫾ standard deviation. Abbreviation: SNP, sodium nitroprusside. Hanamoto et al. Esmolol and SNP-Induced Reflex Tachycardia. J Oral Maxillofac Surg 2012.
sympathetic predominance compared with the ESM group. SNP decreased the MAP to a similar extent in the 2 groups. However, SNP caused a greater increase in HR (106.7 ⫾ 7.4 beats/min) in the ESM group compared with that in the non-ESM group (87.7 ⫾ 5.7 beats/min). The tachycardia in the ESM group was associated with an increased SBP-LF and a decreased HR-HF, with the increase in SBP-LF indicating an increase in sympathetic tone and a decrease in HR-HF indicating a decrease in parasympathetic tone. There were significant differences in SBP-LF and HR-HF between the 2 groups. Esmolol was given to 19 of 27 patients (ESM group). The increased HR after SNP administration decreased to 86.9 ⫾ 6.2 beats/min with esmolol without a significant change in the MAP. Esmolol attenuated the increased SBP-LF and restored the decreased HR-HF to baseline values. Ten patients in the ESM group required additional doses of esmolol at intervals of 15 to 20 minutes.
Discussion The purpose of this study was to investigate the hemodynamic and autonomic nervous system effects of a small bolus of esmolol on SNP-induced reflex tachycardia, using HR and BP variability, and to confirm the hypothesis that a small bolus of esmolol could counteract SNP-induced reflex tachycardia and excessive sympathetic activation without affecting BP. The specific aims of this study were to 1) investigate the incidence of reflex tachycardia with SNPinduced hypotensive anesthesia; 2) compare the characteristics of patients with and without reflex tachycardia; and 3) estimate the effects of esmolol by measuring HR, MAP, SBP-LF, and HR-HF. The results of this study confirmed the authors’ hypothesis, suggesting that a small bolus of esmolol can be used effectively to counteract the tachycardia resulting from SNP-induced hypotensive anesthesia without causing any adverse hemodynamic effects. In the present study, reflex tachycardia was observed in about 70% of patients; this means that reflex tachycardia does not always develop with SNP-induced hypotension under sevoflurane anesthesia. Similar results have been reported under halothane anesthesia.11 An increase in SBP-LF indicates an increase in sympathetic tone, whereas a decrease in HR-HF indicates a decrease in parasympathetic tone. Patients with reflex tachycardia (ESM group) had a higher HR and a lower HR-HF than patients in the non-ESM group, even at baseline. This finding suggests that the ESM group might have had a sympathetic dominance under sevoflurane and nitrous oxide anesthesia. Because sevoflurane and nitrous oxide
1049
HANAMOTO ET AL
Table 2. MEAN ARTERIAL PRESSURE, HEART RATE, LOW-FREQUENCY POWER OF SYSTOLIC BLOOD PRESSURE, AND HIGH-FREQUENCY POWER OF RR INTERVAL CHANGES AT EACH TIME POINT
Outcome Variable
Baseline
TSNP
TESM
P Value
72.4 ⫾ 6.0
60.6 ⫾ 3.7
60.2 ⫾ 4.6
No (non-ESM group) Intergroup comparisons (P value) HR (beats/min) Esmolol exposure Yes (ESM group)
68.4 ⫾ 5.8 .118
57.6 ⫾ 3.9 .072
—
⬍.001* ⬍.001† 1‡ .003
95.9 ⫾ 7.3
106.7 ⫾ 7.4
86.9 ⫾ 6.2
No (non-ESM group) Intergroup comparisons (P value) SBP-LF (mm Hg/Hz½) Esmolol exposure Yes (ESM group)
83.7 ⫾ 5.3 .001
87.7 ⫾ 5.7 ⬍.001
—
0.14 ⫾ 0.10
0.42 ⫾ 0.17
0.25 ⫾ 0.12
No (non-ESM group) Intergroup comparisons (P value) HR-HF (ms/Hz½) Esmolol exposure Yes (ESM group)
0.15 ⫾ 0.14 .729
0.28 ⫾ 0.10 .038
—
1.22 ⫾ 1.53
0.48 ⫾ 0.39
1.08 ⫾ 1.13
No (non-ESM group) Intergroup comparisons (P value)
2.32 ⫾ 1.70 .034
1.62 ⫾ 1.45 .006
—
MAP (mm Hg) Esmolol exposure Yes (ESM group)
⬍.001* ⬍.001† ⬍.001‡ .014
⬍.001* .001† ⬍.001‡ .01
⬍.001* .959† ⬍.002‡ .338
Note: Data are presented as mean ⫾ standard deviation. Abbreviations: baseline, before sodium nitroprusside administration; HR, heart rate; HR-HF, high-frequency (0.15 to 0.4 Hz) component of RR interval; MAP, mean arterial pressure; SBP-LF, low-frequency (0.04 to 0.15 Hz) component of systolic blood pressure; SNP, sodium nitroprusside; TESM, 1 minute after esmolol administration; TSNP, 10 minutes after a stable level of hypotension (mean arterial pressure, 55 to 65 mm Hg). *TSNP versus baseline. †TESM versus baseline. ‡TSNP versus TESM. Hanamoto et al. Esmolol and SNP-Induced Reflex Tachycardia. J Oral Maxillofac Surg 2012.
anesthesia markedly decreases SBP-LF and HR-HF,19 parasympathetic activity, reflected by HR-HF, might have been suppressed to a greater extent in the ESM group. SNP increased SBP-LF in the 2 groups, with a greater increase in the ESM group. In addition, SNP caused a greater decrease in HR-HF in the ESM group. These results suggest that SNP increased sympathetic tone and decreased parasympathetic tone, leading to reflex tachycardia in the ESM group. In contrast, the non-ESM group showed a smaller increase in SBP-LF. The reason for this difference in the autonomic response between the 2 groups in the present study is not known. The autonomic effects of vasodilators have been explored previously. Although SNP has no direct effect on adrenergic receptors, its hypotensive effect causes a reflex increase in sympathetic tone20 and an
increase of SBP-LF21 in awake healthy volunteers. Cloarec et al22 also reported that the sympathetic nervous system is activated during nitroglycerin administration in the awake state. Inhalational anesthetics have an impact on the autonomic nervous system. Sevoflurane and nitrous oxide anesthesia markedly decreases sympathetic and parasympathetic activities.19 However, SNP causes an increase in plasma catecholamine levels during sevoflurane and nitrous oxide anesthesia.23 In the present study, SNP increased SBP-LF, which reflects an increased sympathetic activation. This finding corresponds with a previous study using blood catecholamine levels.23 However, previous studies have not been able to confirm the sympathomimetic effects of other vasodilators, such as nicardipine, nitroglycerin, and prostaglandin E1, during induced hypotension anesthesia.24,25
1050 Beta-adrenergic blockers are commonly used to control tachycardia during SNP-induced hypotension. Previous studies have reported the effectiveness of oral propranolol premedication on reflex tachycardia. However, this method has some disadvantages because of the slow onset and long duration of the action of oral propranolol. Esmolol is a cardioselective intravenous -adrenergic receptor blocking drug with a very rapid onset of action and an extremely short elimination half-life (9 min).12 Esmolol is effective in the management of perioperative hemodynamic responses caused by sympathetic stimulation. Although esmolol can be used alone for the induction of hypotension, its use is associated with marked myocardial depression. Dyson et al26 reported that esmolol 1.5 mg/kg produced an excessive decrease (⬎20%) in SBP. It has been suggested that esmolol may exacerbate the decrease in cardiac output and aggravate cardiac depression when combined with SNP in patients with hypovolemia or heart failure.27 In the present study, a small bolus of esmolol (0.5 mg/kg) was administered for the control of reflex tachycardia during SNP-induced hypotension. Esmolol was able to decrease reflex tachycardia without altering blood pressure during SNP-induced hypotension. The efficacy of esmolol is supported by the evidence from BP and HR variability analyses. Esmolol suppressed the increased SBP-LF and restored the decreased HR-HF. These results reflect the suppression of sympathetic overactivity and restoration of the decreased parasympathetic nervous activity, respectively. Edmondson et al13 stated that esmolol infusion augments induced hypotension by decreasing myocardial contractility, thus enabling a decrease of the SNP dose. In the present study, however, the small bolus dose of esmolol used did not result in a further decrease in the MAP. Hence, the SNP infusion rate could not be decreased. Therefore, the dose of esmolol administered in this study inhibited only reflex tachycardia without causing myocardial depression. A single bolus administration of esmolol is useful and controllable because of its rapid onset and short duration of action. In this study, however, repeated administration of esmolol at intervals of 15 to 20 minutes was required in some patients. This requirement was likely to be dependent on the surgical invasiveness. All patients enrolled in this study were administered atropine sulfate 0.01 mg/kg intramuscularly as preanesthetic medication for its antisialagogue effect. Atropine sulfate is an anticholinergic agent that suppresses parasympathetic activity. Therefore, the autonomic effects of atropine might have influenced the measurements of HR and BP variabilities; this is a
ESMOLOL AND SNP-INDUCED REFLEX TACHYCARDIA
limitation of the present study. For a strict assessment of autonomic parameters, premedication with anticholinergics is undesirable. However, atropine sulfate was used because the study patients were undergoing intraoral surgeries.28 Similarly, all patients were administered meperidine 1 mg/kg intramuscularly 20 minutes before anesthetic induction. Although meperidine has atropine-like effects, these effects would have been small at the time of hypotensive anesthesia, approximately 1 to 2 hours after premedication, because hypotensive anesthesia was commenced 15 minutes before incision of the mandibular bone. All patients were also administered 1% lidocaine 20 mL with 1:100,000 epinephrine as local anesthesia. Although epinephrine has effects on autonomic nervous activities and hemodynamics, the effects are temporary because epinephrine has a short duration of action. Further, the 2 groups of patients included in this study received equal doses of atropine, meperidine, and lidocaine with epinephrine. Hence, although these agents might have had some influence on the autonomic nervous system variables investigated in this study, the main results of this study suggest the beneficial effects of using a small bolus of esmolol in clinical practice. In conclusion, about 70% of patients exhibited reflex tachycardia in response to SNP-induced hypotension. A small dose of esmolol can improve the reflex tachycardia in these patients without changing BP. An increase in SBP-LF indicates an increase in sympathetic tone, whereas a decrease in HR-HF indicates a decrease in parasympathetic tone. Esmolol can suppress SNP-induced excessive sympathetic activation and restore the decreased parasympathetic activation to its original state. Hence, a small bolus of esmolol is useful to counteract the reflex tachycardia of SNPinduced hypotensive anesthesia. Further studies are needed to assess better methods of induced-hypotension anesthesia. Future studies on the efficacy of esmolol in decreasing the tachycardia associated with induced hypotension should be performed without preanesthetic anticholinergic administration to confirm these beneficial effects of esmolol.
References 1. Aken HV, Miller ED: Deliberate hypotension, in Miller RD (ed): Anesthesia (ed 5). New York, Churchill Livingstone, 2000, p 1470 2. Testa LD, Tobias JD: Pharmacologic drugs for controlled hypotension. J Clin Anesth 7:326, 1995 3. Degoute CS: Controlled hypotension: A guide to drug choice. Drugs 67:1053, 2007 4. Friederich JA, Butterworth JF: Sodium nitroprusside: Twenty years and counting. Anesth Analg 81:152, 1995 5. Shah N, Del Valle O, Edmondson R, et al: Esmolol infusion during nitroprusside-induced hypotension: Impact on hemodynamics, ventricular performance, and venous admixture. J Cardiothorac Vasc Anesth 6:196, 1992
HANAMOTO ET AL 6. Zubrow AB, Daniel SS, Stark RI, et al: Plasma renin, catecholamine, and vasopressin during nitroprusside-induced hypotension in ewes. Anesthesiology 58:245, 1983 7. Knight PR, Lane GA, Hensinger RN, et al: Catecholamine and renin-angiotensin response during hypotensive anesthesia induced by sodium nitroprusside or trimethaphan camsylate. Anesthesiology 59:248, 1983 8. Khambatta HJ, Stone JG, Khan E: Propranolol alters renin release during nitroprusside-induced hypotension and prevents hypertension on discontinuation of nitroprusside. Anesth Analg 60:569, 1981 9. Khambatta HJ, Stone JG, Matteo RS, et al: Propranolol premedication blunts stress response to nitroprusside hypotension. Anesth Analg 63:125, 1984 10. Apipan B, Rummasak D: Efficacy and safety of oral propranolol premedication to reduce reflex tachycardia during hypotensive anesthesia with sodium nitroprusside in orthognathic surgery: A double-blind randomized clinical trial. J Oral Maxillofac Surg 68:120, 2010 11. Abdulatif M: Sodium nitroprusside induced hypotension: Haemodynamic response and dose requirements during propofol or halothane anaesthesia. Anaesthesiol Intensive Care 22:155, 1994 12. Wiest D: Esmolol. A review of its therapeutic efficacy and pharmacokinetic characteristics. Clin Pharmacokinet 25:190, 1995 13. Edmondson R, Del Valle O, Shah N, et al: Esmolol for potentiation of nitroprusside-induced hypotension: Impact on the cardiovascular, adrenergic, and renin-angiotensin systems in man. Anesth Analg 69:202, 1989 14. Gold MI, Sacks DJ, Grosnoff DB, et al: Use of esmolol during anesthesia to treat tachycardia and hypertension. Anesth Analg 68:101, 1989 15. Akselrod S, Gordon D, Ubel FA, et al: Power spectrum analysis of heart rate fluctuation: A quantitative probe of beat-to-beat cardiovascular control. Science 13:220, 1981 16. Sugimura M, Hirose Y, Hanamoto H, et al: Influence of acute progressive hypoxia on cardiovascular variability in conscious spontaneously hypertensive rats. Auton Neurosci 141:94, 2008
1051 17. Sugimura M, Hanamoto H, Boku A, et al: Influence of acute hypoxia combined with nitrous oxide on cardiovascular variability in conscious hypertensive rats. Auton Neurosci 156:73, 2010 18. Brychta RJ, Shiavi R, Robertson D, et al: A simplified twocomponent model of blood pressure fluctuation. Am J Physiol Heart Circ Physiol 292:1193, 2007 19. Shin WJ, Kang SJ, Kim YK, et al: Link between heart rate and blood pressure Mayer wave during general anesthesia. Clin Auton Res 21:309, 2011 20. Sanders JS, Mark AL, Ferguson DW: Importance of aortic baroreflex in regulation of sympathetic responses during hypotension. Evidence from direct sympathetic nerve recordings in humans. Circulation 79:83, 1989 21. Schächinger H, Weinbacher M, Kiss A, et al: Cardiovascular indices of peripheral and central sympathetic activation. Psychosom Med 63:788, 2001 22. Cloarec-Blanchard L, Funck-Brentano C, Carayon A, et al: Rapid development of nitrate tolerance in healthy volunteers: Assessment using spectral analysis of short-term blood pressure and heart rate variability. J Cardiovasc Pharmacol 24:266, 1994 23. Yoshikawa F, Kohase H, Umino M, et al: Blood loss and endocrine responses in hypotensive anaesthesia with sodium nitroprusside and nitroglycerin for mandibular osteotomy. Int J Oral Maxillofac Surg 38:1159, 2009 24. Sato J, Saito S, Takahashi T, et al: Sevoflurane and nitrous oxide anaesthesia suppresses heart rate variabilities during deliberate hypotension. Eur J Anaesthesiol 18:805, 2001 25. Kimura T, Ito M, Komatsu T, et al: Heart rate and blood pressure power spectral analysis during calcium channel blocker induced hypotension. Can J Anaesth 46:1110, 1999 26. Dyson A, Isaac PA, Pennant JH, et al: Esmolol attenuates cardiovascular responses to extubation. Anesth Analg 71:675, 1990 27. Takeda S, Masuda R, Kanazawa T, et al: Esmolol attenuates hepatic blood flow responses during sodium nitroprussideinduced hypotension in dogs. Can J Anaesth 51:348, 2004 28. Stoelting RK, Miller RD: Preoperative Medication: Basics of Anesthesia (ed 4). New York, Churchill Livingstone 2000, p 124