Coloma, Margarita MD; Chiu, Jen W. MB, MMed, DEAA; White, Paul F. PhD, MD, FANZCA, and; Armbruster, Steven C. MD
The optimal approach to achieving the dual aims of obtunding the transient autonomic changes that occur in response to noxious surgical stimuli during surgery and facilitating prompt recovery after ambulatory anesthesia is still contentious. It is unclear whether these objectives are best achieved with opioid analgesics, sympatholytic drugs, sedative-hypnotics, or other adjuvants (e.g., adenosine, nicardipine) (1–6).
The opioid analgesic remifentanil is a useful anesthetic adjunct for brief ambulatory surgical procedures because of its rapid onset, titratability and short duration of action (7,8). It also has anesthetic-sparing effects that expedite emergence from anesthesia (1–3,9). In contrast to traditional opioid analgesics, recent studies with remifentanil have suggested that the incidence of opioid-related postoperative nausea and vomiting and residual sedation may not be significantly increased when it is used as an anesthetic adjuvant (2,3). Alternatively, sympatholytic drugs can be used to control acute autonomic responses during surgery. Esmolol has been successfully used for perioperative sympatholysis (4,5,10,11), and reduces the anesthetic requirement during propofol or volatile-based anesthesia (12,13).
This double-blinded study was designed to test the hypothesis that the use of esmolol as an alternative to the opioid remifentanil reduces postoperative side effects after outpatient gynecologic laparoscopic surgery when used as an adjuvant during desflurane-based anesthesia as part of a fast-tracking recovery paradigm. Therefore, we compared esmolol and remifentanil infusions with respect to their effects on intraoperative hemodynamic variables, ability to “bypass the postanesthesia care unit (PACU),” and recovery profiles.
After obtaining IRB approval and written informed consent, 53 healthy outpatients scheduled to undergo laparoscopic tubal ligation procedures were enrolled in this randomized, double-blinded study. Patients were assigned to either the Esmolol or Remifentanil study group according to a computer-generated random numbers table. Exclusion criteria included ASA physical status III, chronic hypertension, chronic use of opioid analgesic or β-blocker medication, asthma or reactive airway disease, obesity (>50% above ideal body weight), menstruation at the time of surgery, and history of allergic reactions to any of the study medications.
On arrival in the operating room, routine monitors were applied for recording heart rate (HR), systolic blood pressure (SBP), and oxygen saturation (Spo2). In addition, the electroencephalographic bispectral index (BIS) value was obtained using a single channel sensor in a frontal temporal montage (A-1050 EEG Monitor; Aspect Medical Systems Inc, Natick, MA). After obtaining baseline values, midazolam (2 mg IV) was administered for premedication and anesthesia was subsequently induced with propofol (2 mg · kg−1 IV) in combination with either esmolol (1.0 mg · kg−1 IV) or remifentanil (1.0 μg · kg−1 IV). Direct laryngoscopy and tracheal intubation were performed after administrating succinylcholine (1 mg · kg−1 IV) and topical intratracheal lidocaine 4% (4 mL). For initial maintenance of anesthesia, desflurane 2.5% (inspired) in combination with nitrous oxide 65% in oxygen was administered and the inspired desflurane concentration was subsequently adjusted to maintain a “targeted” BIS value of 60 during the operation. The inspired desflurane concentration was changed by 50–100% if the BIS value was >70 or <50 for >60 s. Patients received an infusion of either esmolol, 5 to 15 μg · kg−1 · min−1 IV, or remifentanil, 0.025 to 0.125 μg · kg−1 · min−1 IV, to maintain the HR within 25% of the preinduction baseline value, with the targeted HR range between 55–90 bpm.
All patients were mechanically ventilated to maintain the end-tidal carbon dioxide (CO2) concentration in the range of 32 to 36 mm Hg. Bolus doses of mivacurium (0.04 mg/kg IV) were administered to maintain the peak inspiratory pressure within 10% of the postintubation value, and to treat coughing or “bucking.” These small doses of mivacurium did not preclude purposeful movements in response to noxious surgical stimulation. Surgeons instilled a mixture of lidocaine 1% and bupivacaine 0.25% (10 mL) on the surface of each tube before ligation, and injected this mixture at the fascial level of the surgical portals on closure of the incisions. All patients received a combination of prophylactic antiemetics consisting of dexamethasone 4 mg IV, droperidol 0.625 mg IV, and ondansetron 4 mg IV, as well as acetaminophen (1300 mg pr) and ketorolac (30 mg IV) for preventative analgesia. Desflurane was discontinued when the laparoscope was withdrawn, and the nitrous oxide and study drug infusion were discontinued after the last skin suture was applied. No neuromuscular reversal drugs were administered in either study group.
Hemodynamic variables were recorded at baseline, induction of anesthesia, tracheal intubation, skin incision, and subsequently at 5-min intervals until the end of surgery. The age-adjusted average of the desflurane minimum alveolar concentration (MAC) over time (i.e., MAC · h = sum of end-tidal concentration divided by the MAC value multiplied by the duration [h] at that concentration) was also determined. The following autonomic responses were considered indicative of an inadequate “depth of anesthesia”: 1) increase in SBP >25% above baseline or >180 mm Hg for >1 min; 2) increase in HR >25% above baseline or >90 bpm for >1 min; 3) somatic signs (e.g., purposeful movements, swallowing or grimacing); and 4) autonomic signs (e.g., lacrimation, mydriasis, facial flushing, or diaphoresis).
Patients who fulfilled a standardized fast-tracking criteria (score >12) (14) were transported directly from the operating room to the day-surgery (Phase II) recovery area, bypassing the Phase I PACU. Recovery times were assessed by a blinded observer from the time the study drugs were discontinued. Times to awakening (e.g., opening eyes on verbal command) and orientation to person, date, and place were assessed at 1-min intervals, whereas the time to home-readiness was evaluated at 15-min intervals using standardized discharge criteria (15). Postoperative side effects (e.g., nausea, vomiting, pain and intraoperative recall), requirement for “rescue” analgesics and antiemetic therapy, as well as patient satisfaction were assessed on discharge from the Phase II recovery area and at 24 h after the procedure. The patient’s assessment of their postoperative pain was rated as none, mild, moderate, or severe, and satisfaction with their anesthetic experience was recorded as poor, good, or excellent.
Data were analyzed using the Number Cruncher Statistical System 6.0 statistical analysis program (NCSS, Kaysville, UT). Based on earlier studies (3,5,9) involving a similar patient population, an a priori power analysis indicated that a sample size of 26 patients in each group would be adequate to detect a 30% reduction in the incidence of postoperative nausea with a power of 0.8 (α = 0.05). Continuous data were analyzed using Student’s t-tests, with values presented as means ± sd. Categorical variables were analyzed using χ2 test, with data expressed as median values or percentages. P- values <0.05 were considered statistically significant.
The two study groups were similar with respect to demographic characteristics, durations of anesthesia and surgery, and the desflurane anesthetic requirement (MAC · h) (Table 1). The average infusion rates of esmolol and remifentanil were 12.8 ± 13.1 μg · kg−1 · min−1 and 0.04 ± 0.02 μg · kg−1 · min−1, respectively. Compared with esmolol, use of remifentanil was associated with a decrease in the mivacurium maintenance requirement (P < 0.05).
The perioperative SBP and HR values in the two treatment groups are summarized in Figures 1A and 1 B. Although there were no significant differences in HR values (with individual HR values ranging from 57 to 95 and 56 to 94 in the Esmolol and Remifentanil groups, respectively), SBP values were consistently decreased during the maintenance period in the Remifentanil group. However, SBP values did not exceed the preoperative baseline value during the maintenance period in the Esmolol group (Fig. 1 A). No purposeful movements or clinical signs of inadequate anesthesia were observed during surgery in either treatment group.
Times to awakening and orientation were similar in the two groups (Table 2). Times to achieve a fast-track score >12 and an Aldrete score of 10 were also comparable in the two groups, as well as the times to oral intake, home readiness, discharge home, and resumption of normal activities. Of importance, approximately 80% of patients in both groups were able to “bypass” the PACU after surgery (Table 2). The times to home readiness and actual discharge were significantly shorter in the bypassed patients (112 ± 46 and 159 ± 63 min vs 151 ± 50 and 206 ± 46 min, respectively). Although the use of remifentanil was associated with an increased incidence of nausea in the early recovery period, vomiting did not differ between the two groups. (Table 3). None of the patients required supplemental oxygen in the Phase II recovery area. There was no significant difference in the incidence or severity of postoperative pain before discharge home; however, more patients in the Esmolol group required oral hydrocodone during the first 24 h after discharge (Table 3). Over 80% of the patients in both treatment groups rated their level of satisfaction with their anesthetic experience as excellent, and none of the patients reported intraoperative recall or complained of myalgias at 24 h after surgery.
The concept of fast tracking has been introduced into the ambulatory setting in an attempt to facilitate the early recovery process and thereby reduce recovery care costs (16). The use of rapid and short-acting anesthetic, analgesic, and muscle relaxant drugs combined with minimally-invasive (so-called keyhole) surgical approaches has led to increasing acceptance of this recovery paradigm for patients undergoing ambulatory surgical procedures (17). In this study, approximately 80% of the patients were fast-tracked and satisfied criteria for discharge home in an average of two hours after gynecologic laparoscopic surgery. Compared with the conventional recovery pathway, fast-tracked patients were discharged home an average of 47 minutes earlier.
In patients undergoing laparoscopic tubal ligation procedures, transient acute hemodynamic responses typically occur at laryngoscopy and tracheal intubation, during insertion of the Veress needle and trocars, and during creation of the pneumoperitoneum. The sympathetic effects associated with insufflation of CO2, as well as the shifts in intravascular volume resulting from the Trendelenburg position, can also lead to hemodynamic perturbations during surgery. Both opioid analgesics and sympatholytic drugs have been used to control acute hyperdynamic responses during the intraoperative period (2,5,6). When using IV adjuvants like remifentanil and esmolol to maintain hemodynamic stability during surgery, it is imperative that the patient be adequately anesthetized. The inspired concentration of the volatile anesthetic (desflurane) was increased if the BIS value increased above the targeted value (60) or the patient manifested signs of inadequate hypnosis (e.g., purposeful movement, eye opening).
The pharmacologic profiles and anesthetic-sparing effects of esmolol and remifentanil suggested that these drugs could be suitable anesthetic adjuvants for attenuating acute intraoperative hemodynamic stress responses without interfering with the recovery process (2,3,9,12,13). When remifentanil (0.25 μg · kg−1 · min−1 IV) was administered as an alternative to alfentanil for total IV anesthesia with propofol during ambulatory surgery (18), its use was associated with more effective suppression of intraoperative hemodynamic responses and fewer postoperative side effects (e.g., postoperative nausea and vomiting, psychomotor impairment). Wilhelm et al. (19) reported that combining a remifentanil infusion (0.25 μg · kg−1 · min−1) with 0.5 MAC isoflurane during general anesthesia for arthroscopic surgery allowed for a rapid recovery of spontaneous ventilation and early extubation. These patients achieved an Aldrete recovery score of nine within ten minutes after discontinuing anesthesia. More recently, it has been reported that even smaller-dose remifentanil infusions (0.07–0.09 μg · kg−1 · min−1) can provide effective control of acute adrenergic responses during outpatient laparoscopic procedures with 47–54% smaller end-tidal concentrations of desflurane (3) or sevoflurane (9). This “balanced” approach to providing general anesthesia facilitates a more rapid emergence from anesthesia without increasing postoperative side effects, thereby optimizing conditions for “bypassing the PACU.”
Analogous to remifentanil, esmolol reduces the anesthetic requirement (12,13). Therefore, it is not surprising that it can effectively blunt the sympathetically mediated cardiovascular changes during laparoscopic surgery. In fact, we have previously demonstrated that esmolol can be used as an alternative to alfentanil for maintaining hemodynamic stability during propofol-N2O anesthesia (4). Although esmolol was associated with a more rapid emergence from anesthesia than alfentanil (4), awakening times in the Esmolol and Remifentanil groups were identical in the current study. Although there were no differences in the incidences of emetic sequelae after surgery, esmolol-treated patients experienced less nausea than the Remifentanil group. Importantly, all of these high-risk outpatients had received prophylactic antiemetics to minimize emetic sequelae (20).
Although both esmolol and remifentanil infusions were similarly effective in maintaining hemodynamic stability during the procedure, pain on emergence from anesthesia is a concern with these fast-tracking anesthetic techniques. Esmolol is a β-blocking drug that is devoid of analgesic properties and remifentanil possesses minimal residual analgesic activity because of its unique pharmacokinetic-dynamic profile (7) and the possibility of acute tolerance to its analgesic effects (21). However, as a result of the use of a multimodal “balanced” analgesic regimen (22,23) consisting of local anesthesia, ketorolac, and acetaminophen, only 11–16% of the patients complained of either moderate or severe pain in the early recovery period. Although the incidence of postoperative nausea was increased in the Remifentanil group (35% vs 4%), there was no difference in the time required to achieve a “home ready” state. These findings confirm other recent studies involving the use of remifentanil as an adjuvant to a desflurane-N2O based anesthetic technique (2,3). In this study, the use of remifentanil was associated with a significant muscle relaxant-sparing effect. Of interest, Stevens and Wheatley (24) reported that induction of anesthesia with a remifentanil-propofol combination could provide adequate intubating conditions without the need for muscle relaxants.
In addition to facilitating fast-tracking after ambulatory surgery, a rapid emergence from anesthesia results in a shorter case-turnover time and can improve operating room efficiency (25). Desflurane-N2O was chosen for maintenance of anesthesia because this combination is associated with shorter times to achieving fast-track eligibility (14,26). These data validate the earlier studies suggesting that a large percentage of intubated outpatients undergoing gynecologic laparoscopic surgery could safely bypass the PACU. The high degree of patient satisfaction in this study suggests that these fast-tracking anesthetic techniques did not compromise patient well being.
In conclusion, an esmolol infusion (13 μg · kg−1 · min−1) could be used as an alternative to remifentanil infusion (0.04 μg · kg−1 · min−1) for providing hemodynamic stability during desflurane-N2O anesthesia. Both adjuvants provided for a rapid emergence from anesthesia with few side effects, thereby facilitating the fast-tracking process. Most of these healthy outpatients undergoing laparoscopic tubal ligation surgery were able to safely bypass the PACU and rapidly achieve home readiness while maintaining a high degree of patient satisfaction.
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