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Original Article

Preoperative oral dextromethorphan vs. clonidine to prevent tourniquet-induced cardiovascular responses in orthopaedic patients under general anaesthesia

Honarmand, A.*; Safavi, MR.*

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European Journal of Anaesthesiology: June 2007 - Volume 24 - Issue 6 - p 511-515
doi: 10.1017/S0265021506002055



Tourniquet inflation, which is used in orthopaedic surgery of the upper and lower limbs, is often accompanied by a progressive increase in systemic arterial pressure [1-5]. Tourniquet-induced hypertension [4,6,7] is often resistant to analgesic drugs, antihypertensive drugs and profound anaesthesia depth [4,5,7]. It is more common under general anaesthesia (53–67%) than spinal anaesthesia (2.7–6.7%) [4,7] and occurs more often in lower limb surgery than in upper limb surgery [4]. Zalunardo and colleagues showed that preoperative intravenous (i.v.) clonidine blunts these responses resulting from prolonged tourniquet inflation under general anaesthesia in ASA class I–II patients [8]. Yamashita and colleagues showed that preoperative oral dextromethorphan (DM) significantly attenuates arterial pressure, and heart rate (HR) increases during tourniquet inflation under general anaesthesia [9]. The effects of preoperative oral clonidine on attenuation of haemodynamic response during tourniquet inflation have not been investigated in previous studies. Clinically, in comparison with oral DM, it seems that preoperative oral clonidine may be more effective in blunting hyperdynamic responses during tourniquet inflation. Therefore, to test this hypothesis, we investigated the effect of preoperative oral clonidine or DM on arterial pressure and HR changes during prolonged tourniquet inflation of the lower limbs in patients undergoing general anaesthesia.


The study protocol was approved by our Ethics Committee and was performed in a randomized, double-blind, prospective fashion. Written informed consent was obtained from each patient. Seventy-five patients, ASA I or II, aged 14–65 yr, under general anaesthesia undergoing elective orthopaedic surgery with tourniquet inflation of the lower limbs, were included in this study. Patients with a history of cardiac arrhythmias or cardiovascular disease, including hypertension, atrioventricular block, ischaemic heart disease, congestive heart failure, cardiac medication, expected tourniquet time shorter than 60 min or longer than 150 min and diabetes mellitus were excluded from the study. The participating patients were randomly assigned into one of the three groups using a random number card. Ninety minutes before induction of anaesthesia, patients in the DM group received oral DM 30 mg, patients in the clonidine group received clonidine 3 μg kg1 orally and patients in the control group received oral placebo. The oral preparations were prepared and blinded in advance by an anaesthesia nurse according to the randomization list. After i.v. infusion of acetated Ringer's solution 10 mL kg1, anaesthesia was induced with fentanyl 1–2 μg kg1 and thiopental 5 mg kg1 i.v., and the trachea was intubated after the administration of atracurium 0.5 mg kg1 i.v. Systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP) and HR before induction of anaesthesia were measured non-invasively in the right arm using an automated non-invasive monitor (Datex, CH-2S-23-02; Helsinski, Finland). After application of routine monitors, the affected extremity was exsanguinated by elevating and wrapping with an Esmarch bandage. Then tourniquet inflation was performed at the thigh level with 300 mmHg of pressure. Anaesthesia was maintained with isoflurane 1.2% and N2O in 50% oxygen. Muscle paralysis was maintained with atracurium. Ventilation was controlled mechanically to maintain end-tidal CO2 at 35–40 mmHg. During anaesthesia, non-invasive arterial pressure, electrocardiograph, oxygen saturation and HR were monitored. The end-tidal isoflurane concentration was kept at 1.0% during the study period regardless of arterial pressure. If SAP increased to more than 170 mmHg [10], fentanyl 100 μg was given i.v. and these patients were excluded from further analysis. All variables (SAP, DAP, MAP, HR, end-tidal CO2- concentration, and end-tidal isoflurane concentration) were measured at the following three time points: (a) before tourniquet inflation; (b) during surgery at 0 (TI0), 30 (TI30), 45 (TI45), 60 (TI60) min after the start of tourniquet inflation; (c) immediately before tourniquet release (BTR); (d) 20 min after tourniquet release (ATR). After surgery, the anaesthetics were terminated, and the patient's trachea was extubated after neuromuscular blockade was antagonized using neostigmine 0.05 mg kg1 i.v. and atropine 0.02 mg kg1 i.v. Patient characteristics data were expressed as mean ± SD and compared among the three groups by using analysis of variance (ANOVA). Haemodynamic changes were statistically compared with their baseline values and among the three groups by using two-way repeated measures ANOVA followed by Bonferroni's test. The number of patients who developed tourniquet-induced hypertension, defined as more than a 30% increase in SAP [1,4,7] during tourniquet inflation, were compared between groups using χ2-test. A personal computer software package, SPSS version 11.0, was used in the statistical analysis. P < 0.05 was considered statistically significant.


Both groups of patients were similar with regard to patient characteristics, duration of surgery and tourniquet time (Table 1). No patient complained of symptoms related to the side-effects of DM, such as dizziness, before anaesthesia. There was no significant difference between three groups in haemodynamic values before induction (BI) or at start of tourniquet inflation (baseline) (Table 2). Haemodynamic parameters at TI45, TI60, BTR and 20 ATR were significantly different in the three groups (P < 0.05) (Table 3). The control group had a significantly larger number of patients who developed tourniquet-induced hypertension than the clonidine or DM group (P < 0.05) (Fig. 1). Table 2 shows the haemodynamic changes during tourniquet inflation and 20 min after tourniquet release. SAP and MAP were significantly decreased at baseline compared with BI in the clonidine group (P < 0.05). Haemodynamic values at baseline were not significantly different between the three groups. Figure 2 demonstrates the percentage increase of baseline HR and SAP during tourniquet inflation. HR was significantly increased at 60 min after the start of tourniquet inflation and BTR (P < 0.05) within groups but to a significantly lesser extent in the clonidine and DM groups (P < 0.05). SAP was significantly increased at 30, 45, 60 min and BTR (P < 0.05) within groups but, in comparison with control group, to a significantly lesser extent in the clonidine and DM groups (P < 0.05). HR changes at 60 min after tourniquet inflation and BTR was significantly attenuated in the clonidine or DM group when compared with that in the control group (P < 0.05). HR changes after tourniquet inflation relative to the baseline were not significantly different between the clonidine and DM groups (P > 0.05) (Table 3). The magnitude of SAP changes in all times after tourniquet inflation was not significantly different between the three groups.

Table 1
Table 1:
Patient characteristics data, tourniquet and surgical time of patients.
Table 2
Table 2:
Haemodynamic data (mean ± SD).
Table 3
Table 3:
Two-way ANOVA analyses of haemodynamic data.
Figure 1.
Figure 1.:
The number of patients who developed a SAP increase more than 30% of the value before the start of tourniquet inflation for each group. The clonidine and DM groups showed that fewer patients developed a SAP increase of more than 30% compared with the control group. DM: dextromethorphan; SAP: systolic arterial pressure.
Figure 2.
Figure 2.:
The percentage increase of baseline haemodynamic data during tourniquet inflation. The percentage increase in heart rate at 60 and BTR in the clonidine or DM group was reduced when compared with that in the control group (*P ≤ 0.05). The percentage increase in systolic arterial pressure at 30, 45, 60 and BTR in the clonidine or DM group was significantly attenuated when compared with that in the control group (*P ≤ 0.05). ♦: clonidine group; ▴: DM group; ▪: control group. DM: dextromethorphan; BTR: before tourniquet release. Values are expressed as mean ± SD. ‡P ≤ 0.05 when compared with the clonidine group. †P ≤ 0.05 when compared with baseline.


We have demonstrated that preoperative oral clonidine or DM significantly attenuated HR increases during prolonged tourniquet inflation in patients undergoing lower limb surgery under general anaesthesia. Our study also showed that preoperative oral clonidine significantly blunted SAP, DAP and MAP increases during tourniquet inflation. Preoperative oral DM decreased these variables but it was not significant. The precise mechanism of tourniquet hypertension is unknown. However, a few hypotheses have been discussed. Satsumae and colleagues [11] recently argued that tourniquet hypertension might be related to N-methyl-d-aspartic acid (NMDA) receptor activation by peripheral noxious stimuli from the extremities. Another hypothesis on tourniquet-induced hypertension regards the correlation with autonomic nervous system changes. On the basis of power spectral HR analysis, Tetzlaff and colleagues [2] showed that tourniquet hypertension correlates with the activation of the sympathetic nervous system. Heropoulos and colleagues [12] demonstrated that tourniquet hypertension is associated with an increase in plasma catecholamines. Clonidine reduces presynaptic norepinephrine release, decreases the ‘set point' around which blood pressure (BP) is regulated, and has a substantial analgesic and sedative action [13,14]. DM is not a direct antinociceptive drug, but a non-competitive NMDA receptor antagonist that may suppress central sensitization of the dorsal horn neurons in the spinal cord triggered by nociceptive afferent input from the periphery. Experimental animal studies have shown that DM can reduce the wind-up phenomenon [15], formalin-induced increases in spinal cord c-fos messenger RNA expression and pain behaviour [16]. Accordingly, we hypothesized that preoperative oral DM, as an NMDA receptor antagonist, might attenuate tourniquet-induced arterial pressure increases by modulating a wind-up process of nerve transmission of peripheral noxious stimuli from the extremities toward high brain centres. The reason why clonidine was more effective than DM in modulation of haemodynamic response to the tourniquet inflation is probably because the main mechanism of cardiovascular response to tourniquet inflation is increasing sympathetic outflow. Clonidine premedication blunted this hyperadrenergic state. Kauppila and colleagues [17] found that DM 100 mg given orally to eight healthy volunteers did not attenuate pain intensity induced by tourniquet ischaemia to the hand. A larger dose of DM may be more effective to attenuate the haemodynamic changes related to tourniquet inflation. Further studies to investigate the appropriate dose of DM for use in orthopaedic surgery involving a tourniquet are needed.

There are four limitations in our study. First, we could not show the effect of clonidine or DM on tourniquet-induced pain itself or the relationship between tourniquet-induced pain and arterial pressure increase because this study was performed with patients under general anaesthesia. Second, although the minimum alveolar concentration (MAC) of isoflurane was the same in all patients, anaesthetic depth might not be identical among the patients although the end-tidal isoflurane concentration was maintained at 1.0% during the study period. A third limitation might be that we might not be using equivalent doses. Fourth, we did not measure plasma catecholamines to study the central effect of clonidine or DM on sympathetic response.

In conclusion, preoperative oral clonidine significantly blunts BP and HR responses to prolonged tourniquet inflation of the lower limbs under general anaesthesia in ASA I and II patients better than oral DM. 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 clonidine treatment.


1. Kaufman RD, Walts LF. Tourniquet-induced hypertension. Br J Anaesth 1982; 54: 333–336.
2. Tetzlaff JE, O'Hara J, Yoon HJ, Schubert A. Tourniquet-induced hypertension correlates with autonomic nervous system changes detected by power spectral heart rate analysis. J Clin Anesth 1997; 9: 138–142.
3. Hagenouw RR, Bridenbaugh PO, van Egmond J, Stuebing R. Tourniquet pain: a volunteer study. Anesth Analg 1986; 65: 1175–1180.
4. 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: 279–283.
5. Kam PC, Kavanaugh R, Yoong FF. The arterial tourniquet: pathophysiological consequences and anaesthetic implications. Anaesthesia 2001; 56: 534–545.
6. Kaufman RD, Walts LF. Tourniquet-induced hypertension. Br J Anaesth 1982; 54: 333–336.
7. 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: 142–147.
8. Zalunardo MP, Serafino D, Szelloe P et al. Preoperative clonidine blunts hyperadrenergic and hyperdynamic responses to prolonged tourniquet pressure during general anaesthesia. Anesth Analg 2002; 94: 615–618.
9. Yamashita S, Yamaguchi H, Hisajima Y et al. Preoperative oral dextromethorphan attenuated tourniquet-induced arterial blood pressure and heart rate increases in knee cruciate ligament reconstruction patients under general anesthesia. Anesth Analg 2004; 98: 994–998.
10. Rosental RA, Zenilman ME, Katlic MR. Principles and practice of geriatric surgery. In: Rogers MC, Tinker JH, Covino BC, Longnecker DE. Principles and Practice of Anesthesiology. Mosby: St. Louis, 1993: 60.
11. Satsumae T, Yamaguchi H, Sakaguchi M et al. Preoperative small-dose ketamine prevented tourniquet-induced arterial pressure increase in orthopedic patients under general anesthesia. Anesth Analg 2001; 92: 1286–1289.
12. Heropoulos M, Schieren H, Seltzer JL et al. Intraoperative hemodynamic, renin, and catecholamine responses after prophylactic and intraoperative administration of intravenous enalaprilat. Anesth Analg 1995; 80: 583–590.
13. Hayashi Y, Maze M. Alpha 2 adrenoceptor agonists and anaesthesia. Br J Anaesth 1993; 71: 108–118.
14. Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists: their pharmacology and therapeutic role. Anaesthesia 1999; 54: 146–165.
15. Dickenson AH, Sullivan AF, Stanfa LC, Mcquay HJ. Dextromethorphan and levorphanol on dorsal horn nociceptive neurons in the rat. Neuropharmacology 1991; 30: 1303–1308.
16. Elliott KJ, Brodsky M, Hynansky AD et al. Dextromethorphan suppresses both formalin-induced nociceptive behavior and the formalin-induced increase in spinal cord c-fos mRNA. Pain 1995; 61: 401–409.
17. Kauppila T, Gronroos M, Pertovaara A. An attempt to attenuate experimental pain in humans by dextromethorphan, an NMDA receptor antagonist. Pharmacol Biochem Behav 1995; 52: 641–644.


© 2007 European Society of Anaesthesiology