The objective of functional endoscopic sinus surgery (FESS) is to restore the drainage and aeration of the paranasal sinuses, and seeks to preserve the normal anatomical structures and function . FESS, a widely used endoscopic surgical technique, can be achieved with the use of local anaesthesia with topically applied vasoconstrictors or general anaesthesia associated with controlled hypotension. Access for nasal surgery is limited by both the anatomy of the nose and its vascularity. In order to reduce the incidence of complications, it is important to have a surgical field that is free of blood as far as possible to improve visibility. Bleeding control, however, is only performed with local application of epinephrine . Insurance of co-operation between the surgeon and the patient is essential for the success of FESS. Ocular pain is an important finding for the surgeon because of the adjacency of the sinuses to the neurovascular structures. The lesser amount of haemorrhage provides better quality of vision of the surgical area. This is particularly important in the ethmoid and sphenoid sinuses, in which even minimal bleeding may seriously impair the ability to complete the intended surgery. Sympathetic stimulation occurs in restless patients who feel pain; tachycardia and hypertension causes augmentation of haemorrhage in the surgical area [2-4].
Dexmedetomidine, an imidazole compound, is the pharmacologically active dextroisomer of medetomidine, and is the most selective central α-2-adrenoceptor agonist available clinically. This agonist has eight times higher affinity for the α-2-adrenoceptor than clonidine . Dexmedetomidine offers beneficial pharmacological properties, providing dose-dependent sedation, analgesia, sympatholysis and anxiolysis without relevant respiratory depression. Dexmedetomidine displays a biphasic, dose-dependent blood pressure (BP) response. Although high doses produce a hypertensive response caused by the activation of α-2B-adrenoceptors on vascular smooth muscles, the dominant action of α-2-adrenoceptor agonists with low and clinically recommended concentrations is hypotension .
Dexmedetomidine has been studied for sedation and analgesia sparing properties in surgical settings, but not in FESS. Therefore, the purpose of this study was to evaluate the haemodynamic effects of perioperatively administered dexmedetomidine in patients for FESS and to compare with placebo. Since nitric oxide (NO) is a well-known endogenous vasodilator mediator, we also measured plasma NO levels during dexmedetomidine administration and compared them with preoperative and postoperative levels.
After obtaining local research Ethics Committee approval and informed patient consent, we studied 62 ASA I-II patients, aged 30-60 yr, who were consecutively operated on for chronic sinusitis, dacryocystitis or nasal polyposis with FESS under local anaesthesia by the same surgeon (SM) for FESS between January and June 2005. Patients were excluded if they had severe cardiac disease, chronic obstructive lung disease, renal and hepatic insufficiency, endocrine, metabolic or central nervous system disorders, α-2-agonist or antagonist therapy taken, and active upper respiratory infection.
Monitored anaesthesia care was applied. Haemodynamic parameters, sedation scores, analgesia levels, surgical conditions and postoperative adverse effects were compared with the placebo group. Perioperative parameters (arterial pressure, heart rate (HR), peripheral oxygen saturation (SPO2)) were measured and recorded at 10-min intervals. Sedation scales and surgical satisfaction were recorded perioperatively. Adverse effects were evaluated postoperatively. Thirty minutes prior to operation, each patient received intramuscularly 0.5 mg atropine and 1 mg kg−1 meperidine (Aldolan Ampoule 100 mg per 2 mL; Liba, Istanbul, Turkey) for premedication. Routine monitoring was performed with electrocardiogram SPO2 and non-invasive BP (Nihon-Kohden BSM-4113K; Tokyo, Japan). An 18-G angiocath was inserted into a vein in the antecubiteal area. All patients received 2 L min−1 oxygen via nasal catheters preoperatively. For topical vasoconstriction and local anaesthesia, pantocaine 4% and 1/1000 epinephrine (2 : 1 v/v) were applied via the nasal cavity for 5-10 min with cotton-wool pledgets. Later on the medial concha and lateral concha nasal walls were anaesthetized with lidocaine (40 mg per 2 mL) + epinephrine (0.025 mg per 2 mL; Jetocaine, Adeka, Istanbul, Turkey). The posterior ethmoid cavity or sphenoid sinus in the operating area sphenopalatine neurovascular branch was also anaesthetized with local anaesthetic injection. Infiltration anaesthesia was applied to the septal mucosa for patients who were scheduled for septoplasty or submucosal resection.
In this double-blind study, patients were allocated to Groups 1 or 2 using a computer-generated table of random numbers. Group 1 (n = 32) was the placebo group and received an intravenous (i.v.) saline infusion. Group 2 (n = 30) was the dexmedetomidine group. They received a loading dose of dexmedetomidine (Precedex, 200 μg per 2 mL; Abbott, USA) and an infusion (1 μg kg−1 i.v.) was started 10 min prior to operation. Dexmedetomidine was diluted with 0.9% NaCl to a concentration of 4 μg mL−1 in 50 mL. Dexmedetomidine or saline was prepared by one of the authors who was blinded to the recorded data and administered using a syringe pump (Fresenius-Vial-Pilot A2 perfuser; Homburg, Germany). The maintainance dose was 0.7 μg kg−1 h−1. The infusion was stopped 15 min before the end of surgery. The same amount of saline was given to the patients in placebo group.
Changes of haemodynamic parameters in the perioperative period, sedation score (Ramsay sedation scale (RSS) ), intensity of pain and satisfaction of the surgeon were recorded. The observer's assessment of alertness/sedation (OAS/S) score at the first loss of auditory response was also used. An independent observer rated the alertness of the patient using the OAS/S , and pain intensity was evaluated using a 10-cm visual analogue scale (VAS; 0 = no pain and 10 = worst pain imaginable) system. The VAS was explained to the patients during the preoperative visit. Sedation and pain intensity were evaluated by the same researcher. RSS, OAS/S and VAS assessments were performed after the dexmedetomidine was discontinued.
Surgical satisfaction was evaluated by one surgeon (SM) and recorded on a points system between 0 and 10: 0-2 points very bad, 2-4 points bad, 4-6 points medium, 6-8 points good and 8-10 points excellent. Perioperative parameters (systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), HR, and SPO2) were measured and recorded at 10-min intervals. Adverse events including nausea, vomiting, hypotension (MAP < 60 mmHg), bradycardia (with hypotension, HR < 45), hypertension (DAP > 100 mmHg) and hypoventilation (SPO2 < 90) were recorded. Hypotension was treated with fluid replacement, and when this therapy was inadequate, a vasoconstrictor drug was added. When depression in breathing occurred, the patient was advised to take deep breaths and oxygen support was applied. Bradycardia was treated with 0.5 mg i.v. atropine. Adverse events were recorded over 2 h in the postoperative period. Metamizole (Dipyrone) sodium was used for postoperative analgesia as needed.
The effect of dexmedetomidine on peripheral vasodilatation has been investigated by measuring plasma NO levels. Nitrate and nitrite are the primary oxidation products of NO, and therefore, the nitrate/nitrite level in plasma can be used as an indicator of NO formation . The plasma samples were deproteinized with absolute ethanol at 0°C in a 1 : 2 v/v mix, incubated for 30 min at 0°C followed by centrifugation at 7000g for 5 min. The pellets were discarded and the supernatant was used to measure NO levels. For measurement of NO, we employed the NO/ozone chemiluminescence technique (Model 280i NOA; Sievers Instruments, Boulder, CO, USA). Briefly, a saturated solution of the reducing agent (vanadium (III) chloride dissolved in 1 mol HCl) was prepared and filtered before use. Five millilitres of this agent was added to purge the vessel with nitrogen for 5-10 min before use and heated to 95°C. A continuous stream of pure nitrogen purged the resultant NO from the reaction vessel to the chemiluminescence chamber. A standard curve was established with a set of serial dilutions (0.1-100 μmol) of sodium nitrate. Samples and standards were injected into the purge vessel to react with the reducing agent, which converted nitrate, nitrite and S-nitrosocompounds to NO. The concentrations of NO metabolites in the samples were determined by comparison with the standard curve and expressed as μmol. Data collection and analysis was performed using the NOAnalysis™ software (version 3.21; Sievers, Boulder, CO, USA) . NO levels were measured in a blind manner in plasma samples taken before premedication, after meperidine injection, after dexmedetomidine infusion and postoperatively.
All data are expressed as mean ± SD. Statistical analysis was carried out using the unpaired t-test for SAP, DAP and HR differences between groups. Statistical comparison of more than two groups was performed by a one-way analysis of variance followed by Student-Newman-Keuls test. χ2-test was used for nausea, vomiting and other adverse events. The sedation score was analysed with a U-test. P < 0.05 was considered statistically significant. All statistical analyses were performed with SPSS version 11.0 (SPSS Inc., Chicago, IL, USA).
Patient characteristics of patients in placebo and dexmedetomidine groups were shown in Table 1. Patient charecteristics data were similar for the two groups. There was no difference between the groups before anaesthesia induction. SAP, DAP, MAP, HR and SPO2 values did not change markedly when compared to preoperative measurements. However, there were significant reductions in the SAP, DAP, MAP and HR values following dexmedetomidine infusion in the perioperative period. These decreases were significant between 10 and 60 min of infusion in the dexmedetomidine group when compared to the placebo group (P < 0.05, Fig. 1). Two patients developed a decrease in HR to 40 beats min−1 in the dexmedetomidine group, and these patients were treated with 0.5 mg i.v. atropine. Hypertension did not develop in any patient.
SPO2 values were similar in both groups. No significant changes were found in oxygen saturation between the two groups. Haemoglobin saturation measured by pulse oximetry did not decrease in any patient.
There was a significant difference in the RSS, OAS/S, VAS scores and surgical satisfaction in the dexmedetomidine group compared to the placebo group (P < 0.005) (Table 2). While OAS/S and VAS decreased, RSS and surgical satisfaction markedly increased in the dexmedetomidine group.
Postoperative nausea and vomiting was significantly lower in the dexmedetomidine group when compared to placebo group (Table 3). Postoperative mouth dryness was not found to be statistically significant. Averse events were not observed any patients.
Plasma NO levels were not significantly different between the two groups or within the groups. Meperidine and dexmedetomidine did not significantly modify plasma NO levels (Fig. 2).
Our study has demonstrated that dexmedetomidine infusion as a supporting drug during local anaesthesia in patients undergoing FESS improved quality of care without causing side-effects when compared to placebo. We used lidocaine for local anaesthesia and epinephrine for vasoconstriction. As the anatomy of the nose limits access for intranasal surgery, the use of this combination reduced bleeding and improved visualization.
Dexmedetomidine provides appropriate levels of sedation with features of gaining consciousness with verbal stimulation. Dexmedetomidine may be the drug of choice because there are less adverse effects (respiratory depression, delayed recovery, nausea, vomiting) when compared to other sedative or analgesic drugs. It has been shown that the addition of 0.5 mg kg−1 dexmedetomidine to lidocaine for i.v. regional anaesthesia delayed the onset of tourniquet pain, and reduced intra- and postoperative analgesic requirement, improved quality of anaesthesia and perioperative analgesia without causing side-effects . The use of an α-2-agonist as an adjunct in pain management is attractive because of the potentiation that occurs through their action at the central and peripheral sites . α-2-Adrenergic receptors located at nerve endings may have a role in the analgesic effect of the drug by preventing norepinephrine release . Dexmedetomidine has been shown to increase the quality of anaesthesia and decrease the postoperative analgesic requirements in elective hand surgery .
We have found that HR and BP decreased during dexmedetomidine infusion. These results are supported by the previous observation that HR, BP and plasma catecholamine concentrations decreased during dexmedetomidine infusion in patients recovering from transphenoidal pituitary hypophysectomy . Dexmedetomidine causes a dose-dependent decrease in BP and HR associated with decreased concentration of plasma norepinephrine . It has been demonstrated that in awake volunteers with an intact cardiovascular regulatory system and normal sympathetic nervous system tone, increasing doses of dexmedetomidine decreased BP . In contrast, in anaesthetized subjects with reduced sympathetic nervous system tone, increasing doses of dexmedetomidine increased BP. These differing effects on BP are consistent with known effects of α-2-agonists: a centrally mediated decrease in BP and peripherally mediated vasoconstriction [14,16,17]. An increase in vagal activity may also be involved in the haemodynamic effects of dexmedetomidine . Therapeutic doses have been used in the present study and marked decreases in MAP and HR were observed during surgery, suggesting the dominant action of α-2-adrenoceptor agonists with low and clinically recommended concentrations in hypotension caused by a centrally mediated sympatholysis and by the inhibition of neurotransmission in sympathetic nerves. Dexmedetomidine also possesses a dose-dependent bradycardiac effect, mediated primarily by the decrease in sympathetic tone and partly by baroreceptor reflex and enhanced vagal activity .
Dexmedetomidine is known to decrease sympathetic outflow and circulating catecholamine levels and would, therefore, be expected to cause decreases of MAP [14,16]. This haemodynamic effect was, in part, mediated by the sympatholytic properties of dexmedetomidine. There is experimental evidence that dexmedetomidine produces a dose-dependent, reversible decrease in cyclic guanosine 3′,5′-monophosphate (cGMP) in mouse cerebellum at concentrations that decrease the anaesthetic requirement of volatile anaesthetics. The cGMP response to dexmedetomidine is eliminated when NO synthase (NOS) is inhibited. This implies that the decrease in cGMP is secondary to inhibition of NO synthesis . However, the contribution of NO to haemodynamic effects of dexmedetomidine is not known in patients. Dexmedetomidine has two opposing effects: direct vasoconstriction and indirect vasodilatation (in which NO may play an important role). The net effect of vascular α-2-adrenergic stimulation is presumably determined by the basal level of α-2-adrenergic activity in the vascular smooth muscle and endothelium. In an in vitro study, Bryan and colleagues [20,21] demonstrated that α-2-adrenergic receptor-mediated dilations of rat middle cerebral arteries were blocked after removal of the endothelium or inhibition of NOS. In addition, a number of studies have demonstrated that stimulation of α-2-adrenoceptors in many, but not all, preconstricted arteries and veins produces a vasodilatation that can be abolished or attenuated by inhibition of NOS or by removal of the endothelium [20-22]. It has been demonstrated that pretreatment with l-nitroarginine methyl ester (l-NAME), an inhibitor of NOS, did not alter dexmedetomidine-induced vasoconstriction in cerebral vessels in dogs , and McPherson and colleagues  also indicated that systemic l-NAME did not affect dexmedetomidine-induced cerebral blood flow decrease in dogs. However, Coughlan and colleagues  reported that l-NAME led to an exaggerated constrictor response to dexmedetomidine in coronary arteries in vitro. The data show that plasma NO levels remain unaffected by dexmedetomidine in this study. Therefore, it is likely that NO was not involved in the dexmedetomidine-induced hypotension in patients. The relationship between dexmedetomidine and NO production clearly requires further investigation.
In conclusion, the present study revealed that dexmedetomidine provides analgesia, adequate sedation and surgical comfort during FESS under local anaesthesia. Since dexmedetomidine has the potential to attenuate perioperative increases in BP and HR and does not cause respiratory depression, clinical use of dexmedetomidine may be suggested in patients undergoing FESS under local anaesthesia by monitored anaesthesia care.
The NO analyser used in this study was provided by a Project Grant (TF.03.03) from the University of Gaziantep.
1. Slack R, Bates G. Functional endoscopic sinus surgery
. Am Fam Phys
1998; 58: 707-718.
2. Danielsen A, Gravningsbraten R, Olofsson J. Anaesthesia in endoscopic sinus surgery
. Eur Arch Otorhinolaryngol
2003; 260: 481-486.
3. Lee WC, Kapur TR, Ramsden WN. Local and regional anesthesia for functional endoscopic sinus surgery
. Ann Otol Rhinol Laryngol
1997; 106: 767-769.
4. Fedok FG, Ferraro RE, Kingsley CP, Fornadley JA. Operative times, postanesthesia recovery times, and complications during sinonasal surgery
using general anesthesia and local anesthesia with sedation
. Otolaryngol Head Neck Surg
2000; 122: 560-566.
5. Kamibayashi T, Maze M. Clinical uses of α2
-adrenergic agonists. Anesthesiology
2000; 93: 1345-1349.
6. Paris A, Tonner PH. Dexmedetomidine
in anaesthesia. Curr Opin Anaesthesiol
2005; 18: 412-418.
7. Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation
with alphaxalone-alphadolone. Br Med J
1974; 2: 656-659.
8. Chernik DA, Gillings D, Laine H et al
. Validity and reliability of the observer's assessment of alertness/sedation
scale: study with intravenous midazolam. J Clin Psychopharmacol
1990; 10: 244-251.
9. Baylis C, Vallance P. Measurement of nitrite and nitrate levels in plasma and urine - what does this measure tell us about the activity of the endogenous nitric oxide
system? Curr Opin Nephrol Hypertens
1998; 7: 59-62.
10. Alasehirli B, Demiryurek S, Arica E, Gursoy S, Demiryurek AT. No evidence for an association between the Glu298Asp polymorphism of the endothelial nitric oxide
synthase gene and fibromyalgia syndrome. Rheumatol Int
2007; 27: 275-280.
11. Memis D, Turan A, Karamanlioglu B, Pamukcu Z, Kurt I. Adding dexmedetomidine
to lidocaine for intravenous regional anesthesia. Anesth Analg
2004; 98: 835-840.
12. Sato J, Perl ER. Adrenergic excitation of cutaneous pain receptors induced by peripheral nerve injury. Science
1991; 251: 1608-1610.
13. Esmaoglu A, Mizrak A, Akin A, Turk Y, Boyaci A. Addition of dexmedetomidine
to lidocaine for intravenous regional anaesthesia. Eur J Anaesthesiol
2005; 22: 447-451.
14. Talke P, Richardson CA, Scheinin M, Fisher DM. Postoperative pharmacokinetics and sympatholytic effects of dexmedetomidine
. Anesth Analg
1997; 85: 1136-1142.
15. Kallio A, Scheinin M, Koulu M et al
. Effects of dexmedetomidine
, a selective α2
-adrenoceptor agonist, on hemodynamic control mechanisms. Clin Pharmacol Ther
1989; 46: 33-42.
16. Talke P, Lobo E, Brown R. Systemically administered α2
-agonist-induced peripheral vasoconstriction in humans. Anesthesiology
2003; 99: 65-70.
17. Piascik MT, Soltis EE, Piascik MM, Macmillan LB. α-Adrenoceptors and vascular regulation: molecular, pharmacologic and clinical correlates. Pharmacol Ther
1996; 72: 215-241.
18. De Jonge A, Timmermans PB, Van Zwieten PA. Participation of cardiac presynaptic α2
-adrenoceptors in the bradycardic effects of clonidine and analogues. Naunyn Schmiedebergs Arch Pharmacol
1981; 317: 8-12.
19. Vulliemoz Y. The nitric oxide
-cyclic 3′,5′-guanosine monophosphate signal transduction pathway in the mechanism of action of general anesthetics. Toxicol Lett
1998; 100-101: 103-108.
20. Bryan RM Jr, Steenberg ML, Eichler MY, Johnson TD, Swafford MW, Suresh MS. Permissive role of NO in α2
-adrenoceptor-mediated dilations in rat cerebral arteries. Am J Physiol
1995; 269: H1171-H1174.
21. Bryan RM Jr, Eichler MY, Swafford MW, Johnson TD, Suresh MS, Childres WF. Stimulation of α2
-adrenoceptors dilates the rat middle cerebral artery. Anesthesiology
1996; 85: 82-90.
22. Miller VM, Flavahan NA, Vanhoutte PM. Pertussis toxin reduces endothelium-dependent and independent responses to α2
-adrenergic stimulation in systemic canine arteries and veins. J Pharmacol Exp Ther
1991; 257: 290-293.
23. Ishiyama T, Dohi S, Iida H, Watanabe Y, Shimonaka H. Mechanisms of dexmedetomidine
-induced cerebrovascular effects in canine in vivo
experiments. Anesth Analg
1995; 81: 1208-1215.
24. McPherson RW, Kirsch JR, Traystman RJ. Inhibition of nitric oxide
synthase does not affect α2
-adrenergic-mediated cerebral vasoconstriction. Anesth Analg
1994; 78: 67-72.
25. Coughlan MG, Lee JG, Bosnjak ZJ, Schmeling WT, Kampine JP, Warltier DC. Direct coronary and cerebral vascular responses to dexmedetomidine
. Significance of endogenous nitric oxide
1992; 77: 998-1006.