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ANESTHETIC PHARMACOLOGY

Recovery Profiles from Dexmedetomidine as a General Anesthetic Adjuvant in Patients Undergoing Lower Abdominal Surgery

Norimasa Ohtani, MD^*, Kotaro Kida, MD, Kazuhiro Shoji, MD, Yutaka Yasui, MD, and Eiji Masaki, MD, PhD^*

From the Departments of Anesthesiology, *Tohoku University Hospital, Sendai; and Jikei University School of Medicine, Tokyo, Japan.

Address correspondence and reprint requests to Eiji Masaki, MD, PhD, Department of Anesthesiology, Tohoku University Hospital, 1-1 Seiryomachi, Aoba-ku, Sendai 980-8574, Japan. Address e-mail to ejmasaki{at}mail.tains.tohoku.ac.jp.

	Abstract

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BACKGROUND: Dexmedetomidine induces less change in hemodynamic values during the extubation period. This drug may be useful in anesthetic management requiring smooth emergence from anesthesia. We sought to determine the effects of co-administration of dexmedetomidine on the recovery profiles from sevoflurane and propofol, which usually provide safe and rapid recovery when administered alone.

METHODS: Sixty patients undergoing lower abdominal surgery were randomly divided into four groups according to the anesthetic to be administered; namely, sevoflurane (group S), propofol (group P), both sevoflurane and dexmedetomidine (group SD), or propofol and dexmedetomidine (group PD) as maintenance general anesthetics. After induction, anesthesia was maintained with sevoflurane (0.6%–1.5%) in group S, propofol (2–5 mg/kg/h) in group P, sevoflurane and dexmedetomidine (1 µg/kg over 10 min followed by 0.4 µg/kg/h until the end of surgery) in group SD, and propofol and dexmedetomidine in group PD with continuous epidural infusion. Bispectral Index values were maintained within 45 ± 5 by changing the concentration of sevoflurane or the infusion rate of propofol in all groups. The time between the interruption of maintenance general anesthetics and eye opening was measured. Postoperative cognitive function was evaluated using the Short Orientation Memory Concentration Test.

RESULTS: The time to eye opening of groups S (8.5 ± 2.5 min, mean ± sd; n = 15) and SD (12.0 ± 3.3 min) were comparable, whereas that of group PD (21.7 ± 7.1 min) was longer than that of group P (11.0 ± 4.4 min). The time to eye opening of group PD was significantly (P < 0.001) longer than those of the other three groups. The scores of Short Orientation Memory Concentration Test between groups S and P were similar and were not changed by co-administration of dexmedetomidine.

CONCLUSION: When co-administered with dexmedetomidine, sevoflurane produced a shorter time to eye opening than propofol. Postoperative cognitive function was not affected by dexmedetomidine administration. These results suggest dexmedetomidine may delay recovery when given as an adjuvant to propofol during total IV anesthesia.

	Introduction

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Dexmedetomidine, a specific ₂-receptor agonist, may be a useful adjuvant during general anesthesia by promoting hemodynamic stability1 and decreasing the doses of anesthetics and analgesics.2,3 However, dexmedetomidine's cardiovascular and sedative properties could conceivably prolong recovery from anesthesia. The purpose of this study was to examine the effects of co-administration of dexmedetomidine on the recovery profiles from sevoflurane and propofol.

	METHODS

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After obtaining the approval of our institutional human ethics committee and individual written informed consent, 60 ASA I or II patients undergoing open lower abdominal surgery for benign gynecological disease (total abdominal hysterectomy, myomectomy, salpingo-oophorectomy or ovarian cystectomy) were randomly divided, via sealed envelope assignment, into four groups: sevoflurane and placebo infusion (group S), propofol and placebo infusion (group P), sevoflurane and dexmedetomidine infusion (group SD), or propofol and dexmedetomidine infusion (group PD). The patients and anesthesiologists were blinded to whether the patient was receiving dexmedetomidine or placebo. We excluded patients older than 50 yr, and those with a history of mental illness, recent use of sedatives or analgesics and with impaired sensation.

Patients received oral zopiclone (7.5 mg, an ultrashort benzodiazepine receptor acting drug), atropine (1.0 mg), and ranitidine (150 mg) administered 90 min before arrival in the operating room. On arrival in the operating room we placed an epidural catheter at the L1-2 interspace via a 17-gauge Tuohy needle. After a negative test dose with 3 mL of 0.375% ropivacaine, we injected 7 mL of 0.375% ropivacaine through the epidural catheter before the induction of general anesthesia. The dermatomal analgesic level was evaluated using an alcohol swab 10 min after ropivacaine administration. Patients were excluded from the study if the epidural catheter could not be placed or dosed to a T9 sensory level before induction of anesthesia.

General anesthesia was induced with propofol (2 mg/kg). Vecuronium (0.1 mg/kg) was used to facilitate tracheal intubation. After induction of general anesthesia, groups SD and PD received an initial dexmedetomidine dose of 1 µg/kg over 10 min, followed by a continuous infusion at 0.4 µg/kg/h until the end of surgery, or a placebo infusion of normal saline given at identical rates. Sevoflurane (groups S and SD) or propofol (groups P and PD) was titrated as required to maintain the Bispectral Index (BIS) within 45 ± 5. Patients received intermittent doses of vecuronium (1–2 mg) as needed to maintain muscle relaxation. A continuous epidural infusion of 0.2% ropivacaine at 4 mL/h was started 30 min after the start of surgery and maintained for the following 25 h. Three to five milliliters of additional ropivacaine 0.375% was administered if the patient had signs of intraoperative pain (e.g., increase in mean arterial blood pressure (MAP), and heart rate (HR), or pupil dilation). MAP was measured every 5 min, and electrocardiogram, end-tidal CO₂ (EtCO₂), end-tidal concentration of sevoflurane, and hemoglobin oxygen saturation were continuously monitored throughout the surgery. A decrease in MAP of more than 20% below the preanesthetic baseline level was corrected by IV ephedrine (4–8 mg) and IV fluid administration.

At the end of surgery, the infusion of dexmedetomidine or placebo was stopped, sevoflurane or propofol was discontinued without tapering and the patient's lungs were ventilated with 100% oxygen. We called patients by name every 30 s, asking (in Japanese) "Are you awake? Open your eyes." We measured the time from the end of the general anesthetic to BIS values of 60, 70, 80, and eye opening. When the patients opened their eyes, neuromuscular blockade was reversed with IV administration of neostigmine (0.04 mg/kg) and atropine (0.02 mg/kg). Tracheal extubation was performed when the patients achieved a regular breathing pattern and were able to follow the verbal command to squeeze the anesthesiologist's hand.

Cognitive function was evaluated using the modified Short Orientation Memory Concentration Test (SOMCT)4 at 20 and 50 min after tracheal extubation. The SOMCT was modified because numbers are assigned to months instead of names in Japan. The modified SOMCT required subjects to recall the current year and month and the details of a short story, count backwards from 20 to 1, and enumerate the sequence of the days of the week in reverse order. These five questions yield scores ranging from 0 to 25, with higher scores indicating better cognitive function.

Hemodynamic events induced by the intraoperative infusion of dexmedetomidine such as hypertension, hypotension and bradycardia, and side effects such as nausea, vomiting, and pruritus were assessed and recorded during the first 24 h after surgery. Nausea, vomiting, and pruritus were assessed based on the complaint of patients alone. Nausea and vomiting were treated with IV metoclopramide (10 mg) upon patient request.

A sample size of 15 patients in each group was calculated to have at least 80% power with an of 0.0083 (two-sided) using STATA (version 8.0; Stata Corporation, College Station, TX) in order to detect the prolongation of time to eye opening from 10 ± 4 min to 20 ± 8 min (mean ± sd) between the two groups. These numbers are selected with the assumption that dexmedetomidine has the same effect as that in our pilot study, which was performed in a nonblinded fashion using a few cases at our institution. The data were analyzed using repeated measures analysis of variance with subsequent intergroup comparisons using Shéffe's F test. A P value <0.05 was considered significant.

	RESULTS

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Patient details (height, weight, and age) and the duration of operation were not different among groups. The surgical procedures performed in this study were compatible among groups. BIS values and EtCO₂ just before the interruption of maintenance general anesthetics was not significantly different among the groups. The total doses of intraoperative 0.375% ropivacaine and vecuronium were similar among groups.

Dexmedetomidine reduced the anesthetic requirements required to maintain a BIS of approximately 45 by 20%–30% for both groups: decreasing sevoflurane from 1.1 ± 0.2% in group S to 0.8 ± 0.2% in group SD, and propofol from 4.4 ± 0.8 mg/kg/h in group P to 3.1 ± 1.0 mg/kg/h in group PD (Table 1). Dexmedetomidine significantly delayed recovery in patients receiving propofol, but had relatively little effect on patients receiving sevoflurane (Fig. 1).

View larger version (11K): [in this window] [in a new window]   Figure 1. Time after interruption of maintenance general anesthetics. Times from the interruption of maintenance general anesthetic [Bispectral Index (BIS) of 45] to BIS values of 60, 70, and 80, and eye opening were measured. Data are expressed mean ± sd (n = 15). *P < 0.005; **P < 0.001 vs groups S, SD, and PD.

Postoperative cognitive function evaluated using the modified SOMCT was similar in patients anesthetized with sevoflurane and propofol. The scores of the modified SOMCT 20 min after tracheal extubation (20.2 ± 5.2 in. group S, 21.9 ± 3.6 in. group SD, 22.1 ± 2.6 in. group P, and 18.7 ± 7.4 in. group PD) and 50 min after extubation (22.5 ± 4.2 in. group S, 24.5 ± 1.2 in. group SD, 24.1 ± 1.8 in. group P, and 23.9 ± 2.7 in. group PD) were not affected by co-administration of dexmedetomidine.

Systolic blood pressure increased to approximately 180 mm Hg in one patient during the initial loading phase of dexmedetomidine administration, but the effect was transient and required no treatment. Dexmedetomidine decreased HR by about 25% compared with saline controls, with no discernable effect on MAP. We did not observe severe hypotension (MAP <60 mm Hg) or bradycardia (HR <40 bpm) in any subjects.

One patient in each group complained of nausea and vomiting. All four patients were successfully treated with metoclopramide (10 mg).

	DISCUSSION

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The main findings of this study are as follows: 1) dexmedetomidine delays recovery from propofol, but not from sevoflurane, and 2) postoperative cognitive function, evaluated using the modified SOMCT, is not affected by co-administration of dexmedetomidine in patients anesthetized with both sevoflurane and propofol. This is similar to a finding in dogs that dexmedetomidine delayed recovery from propofol, but not from isoflurane.5 Although these authors postulated a pharmacokinetic explanation, Dutta et al.6 showed that the pharmacokinetic parameters of propofol are not affected by the administration of dexmedetomidine in healthy volunteers. Furthermore, dexmedetomidine and propofol show pharmacodynamic interaction for the sedation and suppression of the motor response.6 Thus, the mechanism by which dexmedetomidine delays emergence from propofol anesthesia is unclear, and could have either a pharmacokinetic or pharmacodynamic explanation.

The modified SOMCT scores were not affected by dexmedetomidine. Patients receiving dexmedetomidine were receiving lower doses of propofol and sevoflurane at the end of surgery. Additionally, these patients required more time to recover, suggesting that their concentrations of propofol or sevoflurane should have been lower than patients not receiving dexmedetomidine. As SOMCT scores were the same in all four groups, it follows that the SOMCT score is not affected by whether the sedation arises from propofol, sevoflurane, or the concurrent effects of dexmedetomidine on sedation from propofol or sevoflurane. This is consistent with the observation that dexmedetomidine impairs cognitive functions. For example, dexmedetomidine infusion at 0.2 and 0.6 µg/kg/h reduced the scores of a digit substitution test and a memory recall test in healthy volunteers.7

No patients needed intervention for bradycardia or hypotension. The patients were administered atropine (1 mg) as premedication before surgery to prevent dexmedetomidine-induced bradycardia requiring intervention. Except for a few patients who experienced nausea and vomiting that were easily treatable, no other severe adverse effects were observed. These findings support the safety of co-administration of dexmedetomidine under sevoflurane or propofol anesthesia.

There are several limitations in this study. First we titrated the anesthesia to maintain equivalent BIS scores. The BIS is a measure of drug effect, and it is not clear whether a BIS of 45 is the same level of anesthesia in patients receiving propofol and sevoflurane with or without dexmedetomidine. It has been reported that BIS values at the time of loss of consciousness in patients anesthetized with sevoflurane were significantly higher than those in patients anesthetized with propofol.8 Moreover, at an equivalent decrease in BIS values, sevoflurane suppressed the blink reflex more than propofol.9 Second, we administered propofol with a manually controlled infusion rather than a target-controlled infusion. Propofol target-controlled infusion would have been better, as it would have allowed for an easier comparison with sevoflurane. Third, the continuous epidural infusion precluded useful assessment of postoperative analgesia. Fourth, the intensity of the verbal stimulus for eye opening was not standardized in the present study. Lastly, we did not measure serum propofol, sevoflurane, or dexmedetomidine concentrations, precluding our ability to distinguish pharmacokinetic interactions from pharmacodynamic interactions.

In conclusion, dexmedetomidine delayed emergence from propofol anesthesia, but not from sevoflurane anesthesia. The presence of dexmedetomidine did not alter the assessment of cognitive function, suggesting that the anesthetic sparing achieved with dexmedetomidine is not associated with faster cognitive recovery.

	ACKNOWLEDGMENTS

 
The authors thank Dr. Nobuyoshi Seki, Dr. Hikaru Kobayashi, Dr. Zenya Saito, Dr. Masami Machida, Dr. Mutsumi Ohishi, Dr. Taichi Wakabayashi, and Dr. Shinichiro Nishio (Residents of Jikei University Aoto Hospital, Tokyo, Japan) for their help in data collection.

	Footnotes

 
Accepted for publication July 28, 2008.

Supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to E.M.) (No. 18591720).

	REFERENCES

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2. Khan ZP, Munday IT, Jones RM, Thornton C, Mant TG, Amin D. Effects of dexmedetomidine on isoflurane requirements in healthy volunteers. 1: Pharmacodynamic and pharmacokinetic interactions. Br J Anaesth 1999;83:372–80[Abstract/Free Full Text]
3. Jaakola M-L, Salonen M, Lehtinen R, Scheininet H. The analgesic action of dexmedetomidine—a novel ₂-adrenoceptor agonist—in healthy volunteers. Pain 1991;46:281–5[Web of Science][Medline]
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