Randomized Comparison of Isoflurane versus Sevoflurane and Desflurane for Maintenance of Ambulatory Anesthesia

Abstract

Background:

Ambulatory surgeries demand safe anesthesia with faster recovery which makes it expensive due to the cost of inhalational anesthetic agents such as sevoflurane and desflurane. Isoflurane is inexpensive agent but can cause delayed recovery. The aim of this study was to evaluate cost-benefit ratio of all three agent with respect to recovery and safety profile

Materials and Methods:

Patients posted for elective ambulatory surgeries were divided into three groups. Suitable size laryngeal mask airway was inserted following induction with propofol and vecuronium. Anesthesia was maintained on low-flow anesthesia with inhalational agent as isoflurane for Group I, sevoflurane for Group II and Group III received desflurane. Patients were monitored for recovery as per modified Aldrete score and as per postanesthesia discharge scoring system for discharge from hospital. Cost analysis was done by Dion's formula. Statistical analysis was done with analysis of variance for recovery profile, Chi-square test for safety profile and Kruskal Wallis test for cost comparison between groups.

Results:

Patient characteristics and duration of anesthesia were similar in all three groups. Time to eye-opening was significantly less with desflurane than sevoflurane and isoflurane (P = 0.001). Time to home readiness was similar in all three groups (P = 0.451). The incidence of airway irritation, pain, and nausea/vomiting was similar in all three groups. Cost of Group I was statistically lower than other two groups (P = 0.00).

Conclusion:

Home readiness and safety profile were comparable between agents; the cost involved was the least with isoflurane.

INTRODUCTION

Ambulatory surgeries are becoming more and more popular due to the convenience and economy associated with shortened hospital stay, resulting in the majority of elective surgical procedures as day-care surgeries.[1] Early mobilization and discharge from hospital necessitates speedy recovery from anesthesia. Delivery of safe and economical anesthesia with faster recovery is challenging considering the cost of sophisticated anesthetic agents, which are necessary to achieve this. Inhalational anesthetic agents such as sevoflurane and desflurane, for maintenance of anesthesia have been proved effective as ambulatory anesthetic agents. Different techniques of measurement and formulas for calculations are used for cost analysis of expensive inhalational agents while considering various clinical factors. In addition to this variation in cost of inhalational agents in different institutes poses difficulty in the actual cost analysis. Although the majority of literature says sevoflurane as cost-effective agent, fresh gas flow (FGF) rate is not taken into account in those studies.[2] Low-flow anesthesia (LFA) results in up to 75% of savings and at lowest allowable FGF, the cost involved in the use of sevoflurane and desflurane is same.[2,3] LFA with isoflurane appears to be the strategy to reduce the cost.[4] Isoflurane due to its pharmacological properties is not considered as an inhalational agent for day-care surgery.[5] The ideal anesthetic agent for ambulatory surgery has to deliver safe intraoperative period with a smooth recovery and early discharge from hospital while maintaining the economy. At equivalent FGF sevoflurane and desflurane cost 2–3 times more than equipotent concentrations of isoflurane, hence to justify the cost involved in usage of sevoflurane and desflurane against inexpensive isoflurane, a significant clinical benefit of sevoflurane and desflurane over isoflurane has to be established. Although isoflurane is the most inexpensive agent, it has disadvantages such as delayed return of consciousness and drowsiness as compared to other two agents. However, it scores equally with desflurane and sevoflurane on account of time to home readiness.[6] Laryngeal mask airway (LMA) is the preferred airway device for ambulatory anesthesia.[7] Desflurane and isoflurane both being irritant to respiratory mucosa; can cause airway reactions when used with LMA. Desflurane is found to be more irritant than isoflurane and sevoflurane; however, incidence of airway reactions was comparable between desflurane and sevoflurane when used with LMA.[8,9] Studies comparing the effectiveness of all three agents, isoflurane, sevoflurane, and desflurane together are limited. To the best of our knowledge, studies comparing isoflurane against sevoflurane and desflurane for cost/benefit analysis are not available.

The objective of the study was to compare clinical efficacy and cost of isoflurane against sevoflurane and desflurane for ambulatory surgery. The primary outcome of the study was to compare time from immediate recovery to home readiness and the secondary outcome was to compare time to immediate recovery and safety profile and costs of used inhalational agents.

MATERIALS AND METHODS

This was a prospective randomized double-blind study conducted over a period of 1 year from March 2016 to February 2017 after approval from the Institutional Ethics Committee. Patients between 18 and 60 years of age of the American Society of Anesthesiologist (ASA) physical status I and II, of either sex, posted for elective day-care surgeries with anticipated duration between 30 to 90 min were included in the study. Patients with physical status ASA III and above posted for emergency and laparoscopic surgeries, pregnant patients and patients not willing to participate in the study, with psychiatric illness and with a history of recent upper respiratory tract infection were excluded from the study. Surgeries expected to last for <30 min and >90 min were excluded from the study. Protocol was explained to all patients and informed valid consent was obtained. All patients were fasting 8 h before start of anesthesia. Patients were randomly divided into three groups by block randomization method with block size of four depending on the inhalational agent they would receive. Group I received isoflurane, Group II received sevoflurane, and Group III received desflurane. After shifting the patients to operation table, pulse oximeter (SpO₂), electrocardiogram (ECG), and noninvasive blood pressure (NIBP) monitors were connected. Baseline parameters were noted. Intravenous (IV) line was started with 18-guage cannula. Preoxygenation was done for 5 min with near 100% oxygen (O₂). All patients received injection midazolam 0.02 mg/kg IV and injection fentanyl 2 mcg/kg IV. Induction was done with injection propofol 2 mg/kg IV and subsequent muscle relaxation was achieved with injection vecuronium 0.1 mg/kg. Appropriate size LMA-proseal was inserted and secured with tape. End-tidal carbon dioxide (EtCO₂) monitor was connected. After that patients were started on nitrous oxide (N₂O) and inhalational agent depending on the group it belonged to. For isoflurane and sevoflurane TEC 7 vaporizer was used and for desflurane Drager, D-vapor was used. All the vaporizers were calibrated before start of the study. All three inhalational agents were Baxter Company (imported and marketed by Baxter India, Pvt. Ltd.,). FGF was kept at 6 L/min which constituted O₂ 2 L/min and N₂O 4 L/min for first 10 min through circle system (GE Datex-Ohmeda ZY9100). This initial duration of 10 min with high flows was taken as loading phase of inhalational agent. After this, flow was reduced to 1 L/min, [500 ml/min of O₂ and 500 ml/min of N₂O] till the end of surgery. The time from reduction of FGF to the switching off of vaporizer was taken as maintenance phase of inhalational agent. The vaporizer was set at 1.5% for Group I and 4.5% for Group III till the end of surgery. For Group II, vaporizer was set at 2.5% for initial 10 min and later changed to 3.5% to maintain the desired minimum alveolar concentration, till the end of surgery.[10] Intraoperatively, heart rate (HR), NIBP, SPO₂, EtCO₂ were recorded every 15 min till the end of surgery. Ventilatory settings were adjusted as needed to maintain EtCO₂ value between 30 and 40 mmHg. Additional supplementation of analgesia, sedation and muscle relaxation was to the discretion of concerned anesthesiologist to maintain the bispectral index value of 40–60. Fall in mean arterial pressure (MAP) of >20% from baseline value was taken as hypotension and was treated with vasopressors and intravenous fluids. Increase in MAP of >20% was taken as hypertension and treatment was to the decision of consultant anesthesiologist without altering the vaporizer settings. Inhalational agent was cut off at the start of skin suturing and the time was noted. N₂O was discontinued at the end of surgery. The total duration of surgery was noted. At the end of surgery, all patients received appropriate analgesic nerve block with 0.25% ropivacaine with the volume as per needed for the block. Injection ondansetron in dosage of 4 mg IV was given as prophylaxis for nausea and vomiting (N/V). LMA was removed after reversal of neuromuscular blockade. Immediate recovery time was taken as time between switching off of vaporizer to the time of eye-opening. Patients were monitored for airway irritation as, Grade 0 – no irritation, grade 1-coughing, grade 2-breath holding, and grade 3-laryngospasm. Breath holding and laryngospasm for >15 s were treated with injection propofol and continuous positive airway pressure (CPAP) ventilation. Patients were shifted to postanesthesia care unit (PACU-I). Patients were monitored every 5 min for initial 30 min as per modified Aldrete scoring system.[11] Patients were shifted to phase II recovery room (PACU-II) once score of ≥9 was achieved. In phase II recovery room patients were monitored every 15 min as per postanesthesia discharge scoring system (PADSS).[12] Score of ≥9 was taken as home readiness and that time was noted. Time to home readiness was taken as study endpoint. Respiratory distress (SPO₂ <94%), was treated with O₂ by Hudson mask. Pain was treated by injection diclofenac 1.5 mg/kg IM. At the end of study, protocol was returned to investigator in sealed envelope.

The cost analysis was done by Dion's formula,[13] as ([concentration % of gas] [FGF, L/min] [duration in minutes] [Molecular weight] [cost/ml]) ÷ ([2412] [Density]). Using above-mentioned formula calculation was done for the cost in INR of loading phase and maintenance phase of inhalational agent.

Statistical analysis

Sample size calculations were done based on a previous study[14] according to time to home readiness. Applying the results of the previous study (difference of 26 min and standard deviation [SD] of 36) to the analysis of variance (ANOVA) for three group comparison, 31 patients were needed in each group with the significance of 5% and power of 80%. So 35 patients were included in each group to allow possible dropouts from study. The statistical analysis was done using Statistical Package for the Social Sciences (SPSS) for Windows, version 23, IBM Corporation, Armonk, NY, USA and its licensors 2015. Demographic characteristics and recovery profiles parameters were assessed with ANOVA and expressed as mean ± SD. Safety profile parameters were analyzed with Chi-square test and are expressed as frequency and number. Comparison of cost involved was done using Kruskal–Wallis test. Post hoc cost analysis between groups was done with Mann–Whitney U-test. P < 0.05 was taken as statistically significant for a two-sided test.

RESULTS

A total of 105 patients were randomized and included in this study, 35 patients in each group [Figure 1]. One patient from Group I and one patient from Group II were excluded from analysis for prolonged duration of surgery. One patient from Group II and one from Group III were not analyzed due to protocol violation because of improper LMA seal resulting into the usage of high flow rate.

Figure 1.

Consort diagram

The demographic characteristics and duration of surgery [Table 1] were comparable in all groups. Duration of anesthesia was comparable among the groups [Table 2]. Time to responsiveness and eye-opening was significantly less in desflurane group (P = 0.001) as compared to other two groups. The mean time to eye opening in desflurane group was 9.69 min, with 95% confidence interval (CI) of 8.2–11.1. Time to home readiness was the least in sevoflurane group and maximum in isoflurane group. This time difference of 11 min between sevoflurane and isoflurane while 6 min between isoflurane and desflurane, was statistically insignificant (P = 0.45). Safety profile of all the three agents was comparable [Table 3]. Thirty-one patients were free of any airway irritation in all the groups. The incidence of sore throat was similar all three groups. Two patients in isoflurane group and two patients in desflurane group went for Grade I airway irritability (cough) after LMA removal. Incidence of pain and N/V were comparable in all the groups. Two patients in sevoflurane group and three in desflurane group had episode of intraoperative hypotension which responded to vasopressors. PADSS score of 10 was achieved in 21 patients in desflurane group, 24 in sevoflurane and 28 patients in isoflurane group. Pain and N/V were the main reasons for not reaching the score of 10. Costs [Table 2] of loading phase, as well as maintenance phase, were significantly lower with isoflurane than sevoflurane and desflurane (P = 0.00). Cost of sevoflurane was significantly lower than that of desflurane for both loading phase (P = 0.000) and maintenance phase (P = 0.006).

Table 1.

Demographic characteristics

Table 2.

Recovery profile

Table 3.

Safety profile

DISCUSSION

Our results suggest that time to home readiness was similar with all three inhalational agents. Immediate recovery measured in terms of eye-opening and response to verbal commands was early in desflurane group. Safety profile compared in terms of hemodynamic parameters, N/V and pain was similar with isoflurane, sevoflurane, and desflurane. The cost involved was the least with isoflurane followed by sevoflurane. There are few meta-analyses comparing all three inhalational agents for ambulatory anesthesia but they are based on analysis of randomized controlled trials (RCTs) comparing three agents separately.[6,8] Very few studies are available, which compared recovery profile of all three agents together against each other in a single study.[15,16,17,18] These studies have compared different parameters including immediate recovery and safety profile, but time to home readiness was not compared in any of those studies. To our knowledge, this the first study comparing isoflurane against sevoflurane and desflurane for day-care surgery.

Isoflurane is considered inferior as compared to desflurane and sevoflurane due to its high blood gas (B/G) coefficient resulting into delayed recovery. Clinically, this delay in recovery is seen only for immediate and early recovery manifesting as delay in regaining consciousness and psychomotor functions. Gupta et al. did systemic analysis of recovery after ambulatory surgery comparing isoflurane, sevoflurane, and desflurane with a conclusion that early recovery and time to obey was significantly less with desflurane when compared to sevoflurane and isoflurane. They also observed that time to home readiness was 5 min earlier with sevoflurane as compared to isoflurane and other parameters such as pain, N/V were comparable.[6] In this analysis, there was a difference of 5 min between sevoflurane and desflurane for time to home readiness, which was found significant after analysis of 16 RCTs. In our study we found that time to the home readiness with sevoflurane was 5 min earlier than desflurane and 11 min earlier than isoflurane, but this difference was statistically insignificant, while all other parameters were comparable between three groups. The difference between the costs involved was of statistical significance between isoflurane and sevoflurane. Considering the difference between the cost of sevoflurane and isoflurane, 5–10 min of difference in home readiness seems to be of theoretical and scientific significance. The study evaluating efficacy of isoflurane for day care surgery has mentioned mean time for home readiness was 2.06 ± 1.64 h, and concluded that all patients were fit to be discharged within 6 h.[19] We found that in isoflurane group mean time to home readiness was around 3 h, which was not statistically different from sevoflurane and desflurane.

Chemically, both isoflurane and desflurane are methyl ethyl ether. The replacement of chlorine atom of isoflurane with fluorine in desflurane results in low B/G solubility and faster, early recovery. However, this change of atoms has not reduced the pungent qualities of desflurane.[9] Stevanovic et al. have done meta-analysis comparing desflurane with isoflurane and sevoflurane with respect to airway irritation and recovery while using LMA.[8] They concluded from 14 trials that incidence of airway reaction was similar with inhalational anesthetic agents but time to eye-opening was significantly shorter with desflurane than other agents. Our study showed similar results with faster eye-opening and immediate recovery with desflurane and no significant airway irritability was seen with isoflurane as compared to other two agents. Sahu et al. compared isoflurane with sevoflurane for daycare surgeries using classic LMA and found that time for discharge from PACU I is shorter with sevoflurane, however, time to home readiness is same.[20] In this study, one of the criteria for discharge from PACU I was the ability to sit up without dizziness. In our study, the parameters deciding discharge from PACU I was on based on modified Aldrete score, which does not mention about gait and we found that time to discharge from PACU I and was comparable with all three agents. Previous studies done with LMA and minimal flow anesthesia have concluded that drowsiness was more with isoflurane than other inhalational agents.[21,22] In our study, we did not monitor sedation score. Patients were monitored only with modified Aldrete scale which showed no difference among the groups. When isoflurane was compared to sevoflurane for ambulatory surgeries, it was associated with high somnolence and N/V though time to home readiness and patient satisfaction were similar.[23] This study has used high flow rate of 5 L/min for maintenance. The high B/G solubility of isoflurane can lead to the presence of significant amount of agent into circulation after discontinuation of the vaporizer.[24] This could be responsible for more N/V and somnolence as compared to sevoflurane in their study.

Ebert et al. analyzed 8 trials with an average duration of anesthesia around 115 min comparing isoflurane and sevoflurane.[22] They concluded that first analgesic requirement was as early as 8 min in sevoflurane group but no difference between a total analgesic requirement and N/V between two groups. In the present study, we did not find any difference between requirement of analgesics and N/V between three groups. Wherever possible analgesic nerve block was given, this could have been the reason for similar incidence of pain in all groups. A clinical comparison between isoflurane and sevoflurane has concluded that there were insufficient grounds to recommend costly sevoflurane over isoflurane for routine use in day care surgery.[25] Previous studies have shown that hemodynamic parameters are similar with all the three inhalational anesthetic agents.[6,16,18] In our study we did not find any significance between hemodynamic changes with all three agents.

Most of the studies comparing isoflurane with desflurane have not found any difference of clinical significance other than faster early recovery. A study which compared isoflurane with desflurane for daycare arthroscopy has found that patients were more calm and in a good mood in isoflurane group than in desflurane.[14] Neuroexcitability and emergence agitation due to desflurane could be the reason for this observation. In our study, we did not monitor for the incidence of emergence agitation, which is the limitation of our study. Another limitation of the study was that we studied effectiveness of inhalational agents till the discharge criteria were met and did not follow-up patients for any adverse events after discharge and readmission. Prolonged duration of anesthesia has not shown any difference between sevoflurane and desflurane with respect to PACU time and N/V.[26] However, when isoflurane is compared with sevoflurane, prolonged exposure of inhalational agent has resulted into delayed early and late recovery.[22] In our study, average duration of exposure to inhalational agent was 60–70 min and we did not see any difference in recovery or safety profile. Since the majority of the indicated surgeries are becoming ambulatory, future studies are needed to compare clinical profile and cost/benefit of all three agents following long duration of anesthesia.

CONCLUSION

We conclude that isoflurane provides effective and safe anesthesia comparable to sevoflurane and desflurane for daycare surgeries at significantly lower cost.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.