BACKGROUND: Dexmedetomidine (Dex), an α2 agonist, has well-known anesthetic and analgesic-sparing effects. We designed this prospective, randomized, double-blind, and placebo-controlled dose-ranging study to evaluate the effect of Dex on both early and late recovery after laparoscopic bariatric surgery.
METHODS: Eighty consenting ASA II–III morbidly obese patients were randomly assigned to 1 of 4 treatment groups: (1) control group received a saline infusion during surgery, (2) Dex 0.2 group received an infusion of 0.2 μg · kg−1 · h−1 IV, (3) Dex 0.4 group received an infusion of 0.4 μg · kg−1 · h−1 IV, and (4) Dex 0.8 group received an infusion of 0.8 μg · kg−1 · h−1 IV. Mean arterial blood pressure values were maintained within ±25% of the preinduction baseline values by varying the inspired desflurane concentration. Perioperative hemodynamic variables, postoperative pain scores, and the need for “rescue” analgesics and antiemetics were recorded at specific intervals. Follow-up evaluations were performed on postoperative days (PODs) 1, 2, and 7 to assess severity of pain, analgesic requirements, patient satisfaction with pain management, quality of recovery, as well as resumption of dietary intake and recovery of bowel function.
RESULTS: Dex infusion, 0.2, 0.4, and 0.8 μg · kg−1 · h−1, reduced the average end-tidal desflurane concentration by 19, 20, and 22%, respectively. However, it failed to facilitate a significantly faster emergence from anesthesia. Although the intraoperative hemodynamic values were similar in the four groups, arterial blood pressure values were significantly reduced in the Dex 0.2, 0.4, and 0.8 groups compared with the control group on admission to the postanesthesia care unit (PACU) (P < 0.05). The length of the PACU stay was significantly reduced in the Dex groups (81 ± 31 to 87 ± 24 vs 104 ± 33 min in the control group, P < 0.05). The amount of rescue fentanyl administered in the PACU was significantly less in the Dex 0.2, 0.4, and 0.8 groups versus control group (113 ± 85, 108 ± 67, and 120 ± 78 vs 187 ± 99 μg, respectively, P < 0.05). The percentage of patients requiring antiemetic therapy was also reduced in the Dex groups (30, 30, and 10% vs 70% in the control group). However, the patient-controlled analgesia morphine requirements on PODs 1 and 2 were not different among the four groups. Pain scores in the PACU, and on PODs 1, 2, and 7, in the three Dex groups were not different from the control group. Finally, quality of recovery scores and times to recovery of bowel function and hospital discharge did not differ among the four groups.
CONCLUSIONS: Adjunctive use of an intraoperative Dex infusion (0.2–0.8 μg · kg−1 · h−1) decreased fentanyl use, antiemetic therapy, and the length of stay in the PACU. However, it failed to facilitate late recovery (e.g., bowel function) or improve the patients’ overall quality of recovery. When used during bariatric surgery, a Dex infusion rate of 0.2 μg · kg−1 · h−1 is recommended to minimize the risk of adverse cardiovascular side effects.
IMPLICATIONS: This placebo-controlled dose-ranging study found that dexmedetomidine infusion rates from 0.2 to 0.8 &#x03BC;g &#x00B7; kg&#x2212;1 &#x00B7; h&#x2212;1 reduced the volatile anesthetic requirement and the need for opioid analgesics and antiemetics in the early postoperative period. Although adjunctive use of dexmedetomidine facilitated early recovery (e.g., postanesthesia care unit stay), it failed to improve later recovery end-points (e.g., hospital discharge, recovery of bowel function).
From the Departments of *Surgery, †Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
Accepted for publication February 8, 2008.
This investigator–initiated, Food and Drug Administration-approved study was supported, in part, by an unrestricted educational grant from Hospira, Inc. (Lake Forest, IL), endowment funds from the Margaret Milam McDermott Distinguished Chair in Anesthesiology, and the White Mountain Institute, a non-profit private foundation (Paul F. White, President).
Address correspondence and reprint requests to Dr. Paul F. White, Professor and Holder of the Margaret Milam McDermott Distinguished Chair in Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9068. Address e-mail to email@example.com.
Dexmedetomidine (Dex) is a highly selective α2-adrenoreceptor agonist, which possesses hypnotic, sedative, anxiolytic, sympatholytic, and analgesic properties without producing significant respiratory depression.1–4 Its sympatholytic effect decreases mean arterial blood pressure (MAP) and heart rate (HR) by reducing norepinephrine release.5,6 In addition, Dex has the ability to reduce both the anesthetic and opioid analgesic requirements during the perioperative period.7–9
As a result of the prevalence of obesity in modern societies, bariatric surgery continues to grow throughout the world. Morbidly obese patients are at an increased risk of developing postoperative obstructive sleep apnea and opioid-induced ventilatory depression. Since Dex possesses an opioid-sparing effect without causing respiratory depression, it has been increasingly used “off-label” during bariatric surgery.10,11 However, there is only one study describing the use of an arbitrarily chosen Dex infusion rate in this patient population.12
In this prospectively randomized, double-blind, placebo-controlled, dose-ranging study, we tested the hypothesis that Dex infusion would produce dose-related reductions in the anesthetic and analgesic requirements in patients undergoing laparoscopic bariatric surgery. The secondary objectives were to determine if the use of Dex facilitated the recovery process and improved patient outcome.
After obtaining IRB approval at the University of Texas Southwestern Medical Center at Dallas, and written informed consent, 80 morbidly obese patients, aged 22–66-yr-of-age, scheduled for laparoscopic bariatric surgery (either gastric banding or gastric bypass) were studied according to a randomized, double-blind, placebo-controlled protocol. This investigation was registered with ClinicalTrials.gov (NCT00363935). Patients were excluded if they had: (1) an allergy to α2 adrenergic agonist or sulfa drugs, (2) a history of uncontrolled hypertension, (3) heart block greater than first degree, (4) a history of alcohol or drug abuse, (5) clinically significant neurologic, cardiovascular, renal, hepatic, or gastrointestinal diseases, (6) received an opioid analgesic medication within a 24 h period before the operation, (7) were pregnant or breast-feeding, and (8) were unable to speak and read English.
The patients were randomly assigned using a computer-generated random number table to one of the following four treatment groups: (1) control group received saline, (2) Dex 0.2 group received 0.2 μg · kg−1 · h−1 IV, (3) Dex 0.4 group received 0.4 μg · kg−1 · h−1 IV, and (4) Dex 0.8 group received 0.8 μg · kg−1 · h−1 IV. The study medication was prepared by the operating room (OR) pharmacist in identical 60-mL syringes. Dex 0, 200, 400, or 800 μg was added to saline to achieve a total volume of 40 mL, resulting in concentrations of 0 μg/mL (control), 5 μg/mL, (Dex 0.2), 10 μg/mL, (Dex 0.4), and 20 μg/mL, (Dex 0.8), for the 4 study groups. The weight-adjusted doses of all study medications were based on the patient’s actual body weight. The investigators, attending anesthesiologists, OR, recovery and ward nurses, as well as the patients were blinded to the computer-generated randomization schedule.
In the preoperative holding area, the patients used 11-point verbal rating scales (VRS) to assess their baseline pain and nausea levels, with 0 = none to 10 = maximum. Celecoxib, 400 mg orally, was given 30–60 min before induction of anesthesia. Immediately before entering the OR, patients were premedicated with midazolam, 20 μg/kg IV. Intraoperative monitoring devices included noninvasive arterial blood pressure, electrocardiography, capnography, and pulse oximetry, as well as the cerebral state monitor (Danmeter, Odense, Denmark).
After obtaining baseline measurement of HR and MAP, an infusion of the study medication was started at 0.04 mL · kg−1 · h−1. Anesthesia was induced 3–5 min after starting the study drug infusion with propofol, 1.25 mg/kg IV, in combination with lidocaine, 0.75 mg/kg IV. Rocuronium, 0.6 mg/kg IV, and 4 mL of topical 4% lidocaine were administered before tracheal intubation. Anesthesia was initially maintained with 4% inspired concentration of desflurane in combination with air (1 L/min) and oxygen (1 L/min) mixture.
The intraoperative HR, MAP, end-tidal desflurane concentration, and cerebral state index (CSI) values were recorded at 5 min intervals for 30 min, and subsequently at 10 min intervals until discontinuation of the anesthetic drugs. Hemodynamic values were also recorded at specific end-points (e.g., induction of anesthesia, 1 min after induction, tracheal intubation, 5 min after tracheal intubation, at skin incision, at 5 and 10 min after the skin incision). After induction of anesthesia, MAP values were maintained within ±25% of the baseline values by varying the inspired desflurane concentration. Hypotension (defined as MAP value <25% of the baseline value on two consecutive readings within 2–3 min), not responding to a 2% (vol %) decrease in the inspired desflurane concentration and a 200 mL fluid bolus, was treated with phenylephrine, 100 μg IV, boluses. The infusion of study medication was discontinued if the hypotension persisted >2 min after these interventions. Upon return of the MAP to ±25% of the baseline value, the study medication infusion was resumed at 50% of the initial infusion rate. In the presence of hypertension (defined as MAP value >25% of the baseline value on two consecutive readings within 2–3 min) and/or tachycardia (defined as HR value >25% of the baseline value > 2 min) despite a 2% (vol %) increase in the inspired desflurane concentration, labetalol, 5 mg IV, boluses were administered. Bradycardia (HR <45) persisting for >2 min was treated with glycopyrrolate, 0.2 mg IV, boluses.
During the operation, patients received similar amounts of IV crystalloid solutions (namely, 25 mL/kg during gastric bypass and 10 mL/kg during gastric banding procedures). Ondansetron, 4 mg IV, was given for prevention of postoperative nausea and vomiting when the laparoscope was withdrawn. Before wound closure, bupivacaine 0.25% was infiltrated at the fascial level of all portals, and residual neuromuscular block was reversed with neostigmine, 40 μg/kg IV, and glycopyrrolate, 5 μg/kg IV. The infusion of study medication was discontinued at the start of the wound closure. Upon completion of wound closure, desflurane was discontinued and the inspired oxygen flow rate was increased to 5 L/min. Times from discontinuation of desflurane to eye opening, obeying simple commands (e.g., open mouth, squeeze hand) and tracheal extubation were recorded. After emergence from anesthesia, patients were administered fentanyl, 25–50 μg IV, boluses to control acute pain in the early postoperative period.
After arrival in the postanesthesia care unit (PACU), patients were connected to a patient-controlled analgesia (PCA) delivery system that was programmed to deliver morphine, 2 mg IV, boluses on demand with a lockout interval of 10 min. When patient’s VRS pain score was <7 and they were judged to be recovered from anesthesia by the PACU staff, they were allowed to self-administer morphine using the PCA delivery system. The parenteral opioid analgesic requirements were determined in the PACU, as well as on postoperative day (POD) 1 and 2 (with the exception of the patients who had been discharged home on POD 1). Hemodynamic values and VRS pain scores were recorded at 5 min intervals for the first 15 min after arrival in the PACU, and subsequently at 15 min intervals until discharge. The VRS nausea scores and episodes of emesis, as well as the need for rescue antiemetic therapy, were recorded at 30 min intervals until PACU discharge. Patients reporting a VRS nausea score >3 on two consecutive evaluations were administered promethazine, 6.25 mg IV. VRS pain and nausea scores, quality of recovery scores [using a validated 9-item questionnaire13], and patient satisfaction with their pain management (on a 100-point scale with 1 = completely dissatisfied to 100 = completely satisfied) were recorded on PODs 1, 2, and 7. Finally, recovery times from tracheal extubation to ambulation without assistance, tolerating liquids, and passage of flatus were also noted. Patients were asked to note the time they were able to tolerate liquids and their first passage of flatus (“gas”) in a diary.
Data are expressed as mean ± sd, medians (and interquartile ranges), percentages (%), and numbers (n). The statistical analysis was performed using a standard SPSS software package (Chicago, IL). For continuous variables, one-way analysis of variance (ANOVA) and repeated measures of ANOVA (RMANOVA) were used to evaluate changes among the groups. Student’s t-test was used to analyze the parametric data, and discrete (categorical) variables were analyzed using the χ2 test, with a P < 0.05 was considered statistically significant. Bonferonni corrections were performed for variables with multiple comparisons over time (i.e., RMANOVA). The group sizes (n = 20) were calculated to detect a >40% reduction in the volatile anesthetic7,8 and/or postoperative opioid analgesic requirement9 with a power of 80% [assuming a variability (sd) of ±20%] and a significance level of 0.05.
A total of 125 patients were screened for eligibility to participate in the study, and 80 patients were subsequently enrolled (n = 20 per group). Three patients (one from each of the Dex 0.2, 0.4, and 0.8 groups) were admitted to the intensive care unit from the postsurgical ward because of surgical complications at the gastrointestinal anastomosis site (e.g., bleeding, obstruction) and their postoperative data were excluded from the final analysis. There were no significant differences among the four groups with respect to age, gender, weight, height, ASA physical status, type of laparoscopic bariatric surgery, perioperative CSI values, and the durations of study medication infusion, surgery, and anesthesia times (Table 1 and Fig. 1). Recovery times after discontinuation of the study medication and desflurane to tracheal extubation, spontaneous eye opening, and obeying simple commands did not differ among the four groups (Table 2).
End-tidal concentrations of desflurane during the operation were significantly lower in the Dex 0.2, 0.4, and 0.8 groups compared with the control group during surgery (>30 min after induction) (Fig. 1, P < 0.05). In addition, the percentage of patients who required rescue treatment with phenylephrine for persistent hypotension during surgery was significantly higher in the Dex 0.8 group compared with the control group (50% vs 20%, P < 0.05). The study medication infusion was transiently discontinued (<10 min) in 2 (10%), 2 (10%), 3 (15%), and 3 (15%) patients in the control, Dex 0.2, Dex 0.4, and Dex 0.8 groups, respectively, because of an inability to maintain the MAP values in the desired range (±25% of the baseline values) under the conditions of the study [i.e., ensuring that the patients CSI values were in a range consistent with a “state of unconsciousness” (<60)].
Compared with the control group, MAP values at the time of skin incision were significantly reduced in the Dex 0.2, Dex 0.4, and Dex 0.8 groups (Fig. 2a). However, the HR values were not different (Fig. 2b). Although the MAP values at 70 and 100 min after the start of the study drug infusion were significantly lower in the Dex 0.4 and Dex 0.8 groups compared with the control group (86 ± 15 and 81 ± 16 vs 97 ± 12 and 85 ± 11 and 84 ± 14 vs 96 ± 14, respectively, P < 0.05, Fig. 2c), these minor differences were not clinically significant. However, the MAP values during the first 45 min in the PACU were significantly lower in the Dex 0.2, 0.4, and 0.8 groups compared with the control group (Fig. 3a). The perioperative HR values did not differ among the four study groups (Figs. 2d and 3b).
Pain scores in the PACU, as well as the average pain scores on POD 1, 2, and 7, did not differ significantly among the four groups. However, the amount of fentanyl administered in the PACU after emergence from anesthesia was significantly reduced in the Dex 0.2, 0.4, and 0.8 groups compared with the control group (113 ± 85, 108 ± 67, 120 ± 78 vs 187 ± 99 μg, respectively, P < 0.05). The total amount of PCA morphine self-administered on PODs 1 and 2 did not differ among the four treatment groups (Table 3).
The overall incidences of postoperative emetic symptoms during the first 24 h after surgery were reduced in the Dex 0.2, 0.4, and 0.8 groups compared with the control group (25, 30, and 45 vs 65%, respectively). The VRS nausea scores on arrival in the PACU and at 30 min were also significantly lower in the Dex 0.2, 0.4, and 0.8 groups compared with the control group (Table 4). Similarly, the need for rescue antiemetic drugs in the PACU was significantly reduced in all three Dex groups (Table 4). The durations of the PACU stay were significantly reduced in the three Dex groups compared with the control group (81 ± 31, 82 ± 24, 87 ± 24 vs 104 ± 33, respectively, P < 0.05). However, the time to hospital discharge did not differ among the four groups (Table 4).
Finally, quality of recovery scores, patient satisfaction with their pain management on POD 1, 2, and 7, as well as times to ambulation without assistance, tolerating oral liquids, and resumption of bowel function, did not differ among the four treatment groups (Table 4).
Dex infusion, 0.2–0.8 μg · kg−1 · h−1, produced anesthetic-sparing effects and a reduction in the need for opioid analgesics and antiemetic drugs, as well as lower MAP values in the early postoperative period in this laparoscopic bariatric surgery patient population. However, the anesthetic and analgesic-sparing effects of Dex were not strictly dose-related over the four-fold drug concentration range studied. Although Dex facilitated the early recovery (e.g., PACU stay), later recovery events (e.g., hospital discharge, resumption of oral intake and bowel function) were similar in all four groups. The reduced need for potent opioid analgesics and less severe emetic symptoms in the Dex groups probably contributed to the reduced PACU stay.
Dex is only Food and Drug Administration-approved for sedation of initially intubated and mechanically ventilated patients by continuous infusion for <24 h in the intensive care setting. There are numerous clinical reports describing the “off label” use of Dex infusion as an adjuvant during and/or after surgery.7–12,14–18,19 A previous study evaluated different bolus doses of Dex for premedication20; however, dose-ranging studies are lacking for when the drug is administered as a continuous infusion during surgery. Given the propensity of the drug to produce hypotension and/or bradycardia when it is administered to volunteers or patients,15–17,21–23 it was important to determine an infusion rate that would maximize the anesthetic and analgesic-sparing effect while minimizing the occurrence of adverse cardiovascular side effects requiring therapeutic interventions (e.g., phenylephrine, labetalol).
In several reports, Dex infusion rates ranging from 0.4 to 10 μg · kg−1 · h−1 have been used during bariatric surgery.10–12 In contrast to the case report19 in which a high-dose infusion (>1 μg · kg−1 · h−1) of Dex was administered as the primary drug in a total IV anesthetic technique, we used Dex as an adjuvant to the volatile anesthetic desflurane. Therefore, in our prospective dose-ranging study, we evaluated Dex infusion rates of 0.2, 0.4, and 0.8 μg · kg−1 · h−1 during anesthesia. Patients assigned to the control group required more frequent use of antihypertensive rescue medication, and the high-dose Dex group required greater use of cardiovascular medication to treat hypotensive episodes during surgery. Hence, these data would suggest that the selected infusion rates of Dex (0.2–0.8 μg · kg−1 · h−1) were in the appropriate therapeutic range when it is used as part of a “balanced” anesthetic technique.10
Analogous to the findings of Feld et al.12 when Dex, 0.4 μg · kg−1 · h−1, was administered during bariatric surgery as an alternative to fentanyl, we found statistically significant reductions in the volatile anesthetic requirement and the need for potent opioid analgesics in the PACU. The use of Dex infusion, 0.2–0.8 μg · kg−1 · h−1, reduced the end-tidal desflurane concentration by 19%–22% during surgery and the fentanyl requirement by 36%–42% in the PACU, contributing to a reduction in postoperative nausea and in the need for rescue antiemetic therapy in the early postoperative period. The failure of Dex to produce a sustained opioid-sparing effect in the later postoperative periods was probably related to its short elimination half-life of 2 h.2–4 These data also support the findings of Angst et al.,24 which suggested that systemic administration of Dex lacks significant preemptive analgesic activity with respect to minimizing postoperative pain.
Preliminary clinical reports10,12 have suggested that a continuous infusion of Dex, 0.4–0.7 μg · kg−1 · h−1, may be a useful anesthetic adjunct for morbidly obese patients undergoing bariatric surgery. Our findings would suggest that the modest anesthetic-sparing effect was of little (if any) clinical significance because dexmedtomidine failed to facilitate a faster emergence from desflurane anesthesia after bariatric surgery. Although the intraoperative use of Dex decreased the amount of fentanyl used in the early postoperative period, it only reduced the length of stay in the PACU by an average of 15–25 min. Use of Dex failed to reduce the length of the hospital stay after either gastric bypass or banding procedures. Therefore, the primary benefit of Dex in this study appeared to be related to its ability to reduce emetic sequelae by decreasing the need for the desflurane during the operation and fentanyl immediately after surgery. The anesthetic and opioid-sparing effects of Dex in the early postoperative period may decrease the risk of respiratory depression in the PACU for morbidly obese patients who are at greater risk for obstructive sleep apnea and oxygen desaturation.
This study can be criticized because a constant infusion was used. However, the administration of an initial loading bolus of Dex (0.5 μg/kg IV) resulted in a high incidence of hypotension immediately after tracheal intubation in a “pilot” experience before initiating the current protocol. Although use of a variable-rate infusion may minimize both hypo- and hypertensive responses during surgery, it would have confounded our findings and precluded a direct comparison of the four treatment groups. Another criticism of this study relates to our failure to continue the infusion of the study medication into the postoperative period to achieve a more sustained opioid-sparing effect.17 However, the use of a Dex infusion is not recommended outside of closely monitored areas (e.g., intensive care unit). Finally, the use of noninvasive blood pressure (vs intraarterial) monitoring for titrating the volatile anesthetic, and fentanyl for pain control in the early postoperative period before initiating maintenance PCA therapy, were intended to mimic standard clinical practice for this surgical procedure.
It has been suggested that Dex infusion is a useful alternative to opioid analgesics, despite its high cost because it lacks the respiratory-depressant effects produced by opioid compounds.12,19 In an editorial by Ebert and Maze,25 it was suggested that α2 adrenergic receptor agonists may also be useful in the perioperative period because of their sedative/hypnotic, anxiolytic, and sympatholytic properties. Although we did not assess Dex’s anxiety-relieving properties, our data would suggest that a pharmacoeconomic analysis of the cost:benefit ratio of Dex in this patient population is clearly needed. Given the growing importance of multimodal analgesia in facilitating the recovery process,26,27 Dex may prove to be a cost-effective adjuvant in morbidly obese patients who are at increased risk for respiratory complications in the early postoperative period.
In summary, the anesthetic and analgesic-sparing effects of Dex infusion, 0.2–0.8 μg · kg−1 · h−1, facilitated early but not late recovery of morbidly obese patients undergoing bariatric surgery. When using a Dex infusion as an anesthetic adjuvant, an infusion rate of 0.2 μg · kg−1 · h−1 is recommended to facilitate early recovery while minimizing adverse perioperative cardiovascular side effects.
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