Deliberate hypotension has been used for a long time to decrease bleeding in some otorhinolaryngological operations such as tympanoplasty and septorhinoplasty [1,2]. Many anaesthetic and vasoactive drugs have been used successfully to produce deliberate hypotension, including volatile anaesthetics, direct-acting vasodilators, autonomic ganglion-blocking drugs, β-adrenergic receptor-blocking drugs, combined α- and β-adrenergic receptor-blocking drugs, calcium channel-blocking drugs and prostaglandin E1 . These drugs, excluding local anaesthetics with vasoconstrictors agents, decrease blood pressure (BP) via dilated peripheral vessels . Clonidine, an α2-adrenoceptor agonist, has been used for deliberate hypotension successfully . Dexmedetomidine is a potent, highly selective α2-adrenoceptor agonist that may provide analgesia and sedation without respiratory depression. Dexmedetomidine has sedative and analgesia-sparing effects via central actions in the locus coeruleus and in the dorsal horn of the spinal cord, respectively [4,5]. The primary action of all α2-adrenoceptor agonists is an inhibition of norepinephrine release causing attenuation of excitation in the central nervous system, especially in the locus coeruleus . Central nervous system activation of postsynaptic receptors by α2-agonists leads to inhibition of sympathetic activity, which decreases BP and heart rate (HR) and results in sedation [7,8]. Peripheral antinociception by α2-adrenoceptor-mediated local release of encephalin-like substances is also possible .
The aim of this double-blind, controlled, prospective study was to determine the efficacy of dexmedetomidine on intraoperative bleeding, perioperative haemodynamics, anaesthetic drug requirement and postoperative pain.
After Ethics Committee approval and written informed consent, 40 ASA I–II patients aged 18–60 yr undergoing tympanoplasty and septorhinoplasty under general anaesthesia were included in the study. Deliberate hypotension was planned before the operation. Patients were excluded if there was a history of significant cardiovascular, respiratory, renal or hepatic diseases, psychiatric disorders, chronic pain syndromes, or drug and alcohol abuse. Patients receiving regular opioids or drugs with known analgesic properties in the 24 h before surgery were also excluded. Other exclusion criteria included hypertension (systolic BP > 160 mmHg) and bradycardia (HR < 50 beats min−1).
No preanaesthetic medication was prescribed, and the patients were fasted from midnight before the operation. Patients were randomly assigned, using computer-generated random numbers and concealed opaque envelopes for control (n = 20) and dexmedetomidine (n = 20) groups. Study drugs were prepared by an independent anaesthesiologist. All operating room anaesthesiologists, surgeons, nurses and recovery room staff were blinded to the study protocol. The surgeon was prevented from seeing the monitor screen or hearing audio outputs from the monitors to ensure that they were blind to the patient group. Recovery times and postoperative pain were determined by an attending anaesthesiologist. On arrival in the operating room, the patient's HR and BP and oxygen saturation were monitored by lead II of the ECG, a non-invasive BP monitor and a pulse oximeter, respectively, before a 20-G intravenous (i.v.) cannula was inserted. Patients then received lactated Ringer's solution 10 mL kg−1 h−1 i.v. as a standard protocol. In the dexmedetomidine group, dexmedetomidine was supplied in 2 mL ampoules in a concentration of 100 μg mL−1, which was diluted with 48 mL normal saline to a final concentration of 4 μg mL−1. In the control group, the placebo of 50 mL saline solution was prepared in a similar fashion. Ten minutes before induction of anaesthesia, patients in the dexmedetomidine group received an infusion of 1 μg kg−1 dexmedetomidine as a loading dose over 10 min and 0.5 μg kg−1 h−1 infusion for maintenance and those in the control group received the corresponding volume of the placebo. Induction of anaesthesia was similar in both the groups. After preoxygenation, anaesthesia was induced with lidocaine 2% 1 mg kg−1, fentanyl 1 μg kg−1, and propofol 1–3 mg kg−1 till the eyelash reflex had disappeared. Vecuronium bromide 0.1–0.2 mg kg−1 was administered to facilitate tracheal intubation and maintained by bolus injections of 0.01 mg kg−1 by monitoring of train-of-four applied to the ulnar nerve. Anaesthesia was then maintained with nitrous oxide 60% and isoflurane 1.0–1.5% in oxygen. Controlled mechanical ventilation with an initial tidal volume of 10 mL kg−1 and a respiratory frequency of 10 breaths min−1 was adjusted to maintain the end-tidal CO2 (etCO2) between 35 and 40 mmHg. Body temperature was maintained between 35.5 and 36.5°C and the patients were in supine position throughout surgery.
The lowest mean arterial pressure (MAP) accepted was 60 mmHg. Deliberate hypotension was obtained by titration of isoflurane up to 1.5% and fentanyl 1–5 μg kg−1 to maintain MAP at 60–80 mmHg in all patients. End-tidal isoflurane concentration was recorded every 10 min. When isoflurane and fentanyl failed to maintain hypotension, nitroglycerin (0.2 mg increments) was administered. Bradycardia (HR < 50 beats min−1) was treated with atropine 0.01 mg kg−1. When hypotension occurred (MAP < 60 mmHg), i.v. ephedrine (10 mg increments) was applied.
Mean arterial BP and HR were measured and recorded at the following times: upon arrival in the operating theatre as the mean of three measurements (baseline); before induction of anaesthesia, after induction of anaesthesia, 1, 3, 5 min after endotracheal intubation, 1, 3, 5 and then every 10 min after commencement of surgery, before extubation, and 1 and 5 min after extubation.
Bleeding during the operation was assessed by the surgeon both intraoperatively (intraoperative bleeding score (IBS)) and postoperatively as a final personal opinion about the whole surgical process (final opinion on bleeding score (FOBS)). IBS was assessed every 10 min, on a four-point scale from 0 = no bleeding (excellent surgical conditions), 1 = minimum bleeding (sporadic suction), 2 = diffuse bleeding (repeated suction) and 3 = considerable (troublesome) bleeding (continuous suction) , by the same surgeon who performed the operation. The mean value of IBS for the patient was calculated as the mean of all values measured every 10 min. After the operation, the FOBS was assessed on a five-point scale from 1 = very low, 2 = low, 3 = average, 4 = high and 5 = very high as compared to preceding surgery.
After skin closure at the end of surgery, residual neuromuscular blockade was antagonized with i.v. neostigmine 50 μg kg−1 and atropine 20 μg kg−1. Anaesthetic agents were stopped and then patients were extubated.
After extubation all patients were transferred to the recovery room. In the recovery room, a visual analogue pain score (VAS, 0–100) and time to response to verbal stimulus and time to discharge were assessed. If the VAS was more than 40, meperidine 10 mg was administered i.v. After a modified Aldrete score  higher than 8, patients were discharged from the recovery room to the wards.
The number of patients enrolled in this study was determined based on our preliminary study and a power of 80% and a clinically significant difference of 30% in bleeding between control and dexmedetomidine groups with a significance level of 5%. The statistical analysis of data was performed with SPSS® 11.0 (SPSS Inc., Chicago, IL, USA). Data are expressed as mean ± SD or absolute values (sex, age, height and weight). The paired-sample t-test was used for comparisons of repeated measurements within groups and the independent-sample t-test for comparisons between groups. The non-parametric data were evaluated with χ2-test or Fisher's exact test, when appropriate. P < 0.05 was considered as significant.
There was no significant difference between groups regarding age, gender, weight and lengths of operation and anaesthesia (Table 1).
The IBS was significantly lower in the dexmedetomidine group than in the control group throughout the study period (P < 0.05) (Fig. 1). FOBS was significantly lower in the dexmedetomidine group than in the control group (P < 0.001) (Fig. 2). The propofol dose required for induction of anaesthesia was significantly lower in the dexmedetomidine group than in the control group (P < 0.05) (Table 1).
Neither hypertension nor hypotension was seen after a loading dose of dexmedetomidine. Hypotension, which occurred after induction of anaesthesia with propofol, was greater in the placebo group (P < 0.05) (Fig. 3). There was no statistically significant difference between groups regarding the amount of ephedrine administered to patients due to hypotension intraoperatively. The amount of nitroglycerin administered to achieve a target decrease in BP was higher in the control group than in the dexmedetomidine group (P < 0.05) (Table 1). The HR was significantly lower in the dexmedetomidine group throughout the study period (P < 0.05) (Fig. 4). The number of patients who need atropine was higher in the dexmedetomidine group than in the placebo group (P < 0.05) (Table 1).
The end-tidal isoflurane concentrations (Fig. 5) and total amount of fentanyl (Table 1) required to maintain haemodynamic stability were lower in the dexmedetomidine group (P < 0.05).
Extubation times were similar in the two groups. The time to response to verbal stimulus and discharge times were significantly shorter in the control group (P < 0.05) (Table 1). The number of patients who received meperidine for control of pain was 15 in the control group, whereas no patient needed meperidine in the dexmedetomidine group.
The results of this study have shown that preoperative administration of dexmedetomidine provided lower intraoperative and postoperative bleeding scores and decreased isoflurane and fentanyl consumption with a small extension to early recovery times.
Many studies have thoroughly examined the efficacy of various deliberate hypotension methods on bleeding in the course of anaesthesia [2,3, 11–13]. Although the approach is multifactorial, the principal mechanism employed is the reduction of vascular tone. Even a little bleeding may impair the view of the surgical field and affect the surgical progress, could cause surgical problems or prolong surgical time [14,15]. Deliberate hypotension effectively reduces surgical blood loss and improves surgical conditions. If inhaled anaesthetics are used to decrease BP, larger inspired concentrations are used than required to provide surgical anaesthesia and it can cause more bleeding because of their peripheral vasodilatory effects . The effect of anaesthetic agents on bleeding is controversial. Albera and colleagues  have stated that sevoflurane has a protective effect on inner ear microcirculation while propofol does not. It seemed that the protective effect of sevoflurane on cochlear blood flow is based on its action on local factors, mediated by sympathomimetic and parasympathomimetic activity, leading to a decrease in the resistance of arterial blood and to the pooling of venous blood. From another point of view, high levels of anaesthetics are prone to affect thrombocyte function, but this experimental environment does not take place in the human body . There is no strong evidence if dexmedetomidine does have an effect on thrombocyte function.
All patients of both groups of our study were well matched regarding their patient data characteristics, operations, surgeon and intraoperative conditions. The appropriate body positioning was performed by the same surgeon in our study. The etCO2 level was maintained between 30 and 35 mmHg, while body temperatures of the patients were maintained at 35.5–36.5°C. Bleeding scores used to evaluate surgical fields were significantly lower in patients who had received dexmedetomidine. Similar results have also been reported by Marchal and colleagues  where clonidine was used. They found that surgical field quality and recovery times were better in the clonidine group. Recovery times were faster in Marchal's  study because they did not maintain clonidine administration intraoperatively. They also reported that patients in the clonidine group scored significantly lower in the intraoperative bleeding assessment than the placebo group. This may be due to the peripheral vasoconstrictive effects of α2-agonists. Similar results were found in an animal study conducted by Lawrence and colleagues  where dexmedetomidine reduced bleeding especially in the skin. This result is compatible with peripheral vasoconstrictive effects of dexmedetomidine.
I.v. administration of dexmedetomidine typically results in a biphasic response of mean arterial BP: an initial rise of MAP 5–10 min after i.v. dexmedetomidine followed by a decrease of approximately 10–20% from baseline values . In our study, we did not find any hypotension or hypertension compared with baseline values after dexmedetomidine administration. Bloor and colleagues  reported transient increase in MAP (peak at 3 min lasting < 11 min) after a 2 μg kg−1 loading dose of dexmedetomidine. Controlled hypotension was effectively obtained in both study groups. Due to the stable haemodynamic situation there was no difference between the groups regarding the number of patients who needed ephedrine. It was stated that perioperative use of dexmedetomidine decreased the consumption of inhalational agents [7,22], fentanyl  and analgesics [6,24] in a dose-dependent manner .
Endotracheal intubation may increase BP and HR. There are several strategies including pre-treatment with dexmedetomidine to decrease this temporary haemodynamic side-effect of intubation. In our study, it was found that haemodynamic values obtained after endotracheal intubation showed less fluctuation in patients treated with dexmedetomidine than with placebo. More stable haemodynamic values were also obtained after induction of anaesthesia in patients treated with dexmedetomidine because of less propofol administration to obtain an adequate depth of the anaesthesia for endotracheal intubation than in placebo-treated patients. Peden and colleagues  implied this haemodynamic stability in their study evaluating the effects of dexmedetomidine premedication on propofol requirement during induction of anaesthesia. These findings are compatible with the study of Aantaa and colleagues  with thiopental.
Although the mechanisms responsible for haemodynamic changes during extubation are not exactly known, possible factors may be wound pain, emergence from anaesthesia and tracheal irritation [26,27]. Although not normally causing any serious problem, some previous studies have revealed a moderate increase in BP and HR lasting 5–15 min after extubation [28,29]. Dexmedetomidine attenuated the increase in HR and arterial BP during extubation in our study, although we found that early recovery was faster in the control group.
Dexmedetomidine has sedative and analgesia-sparing effects via central actions in the locus coeruleus and in the dorsal horn of the spinal cord, respectively [4,5]. During the recovery period, patients who received dexmedetomidine accomplished successful analgesia compared with patients in the control group. Aho and colleagues  have studied the haemodynamic and endocrine effects of three different doses of dexmedetomidine, oxycodone and saline solution injected intramuscularly 45–60 min before induction of general anaesthesia involving 100 women undergoing gynaecologic diagnostic laparoscopy. They found that the need for analgesia in the postoperative period was significantly lowered in the dexmedetomidine groups. Also, Arain and Ebert  reported that patients who had received dexmedetomidine during surgery had significantly smaller needs for morphine sulphate throughout the recovery period which were similar to our study.
In conclusion, this study has shown that using dexmedetomidine intraoperatively reduces bleeding during middle ear surgery and septorhinoplasty supplying better operative field probably in relation to haemodynamic stability. Dexmedetomidine also reduced isoflurane and fentanyl requirements for deliberate hypotension and attenuated cardiovascular responses during the induction of anaesthesia and extubation.
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