Preoperative dexmedetomidine prevents tourniquet-induced hypertension in orthopedic operation during general anesthesia

Kaohsiung Journal of Medical Sciences (2013) 29, 271e274

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ORIGINAL ARTICLE

Preoperative dexmedetomidine prevents tourniquetinduced hypertension in orthopedic operation during general anesthesia Yao Lu a, Ye Zhang b,*, Chun-Shan Dong a, Jun-Ma Yu a, Gordon Tin-Chun Wong c a

Department of Anesthesiology, Third Affiliated Hospital of Anhui Medical University, Hefei, China Department of Anesthesiology, Second Affiliated Hospital of Anhui Medical University, Hefei, China c Department of Anesthesiology, University of Hong Kong, Hong Kong b

Received 5 January 2012; accepted 20 March 2012 Available online 20 December 2012

KEYWORDS Dexmedetomidine; General anesthesia; Hypertension; Tourniquet

Abstract This study was a double-blinded randomized control trial designed to investigate the hemodynamic effects of dexmedetomidine on prolonged tourniquet inflation. Thirtyseven patients scheduled for elective orthopedic surgery of the lower limb under general anesthesia were recruited. They were randomly assigned to receive intravenous dexmedetomidine (DEX, 0.5 mg/kg; n Z 18) or normal saline (CON; n Z 19) before tourniquet inflation. Arterial blood pressure and heart rate were recorded every 10 minutes until 60 minutes after the start of tourniquet inflation and again immediately after deflation. In the DEX group, arterial pressure was not significantly changed, but in the CON group arterial pressure was significantly increased at 40, 50, and 60 minutes after the start of tourniquet inflation. Development of more than 30% increase in arterial pressure during tourniquet inflation was more frequent in the CON group than in the DEX group. Preoperative intravenous dexmedetomidine could therefore prevent tourniquet-induced hypertension in patients undergoing general anesthesia. Copyright ª 2012, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved.

Introduction Tourniquets are widely used in orthopedic surgery of the extremities to reduce surgical bleeding, but prolonged * Corresponding author. Department of Anesthesiology, Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China. E-mail address: [email protected] (Y. Zhang).

inflation is also associated with severe pain which, in turn, is often accompanied by a progressive increase in systemic arterial pressure [1,2]. Tourniquet-induced hypertension (TIH) is generally defined as a progressive increase of more than 30% in arterial blood pressure after tourniquet inflation under general anesthesia [3,4]. The onset of TIH is delayed, and its treatment is difficult and often ineffective, even with increased doses of anesthetics and antihypertensive drugs [4]. Clonidine [5], ketamine [6], magnesium

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272 [7], and stellate ganglion block [8] have been used prophylactically to prevent TIH. Although the mechanism of TIH is unknown, the autonomic nervous system is involved [1]. Dexmedetomidine is a potent a2-adrenoceptor agonist with eight times higher affinity for the a2-adrenoceptor than clonidine, and it has shown sedative, analgesic, and anxiolytic effects after intravenous administration [9]. Dexmedetomidine attenuates hyperadrenergic responses and therefore may be of therapeutic or prophylactic value for TIH. In this study, we investigated the effect of preoperative intravenous dexmedetomidine on arterial blood pressure and heart rate in patients undergoing general anesthesia for orthopedic surgery of the lower limbs with a tourniquet.

Methods This study was randomized, double-blinded, and placebocontrolled. After approval was obtained from the ethics committee of the Third Affiliated Hospital of Anhui Medical University and written informed consent was received from each patient, 37 ASA (American Society of Anesthesiologists) physical status class I and II patients scheduled for orthopedic operation requiring tourniquet inflation of the lower limbs under general anesthesia were enrolled. Patients with known contraindications to dexmedetomidine; who had ischemic heart disease, hypertension, kidney dysfunction, or diabetes mellitus; and with expected tourniquet inflation time shorter than 60 minutes were excluded. All patients received intramuscular phenobarbital (0.5 mg) 30 minutes before induction of anesthesia. Patients in the dexmedetomidine group (DEX; n Z 18) received intravenous dexmedetomidine (0.5 mg/kg) diluted in 10 mL normal saline infused over 10 minutes, immediately before induction of anesthesia. Patients in the control group (CON; n Z 19) received the same volume of normal saline infused over the same period. The infusions were prepared by a nurse anesthetist not involved with the case according to a computer-generated sequence. Anesthesia was induced with fentanyl (2e4 mg/kg) and propofol (2 mg/ kg), and vecuronium (0.1 mg/kg) was given intravenously to facilitate intubation of the trachea. Arterial pressure before induction of anesthesia was measured noninvasively. After anesthesia induction, a radial artery catheter was inserted for invasive blood pressure measurements. Anesthesia was maintained with propofol (75 mg/kg/min) and remifentanil (0.1 mg/kg/min). Muscle paralysis was maintained with vecuronium. Tidal volume was adjusted to keep the end-tidal CO2 concentration 35e45 mmHg. After skin incision, the tourniquet was inflated to a pressure of 300 mmHg. If systolic arterial pressure exceeded 180 mmHg despite increased doses of propofol and remifentanil, an additional bolus of nitroglycerol was given intravenously. Blood pressure and heart rate were recorded at 0, 10, 20, 30, 40, 50, and 60 minutes after the start of tourniquet inflation and immediately after tourniquet deflation. The number of patients who developed TIH, as defined by an increase in arterial blood pressure greater than 30% of the baseline value, was recorded. The patients were extubated at the end of surgery after reversal with atropine (0.5 mg) and neostigmine (1 mg). Statistical analysis was performed using the SPSS 10.0 program (SPSS Inc., Chicago, IL, USA). All data are presented

Y. Lu et al. as mean  standard deviation. Demographic data for the patients were compared among the groups using one-way analysis of variance with the post hoc Scheffe ´ test. The hemodynamic changes were compared with the baseline values and among the groups by using two-way repeatedmeasures analysis of variance with Tukey’s post hoc test. The c2 test was used to compare the number of patients with TIH. Statistical differences were considered significant if the p value was less than 0.05.

Results There were no statistically significant differences between the groups with respect to the patients’ demographic characteristics, dose of propofol and remifentanil, time for duration of tourniquet inflation, and anesthesia (Table 1). In the DEX group, systolic and diastolic arterial pressures were not changed during the study period, but in the CON group, systolic arterial pressure and diastolic arterial pressure were significantly increased at 40, 50, and 60 minutes after the start of tourniquet inflation. In all patients, the heart rate did not change significantly during tourniquet inflation, but there was a significant increase immediately after deflation in the CON group (Fig. 1). The CON group had a greater percentage of patients who developed TIH when compared with the DEX group.

Discussion The results from this study showed that preoperative intravenous dexmedetomidine significantly prevented a systemic arterial pressure increase during prolonged tourniquet inflation in patients under general anesthesia. Perioperative hypertension may be associated with serious cardiac complications [10e12]. Furthermore, the level of hypertension is correlated with the occurrence of postoperative silent myocardial ischemia [12]. The intraoperative hypertension induced by prolonged tourniquet inflation of the lower limbs is often unresponsive to increased doses of anesthetics and antihypertensive drugs

Table 1 Demographic data, dose of propofol and remifentanil, duration of tourniquet inflation, and anesthesia. Variable Age (y) Sex (m/f) Height (cm) Weight (kg) Tourniquet (min) Propofol dose (mg) Remifentanil dose (mg) Duration of anesthesia (min)

CON (n Z 19) 37 11/8 173 70 67 407 1062 96

 11      

5 8 6 49 288 18

DEX (n Z 18) 40  12/6 170  67  69  387  983  104 

12 7 11 7 32 168 18

Values are presented as mean  SD. There were no significant differences between groups. CON Z group receiving normal saline; DEX Z group receiving dexmedetomidine; Tourniquet Z duration of tourniquet inflation.

Dexmedetomidine prevents hypertension

Figure 1. Hemodynamic changes in the two groups. Values are presented as mean  SD. After Z immediately after tourniquet deflation; Baseline Z immediately before anesthesia induction; Before Z after anesthesia induction and immediately before tourniquet inflation; CON Z group receiving normal saline; DBP Z diastolic blood pressure; DEX Z dexmedetomidine; HR Z heart rate; SBP Z systolic blood pressure.

[4]. Once tourniquet-induced arterial pressure increase develops, it is often difficult to control. In these patients, intravenous dexmedetomidine before tourniquet inflation may have a role in attenuating these blood pressure increases. Tetzlaff et al. [1] showed that tourniquetinduced arterial pressure increases correlate with the activation of the sympathetic nervous system, as measured by power spectral heart rate analysis. An increase in plasma norepinephrine levels was related to the tourniquet-

273 induced arterial pressure increase under general anesthesia [13]. Catecholamine release after the activation of the sympathetic nervous system may contribute to the increase in systemic arterial pressure during prolonged tourniquet inflation. Dexmedetomidine is an a2-receptor agonist with both sedative and analgesic properties that reduce the sedation, anxiolytic, and analgesic requirements in the perioperative setting [9]. Dexmedetomidine improves hemodynamic stability in the perioperative period by exerting sympatholytic effects via activation of the inhibitory a2-receptors both in the central nervous system and on peripheral sympathetic nerve endings [14,15], and reduces plasma epinephrine and norepinephrine levels [16,17]. Dexmedetomidine has been reported to be useful in attenuating hemodynamic stress secondary to hyperadrenergic over-reactivity [18]. In awake patients, the addition of dexmedetomidine to the local anesthetic solution in intravenous regional anesthesia decreases tourniquet pain [19]. Preoperative intravenous clonidine blunts both the increase in sympathetic out flow and arterial hypertension associated with tourniquet inflation under general anesthesia [5]. In this study, we have shown that preoperative intravenous dexmedetomidine could also prevent TIH. The use of dexmedetomidine may have added benefits such as attenuating the cardiovascular and sympathoadrenal response to intubation and extubation [20] and reducing opioid requirements during and after surgery [20,21]. Dexmedetomidine decreases the incidence and frequency of delirium in children [22] and adults [23]. There are several limitations in this study. First, we did not perform a doseeresponse study having only used one dose. Future studies could evaluate whether smaller doses can achieve the same benefit or whether larger doses can reduce TIH to a greater extent. Second, the effect of dexmedetomidine on the relationship between tourniquetinduced pain and hypertension was not evaluated, because this study was performed in patients receiving general anesthesia. Lastly, the depth of anesthesia might have been different in the two groups as we did not use any depth of anesthesia monitoring However, there were no significant differences in propofol and remifentanil consumption during the study period and arterial pressure before tourniquet inflation between the groups. In conclusion, preoperative intravenous dexmedetomidine significantly prevents hemodynamic responses to prolonged tourniquet inflation of the lower limbs under general anesthesia in patients. On the basis of the results of this study, further investigations are needed to show whether perioperative outcome in patients with arterial hypertension or cardiovascular disease is improved by dexmedetomidine treatment.

References [1] Tetzlaff JE, O’Hara J, Yoon HJ, Schubert A. Tourniquetinduced hypertension correlates with autonomic nervous system changes detected by power spectral heart rate analysis. J Clin Anesth 1997;9:138e42. [2] Hagenouw RR, Bridenbaugh PO, van Egmond J, Stuebing R. Tourniquet pain: a volunteer study. Anesth Analg 1986;65: 1175e80.

274 [3] Valli H, Rosenberg PH, Kytta J, Nurminen M. Arterial hypertension associated with the use of a tourniquet with either general or regional anaesthesia. Acta Anaesthesiol Scand 1987;31:279e83. [4] Valli H, Rosenberg PH. Effects of three anaesthesia methods on haemodynamic responses connected with the use of thigh tourniquet in orthopaedic patients. Acta Anaesthesiol Scand 1985;29:142e7. [5] Zalunardo MP, Serafino D, Szelloe P, Weisser F, Zollinger A, Seifert B, et al. Preoperative clonidine blunts hyperadrenergic and hyperdynamic responses to prolonged tourniquet pressure during general anesthesia. Anesth Analg 2002;94:615e8. [6] Satsumae T, Yamaguchi H, Sakaguchi M, Yasunaga T, Yamashita S, Yamamoto S, et al. Preoperative small-dose ketamine prevented tourniquet-induced arterial pressure increase in orthopedic patients under general anesthesia. Anesth Analg 2001;92:1286e9. [7] Lee DH, Jee DL, Kim SY, Kim JM, Lee HM. Magnesium sulphate attenuates tourniquet-induced hypertension and spinal c-fos mRNA expression: a comparison with ketamine. J Int Med Res 2006;34:573e84. [8] Arai YC, Ogata J, Matsumoto Y, Yonemura H, Kido K, Uchida T, et al. Preoperative stellate ganglion blockade prevents tourniquet-induced hypertension during general anesthesia. Acta Anaesthesiol Scand 2004;48:613e8. [9] Bhana N, Goa KL, McClellan KJ. Dexmedetomidine. Drugs 2000;59:263e8. [10] Seltzer JL, Gerson JI, Grogono AW. Hypertension in perioperative period. N Y State J Med 1980;80:29e31. [11] Howell SJ, Hemming AE, Allman KG, Glover L, Sear JW, Foex P. Predictors of postoperative myocardial ischaemia. The role of intercurrent arterial hypertension and other cardiovascular risk factors. Anaesthesia 1997;52:107e11. [12] Forrest JB, Rehder K, Cahalan MK, Goldsmith CH. Multicenter study of general anesthesia: III. Predictors of severe perioperative adverse outcomes. Anesthesiology 1992;76:3e15. [13] Crews JC, Sehlhorst CS. Response to maintenance of tourniquet inflation in a primate model. Reg Anesth 1991;16:195e8.

Y. Lu et al. [14] Schmelling W, Farber N. The effects of alpha-2 adrenergic agonists on cardiovascular system. Semin Cardiothor Vasc Anesth 1997;1:1e20. [15] Lawrence C, DeLange S. Effects of a single pre-operative dexmedetomidine dose on isoflurane requirements and perioperative haemodynamic stability. Anaesthesia 1997;52: 736e44. [16] Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000;93:382e94. [17] Talke P, Chen R, Thomas B, Aggarwall A, Gottlieb A, Thorberg P, et al. The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery. Anesth Analg 2000;90:834e9. [18] Kulkarni A, Price G, Saxena M, Skowronski G. Difficult extubation: calming the sympathetic storm. Anaesth Intensive Care 2004;32:413e6. [19] Ramadhyani U, Park JL, Carollo DS, Waterman RS, Nossaman BD. Dexmedetomidine: clinical application as an adjunct for intravenous regional anesthesia. Anesthesiol Clin 2010;28:709e22. [20] Scheinin B, Lindgren L, Randell T, Scheinin H, Scheinin M. Dexmedetomidine attenuates sympathoadrenal responses to tracheal intubation and reduces the need for thiopentone and peroperative fentanyl. Br J Anesthesia 1992;68:126e31. [21] Lin TF, Yeh YC, Lin FS, Wang YP, Lin CJ, Sun WZ, et al. Effect of combining dexmedetomidine and morphine for intravenous patient-controlled analgesia. Br J Anesthesia 2009;102:117e22. [22] Shukry M, Clyde MC, Kalarickal PL, Ramadhyani U. Does dexmedetomidine prevent emergence delirium in children after sevoflurane-based general anesthesia? Pediatr Anaesth 2005; 15:1098e104. [23] Shehabi Y, Grant P, Wolfenden H, Hammond N, Bass F, Campbell M, et al. Prevalence of delirium with dexmedetomidine compared with morphine based therapy after cardiac surgery: a randomized controlled trial (DEXmedetomidine COmpared to Morphine-DEXCOM Study). Br J Anesthesia 2009; 111:1075e84.