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Under "real world" conditions, desflurane increases drug cost without speeding discharge after short ambulatory anesthesia compared to isoflurane

[Dans les conditions du «monde réel», le desflurane augmente le coût des médicaments sans hâter le départ après une anesthésie ambulatoire de courte durée comparé à l’isoflurane]

From the Centre for Anesthesia and Analgesia, Departments of Anesthesia and Pharmacology Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada.

Address correspondence to: Dr. Stephan Schwarz, Department of Pharmacology and Therapeutics, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, B.C. V6T 1Z3, Canada. Phone: 604-822-5565; Fax: 604-822-6012; E-mail: stephan.schwarz{at}ubc.ca

	Abstract

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Purpose: To compare the measured "real world" perioperative drug cost and recovery associated with desflurane- and isoflurane-based anesthesia in short (less than one hour) ambulatory surgery.

Methods: We conducted a prospective, randomized, blinded trial with patients undergoing arthroscopic meniscectomy under general anesthesia. Following iv induction, patients received either isoflurane (group I; n = 25) or desflurane (group D; n = 20) for maintenance. The primary outcome variable was total perioperative drug cost per patient in Canadian dollars. Secondary outcome variables included volatile agent consumption and cost, adjuvant anesthetic and postanesthesia care unit (PACU) drug cost, readiness for PACU discharge, and incidence of adverse events.

Results: Total perioperative drug cost per patient was $14.58 ± 6.83 (mean ± standard deviation) for group I, and $21.47 ± 5.18 for group D (P < 0.001). Isoflurane consumption per patient was 6.0 ± 3.0 mL compared to 18.6 ± 7.7 mL for desflurane (P < 0.0001); corresponding costs were $0.83 ± 0.42 vs $7.61 ± 3.15 (P < 0.0001). There were no differences in adjuvant anesthetic or PACU drug cost. All but one patient from each group were deemed ready for PACU discharge at 15 min postoperatively (Aldrete score 9). One patient in group D experienced postoperative nausea. No other adverse events were noted.

Conclusions: Measured total perioperative drug cost for a short ambulatory procedure (less than one hour) under general anesthesia was higher when desflurane rather than isoflurane was used for maintenance, essentially due to volatile agent cost. Desflurane use did not translate into faster PACU discharge under "real world" conditions.

	Introduction

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SINCE their introduction in Canada in the 1990s, the volatile anesthetic agents, sevoflurane and desflurane, have enjoyed increasing popularity in ambulatory anesthesia, partly due to their potential for more rapid emergence and faster recovery compared to isoflurane.^1–4 However, the difference in cost between the newer volatile agents and isoflurane in the ambulatory anesthesia setting, when measured under "real world" conditions in the context of standard clinical practice,⁵ remains uncertain. As the second part in a miniseries of trials targeted to determine the impact on perioperative drug cost of changing from isoflurane to one of the newer agents,⁶ we conducted a prospective randomized study to compare desflurane to isoflurane in healthy patients undergoing a short (less than one hour) ambulatory procedure, arthroscopic meniscectomy. Our primary objective was to test the hypothesis that desflurane anesthesia is associated with higher total perioperative drug cost per patient than isoflurane anesthesia. Secondary objectives were to compare readiness for discharge from the postanesthesia care unit (PACU) and perioperative adverse events.

	Methods

TOP Abstract Introduction Methods Results Discussion References

 
With approval of the Institutional Human Research and Ethics Committees, we conducted a prospective, randomized, blinded, parallel-group, single-centre (Vancouver Hospital and Health Sciences Centre, University of British Columbia site) trial in patients undergoing arthroscopic meniscectomy under general anesthesia. After obtaining written informed consent, a total of n = 50 patients were randomly assigned to receive either isoflurane (group I) or desflurane (group D) via a laryngeal mask airway (LMA) as part of a balanced anesthetic (iv induction).⁷ Included in the study were male or female patients who were scheduled for arthroscopic meniscectomy at the study centre, aged 18–65 yr, ASA physical status I or II, and provided written informed consent. Excluded were patients with a possibility of pregnancy, inability to give informed consent, significant drug or alcohol abuse as judged by an investigator or attending anesthesiologist, scheduled endotracheal intubation, a known history of allergy or sensitivity to local anesthetics, acetaminophen or opioids, or a known history or family history or a high level of susceptibility to malignant hyperthermia as judged by the anesthesiologist. Also excluded were patients who received a general anesthetic within the week prior or participated in clinical studies within 14 days prior. Patients were randomly assigned to either group in blocks of four with the use of a computer-generated randomization protocol.

All patients received a balanced general anesthetic with iv induction and maintenance with either isoflurane or desflurane in nitrous oxide and oxygen administered via an LMA under spontaneous respiration as per institutional standard. In order to most closely reflect "real world" conditions in the context of standard clinical practice, the choice of premedication, induction, or adjuvant anesthetic agents was left at the discretion of the patients’ attending anesthesiologists. The administration of inhaled agents was conducted using dedicated semi-closed Ohmeda Modulus® CD or Modulus® II Anesthesia Systems (Ohmeda, Madison, WI, USA) and followed standardized procedures. Prior to iv induction, patients were denitrogenated with 100% oxygen at a fresh gas inflow rate of 6.0 L·min^–1. Following induction, patients in group D received desflurane using vaporizer settings and total fresh gas inflow rates as per manufacturer’s supplied guidelines:^A after LMA insertion and confirmation of airway integrity, desflurane was administered at an initial vaporizer setting of 3% with nitrous oxide 3 L·min^–1 and oxygen 3 L·min^–1 to achieve a total fresh gas inflow rate of 6.0 L·min^–1 during the initial uptake. The delivered desflurane concentration was gradually increased in increments of 1% or less every two to three breaths until desired anesthetic depth was reached. Oxygen and nitrous oxide inflow were then reduced to 0.5 L·min^–1, respectively, to achieve a total fresh gas inflow rate of 1.0 L·min^–1. Patients in group I received isoflurane according to institutional standard, with the vaporizer initially set at 1.5% and nitrous oxide/oxygen inflow at 3 L·min^–1 each. After three to five minutes and once desired anesthetic depth was achieved, nitrous oxide and oxygen inflow were reduced to 0.5 L·min^–1, respectively, to achieve a total fresh gas inflow rate of 1.0 L·min^–1. At the end of surgery, the volatile agent and nitrous oxide were discontinued for both groups and fresh gas inflow rate increased to deliver 100% oxygen at 10 L·min^–1. Patient transfer to the PACU as well as postoperative management were conducted according to routine institutional procedures. Recovery and readiness for PACU discharge were assessed every 15 min using the Aldrete scoring system⁸ and the question "How are you feeling?" The incidences of nausea, vomiting, and all other perioperative adverse events were recorded. Adverse events were defined as any unintended or unfavourable clinical sign or symptom, any new illness or disease or deterioration of existing illness or disease, or any clinically relevant deterioration in laboratory assessments or other clinical test, whether or not considered treatment-related. Serious adverse events were defined as adverse events that are life-threatening or resulting in death, permanent or significant disability/incapacity, hospitalization or prolongation of existing hospitalization, or medical/surgical intervention to prevent permanent impairment of function or permanent damage to a body structure.

The primary outcome variable was total perioperative drug cost per patient in Canadian dollars according to institutional pharmacy cost in 2003 as per hospital drug formulary. Secondary outcome variables were liquid volatile agent consumption per patient in mL, volatile agent cost per patient, adjuvant anesthetic and PACU drug cost, readiness for PACU discharge (Aldrete score 9), time to actual PACU discharge, and incidence of adverse events. Non-invasive mean arterial blood pressure (MAP), heart rate, and inspired/expired end-tidal fractional volatile agent concentrations were recorded intraoperatively onto disk via an Ohmeda Modulus® CD Anesthesia System and/or manual data entry for comparison between the groups.

Determination of volatile drug cost
Measured volatile drug costs were determined using a modified version of our previously described method,⁶ based on the procedure by Boldt et al.⁹ In brief, isoflurane and desflurane were administered using agent-specific vaporizers dedicated to this study only. "Real world" total consumed volumes of liquid isoflurane and desflurane per patient and per group were determined using bottles containing liquid volatile agent dedicated to this study only. The bottles were clearly labelled and securely stored at room temperature in the institutional anesthesia research office. Following randomization and group allocation, and prior to the start of each case, the bottles were weighed with a calibrated digital precision balance (Mettler PB3000, Mettler, Greifensee, Switzerland) to record the "before" weight. Cases were conducted using dedicated, completely filled agent-specific vaporizers (isoflurane, Ohmeda Isotec 5; desflurane, Ohmeda Tec 6; Ohmeda, Madison, WI, USA) as allocated. At the end of each case, the vaporizers were completely refilled using the dedicated bottles, which were then weighed again to determine the "after" weight. Liquid volatile agent consumption in mL per patient was computed by multiplying the difference between "before" and "after" weights with the agent’s specific gravity at 20°C (isoflurane, 1.5019; desflurane, 1.4651)¹⁰ as follows:

In order to assess sampling variability and validate per-patient consumption, the total consumption of volatile agent per group at the end of the study was determined from the number of bottles administered plus the residual weight in the last bottle, and compared to the sum of all values for individual per-patient consumption. Following validation, volatile agent cost per patient was calculated from the consumed volume using the institutional pharmacy unit cost for 2003 in Canadian dollars (isoflurane, $0.14/mL; desflurane, $0.41/mL). Not included in the volatile agent cost determination were: i) desflurane Tec 6 vaporizer purchase; ii) conversion of anesthetic gas analyzing instruments; iii) maintenance of desflurane inventory; and iv) oxygen/nitrous oxide.

Determination of adjuvant and PACU drug cost
All adjuvant anesthetic drugs administered intraoperatively and all drugs administered postoperatively in the PACU/surgical daycare centre prior to discharge were recorded. For single-use vials, cost determination was based on the number of vials opened so as to include wastage. For multi-use vials, oral, and rectal medications, cost determination was based on the actual dose/volume of the agent administered. All cost calculations were based on the institutional pharmacy unit cost in 2003 as per hospital drug formulary. Table I provides an overview of the cost of the most commonly administered agents. For determination of the primary outcome variable, total perioperative drug cost per patient, the adjuvant and PACU drug cost was added to the volatile agent cost as outlined above. All drugs were supplied through the hospital pharmacy as per institutional routine. Not included in the cost determination were: i) disposable equipment (e.g., syringes, needles); ii) staff (e.g., nurses, pharmacists, physicians); or iii) maintenance of drug inventory.

Statistical analyses and sample size projection
Statistical analyses were completed using unpaired Student’s t tests for continuous data and Fisher’s exact test for categorical data as appropriate. Normality was assessed with the Kolmogorov-Smirnov test. Statistical tests were two-tailed and comparisons considered statistically significant at P 0.05. Data are presented as mean ± standard deviation unless specified otherwise.

The target sample size for this trial was based on data from our first trial in the miniseries⁶ and projected to detect a minimum important difference of 25% in mean total perioperative drug cost per patient between the two groups. In order to achieve 80% power and a type I error not exceeding 5%, n = 20 valid patients per group were required, assuming equal variances and normal distributions. In order to maximize power and compensate for patients to be excluded from the analysis, an initial total sample size of n = 25 per group was selected.

	Results

TOP Abstract Introduction Methods Results Discussion References

 
Twenty-five patients in group I and 20 patients in group D were eligible for analysis based on satisfactory study protocol adherence (P > 0.05). Twelve anesthesiologists and five surgeons completed the cases. Patient demographics and the duration of the procedures were similar in both groups (Table II). Satisfactory anesthesia was obtained for all patients. There were no differences between the groups in intraoperative vital signs (median heart rate: group I, 60 ± 9 min^–1; group D, 61 ± 9 min^–1; median MAP: group I, 80 ± 11 mmHg; group D, 81 ± 20 mmHg). Propofol was used to induce anesthesia in all patients included in the analysis.¹¹ No neuromuscular blocking agents were administered. Both groups were similar with regard to the intraoperative use of anesthetic and adjuvant drugs, with the exception of volatile anesthetic consumption (Table III). Liquid isoflurane consumption averaged 6.0 mL per patient [95% confidence interval (CI), 4.7–7.2 mL]; mean desflurane consumption per patient was 18.6 mL (95% CI, 15.0–22.3 mL; P < 0.0001). Total perioperative drug cost per patient was higher in group D (mean, $21.47; 95% CI, $19.04–$23.98) compared to group I (mean, $14.58; 95% CI, $11.76–$17.39, P < 0.001). Volatile agent cost averaged $7.61 (95% CI, $6.13–$9.08) in group D, and $0.83 in group I (95% CI, $0.66–$1.01; P < 0.0001). No differences between the groups were observed in intraoperative non-volatile anesthetic and adjuvant drug cost or cost of drugs administered postoperatively in the PACU and surgical day care centre. Table IV provides a summary of the perioperative drug cost data. The ratios of average end-tidal volatile anesthetic concentration to minimal alveolar concentration in 60 to 70% nitrous oxide in adults^12,13 were similar for both groups (group I, 1.1 ± 0.4; group D, 1.3 ± 0.2; P > 0.05), indicating approximate equipotency of the administered isoflurane and desflurane concentrations. All but one patient from each group were deemed ready for discharge from the PACU (Aldrete score 9) 15 min postoperatively (P > 0.05). No differences in actual times to PACU discharge were observed (group I, 49 ± 10 min; group D, 46 ± 12 min; P > 0.05). One patient in group D experienced postoperative nausea. No respiratory or other perioperative adverse events/serious adverse events were noted.

	Discussion

TOP Abstract Introduction Methods Results Discussion References

The measured consumption of isoflurane and desflurane per patient was consistent with calculated and measured data from the literature,^9,14,15 and, for isoflurane, comparable to our previous study and the findings of others.^6,17 Our cost results are in contrast to those of Boldt et al.,⁹ who found no difference between isoflurane and desflurane anesthesia in patients undergoing subtotal thyroidectomy or laparoscopic cholecystectomy. However, these data are to be interpreted in the context of a comparatively high isoflurane price to their centre at the time [isoflurane, $142.22 (USD)/250 mL; desflurane, $65.69 (USD)/240 mL) and would be similar to our results if based on the 2003 prices of our institution. Similarly, Meyer-McCright et al.¹⁸ found no cost difference between isoflurane and desflurane anesthesia in patients undergoing dilatation and curettage; however, the study was retrospective and the authors neither quoted unit prices for the agents nor liquid consumption. Collectively, these observations serve to reemphasize the fact that drug pricing may be highly variable depending on institutional contracts, marketplace competition, patents, and country.¹⁹ It is possible that the cost of desflurane compared to isoflurane may decrease in the future, potentially necessitating reinterpretation of our data. However, at our institution, the desflurane-to-isoflurane cost ratio on a mL-to-mL basis (ignoring the difference in potency) has increased from 2.1 to 3.4 between 2000 and 2003, and it seems unlikely at this time that desflurane anesthesia in the foreseeable future will be associated with significantly lower drug costs in the ambulatory setting compared to isoflurane anesthesia. Another potential shortcoming of our study includes the fact that volatile consumption may have been lower had the agents been administered using closed anesthesia systems and minimal fresh gas inflow rates.¹⁵ However, based on a recent prospective randomized trial that studied this question in a heterogeneous group of patients undergoing a wide variety of procedures of different duration,²⁰ it appears that such a regimen would not have changed the overall conclusion of the present trial. In any event, our results provide an insight into a current "real world" scenario in a Canadian university hospital setting, and our data may be used to extrapolate the impact of future drug pricing changes from the measured volatile anesthetic consumption.

Based on the results of this study, one may be tempted to conclude that volatile anesthetic costs overall are small regardless of the agent used, particularly when compared to the cost of running an operating room or anesthesiology fees.²¹ However, in this study, using desflurane in the ambulatory setting was more than nine times as expensive as isoflurane. To put the results in perspective, assuming seven comparable procedures per day five days a week 48 weeks a year, the use of desflurane instead of isoflurane would produce on average an additional total drug expense of $11,861 per annum and operating room. In other words, for every five operating rooms, potential savings could be made in a magnitude similar to a registered nurse’s or medical resident’s annual salary. This is particularly noteworthy since despite desflurane’s potential for a more rapid emergence,¹ its use did not translate into potential savings due to faster PACU discharge or even faster readiness to PACU discharge; on the other hand, neither of these variables were primary outcome measures in this trial. Yet, our results echo those of several other studies with desflurane,^1,22–24 and are similar to the data of Philip et al. comparing isoflurane and sevoflurane in ambulatory anesthesia.²⁵ Consequently, another corollary of our data is that isoflurane anesthesia per se does not preclude patients from fast-tracking in ambulatory anesthesia.²⁶

It is of note, though, that we did not observe any intraoperative respiratory adverse events²⁷ in patients receiving desflurane (or isoflurane) through an LMA. These findings are consistent with those of Ashworth and Smith,⁷ who compared the use of desflurane with isoflurane and propofol in spontaneously breathing ambulatory patients undergoing superficial procedures. The authors reported no significant respiratory adverse events due to maintenance with desflurane, and there were no differences between the three agents in emergence or recovery times. Similarly, two recent trials compared desflurane with sevoflurane administered via LMA and found no differences in airway responses in short (mean, 18 min)²⁸ and longer (mean, 78 min)²⁹ procedures. Overall, desflurane appears to be an acceptable agent for maintenance of anesthesia in ambulatory patients breathing spontaneously through an LMA, although it seems questionable whether desflurane confers any significant advantages over isoflurane, sevoflurane, or propofol.

In conclusion, measured total perioperative drug cost for a short ambulatory procedure (less than one hour) was higher when desflurane rather than isoflurane was used for maintenance of general anesthesia in spontaneously breathing patients, essentially due to volatile anesthetic agent cost. Desflurane use did not translate into faster PACU discharge under "real world" conditions and was not associated with other apparent clinically significant advantages compared to isoflurane. We suggest that unless there is a critical need for rapid emergence (e.g., procedures requiring immediate postoperative neurological assessment), isoflurane should continue to be considered a reasonable anesthetic choice for short ambulatory procedures. In general, our results underscore the role of prospective clinical trials reflecting "real world" conditions in the context of routine practice in the pharmacoeconomical analysis of anesthetic agents.

	Acknowledgments

 
We thank Mr. Robin Yu, Mr. Dennis Boparai, Mr. Andrew Numa, Mr. Andrew Purssell, and Dr. Nutan Nafde for their assistance in planning, conducting, and analyzing this trial. We are indebted to the anesthesiologists, nurses, anesthesia assistant, and pharmacists (in particular, Mr. Vince Yu) at UBC Hospital for their invaluable support.

	Footnotes

 
This study was supported exclusively by Institutional/Departmental sources.

Financial arrangements that could lead to conflict: none.

A preliminary account of this work has been presented at the International Anesthesia Research Society 76^th Clinical and Scientific Congress, San Diego, CA, USA, March 16–20, 2002.

Accepted for publication March 2, 2004. Revision accepted June 21, 2004.

^A Zeneca Pharma. Suprane® (desflurane, USP) Basic Technique Card. Mississauga: Zeneca Pharma; 1998.

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