Laparoscopic cholecystectomy has become the standard surgical treatment for symptomatic gall bladder disease , and consequently one of the most frequently performed general surgical procedures in developed countries. On the other hand, the pressure for hospital resources has forced clinicians to develop specific pathways to accelerate recovery from anaesthesia and hospital discharge [2,3].
Sevoflurane and desflurane have a clinical and pharmacological profile making them ideally suited for fast recovery . Moreover, we also have now very short lasting intravenous (i.v.) analgesics like remifentanil, providing intense analgesia of rapid onset, short blood/effect-site equilibration half-time and ultra-short duration due to its high clearance by non-specific blood and tissue esterases . It has been demonstrated that even small doses of remifentanil added to volatile anaesthetics to implement analgesia results in marked reduction of the end-tidal concentration of the volatile agent required to control stress responses induced by surgical stimulation , accelerating postoperative recovery and minimizing opioid-related depressant effects on respiratory function postoperatively .
In a recent meta-analysis comparing postoperative recovery after anaesthesia with sevoflurane or desflurane Macario and colleagues  reported that after surgical procedures lasting up to 3 h patients receiving desflurane recovered quicker from anaesthesia than patients receiving sevoflurane; the faster emergence provided by desflurane could potentially result in positive effects on time for discharge from the postanaesthesia care unit (PACU) or more frequent possibility of bypassing the PACU. To achieve more information on this point, we, therefore, conducted this prospective, randomized, multicentre, blind study to evaluate the effects of sevoflurane and desflurane in combination with i.v. remifentanil on time for PACU discharge and proportion of PACU bypass after elective laparoscopic cholecystectomy.
With the support of the Italian Society of Anaesthesia, Analgesia and Intensive Care, we constituted a study group on Volatile Anaesthesia for Laparoscopy (VAL). The study was funded and supported in each institution with funds of participating hospitals only. Criteria for participation to the study included routine use of both anaesthetic agents. Seven hospitals participated to the study. In each hospital the protocol was first approved by the Institutional Ethics Committee, and written informed consent was obtained from all participating patients.
From May 2004 to February 2005 patients presenting at the participating hospitals for elective laparoscopic cholecystectomy, with an ASA Grade I or II, were consecutively considered for the study. Patients with cardiovascular, respiratory or renal diseases, receiving vasoactive medication (such as antihypertensive agents), known allergies to drugs to be used during the study, chronic use of major analgesic medications or with a history of drugs or alcohol abuse as well as pregnant patients were excluded.
After patients arrived into the operating room, an 18-G i.v. line was placed and lactate Ringer's solution infused at 5 mL kg−1 h−1. Then standard premedication with i.v. midazolam (0.03 mg kg−1) was given 15 min before induction of general anaesthesia.
According to a computer generated sequence of numbers, and using a sealed envelope technique, patients were randomly allocated to receive either sevoflurane–remifentanil (group sevoflurane) or desflurane–remifentanil (group desflurane) as main maintenance anaesthetics. We prepared 15 balanced blocks of randomization with 10 patients per group. After completing the first randomization block (20 patients equally divided between the two groups) each hospital could ask for a second randomization block. We planned a competitive enrolment until achieving the designed number of patients (at least 100 patients per group). The randomization envelope was opened after obtaining the informed written consent from the patient.
Five minutes before inducing general anaesthesia an i.v. infusion of remifentanil was started in all patients at 0.125 μg kg−1 min−1. Standard monitoring was used including automated non-invasive arterial pressure, heart rate (HR) and electrocardiography (Lead II) and pulse oximetry. The depth of hypnosis was monitored using bispectral index (BIS). General anaesthesia was induced with propofol (2 mg kg−1) and cisatracurium (0.2 mg kg−1) for tracheal intubation. Patients were then mechanically ventilated (tidal volume 8 mL kg−1, inspired oxygen concentration 40%) maintaining an end-tidal carbon dioxide concentration ranging between 32 and 35 mmHg by adjusting the respiratory rate. General anaesthesia was maintained by keeping a fixed infusion rate of remifentanil (0.125 μg kg−1 min−1) and adjusting the end-tidal concentration of either desflurane or sevoflurane to maintain the arterial pressure and HR values within ±20% of preoperative values with BIS values ranging between 40 and 60. Arterial pressure, HR and oxygen saturation values were recorded every 5 min during the first hour of surgery, and then every 15 min until completion of surgery. If arterial pressure fell below 20% of preoperative values, the end-tidal concentration of the designed inhalational anaesthetic was reduced by 0.25 minimum alveolar concentration (MAC) and volume infusion increased to 10 mL kg−1 h−1. If blood pressure increased above the 20% threshold from baseline, the end-tidal concentration of the designed anaesthetic was increased by 0.25 MAC steps up to 2 MAC. The MAC value was adjusted to patients' age .
Core temperature was monitored using tympanic or bladder probes, and all patients were actively warmed during surgery using forced-air warming systems, while infused fluids were warmed at 38°C.
The following criteria for haemodynamic side-effects were considered: hypotension was a reduction in systolic arterial pressure >30% of baseline; hypertension was an increase in systolic arterial pressure >30% from baseline values; bradycardia was a decrease in HR <50 bpm; and tachycardia was an increase in HR >100 bpm. Occurrence of haemodynamic side-effects, as above defined, provoked stepwise changes in the inspired concentration of the study drug in order to restore haemodynamic variables.
Remifentanil infusion was stopped when the surgeon removed the gall bladder from the abdominal cavity. After the last skin suture (end of surgery) the volatile anaesthetic agents were discontinued and residual neuromuscular block antagonized with neostigmine (2 mg i.v.) and atropine (1 mg i.v.), while the lungs were manually ventilated with 100% oxygen using a fresh gas flow of 6L min−1 until spontaneous ventilation resumed. Extubation was performed when the patient was judged to be awake (making purposeful movements), breathing regularly, with adequate oxygenation (SPO2 > 92% when breathing room air) with a BIS value >60. Patients were asked to open eyes at verbal command, squeeze the observer's hand, every 2 min until discharge to the PACU, while the modified Aldrete score  as well as haemodynamic stability were evaluated every 5 min from entry into the PACU. Patients were considered eligible to be discharged from the PACU when showing a modified Aldrete score ≥9, stable vital signs, adequate airway and being alert and responsive with pain and nausea controlled . Patients showing an Aldrete score ≥9 when ready to be discharged from the operating room to the PACU were directly transferred to the surgical ward.
The time from discontinuation of the inhalation agent to extubation (extubation time), opening eyes on verbal commands (emergence time), squeezing the observer's hand on command (response time) and being judged suitable for discharge from the recovery area (PACU discharge time) as well as the proportion of patients that were eligible for PACU bypass when discharged from the operating room were also recorded. The independent observers evaluating emergence at the end of the procedure, as well as achievement of discharge criteria (both for PACU and hospital discharge) were blinded to the main volatile anaesthetic used during the maintenance of anaesthesia. Blinding was obtained by preventing the observer from being involved in any part of patient care, including completing the patient chart during surgery and postoperatively on the ward.
Before the end of surgery an i.v. bolus of ketoprofen (100 mg) and tramadol (100 mg) was given; the following postoperative analgesia consisted of ketoprofen (100 mg i.v.) every 8 h, while tramadol (100 mg i.v.) was given as rescue analgesia if the visual analogue pain score was >4 cm. Patients were then evaluated every 6 h until achieving readiness for home discharge (criteria for home discharge were based on the Postanaesthesia Discharge Scoring System (PADSS)) . At the same time the occurrence of postoperative nausea and vomiting (PONV) was also recorded, while routine treatment included the i.v. administration of odansetron 4 mg.
To evaluate the possible occurrence of intraoperative recall patients were asked if they could recall intraoperative events when they were discharged from the PACU and on the first-postoperative day.
To calculate the required study size, we considered results of previous studies performed in similar clinical settings with the two agents [4,12]. We wished to detect a 15 min difference in the time required to achieve readiness for PACU discharge with an effect size to standard deviation ratio of 0.60, accepting a two-tailed α error of 5%, a β error of 5%, with a 95% power. As secondary end-point we also wished to detect a difference of 0.2 in the incidence of PACU bypass between desflurane and sevoflurane, taking into account the reported incidence of PACU bypass after sevoflurane anaesthesia for laparoscopic surgery of 0.3  accepting a one-tailed α error of 5%, a β error of 20%, with an 80% power. Based on these assumptions, a total of 100 patients per group were required .
The primary analysis of population for the efficacy analysis was the intention-to-treat population, which included all randomized patients.
Statistical analysis was performed using Systat 7.0 (SPSS Inc., Chicago, IL, USA). The normal distribution of considered data was first evaluated using the Kolmogorov–Smirnov test; a centre-effect was then excluded before performing complete statistical analysis of the whole population using a two-way analysis of variance using the centre as co-factor. The t-test or U-test was used to compare continuous variables according to data distribution. Categorical variables such as gender, ASA Grade, rate of PACU bypass, and occurrence of PONV were analysed using the contingency table analysis and the Fisher's exact test. A two-way analysis of variance for repeated measures was used to analyse changes over time in arterial pressure and HR values. The Tukey's and Scheffé's tests were used for post-hoc analysis. The Bonferroni's correction was also used for multiple comparisons. Correlation and linear regression analysis were also used if indicated. The time from the end of anaesthesia to fulfilment of criteria for PACU discharge was analysed using a Kaplan–Mayer log-rank test. Continuous variables are presented as mean (±SD or 95% confidence interval) for normally distributed data or median (range) for not normally distributed ones. Categorical variables are presented as numbers (percentage). A value of P ≤ 0.05 was considered as significant.
A total of 231 patients were enrolled in the seven participating hospitals: 105 in the desflurane group and 126 in the sevoflurane group. Before performing statistical analysis a centre-effect was excluded, and no differences in anthropometric characteristics and gender distribution were observed among the seven participating centres. No differences in anthropometric characteristics, duration of surgery and anaesthetic exposure measured as MAC-hour were observed between the two groups (Table 1). Intraoperative normothermia was maintained in both groups, and core temperature at the end of surgery was 36.3 ± 0.4°C in group desflurane and 36.3 ± 0.3°C in group sevoflurane (P = 0.78).
No differences in intraoperative haemodynamic variables were observed between the two groups (Fig. 1). Table 2 shows the incidence of haemodynamic side-effects as above defined reported in the two groups during the intraoperative time.
Emergence, response and extubation times were shorter in patients receiving the desflurane–remifentanil combination (5.4 ± 3 min, 5.5 ± 3 min and 7.5 ± 4 min, respectively) than in those receiving sevoflurane–remifentanil (6.6 ± 3.5 min, 7.2 ± 4 min and 9.1 ± 4.2 min, respectively) (P = 0.0005, 0.05 and 0.003, respectively).
Eligibility for PACU bypass was observed in 44 patients of group desflurane (41%) and 55 patients of group sevoflurane (43%) (P = 0.69). No differences in anthropometric characteristics and gender distribution were reported between those patients eligible for PACU bypass and those who were not. The mean time from anaesthetic discontinuation to fulfilment of PACU discharge criteria was shorter after desflurane (46 min; 25th–75th percentiles: 18–40 min) than sevoflurane (64 min; 25th–75th percentiles: 20–50 min) (P < 0.04) (Fig. 2). No differences in the degree of pain recorded during the first 24 h after surgery were reported between the two groups.
No severe untoward effects or complications were reported during the study in either group, and no patient reported implicit or explicit memory of intraoperative events. The occurrence of PONV requiring the administration of i.v. odansetron during the study was reported in 40 patients of group desflurane (36%) and 53 patients of group sevoflurane (42%) (P = 0.42).
Readiness for hospital discharge was achieved after 56 h (36–72 h) in group desflurane and 65 h (48–72 h) in group sevoflurane (P = 0.38).
Results of this prospective, randomized, multicentre, blinded investigation showed that both desflurane and sevoflurane, co-administered with continuous infusion of remifentanil, provide a similarly effective anaesthesia for laparoscopic cholecystectomy with a stable intraoperative cardiovascular profile, and very fast recovery after discontinuation of the inhalational agents. Desflurane–remifentanil combination resulted in faster emergence and 18 min earlier discharge from the PACU as compared to patients receiving the sevoflurane–remifentanil combination; however, this was not associated with an increased incidence of PACU bypass.
Emergence from anaesthesia was 1–2 min shorter in patients receiving desflurane–remifentanil than those treated with sevoflurane–remifentanil. These findings agree with previous reports  and are related to the different pharmacokinetic properties of the two agents [4,16]. However, though statistically significant, such a small difference in emergence from anaesthesia is really questionable from a clinical point of view, especially in a cohort of relatively healthy adult patients.
Tarazi and colleagues  evaluated clinical use of sevoflurane and desflurane for outpatient laparoscopy and reported a faster recovery of cognitive function with sevoflurane than desflurane. The authors did not find differences in PACU discharge times, while in the present study we observed a 18 min shorter PACU discharge with desflurane than sevoflurane. Similar results, have been reported by Chen and colleagues , who investigated recovery profile in a population of elderly patients undergoing general surgery with sevoflurane or desflurane as main anaesthetic agent, and reported a more rapid emergence from anaesthesia with a 25 min shorter length of stay in the PACU after desflurane than sevoflurane. In the same study these authors also evaluated recovery of cognitive functions, but failed to observe differences between the two agents with mini mental scores returning to preoperative values within 6 h after surgery.
The usefulness of rapid emergence and rapid achievement of PACU discharge criteria is related to the increased drive toward performing surgery on an outpatient basis, since fast-tracking patient directly to the phase two stage, bypassing the PACU, has been demonstrated to increase the efficiency and reduce costs of surgery itself . Irrespective of the faster emergence from anaesthesia we observed with desflurane, the proportion of patients eligible for PACU bypass was similar in the two groups, ranging between 41% and 43%. This finding is in agreement with results previously reported after sevoflurane anaesthesia for laparoscopic surgery . On the contrary, Coloma and colleagues  reported that desflurane anaesthesia was associated with the most rapid emergence and shortest time to achieve fast-track eligibility after outpatient laparoscopy. As indicator of eligibility for PACU bypass we used the Aldrete score measured at discharge from the operating room ; White and colleagues  recently described a new score to judge patients eligibility for bypassing the PACU, and reported that this new scoring system allowed to identify patients eligible for Phase I bypass after laparoscopic procedures more frequently than with the Aldrete score. Using such a more sensitive scoring system to evaluate eligibility for PACU bypass could result in a larger proportion of patients bypassing the phase I recovery, but reasonably would not result in differences between the two agents. Further studies with this new scoring system might be useful to better evaluate phase I bypass after sevoflurane or desflurane anaesthesia.
Both agents provided good stability of cardiovascular parameters during surgery. The most frequent haemodynamic side-effect was represented by hypotension and bradycardia, reasonably related to the depth of anaesthesia. It has been reported in healthy volunteers that desflurane increases HR through an activation of the sympathetic tone , while sevoflurane showed less haemodynamic side-effects than other agents like isoflurane ; nonetheless, in the present investigation we did not report differences in the incidence of haemodynamic side-effects. Although our study was not specifically powered to evaluate the cardiovascular stability, a post-hoc power analysis showed that the study sample population gives a 90% power to exclude a difference of 10% in the incidence of tachycardia between the two groups. Accordingly, it can be concluded that the sympathetic activation induced by desflurane probably does not have clinically relevant effect when desflurane is included in a balanced general anaesthesia with a potent opioid like remifentanil.
The reported doses of remifentanil used during general anaesthesia may vary from 0.01 to 0.5 μg kg−1 min−1. In the present study, we used a pretty low dose that has been reported to be associated with a clinically relevant analgesic implementation during volatile general anaesthesia  with a stable cardiovascular profile . The very fast recovery from opioid-related depression of the central nervous system associated with remifentanyl could be involved in explaining very fast recovery from general anaesthesia; however, since the dose was minimal and stable in all studied patients we can exclude a systematic effect of this variable on main outcome of the study.
Another important side-effect of volatile anaesthesia is represented by PONV, which frequently delays PACU discharge increasing the costs of the procedure . In the present investigation we reported a similar incidence of PONV with the two volatile anaesthetics during the first 2-postoperative days, ranging between 36% and 42%. It has been reported that the pharmacokinetic properties of volatile anaesthetic might affect the incidence of PONV, and faster agents seem to be responsible for higher incidence of PONV as compared to more lipophilic agents . Present findings do not confirm the higher incidence of PONV with desflurane than sevoflurane, and similar incidences of PONV have been reported in other studies comparing desflurane and sevoflurane [25–27]. On the other hand, the relatively high incidence of PONV could be related to both the type of surgery and use of tramadol for pain treatment.
In conclusion, results of this prospective, randomized, blinded study showed that both the desflurane–remifentanil and sevoflurane–remifentanil combinations provide a similarly adequate intraoperative cardiovascular stability with very fast emergence after discontinuation of the inhalational agents in patients undergoing laparoscopic cholecystectomy. Recovery times and PACU discharge were faster with desflurane–remifentanil than sevoflurane–remifentanil; however, this was not associated with a larger proportion of PACU bypass, confirming that no clinically relevant differences in terms of recovery from anaesthesia are present between the two agents.
The study was entirely supported by funding of the seven participating hospitals only.
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Appendix 1: The Italian Study Group on VAL
Michele Dambrosio, Salvatore Meola – Azienda Ospedaliera Università degli Studi di Foggia; Yigal Leykin – Ospedale Santa Maria degli Angeli, Pordenone; Giorgio Della Rocca – Università degli Studi di Udine; Paolo Pietropaoli, Francesco Pugliese – Università degli Studi di Roma ‘La Sapienza’ Roma; Antonio Corcione – Azienda Ospedaliera Monaldi, Napoli; Epifanio Mondello – Università degli Studi di Messina; Cristina Benassi, Grazia Squicciarini, Michela Tosi – Università degli Studi di Parma; Professor R. Tufano – University Federico II of Naples, Naples, Italy. (Note: All clinician participants are co-authors.)