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Dexmedetomidine attenuates tourniquet-induced hyperdynamic response in patients undergoing lower limb surgeries: A randomized controlled study
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Dexmedetomidine attenuates tourniquet-induced hyperdynamic response in patients undergoing lower limb surgeries: A randomized controlled study Hsuan-Chih Lao, MD, MS,a,b Pei-Shan Tsai, PhD,c Jung-Yuan Su, MD,d Tiew-Guan Kwok, MD,d and Chun-Jen Huang, MD, PhDe,f,* a
Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan School of Medicine, National Yang-Ming University, Taipei, Taiwan c Graduate Institute of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan d Department of Orthopedics, Mackay Memorial Hospital, Taipei, Taiwan e Department of Anesthesiology, Buddhist Tzu Chi General Hospital, Taipei Branch, 289, Jianguo Road, Sindian District, New Taipei City 231, Taipei, Taiwan f School of Medicine, Tzu Chi University, Hualien, Taiwan b
article info
abstract
Article history:
Background: Activation of sympathetic nervous system has a crucial role in mediating the
Received 21 August 2011
pneumatic tourniquet inflation induced hyperdynamic response. Dexmedetomidine,
Received in revised form
a selective a2-adrenergic receptor agonist, has potent sympatholytic effects. We conducted
28 December 2011
this prospective, randomized, placebo-controlled, double-blinded study to elucidate the
Accepted 4 January 2012
effects of dexmedetomidine on attenuating the tourniquet-induced hyperdynamic
Available online 4 April 2012
response during general anesthesia. Materials and methods: We included a total of 72 healthy adult patients undergoing
Keywords:
elective lower limb surgery. Under general anesthesia, patients were randomized to the
Dexmedetomidine
dexmedetomidine or the control group (n ¼ 36 in each group). The dexmedetomidine
Tourniquet
group received a loading dose of dexmedetomidine (0.8 mg$kg1 over 10 min) followed by
Hypertension
continuous infusion of dexmedetomidine (0.4 mg$kg1.h1) until tourniquet deflation.
Lower limb
The control group received normal saline instead. We compared tourniquet-induced
Orthopedic surgery
changes in hemodynamic parameters between groups to elucidate the effects of dexmedetomidine. Results: Tourniquet inflation induced significant increases in hemodynamic parameters, including heart rate, systolic arterial pressure, mean arterial pressure, diastolic arterial pressure, rate pressure product, cardiac output, and stroke volume in the control group. The effects of tourniquet inflation on increasing hemodynamic parameters were significantly attenuated by dexmedetomidine: heart rate (P < 0.001), systolic arterial pressure (P ¼ 0.002), mean arterial pressure (P ¼ 0.042), diastolic arterial pressure (P ¼ 0.012), rate pressure product (P < 0.001), and cardiac output (P ¼ 0.001) of the dexmedetomidine group
Part of the study results were presented at the Annual Meeting of the American Society of Anesthesiologists, Orlando, Florida, October 18e22, 2008. * Corresponding author. Department of Anesthesiology, Buddhist Tzu Chi General Hospital, Taipei Branch, 289, Jianguo Rd., Sindian District, New Taipei City 231, Taiwan. Tel.: þ1 886 2 66289779, ext. 2639; fax: þ1 886 2 66289009. E-mail address: [email protected] (C.-J. Huang). 0022-4804/$ e see front matter ª 2013 Elsevier Inc. All rights reserved. doi:10.1016/j.jss.2012.01.008
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were significantly lower than those of the control group. However, the stroke volume of these groups was comparable. Conclusions: Dexmedetomidine attenuates tourniquet-induced hyperdynamic response in general anesthesia patients undergoing lower limb surgeries. ª 2013 Elsevier Inc. All rights reserved.
1.
Introduction
Pneumatic tourniquet is widely used in lower limb surgery to provide optimal operating conditions [1]. However, tourniquet inflation can induce a hyperdynamic response that may be resistant to therapies such as analgesic drugs, antihypertensive drugs, and increases in anesthesia depth [2,3]. Although mechanisms underlying the tourniquet-induced hyperdynamic response are not completely understood, augmented sympathetic outflow caused by tourniquet inflation has been proposed as an essential mechanism [4,5]. The a2-adrenergic receptors are present in the central and peripheral nervous system at autonomic ganglion as well as presynaptic and postsynaptic sites [6]. Activation of the a2-adrenergic receptors significantly decreases activity of the sympathetic nervous system [7]. Dexmedetomidine is a selective, short-acting, agonist of the a2-adrenergic receptors [8]. In addition to sympatholytic effects, dexmedetomidine has antihypertensive, anxiolytic, sedative, and analgesic effects [7]. Dexmedetomidine has been used clinically as an adjunct to anesthesia, analgesia, and intensive care unit sedation [7]. Theoretically, dexmedetomidine might exert significant effects on attenuating tourniquet-induced hyperdynamic response. To elucidate further, we conducted this randomized, placebo-controlled, double-blinded study with the hypothesis that dexmedetomidine can attenuate the tourniquet-induced hyperdynamic response in patients undergoing lower limb surgery.
2.
Materials and methods
2.1.
Participants
The Human Research Review Committee, Mackay Memorial Hospital (MMH-I-S-338) approved this prospective, randomized, placebo-controlled, double-blinded study, which was conducted in Mackay Memorial Hospital, a tertiary referral teaching hospital in Taipei, Taiwan, between August 2007 and December 2008. We approached all eligible patients for recruitment before te operation and enrolled them after obtaining written informed consent. Inclusion criteria were: adult patients (18e75 y old), with American Society of Anesthesiologists physical status I or II, who were scheduled for elective orthopedic lower limb surgeries and required pneumatic tourniquet application during surgeries. We excluded patients if they were taking adrenergic or cholinergic agents. We also excluded patients with fever (38 C), leucocytosis (white blood cells 10,000 cells$ml1), anemia (hematocrit < 20%), or obesity (body mass index > 30 kg.m2). In addition, we excluded patients with a history of hypertension, cardiac arrhythmia, congestive heart failure, diabetes mellitus, renal
dysfunction, hepatic dysfunction, or allergy to dexmedetomidine (or other a2-agonist agents). We also excluded patients with expected tourniquet time of <60 min or >150 min. Because no previous study was available regarding the effect of dexmedetomidine effect in this regard, we estimated the sample size based on previous data derived from a study on another widely used a2-adrenergic receptor agonist, clonidine [5]. Previous data revealed that mean arterial pressure (MAP) after tourniquet deflation in patients who received clonidine was significantly lower than those who received normal saline (84 11 versus 71 8 mm Hg) [5]. Based on these data (expected differences in means, 13; expected standard deviation, 9.5), power analysis revealed that a sample size of 10 patients per group was sufficient to detect a statistically significant between group difference, with an alpha of 0.05 and a power of 82.5%. Nevertheless, because the estimation was based on clonidine data, we decided to include at least 10 patients per group. By the end of the study period approved by the Human Research Review Committee of our institute, a total of 36 patients per group were included. We conducted patient enrollment and subsequent allocation as illustrated in the CONSORT diagram (Fig. 1).
2.2.
Hemodynamic monitoring
We employed continuous electrocardiography (ECG) and noninvasive blood pressure with arm cuff (NIBP) to measure heart rate (HR), systolic arterial pressure (SAP), MAP, and diastolic arterial pressure (DAP). In addition, we noninvasively monitored cardiac output (CO) and stroke volume (SV) using the Finometer, a noninvasive hemodynamic monitoring device (TNO Biomedical Instrumentation, Amsterdam, The Netherlands). We performed validation of the Finometer using upper-arm cuff return-to-flow measurement to calibrate blood pressure, according to the manufacturer’s manual. Myocardial oxygen consumption can be estimated by calculating the rate pressure product (RPP) (i.e., HR SAP) [9]. We thus also calculated RPP in this study.
2.3.
Anesthetic management
We applied standard monitoring devices, including electrocardiogram, noninvasive blood pressure monitoring, pulse oximetry, and capnography. After receiving premedication with midazolam (0.035 mg$kg1, intravenously [IV]) and hydration with Ringer’s lactate solution (500 mL), baseline hemodynamics were measured. We induced general anesthesia with fentanyl (2 mg$kg1, IV) and propofol (2 mg$kg1, IV). We used a bispectral index monitor (BIS) (Aspect A1000 monitor; Medical Systems, Natick, MA) to monitor anesthesia depth. We used rocuronium (1 mg$kg1, IV) to facilitate tracheal intubation. Tracheal intubation was performed after
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Fig. 1 e The CONSORT diagram showing patients’ flow through the study.
loss of response to train-of-four with neuromuscular stimulation and a BIS index <50 was achieved. After tracheal intubation, we controlled ventilation with a tidal volume of 10 mL$kg1 and adjusted the respiratory rate to maintain an end-tidal carbon dioxide of 35e40 mm Hg. All patients’ lungs were mechanically ventilated with 4 L$min1 fresh gas (50% air:50% O2). We maintained anesthesia with sevoflurane and adjusted the concentration was to achieve a BIS index of 40e45.
2.4.
Experimental protocols
An anesthesiologist who was involved only in preparing the medication in a 100-mL syringe randomly allocated patients to the dexmedetomidine or control group using a random number table. The surface of syringe was covered with a tinfoil paper and numbered by order on the surface. All of the participants were blinded to grouping, including patients, anesthesiologists who performed general anesthesia throughout the operations, and anesthesiologists who set up all the monitors, started the infusion of syringe medications, and recorded all data. Patients in the dexmedetomidine group received a loading dose of dexmedetomidine (0.8 mg$kg1 over 10 min), followed by continuous infusion of dexmedetomidine (0.4 mg$kg1$h1) until pneumatic tourniquet deflation. Patients in the control group received an equal amount of 0.9% saline instead. Loading of dexmedetomidine or 0.9% saline started immediately after stable anesthesia status (i.e., a BIS index of 40e45) was achieved. After the beginning of dexmedetomidine or saline infusion, lower limb pneumatic tourniquet was applied at the high thigh level. We determined tourniquet inflation pressure based on the patient’s SAP, i.e., no less than twice the patient’s SAP. The range of inflation pressure was 300e350 mm Hg. We measured HR, SAP, MAP, DAP, and RPP at the following time points: immediately before dexmedetomidine (or saline) loading (Tdose), immediately before tourniquet inflation (Tinflat), every 15 min during tourniquet inflation (T15, T30, T45, T60, T75, and T90, respectively), and 5 min after tourniquet
deflation (Tdeflat). In addition, we measured CO and SV at Tdose, T30, T60, T90, and Tdeflat. Patients who experienced hypertension (i.e., SAP > 160 mm Hg and/or DAP > 90 mm Hg for more than 5 min) during the experiment were treated with nicardipine injection (5 mg, IV, every 5 min). Patients who experienced hypotension (i.e., SAP < 90 mm Hg and/or MAP < 70 mm Hg for more than 5 min) were treated with incremental doses of ephedrine injection (i.e., 4, 8, 10, 12, 14, and 16 mg, IV). Tachycardia (i.e., HR > 100 beats$min1 for more than 5 min) was treated with esmolol injection (5 mg, IV), whereas bradycardia (i.e., HR < 60 beats$min1 for more than 5 min) was treated with atropine injection (0.4 mg, IV).
2.5.
Statistical analysis
We performed statistical analyses using a commercial software package (SPSS 11.5 for Windows; SPSS Science, Chicago, IL). Data are presented as means with standard deviations. We examined differences between groups using Student’s t-test for continuous data and the Chi-square test for categorical data. We performed repeated-measures analysis of variance with Bonferroni corrections to examine the withinsubjects (time) effect, between-subjects (group) effect, and group by time interaction effect in hemodynamic data. A twotailed alpha level of 0.05 was set for all statistical tests, and P < 0.05 was considered statistically significant. The percentages of patients who developed tourniquet-induced hyperdynamic response, defined as more than a 30% increase in SAP during tourniquet inflation [2], were compared between groups.
3.
Results
The demographic data and duration of tourniquet inflation were comparable between groups (Table 1). The incidence of tourniquet-induced hyperdynamic response in the control
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Table 1 e Demographic data, types of surgeries, and duration of tourniquet inflation.
Age (y) Gender (M/F) ASA physical status (I/II) Weight (kg) Height (cm) BMI (kg.m2) Type of surgery (TKR/arthroscopy/ORIF) Tourniquet time (min)
Control group (n ¼ 36)
Dexmedetomidine group (n ¼ 36)
43 19 19/18 22/14 65 10 164 9 24 4 8/11/17 104 22
45 18 12/24 25/11 70 12 166 9 25 4 8/10/18 108 25
ASA ¼ american society of anesthesiologists; TKR ¼ total knee replacement; ORIF ¼ open reduction and internal fixation of lower limb. Values are means standard deviations.
group was significantly higher than that in the dexmedetomidine group (67.6% versus 19.4%; P < 0.001) (Table 2). However, the total doses of nicardipine and atropine consumption in these two groups were comparable (Table 2). In contrast, the total dose of ephedrine consumption in the dexmedetomidine group was significantly higher than that in the control group (P ¼ 0.020) (Table 2). In addition, none of the cases included in this study received esmolol. The baseline hemodynamic data (i.e., HR, SAP, MAP, DAP, CO, and SV) were comparable between groups. Anesthesia induction and tracheal intubation exerted similar hemodynamic effects in both groups, as the HR, SAP, MAP, and DAP values measured at Tdose of the groups were comparable (Fig. 2 AeD ). The HR value in the dexmedetomidine group measured at Tinflat was significantly lower than that measured at Tdose (P < 0.001) (Fig. 2A), which indicates that dexmedetomidine loading caused a significant decrease in HR. In contrast, the SAP, MAP, and DAP values in the dexmedetomidine group measured at Tinflat were comparable to those measured at Tdose (Fig. 2BeD).
significant increases in SAP in the control group, as the SAP values of the control group measured at T15, T30, T45, T60, T75, and T90 were significantly higher than that measured at Tinflat (all P < 0.001) (Fig. 2B). The SAP value in the control group measured at Tdeflat was also significantly higher than that measured at Tinflat (P < 0.001) (Fig. 2B). The SAP values in the dexmedetomidine group measured at T15, T30, and T45 were significantly lower than those in the control group (all P < 0.040) (Fig. 2B), which indicates that dexmedetomidine attenuated the tourniquet-induced SAP increases. However, the SAP values in the dexmedetomidine group measured at T60, T75, and T90 were comparable to those in the control group (Fig. 2B). In contrast, the SAP value in the dexmedetomidine group measured at Tdeflat was significantly lower than that in the control group (P < 0.001) (Fig. 2B). The changes in MAP (Fig. 2C) and DAP (Fig. 2D) paralleled those of SAP (Fig. 2B).
3.1. Dexmedetomidine attenuated tourniquet-induced increases in HR
Repeated-measures analysis of variance revealed that the magnitude of changes in RPP was significantly different between groups (P < 0.001). Tourniquet inflation also caused significant increases in RPP in the control group, as the RPP values measured at T15, T30, T45, T60, T75, and T90 were significantly higher than that measured at Tinflat (all P < 0.050)
Repeated-measures analysis of variance revealed that the trend of HR was significantly different between groups (P < 0.001). Tourniquet inflation caused significant increases in HR in the control group, as the HR values measured at T15, T30, T45, T60, T75, and T90 were significantly higher than that measured at Tinflat (all P < 0.001) (Fig. 2A). The HR value in the control group measured at Tdeflat was also significantly higher than that measured at Tinflat (P < 0.001) (Fig. 2A). In contrast, the HR values in the dexmedetomidine group were significantly lower than those in the control group throughout the experiment (all P < 0.05) (Fig. 2A), which indicates that dexmedetomidine attenuated the effects of tourniquet inflation on inducing HR increases.
3.2. Dexmedetomidine attenuated tourniquet-induced increases in SAP, MAP, and DAP Repeated-measures analysis of variance revealed significant group by time interaction effects in SAP, MAP, and DAP, which indicates that the magnitude of the changes in SAP, MAP, and DAP were significantly different between groups (P ¼ 0.002, 0.042, and 0.012, respectively). Tourniquet inflation caused
3.3. Dexmedetomidine attenuated tourniquet-induced increases in RPP
Table 2 e Incidence of tourniquet-induced hyperdynamic response and total consumption of the rescue medications. Group
Tourniquetinduced hyperdynamic response (Y/N) Nicardipine (mg) Ephedrine (mg) Atropine (mg)
Control (n ¼ 36)
Dexmedetomidine (n ¼ 36)
24/12
7/29
0.4 1.6 0.8 3.7 0.03 0.12
0.1 0.3 3.6 5.8 0.08 0.17
Values are means standard deviations. a P < .050, dexmedetomidine versus control group.
P value
<.001a
.070 .020* .230
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Fig. 2 e Changes in (A) HR, (B) SAP, (C) MAP, (D) DAP, and (E) RPP. We measured HR, SAP, MAP, DAP, and RPP at the following time points: immediately before dexmedetomidine (or saline) loading (Tdose), immediately before tourniquet inflation (Tinflat), every 15 min during tourniquet inflation (T15, T30, T45, T60, T75, and T90, respectively), and 5 min after tourniquet deflation (Tdeflat). Data are represented as means and standard deviations. Dex [ dexmedetomidine (or saline) loading; Inf [ tourniquet inflation; Def [ tourniquet deflation. *P < 0.05, dexmedetomidine group versus control group. yP < 0.05, Tinflat versus Tdose. #P < 0.05 versus Tinflat.
(Fig. 2E). The RPP value measured at Tdeflat was also significantly higher than that measured at Tinflat (P < 0.001) (Fig. 2E). Similar to HR, the RPP values in the dexmedetomidine group measured during and after tourniquet deflation were significantly lower than those in the control group (all P < 0.010) (Fig. 2E).
3.4. Dexmedetomidine attenuated tourniquet-induced increases in CO Repeated-measures analysis of variance revealed that the magnitude of changes in CO was significantly different between groups (P ¼ 0.001). The CO values in the control group measured at T30, T60, T90, and Tdeflat were significantly higher than those measured at Tdose (all P < 0.035) (Fig. 3A). The CO values in the dexmedetomidine group measured at T30, T60, T90, and Tdeflat were significantly lower than those in the control group (all P < 0.010) (Fig. 3A). In contrast to CO, the difference in the pattern of changes in SV between groups was not statistically significant (P ¼ 0.511). The SV values in the two groups were comparable throughout the experiment (Fig. 3B).
4.
Discussion
Data from this study confirmed that tourniquet inflation induced a hyperdynamic response in general anesthesia patients
undergoing lower limb orthopedic surgery. As mentioned earlier, an augmented sympathetic outflow has been proposed to be an essential mechanism contributing to this tourniquetinduced hyperdynamic response [4,5]. Dexmedetomidine stimulates the central presynaptic a2A-adrenergic receptors and exerts central sympatholytic effects that can significantly decrease the plasma concentrations of norepinephrine and epinephrine [10e12]. Judging from these data, we thus hypothesized that dexmedetomidine could attenuate the tourniquet-induced hyperdynamic response. Data from this study confirmed our hypothesis. In concert with clinical data observed in three patients requiring tourniquet for surgery [13], our data provide clear evidence to support the concept that dexmedetomidine can serve as an effective adjunct to general anesthesia in patients using pneumatic tourniquet for lower limb surgery. Because the tourniquet-induced hyperdynamic response is resistant to therapies [3], data from this study thus should have certain clinical significance and warrant further investigations. Our data confirmed the effects of dexmedetomidine on mitigating the tourniquet-induced hyperdynamic response in general anesthesia patients; nevertheless, they also revealed that the efficacy of dexmedetomidine on attenuating the tourniquet-induced hyperdynamic response was gradually decreased in the delayed phase of tourniquet inflation. Mechanisms underlying this observation remain to be elucidated.
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Fig. 3 e Changes in (A) CO and (B) SV. We measured CO and SV at the following time points: immediately before dexmedetomidine (or saline) loading (Tdose), every 30 min during tourniquet inflation (T30, T60, and T90, respectively), and 5 min after tourniquet deflation (Tdeflat). Data are represented as means and standard deviations. Dex [ dexmedetomidine (or saline) loading. Other abbreviations and symbols as in Fig. 2.
However, judging from the time course, we speculate that the gradual decrease in the efficacy of dexmedetomidine might be related to the continuous increases in plasma concentrations of epinephrine and norepinephrine induced by prolonged tourniquet inflation [5]. If so, a gradual increase in the dosage of dexmedetomidine infusion rather than a fixed-dosage infusion in the delayed phase of tourniquet inflation should be considered to achieve better hemodynamic control. Among the hemodynamic parameters investigated, our data revealed that dexmedetomidine exerted sustained effects on mitigating tourniquet-induced increases in HR, RPP, and CO. Because dexmedetomidine posed no significant effects on mitigating tourniquet-induced increases in SV, our data suggest that the sustained effects of dexmedetomidine on RPP and CO may result mainly from to its HR-decreasing effect. Dexmedetomidine was reported to induce significant HR and blood pressure decreases in conscious healthy volunteers through a central sympatholytic mechanism [10,11]. During initial infusion, however, dexmedetomidine could stimulate the peripheral postsynaptic a2B-adrenergic receptors and induce an immediate blood pressure increase and reflex HR decreases in conscious healthy volunteers [10,11]. This effect was not observed in general anesthesia patients [14,15]. In contrast, an immediate HR decrease and relatively stable blood pressure in general anesthesia patients during initial infusion of dexmedetomidine was reported [14,15]. We observed similar results in this study. The discrepancy between conscious and anesthetized patients was postulated to involve the vasodilatation effects of anesthetics (e.g., sevoflurane) and the synergistic negative chronotropic effects of dexmedetomidine and anesthetics [14,15]. Previous data indicated that patients with fewer perioperative hemodynamic fluctuations had lower postoperative mortality [16,17]. To maintain perioperative hemodynamic stability, in this study we treated patients who developed hypertension, hypotension, tachycardia, or bradycardia with medications including nicardipine, ephedrine, esmolol, and atropine, respectively. The total consumption of nicardipine, esmolol, and atropine was comparable in these two groups.
However, the total ephedrine consumption was significantly higher in the dexmedetomidine group, which mostly happened between dexmedetomidine loading and tourniquet inflation. These data indicate that the incidence of perioperative hypotension was higher in the dexmedetomidine group. We determined the loading dose of dexmedetomidine according to previous data showing that a loading dexmedetomidine infusion of 1 mg$kg1 over 10 min followed by a maintenance infusion rate of 0.2e0.7 mg$kg1$h1 could provide effective sedation for intensive care unit patients [18]. Because patients in this study also received sedative and anesthetic agents (i.e., midazolam, fentanyl, propofol, and sevoflurane), we decided to adjust the loading dose of dexmedetomidine to 0.8 mg$kg1$h1 to minimize the hemodynamic effects of dexmedetomidine. However, judging from our data revealing that dexmedetomidine loading caused bradycardia and hypotension, we believe that the loading dose of dexmedetomidine should be lowered. Similar to dexmedetomidine, the widely used a2-agonist clonidine has also been shown to effectively attenuate tourniquet-induced hyperdynamic response in general anesthesia patients [5,19]. Those data [5,19], in concert with data from the present study, confirmed the concept that incorporating a2-adrenergic receptor agonist (either dexmedetomidine or clonidine) in general anesthesia patients requiring tourniquet for surgery is beneficial. However, the question remains unstudied whether one of the a2-adrenergic receptor agonists is superior to the other regarding the efficacy or safety in mitigating a tourniquet-induced hyperdynamic response in general anesthesia patients. More studies are needed before further conclusions can be drawn. Certain study limitations exist. First, the interval between dexmedetomidine loading and tourniquet inflation varied between cases. This factor should be taken into consideration should further data interpretation be intended regarding the effect and safety of dexmedetomidine. Second, we employed only one infusion protocol of dexmedetomidine in this study. The ideal infusion protocols and ideal dosages of dexmedetomidine in this regard remain to be elucidated. Third, although
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the between-group difference regarding the types of surgery was not statistically significant, the types of surgery within group were heterogeneous in our study. Therefore, the impact of this factor should be taken into consideration for further data interpretation. Fourth, this study included only healthy adult patients, to avoid possible confounding factors. For instance, this study chose to exclude patients with a history of hypertension, cardiac arrhythmia, congestive heart failure, diabetes mellitus, and renal dysfunction. It also chose to exclude obese patients, because obesity is closely related to diseases such as hypertension, heart disease, diabetes mellitus, endothelial dysfunction, sleep apnea, and chronic kidney disease [20,21]. Therefore, it might not be possible to extrapolate results from this study to those patients. Fifth, as mentioned earlier, the tourniquet-induced hyperdynamic response is associated with augmented sympathetic outflow [4]. Previous data further indicate that augmented sympathetic outflow would increase energy expenditure and impose adverse effects on vital organs including the heart, lungs, and kidney, if the increased energy expenditure persisted [22]. Although we did not measure basal energy expenditure, previous data indicated that it has a strong correlation with minute ventilation and heart rate [23]. Because we conducted minute ventilation in a preprogrammed style in this study, we did not expect to observe significant between-group differences in this regard. However, our data revealed that subjects receiving dexmedetomidine had a lower heart rate than did those who received saline. Judging from these data, we thus speculate that basal energy expenditure in patients in the dexmedetomidine group was lower than for those in the control group. Sixth, dexmedetomidine can work synergistically with sevoflurane, because previous data indicated a 17% decrease in the minimal alveolar concentration of sevoflurane in adult patients with 0.7-ng$mL1 target dexmedetomidine plasma concentration [24]. According to the STANPUMP computer program, the loading dose of dexmedetomidine employed in this study (i.e., 0.8 mg$kg1 over 10 min) may have resulted in the target plasma concentration of 0.7e0.95 ng$mL1 in our patients. Therefore, it is possible that dexmedetomidine loading could decrease the BIS index level and subsequently cause anesthesiologists to turn down sevoflurane to maintain a BIS index of 40e45. Moreover, this might, in turn, limit the blinding of the anesthesiologists. If so, this possibility should be taken into account if further data interpretation is intended. In conclusion, dexmedetomidine attenuates tourniquetinduced hyperdynamic response in general anesthesia patients undergoing lower limb surgeries.
Acknowledgments The authors thank Dr. Mei-Chi Lin and Ms. Huy-Fang Wang for technical support. They also thank Mr. Yen-Chun Fan for statistical support. This work was mainly conducted at Mackay Memorial Hospital and was supported by grants from the Mackay Memorial Hospital (MMH 9729) and the National Science Council, Taiwan (NSC 96-2314-B-195-004-MY3), awarded to HCL and CJH, respectively.
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[1] Kam PC, Kavanagh R, Yoong FF. The arterial tourniquet: Pathophysiological consequences and anaesthetic implications. Anaesthesia 2001;56:534. [2] Kaufman RD, Walts LF. Tourniquet-induced hypertension. Br J Anaesth 1982;54:333. [3] Gielen MJ, Stienstra R. Tourniquet hypertension and its prevention: A review. Reg Anesth 1991;16:191. [4] Tetzlaff JE, O’Hara Jr J, Yoon HJ, et al. Tourniquet-induced hypertension correlates with autonomic nervous system changes detected by power spectral heart rate analysis. J Clin Anesth 1997;9:138. [5] Zalunardo MP, Serafino D, Szelloe P, et al. Preoperative clonidine blunts hyperadrenergic and hyperdynamic responses to prolonged tourniquet pressure during general anesthesia. Anesth Analg 2002;94:615. [6] Bylund DB. Subtypes of alpha 1- and alpha 2-adrenergic receptors. FASEB J 1992;6:832. [7] Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia 1999;54:146. [8] Coursin DB, Maccioli GA. Dexmedetomidine. Curr Opin Crit Care 2001;7:221. [9] Gobel FL, Norstrom LA, Nelson RR, et al. The rate-pressure product as an index of myocardial oxygen consumption during exercise in patients with angina pectoris. Circulation 1978;57:549. [10] Bloor BC, Ward DS, Belleville JP, et al. Effects of intravenous dexmedetomidine in humans. II. Hemodynamic changes. Anesthesiology 1992;77:1134. [11] Hall JE, Uhrich TD, Barney JA, et al. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg 2000;90:699. [12] Shirasaka T, Qiu DL, Kannan H, et al. The effects of centrally administered dexmedetomidine on cardiovascular and sympathetic function in conscious rats. Anesth Analg 2007; 105:1722. [13] Allee J, Muzaffar AR, Tobias JD. Dexmedetomidine controls the hemodynamic manifestations of tourniquet pain. Am J Ther 2011;18:e35. [14] Biccard BM, Goga S, de Beurs J. Dexmedetomidine and cardiac protection for non-cardiac surgery: A metaanalysis of randomised controlled trials. Anaesthesia 2008; 63:4. [15] Deutsch E, Tobias JD. Hemodynamic and respiratory changes following dexmedetomidine administration during general anesthesia: Sevoflurane vs desflurane. Paediatr Anaesth 2007;17:438. [16] Aronson S, Dyke CM, Stierer KA, et al. The ECLIPSE trials: Comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg 2008; 107:1110. [17] Dyke CMAS, Maier G, Bhatia D, et al. Perioperative blood pressure excursions are an independent predictor of 30-day mortality in patients undergoing valve surgery. Chest 2008; 134. 25004. [18] Venn M, Newman J, Grounds M. A phase II study to evaluate the efficacy of dexmedetomidine for sedation in the medical intensive care unit. Intensive Care Med 2003;29:201. [19] Honarmand A, Safavi MR. Preoperative oral dextromethorphan vs. clonidine to prevent tourniquetinduced cardiovascular responses in orthopaedic patients under general anaesthesia. Eur J Anaesthesiol 2007;24:511. [20] Krauss RM, Winston M, Fletcher BJ, et al. Obesity: impact on cardiovascular disease. Circulation 1998;98:1472.
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Available online at www.sciencedirect.com
journal homepage: www.JournalofSurgicalResearch.com
Dexmedetomidine attenuates tourniquet-induced hyperdynamic response in patients undergoing lower limb surgeries: A randomized controlled study Hsuan-Chih Lao, MD, MS,a,b Pei-Shan Tsai, PhD,c Jung-Yuan Su, MD,d Tiew-Guan Kwok, MD,d and Chun-Jen Huang, MD, PhDe,f,* a
Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan School of Medicine, National Yang-Ming University, Taipei, Taiwan c Graduate Institute of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan d Department of Orthopedics, Mackay Memorial Hospital, Taipei, Taiwan e Department of Anesthesiology, Buddhist Tzu Chi General Hospital, Taipei Branch, 289, Jianguo Road, Sindian District, New Taipei City 231, Taipei, Taiwan f School of Medicine, Tzu Chi University, Hualien, Taiwan b
article info
abstract
Article history:
Background: Activation of sympathetic nervous system has a crucial role in mediating the
Received 21 August 2011
pneumatic tourniquet inflation induced hyperdynamic response. Dexmedetomidine,
Received in revised form
a selective a2-adrenergic receptor agonist, has potent sympatholytic effects. We conducted
28 December 2011
this prospective, randomized, placebo-controlled, double-blinded study to elucidate the
Accepted 4 January 2012
effects of dexmedetomidine on attenuating the tourniquet-induced hyperdynamic
Available online 4 April 2012
response during general anesthesia. Materials and methods: We included a total of 72 healthy adult patients undergoing
Keywords:
elective lower limb surgery. Under general anesthesia, patients were randomized to the
Dexmedetomidine
dexmedetomidine or the control group (n ¼ 36 in each group). The dexmedetomidine
Tourniquet
group received a loading dose of dexmedetomidine (0.8 mg$kg1 over 10 min) followed by
Hypertension
continuous infusion of dexmedetomidine (0.4 mg$kg1.h1) until tourniquet deflation.
Lower limb
The control group received normal saline instead. We compared tourniquet-induced
Orthopedic surgery
changes in hemodynamic parameters between groups to elucidate the effects of dexmedetomidine. Results: Tourniquet inflation induced significant increases in hemodynamic parameters, including heart rate, systolic arterial pressure, mean arterial pressure, diastolic arterial pressure, rate pressure product, cardiac output, and stroke volume in the control group. The effects of tourniquet inflation on increasing hemodynamic parameters were significantly attenuated by dexmedetomidine: heart rate (P < 0.001), systolic arterial pressure (P ¼ 0.002), mean arterial pressure (P ¼ 0.042), diastolic arterial pressure (P ¼ 0.012), rate pressure product (P < 0.001), and cardiac output (P ¼ 0.001) of the dexmedetomidine group
Part of the study results were presented at the Annual Meeting of the American Society of Anesthesiologists, Orlando, Florida, October 18e22, 2008. * Corresponding author. Department of Anesthesiology, Buddhist Tzu Chi General Hospital, Taipei Branch, 289, Jianguo Rd., Sindian District, New Taipei City 231, Taiwan. Tel.: þ1 886 2 66289779, ext. 2639; fax: þ1 886 2 66289009. E-mail address: [email protected] (C.-J. Huang). 0022-4804/$ e see front matter ª 2013 Elsevier Inc. All rights reserved. doi:10.1016/j.jss.2012.01.008
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were significantly lower than those of the control group. However, the stroke volume of these groups was comparable. Conclusions: Dexmedetomidine attenuates tourniquet-induced hyperdynamic response in general anesthesia patients undergoing lower limb surgeries. ª 2013 Elsevier Inc. All rights reserved.
1.
Introduction
Pneumatic tourniquet is widely used in lower limb surgery to provide optimal operating conditions [1]. However, tourniquet inflation can induce a hyperdynamic response that may be resistant to therapies such as analgesic drugs, antihypertensive drugs, and increases in anesthesia depth [2,3]. Although mechanisms underlying the tourniquet-induced hyperdynamic response are not completely understood, augmented sympathetic outflow caused by tourniquet inflation has been proposed as an essential mechanism [4,5]. The a2-adrenergic receptors are present in the central and peripheral nervous system at autonomic ganglion as well as presynaptic and postsynaptic sites [6]. Activation of the a2-adrenergic receptors significantly decreases activity of the sympathetic nervous system [7]. Dexmedetomidine is a selective, short-acting, agonist of the a2-adrenergic receptors [8]. In addition to sympatholytic effects, dexmedetomidine has antihypertensive, anxiolytic, sedative, and analgesic effects [7]. Dexmedetomidine has been used clinically as an adjunct to anesthesia, analgesia, and intensive care unit sedation [7]. Theoretically, dexmedetomidine might exert significant effects on attenuating tourniquet-induced hyperdynamic response. To elucidate further, we conducted this randomized, placebo-controlled, double-blinded study with the hypothesis that dexmedetomidine can attenuate the tourniquet-induced hyperdynamic response in patients undergoing lower limb surgery.
2.
Materials and methods
2.1.
Participants
The Human Research Review Committee, Mackay Memorial Hospital (MMH-I-S-338) approved this prospective, randomized, placebo-controlled, double-blinded study, which was conducted in Mackay Memorial Hospital, a tertiary referral teaching hospital in Taipei, Taiwan, between August 2007 and December 2008. We approached all eligible patients for recruitment before te operation and enrolled them after obtaining written informed consent. Inclusion criteria were: adult patients (18e75 y old), with American Society of Anesthesiologists physical status I or II, who were scheduled for elective orthopedic lower limb surgeries and required pneumatic tourniquet application during surgeries. We excluded patients if they were taking adrenergic or cholinergic agents. We also excluded patients with fever (38 C), leucocytosis (white blood cells 10,000 cells$ml1), anemia (hematocrit < 20%), or obesity (body mass index > 30 kg.m2). In addition, we excluded patients with a history of hypertension, cardiac arrhythmia, congestive heart failure, diabetes mellitus, renal
dysfunction, hepatic dysfunction, or allergy to dexmedetomidine (or other a2-agonist agents). We also excluded patients with expected tourniquet time of <60 min or >150 min. Because no previous study was available regarding the effect of dexmedetomidine effect in this regard, we estimated the sample size based on previous data derived from a study on another widely used a2-adrenergic receptor agonist, clonidine [5]. Previous data revealed that mean arterial pressure (MAP) after tourniquet deflation in patients who received clonidine was significantly lower than those who received normal saline (84 11 versus 71 8 mm Hg) [5]. Based on these data (expected differences in means, 13; expected standard deviation, 9.5), power analysis revealed that a sample size of 10 patients per group was sufficient to detect a statistically significant between group difference, with an alpha of 0.05 and a power of 82.5%. Nevertheless, because the estimation was based on clonidine data, we decided to include at least 10 patients per group. By the end of the study period approved by the Human Research Review Committee of our institute, a total of 36 patients per group were included. We conducted patient enrollment and subsequent allocation as illustrated in the CONSORT diagram (Fig. 1).
2.2.
Hemodynamic monitoring
We employed continuous electrocardiography (ECG) and noninvasive blood pressure with arm cuff (NIBP) to measure heart rate (HR), systolic arterial pressure (SAP), MAP, and diastolic arterial pressure (DAP). In addition, we noninvasively monitored cardiac output (CO) and stroke volume (SV) using the Finometer, a noninvasive hemodynamic monitoring device (TNO Biomedical Instrumentation, Amsterdam, The Netherlands). We performed validation of the Finometer using upper-arm cuff return-to-flow measurement to calibrate blood pressure, according to the manufacturer’s manual. Myocardial oxygen consumption can be estimated by calculating the rate pressure product (RPP) (i.e., HR SAP) [9]. We thus also calculated RPP in this study.
2.3.
Anesthetic management
We applied standard monitoring devices, including electrocardiogram, noninvasive blood pressure monitoring, pulse oximetry, and capnography. After receiving premedication with midazolam (0.035 mg$kg1, intravenously [IV]) and hydration with Ringer’s lactate solution (500 mL), baseline hemodynamics were measured. We induced general anesthesia with fentanyl (2 mg$kg1, IV) and propofol (2 mg$kg1, IV). We used a bispectral index monitor (BIS) (Aspect A1000 monitor; Medical Systems, Natick, MA) to monitor anesthesia depth. We used rocuronium (1 mg$kg1, IV) to facilitate tracheal intubation. Tracheal intubation was performed after
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Fig. 1 e The CONSORT diagram showing patients’ flow through the study.
loss of response to train-of-four with neuromuscular stimulation and a BIS index <50 was achieved. After tracheal intubation, we controlled ventilation with a tidal volume of 10 mL$kg1 and adjusted the respiratory rate to maintain an end-tidal carbon dioxide of 35e40 mm Hg. All patients’ lungs were mechanically ventilated with 4 L$min1 fresh gas (50% air:50% O2). We maintained anesthesia with sevoflurane and adjusted the concentration was to achieve a BIS index of 40e45.
2.4.
Experimental protocols
An anesthesiologist who was involved only in preparing the medication in a 100-mL syringe randomly allocated patients to the dexmedetomidine or control group using a random number table. The surface of syringe was covered with a tinfoil paper and numbered by order on the surface. All of the participants were blinded to grouping, including patients, anesthesiologists who performed general anesthesia throughout the operations, and anesthesiologists who set up all the monitors, started the infusion of syringe medications, and recorded all data. Patients in the dexmedetomidine group received a loading dose of dexmedetomidine (0.8 mg$kg1 over 10 min), followed by continuous infusion of dexmedetomidine (0.4 mg$kg1$h1) until pneumatic tourniquet deflation. Patients in the control group received an equal amount of 0.9% saline instead. Loading of dexmedetomidine or 0.9% saline started immediately after stable anesthesia status (i.e., a BIS index of 40e45) was achieved. After the beginning of dexmedetomidine or saline infusion, lower limb pneumatic tourniquet was applied at the high thigh level. We determined tourniquet inflation pressure based on the patient’s SAP, i.e., no less than twice the patient’s SAP. The range of inflation pressure was 300e350 mm Hg. We measured HR, SAP, MAP, DAP, and RPP at the following time points: immediately before dexmedetomidine (or saline) loading (Tdose), immediately before tourniquet inflation (Tinflat), every 15 min during tourniquet inflation (T15, T30, T45, T60, T75, and T90, respectively), and 5 min after tourniquet
deflation (Tdeflat). In addition, we measured CO and SV at Tdose, T30, T60, T90, and Tdeflat. Patients who experienced hypertension (i.e., SAP > 160 mm Hg and/or DAP > 90 mm Hg for more than 5 min) during the experiment were treated with nicardipine injection (5 mg, IV, every 5 min). Patients who experienced hypotension (i.e., SAP < 90 mm Hg and/or MAP < 70 mm Hg for more than 5 min) were treated with incremental doses of ephedrine injection (i.e., 4, 8, 10, 12, 14, and 16 mg, IV). Tachycardia (i.e., HR > 100 beats$min1 for more than 5 min) was treated with esmolol injection (5 mg, IV), whereas bradycardia (i.e., HR < 60 beats$min1 for more than 5 min) was treated with atropine injection (0.4 mg, IV).
2.5.
Statistical analysis
We performed statistical analyses using a commercial software package (SPSS 11.5 for Windows; SPSS Science, Chicago, IL). Data are presented as means with standard deviations. We examined differences between groups using Student’s t-test for continuous data and the Chi-square test for categorical data. We performed repeated-measures analysis of variance with Bonferroni corrections to examine the withinsubjects (time) effect, between-subjects (group) effect, and group by time interaction effect in hemodynamic data. A twotailed alpha level of 0.05 was set for all statistical tests, and P < 0.05 was considered statistically significant. The percentages of patients who developed tourniquet-induced hyperdynamic response, defined as more than a 30% increase in SAP during tourniquet inflation [2], were compared between groups.
3.
Results
The demographic data and duration of tourniquet inflation were comparable between groups (Table 1). The incidence of tourniquet-induced hyperdynamic response in the control
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Table 1 e Demographic data, types of surgeries, and duration of tourniquet inflation.
Age (y) Gender (M/F) ASA physical status (I/II) Weight (kg) Height (cm) BMI (kg.m2) Type of surgery (TKR/arthroscopy/ORIF) Tourniquet time (min)
Control group (n ¼ 36)
Dexmedetomidine group (n ¼ 36)
43 19 19/18 22/14 65 10 164 9 24 4 8/11/17 104 22
45 18 12/24 25/11 70 12 166 9 25 4 8/10/18 108 25
ASA ¼ american society of anesthesiologists; TKR ¼ total knee replacement; ORIF ¼ open reduction and internal fixation of lower limb. Values are means standard deviations.
group was significantly higher than that in the dexmedetomidine group (67.6% versus 19.4%; P < 0.001) (Table 2). However, the total doses of nicardipine and atropine consumption in these two groups were comparable (Table 2). In contrast, the total dose of ephedrine consumption in the dexmedetomidine group was significantly higher than that in the control group (P ¼ 0.020) (Table 2). In addition, none of the cases included in this study received esmolol. The baseline hemodynamic data (i.e., HR, SAP, MAP, DAP, CO, and SV) were comparable between groups. Anesthesia induction and tracheal intubation exerted similar hemodynamic effects in both groups, as the HR, SAP, MAP, and DAP values measured at Tdose of the groups were comparable (Fig. 2 AeD ). The HR value in the dexmedetomidine group measured at Tinflat was significantly lower than that measured at Tdose (P < 0.001) (Fig. 2A), which indicates that dexmedetomidine loading caused a significant decrease in HR. In contrast, the SAP, MAP, and DAP values in the dexmedetomidine group measured at Tinflat were comparable to those measured at Tdose (Fig. 2BeD).
significant increases in SAP in the control group, as the SAP values of the control group measured at T15, T30, T45, T60, T75, and T90 were significantly higher than that measured at Tinflat (all P < 0.001) (Fig. 2B). The SAP value in the control group measured at Tdeflat was also significantly higher than that measured at Tinflat (P < 0.001) (Fig. 2B). The SAP values in the dexmedetomidine group measured at T15, T30, and T45 were significantly lower than those in the control group (all P < 0.040) (Fig. 2B), which indicates that dexmedetomidine attenuated the tourniquet-induced SAP increases. However, the SAP values in the dexmedetomidine group measured at T60, T75, and T90 were comparable to those in the control group (Fig. 2B). In contrast, the SAP value in the dexmedetomidine group measured at Tdeflat was significantly lower than that in the control group (P < 0.001) (Fig. 2B). The changes in MAP (Fig. 2C) and DAP (Fig. 2D) paralleled those of SAP (Fig. 2B).
3.1. Dexmedetomidine attenuated tourniquet-induced increases in HR
Repeated-measures analysis of variance revealed that the magnitude of changes in RPP was significantly different between groups (P < 0.001). Tourniquet inflation also caused significant increases in RPP in the control group, as the RPP values measured at T15, T30, T45, T60, T75, and T90 were significantly higher than that measured at Tinflat (all P < 0.050)
Repeated-measures analysis of variance revealed that the trend of HR was significantly different between groups (P < 0.001). Tourniquet inflation caused significant increases in HR in the control group, as the HR values measured at T15, T30, T45, T60, T75, and T90 were significantly higher than that measured at Tinflat (all P < 0.001) (Fig. 2A). The HR value in the control group measured at Tdeflat was also significantly higher than that measured at Tinflat (P < 0.001) (Fig. 2A). In contrast, the HR values in the dexmedetomidine group were significantly lower than those in the control group throughout the experiment (all P < 0.05) (Fig. 2A), which indicates that dexmedetomidine attenuated the effects of tourniquet inflation on inducing HR increases.
3.2. Dexmedetomidine attenuated tourniquet-induced increases in SAP, MAP, and DAP Repeated-measures analysis of variance revealed significant group by time interaction effects in SAP, MAP, and DAP, which indicates that the magnitude of the changes in SAP, MAP, and DAP were significantly different between groups (P ¼ 0.002, 0.042, and 0.012, respectively). Tourniquet inflation caused
3.3. Dexmedetomidine attenuated tourniquet-induced increases in RPP
Table 2 e Incidence of tourniquet-induced hyperdynamic response and total consumption of the rescue medications. Group
Tourniquetinduced hyperdynamic response (Y/N) Nicardipine (mg) Ephedrine (mg) Atropine (mg)
Control (n ¼ 36)
Dexmedetomidine (n ¼ 36)
24/12
7/29
0.4 1.6 0.8 3.7 0.03 0.12
0.1 0.3 3.6 5.8 0.08 0.17
Values are means standard deviations. a P < .050, dexmedetomidine versus control group.
P value
<.001a
.070 .020* .230
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Fig. 2 e Changes in (A) HR, (B) SAP, (C) MAP, (D) DAP, and (E) RPP. We measured HR, SAP, MAP, DAP, and RPP at the following time points: immediately before dexmedetomidine (or saline) loading (Tdose), immediately before tourniquet inflation (Tinflat), every 15 min during tourniquet inflation (T15, T30, T45, T60, T75, and T90, respectively), and 5 min after tourniquet deflation (Tdeflat). Data are represented as means and standard deviations. Dex [ dexmedetomidine (or saline) loading; Inf [ tourniquet inflation; Def [ tourniquet deflation. *P < 0.05, dexmedetomidine group versus control group. yP < 0.05, Tinflat versus Tdose. #P < 0.05 versus Tinflat.
(Fig. 2E). The RPP value measured at Tdeflat was also significantly higher than that measured at Tinflat (P < 0.001) (Fig. 2E). Similar to HR, the RPP values in the dexmedetomidine group measured during and after tourniquet deflation were significantly lower than those in the control group (all P < 0.010) (Fig. 2E).
3.4. Dexmedetomidine attenuated tourniquet-induced increases in CO Repeated-measures analysis of variance revealed that the magnitude of changes in CO was significantly different between groups (P ¼ 0.001). The CO values in the control group measured at T30, T60, T90, and Tdeflat were significantly higher than those measured at Tdose (all P < 0.035) (Fig. 3A). The CO values in the dexmedetomidine group measured at T30, T60, T90, and Tdeflat were significantly lower than those in the control group (all P < 0.010) (Fig. 3A). In contrast to CO, the difference in the pattern of changes in SV between groups was not statistically significant (P ¼ 0.511). The SV values in the two groups were comparable throughout the experiment (Fig. 3B).
4.
Discussion
Data from this study confirmed that tourniquet inflation induced a hyperdynamic response in general anesthesia patients
undergoing lower limb orthopedic surgery. As mentioned earlier, an augmented sympathetic outflow has been proposed to be an essential mechanism contributing to this tourniquetinduced hyperdynamic response [4,5]. Dexmedetomidine stimulates the central presynaptic a2A-adrenergic receptors and exerts central sympatholytic effects that can significantly decrease the plasma concentrations of norepinephrine and epinephrine [10e12]. Judging from these data, we thus hypothesized that dexmedetomidine could attenuate the tourniquet-induced hyperdynamic response. Data from this study confirmed our hypothesis. In concert with clinical data observed in three patients requiring tourniquet for surgery [13], our data provide clear evidence to support the concept that dexmedetomidine can serve as an effective adjunct to general anesthesia in patients using pneumatic tourniquet for lower limb surgery. Because the tourniquet-induced hyperdynamic response is resistant to therapies [3], data from this study thus should have certain clinical significance and warrant further investigations. Our data confirmed the effects of dexmedetomidine on mitigating the tourniquet-induced hyperdynamic response in general anesthesia patients; nevertheless, they also revealed that the efficacy of dexmedetomidine on attenuating the tourniquet-induced hyperdynamic response was gradually decreased in the delayed phase of tourniquet inflation. Mechanisms underlying this observation remain to be elucidated.
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Fig. 3 e Changes in (A) CO and (B) SV. We measured CO and SV at the following time points: immediately before dexmedetomidine (or saline) loading (Tdose), every 30 min during tourniquet inflation (T30, T60, and T90, respectively), and 5 min after tourniquet deflation (Tdeflat). Data are represented as means and standard deviations. Dex [ dexmedetomidine (or saline) loading. Other abbreviations and symbols as in Fig. 2.
However, judging from the time course, we speculate that the gradual decrease in the efficacy of dexmedetomidine might be related to the continuous increases in plasma concentrations of epinephrine and norepinephrine induced by prolonged tourniquet inflation [5]. If so, a gradual increase in the dosage of dexmedetomidine infusion rather than a fixed-dosage infusion in the delayed phase of tourniquet inflation should be considered to achieve better hemodynamic control. Among the hemodynamic parameters investigated, our data revealed that dexmedetomidine exerted sustained effects on mitigating tourniquet-induced increases in HR, RPP, and CO. Because dexmedetomidine posed no significant effects on mitigating tourniquet-induced increases in SV, our data suggest that the sustained effects of dexmedetomidine on RPP and CO may result mainly from to its HR-decreasing effect. Dexmedetomidine was reported to induce significant HR and blood pressure decreases in conscious healthy volunteers through a central sympatholytic mechanism [10,11]. During initial infusion, however, dexmedetomidine could stimulate the peripheral postsynaptic a2B-adrenergic receptors and induce an immediate blood pressure increase and reflex HR decreases in conscious healthy volunteers [10,11]. This effect was not observed in general anesthesia patients [14,15]. In contrast, an immediate HR decrease and relatively stable blood pressure in general anesthesia patients during initial infusion of dexmedetomidine was reported [14,15]. We observed similar results in this study. The discrepancy between conscious and anesthetized patients was postulated to involve the vasodilatation effects of anesthetics (e.g., sevoflurane) and the synergistic negative chronotropic effects of dexmedetomidine and anesthetics [14,15]. Previous data indicated that patients with fewer perioperative hemodynamic fluctuations had lower postoperative mortality [16,17]. To maintain perioperative hemodynamic stability, in this study we treated patients who developed hypertension, hypotension, tachycardia, or bradycardia with medications including nicardipine, ephedrine, esmolol, and atropine, respectively. The total consumption of nicardipine, esmolol, and atropine was comparable in these two groups.
However, the total ephedrine consumption was significantly higher in the dexmedetomidine group, which mostly happened between dexmedetomidine loading and tourniquet inflation. These data indicate that the incidence of perioperative hypotension was higher in the dexmedetomidine group. We determined the loading dose of dexmedetomidine according to previous data showing that a loading dexmedetomidine infusion of 1 mg$kg1 over 10 min followed by a maintenance infusion rate of 0.2e0.7 mg$kg1$h1 could provide effective sedation for intensive care unit patients [18]. Because patients in this study also received sedative and anesthetic agents (i.e., midazolam, fentanyl, propofol, and sevoflurane), we decided to adjust the loading dose of dexmedetomidine to 0.8 mg$kg1$h1 to minimize the hemodynamic effects of dexmedetomidine. However, judging from our data revealing that dexmedetomidine loading caused bradycardia and hypotension, we believe that the loading dose of dexmedetomidine should be lowered. Similar to dexmedetomidine, the widely used a2-agonist clonidine has also been shown to effectively attenuate tourniquet-induced hyperdynamic response in general anesthesia patients [5,19]. Those data [5,19], in concert with data from the present study, confirmed the concept that incorporating a2-adrenergic receptor agonist (either dexmedetomidine or clonidine) in general anesthesia patients requiring tourniquet for surgery is beneficial. However, the question remains unstudied whether one of the a2-adrenergic receptor agonists is superior to the other regarding the efficacy or safety in mitigating a tourniquet-induced hyperdynamic response in general anesthesia patients. More studies are needed before further conclusions can be drawn. Certain study limitations exist. First, the interval between dexmedetomidine loading and tourniquet inflation varied between cases. This factor should be taken into consideration should further data interpretation be intended regarding the effect and safety of dexmedetomidine. Second, we employed only one infusion protocol of dexmedetomidine in this study. The ideal infusion protocols and ideal dosages of dexmedetomidine in this regard remain to be elucidated. Third, although
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the between-group difference regarding the types of surgery was not statistically significant, the types of surgery within group were heterogeneous in our study. Therefore, the impact of this factor should be taken into consideration for further data interpretation. Fourth, this study included only healthy adult patients, to avoid possible confounding factors. For instance, this study chose to exclude patients with a history of hypertension, cardiac arrhythmia, congestive heart failure, diabetes mellitus, and renal dysfunction. It also chose to exclude obese patients, because obesity is closely related to diseases such as hypertension, heart disease, diabetes mellitus, endothelial dysfunction, sleep apnea, and chronic kidney disease [20,21]. Therefore, it might not be possible to extrapolate results from this study to those patients. Fifth, as mentioned earlier, the tourniquet-induced hyperdynamic response is associated with augmented sympathetic outflow [4]. Previous data further indicate that augmented sympathetic outflow would increase energy expenditure and impose adverse effects on vital organs including the heart, lungs, and kidney, if the increased energy expenditure persisted [22]. Although we did not measure basal energy expenditure, previous data indicated that it has a strong correlation with minute ventilation and heart rate [23]. Because we conducted minute ventilation in a preprogrammed style in this study, we did not expect to observe significant between-group differences in this regard. However, our data revealed that subjects receiving dexmedetomidine had a lower heart rate than did those who received saline. Judging from these data, we thus speculate that basal energy expenditure in patients in the dexmedetomidine group was lower than for those in the control group. Sixth, dexmedetomidine can work synergistically with sevoflurane, because previous data indicated a 17% decrease in the minimal alveolar concentration of sevoflurane in adult patients with 0.7-ng$mL1 target dexmedetomidine plasma concentration [24]. According to the STANPUMP computer program, the loading dose of dexmedetomidine employed in this study (i.e., 0.8 mg$kg1 over 10 min) may have resulted in the target plasma concentration of 0.7e0.95 ng$mL1 in our patients. Therefore, it is possible that dexmedetomidine loading could decrease the BIS index level and subsequently cause anesthesiologists to turn down sevoflurane to maintain a BIS index of 40e45. Moreover, this might, in turn, limit the blinding of the anesthesiologists. If so, this possibility should be taken into account if further data interpretation is intended. In conclusion, dexmedetomidine attenuates tourniquetinduced hyperdynamic response in general anesthesia patients undergoing lower limb surgeries.
Acknowledgments The authors thank Dr. Mei-Chi Lin and Ms. Huy-Fang Wang for technical support. They also thank Mr. Yen-Chun Fan for statistical support. This work was mainly conducted at Mackay Memorial Hospital and was supported by grants from the Mackay Memorial Hospital (MMH 9729) and the National Science Council, Taiwan (NSC 96-2314-B-195-004-MY3), awarded to HCL and CJH, respectively.
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