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AMBULATORY ANESTHESIA

Bisulfite-Containing Propofol: Is it a Cost-Effective Alternative to Diprivan^TM for Induction of Anesthesia?

Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Address correspondence to Paul F. White, PhD, MD, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9068. Address e-mail to paul.white{at}utsouthwestern.edu

	Abstract

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Propofol (Diprivan^TM; AstraZeneca, Wilmington, DE) is a commonly used drug for the induction of general anesthesia in the ambulatory setting. With the availability of a new bisulfite-containing generic formulation of propofol, questions have arisen regarding its cost effectiveness and safety compared with Diprivan^TM. Two hundred healthy outpatients were randomly assigned, according to a double-blinded protocol, to receive either Diprivan^TM or bisulfite-containing propofol 1.5 mg/kg IV as part of a standardized induction sequence. Maintenance of anesthesia consisted of either desflurane (4%–8% end-tidal) or sevoflurane (1%–2% end-tidal) in combination with a remifentanil infusion (0.125 µg · kg^-1 · min^-1 IV). Patient assessments included pain on injection, induction time, hemodynamic and bispectral electroencephalographic changes during induction, emergence time, and incidence of postoperative nausea and vomiting. The two propofol groups were comparable demographically, and the induction times and bispectral index values during the induction were also similar. However, the bisulfite-containing formulation was associated with less severe pain on injection (5% vs 11%), with fewer patients recalling pain on injection after surgery (38% vs 51%, P < 0.05). None of the patients manifested allergic-type reactions after the induction of anesthesia. The acquisition cost (average wholesale price in US dollars) of a 20-mL ampoule of Diprivan^TM was $15 compared with $13 for the bisulfite-containing propofol formulation. Therefore, we concluded that the bisulfite-containing formulation of propofol is a cost-effective alternative to Diprivan^TM for the induction of outpatient anesthesia.

Implications: Bisulfite-containing propofol and Diprivan^TM (AstraZeneca, Wilmington, DE) were similar with respect to their induction characteristics; however, the generic formulation was associated with a smaller incidence of injection pain. Assuming that the drug costs are similar, these data suggest that the bisulfite-containing formulation of propofol is a cost-effective alternative to Diprivan^TM.

	Introduction

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The original preparation of propofol was formulated as a 1% solution in 16% polyoxyethylated castor oil. This formulation had to be withdrawn from clinical testing because its use was associated with an unacceptably frequent incidence of anaphylactic reactions (1,2). The subsequent commercial preparation of propofol (Diprivan^TM; AstraZeneca, Wilmington, DE) was formulated in a fat emulsion consisting of 10% soybean oil containing long-chain triglycerides, and EDTA was added as a preservative. Although this preparation has gained widespread popularity in clinical practice, its use is associated with a greater incidence of pain on injection (3,4). Moderate-to-severe pain on injection of Diprivan^TM has been reported in 32%–67% of patients receiving a standard bolus dose for the induction of anesthesia (5).

It has been proposed that the solvent can influence the incidence of pain on injection of propofol (6,7). For example, changing the composition of the carrier fat emulsion influenced the incidence of pain on injection without altering the pharmacokinetic or dynamic properties of this IV anesthetic (7). The recently approved generic formulation of propofol (Baxter PPI, Liberty Corners, NJ) has a pH of 6.4 and contains sodium metabisulfite as a preservative. Its safety and efficacy has not been directly compared with the current "gold standard," namely Diprivan^TM.

The objective of this study was to compare the hypnotic properties and side effect profile of this new bisulfite-containing propofol formulation with those of Diprivan^TM when used for the induction of anesthesia. This prospective, randomized, double-blinded investigation tested the hypothesis that an equivalent dose of bisulfite-containing propofol would be associated with less pain on injection than Diprivan^TM.

	Methods

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After we obtained institutional review board approval at University of Texas Southwestern Medical Center in Dallas and written, informed consent, 200 healthy outpatients undergoing ambulatory surgery procedures received either bisulfite-containing propofol or Diprivan^TM for the induction of anesthesia according to a computer-generated randomization scheme. Patients with neurologic, cardiovascular or metabolic diseases, impaired renal or hepatic function, body weight) more than 50% above the ideal, women with a positive pregnancy test or who were breast feeding at the time of surgery, as well as patients with a history of drug abuse or egg lecithin, soybean oil, or sulfite allergies, were excluded from participating in this study. The average wholesale price for 25 of the 20-mL ampoules of Diprivan^TM was US $375 compared with $330 for the bisulfite-containing propofol formulation at Zale Lipshy University Hospital in Dallas, TX.

In addition to routine monitoring devices (heart rate [HR], noninvasive mean arterial pressure [MAP], pulse oximeter), the electroencephalogram-bispectral (BIS) index was recorded by using three electrodes (BIS^TM Model 1050; Aspect Medical System, Natick, MA) applied to the forehead. Midazolam (20 µg/kg IV) was administered for premedication in the preoperative holding area. Baseline values for MAP, HR, and BIS index were averaged for a 2- to 3-min interval before the induction of anesthesia. Anesthesia was induced with remifentanil 1 µg/kg IV followed by propofol 1.5 mg/kg IV injected for 15 s through a 20-gauge IV cannula placed in the dorsum of the hand. The propofol formulation was prepared in unlabeled 20-mL syringes and injected by the same anesthesiologist (KWK). Patients were also blinded as to the propofol formulation.

The MAP, HR, and BIS index values were recorded at 1-min intervals throughout the induction period. Assessment of pain on injection (consisting of a 4-point scale with 0 = no pain; 1 = mild pain [facial grimacing]; 2 = moderate pain [verbal complaint], and 3 = severe pain [verbal complaint and movement of extremity]) was performed at 30 s after the end of the bolus injection of propofol. After loss of consciousness (i.e., failure to respond to a verbal command to "open your eyes"), all patients received rocuronium, 0.6 mg/kg IV, to facilitate tracheal intubation. The quality of the anesthetic induction was assessed by the same anesthesiologist (KWK) on a 4-point scale: 1 = poor (slow onset, hypotension and tachycardia lasting 3–6 min), 2 = fair (transient hypotension and/or tachycardia lasting 1–2 min), 3 = good (15–25% changes in MAP or HR values), and 4 = excellent (rapid onset, 15% changes in MAP or HR values).

Anesthesia was maintained with either desflurane, 4%–8% (end-tidal) or sevoflurane, 1%–2% (end-tidal) in oxygen, 0.5 L/min, and air, 0.5 L/min, in combination with a remifentanil infusion, 0.125 µg · kg^-1 · min^-1 IV. Droperidol 0.625 mg IV was administered to all patients for antiemetic prophylaxis. All anesthetic drugs were discontinued on completion of the skin closure and residual neuromuscular blockade was reversed with atropine 10 µg/kg IV and edrophonium 0.7 mg/kg IV. In the early postoperative period, fentanyl 25-µg IV boluses were administered for acute pain relief and ondansetron 4 mg IV was used to control emetic symptoms.

Emergence time (i.e., opening eyes on command) was determined at 1-min intervals after discontinuation of the anesthetic drugs, and the occurrence of emetic symptoms were recorded at 30-min intervals during the initial 2 h observation period and at 24 h after the operation. All patients were also questioned regarding their recall of any pain on injection of the anesthetic drug at the time of discharge home. A follow-up telephone interview was performed at 24 h after surgery to assess their degree of satisfaction with the overall anesthetic experience.

The sample size used was estimated based on an a priori power analysis performed before initiating the study. Because pain on injection of propofol was the primary outcome variable, and an incidence of 40%–80% has been reported when the drug is injected into small hand veins (5), the analysis suggested that 97 patients per group would provide 80% power to detect a difference of 20% ( = 0.05). Continuous variables (e.g., HR values) were analyzed by using repeated measures of analysis of variance with the Newman-Keuls test used to determine intergroup differences. Categorical data were analyzed by using the ² test. Data were presented as mean values ± SD (Tables 1, 2, and 3) or ± SEM (Figures 1 and 2). A P value of <0.05 was considered statistically significant.

View larger version (13K): [in this window] [in a new window]   Figure 1. Changes in heart rate (HR) after a bolus injection of a 1.5-mg/kg dose of either DiprivanTM (AstraZeneca, Wilmington, DE) (--) or bisulfite-containing propofol (--). Values are mean ± SEM. Bl = baseline values.

View larger version (15K): [in this window] [in a new window]   Figure 2. Changes in the electroencephalographic-bispectral (BIS) index values after the bolus injection of a 1.5-mg/kg dose of either DiprivanTM (AstraZeneca, Wilmington, DE) (--) or bisulfite-containing propofol (--). Values are mean ± SEM. Bl = baseline values.

	Results

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Compared with the Diprivan^TM group, a larger percentage of patients in the bisulfite-containing propofol group reported no pain on injection (55% vs 47%) and fewer patients experienced severe pain (5% vs 11%) (Table 2). However, the induction time, side effects, and quality of the induction were similar in the two propofol groups (Table 2). At the time of discharge, significantly fewer patients in the bisulfite-containing propofol (versus the Diprivan^TM) group recalled pain on propofol injection (38% vs 51%, P < 0.05).

The overall incidence of postoperative nausea and vomiting (PONV) was similar in the two groups during the early (0–2 h) postoperative period (Table 3 ). However, a subset analysis of the interaction between the two propofol formulations and the two volatile anesthetics administered for maintenance of anesthesia revealed that the bisulfite-containing propofol and desflurane combination was associated with less nausea and vomiting/retching than the Diprivan^TM-desflurane combination during the 2–24 h period after surgery (Table 3). However, the patient overall satisfaction rating with their anesthetic experience was similar in all four induction-maintenance treatment groups (Table 3).

	Discussion

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A cost-effectiveness analysis involving a new drug expresses its cost relative to a standard therapy in units of success (e.g., costs per patient free from a given side effect) (8). The advantage of this type of analysis over a cost-benefit model is that it avoids the need to convert outcomes into monetary terms. The present study demonstrated that the recently approved bisulfite-containing generic formulation of propofol was associated with less recall of pain on injection than Diprivan^TM. Analogous to the findings of Doenicke et al. (7) in healthy volunteers, we found that changes in the composition of the propofol carrier solution resulted in decreases in the incidence of severe pain on injection without altering its potency or pharmacodynamic profile. Given the reduced cost for an induction dose of the bisulfite-containing propofol formulation, it would appear to be more cost effective than Diprivan^TM.

Pain during the injection of propofol (Diprivan^TM) is a well known complication during the induction of general anesthesia (5). Many different approaches have been used in an attempt to decrease the pain on injection of propofol (9–14). The most common approach involves injecting 1–2 mL of lidocaine 1% before the injection of propofol or mixing the lidocaine with the propofol in the same syringe (5,10,11). Dilution of propofol with a 5% glucose solution also decreases the pain on injection (13). Propofol has even been injected after administering cold (4°C) isotonic saline to reduce the incidence of injection pain (14). Seki et al. (15) recently recommended central venous injection to reduce the pain on injection. Unfortunately, these strategies involve additional work for the anesthesia provider and/or an increased risk of contamination. Furthermore, many of these maneuvers produce inconsistent results (5).

The new formulation of propofol has a pH of 6.4 compared with a pH of 8.5 for Diprivan^TM. The main difference between the two propofol formulations relates to the antimicrobial agent (namely, EDTA in Diprivan^TM versus sodium metabisulfite in the generic formulation). An equivalent hypnotic dose of the bisulfite-containing formulation was associated with a reduced recall of pain on injection of propofol into small hand veins. These findings support those of Doenicke et al. (7) who have reported that a novel propofol formulation consisting of medium- and long-chain triglycerides also compared favorably with Diprivan^TM with respect to injection pain. However, given the unexpectedly low incidence of severe pain on injection of propofol in this study, a post hoc power analysis (ß = 0.8) indicated that group sizes of 245 patients would be required to achieve a statistically significant difference between the two propofol treatment groups.

Despite the fact that high-risk outpatients were included in this investigation, the incidences of PONV were relatively low in both treatment groups during the early postoperative period (5), consistent with the well known antiemetic properties of propofol. Although the bisulfite-containing propofol formulation appeared to be associated with a lower frequency of PONV than Diprivan^TM during the post discharge period (2–24 hours after surgery), this finding may be related to differences in the use of opioid-containing oral analgesic medication after discharge rather than inherent differences in the two formulations of propofol.

A possible criticism of this study is our exclusion of patients with a history of egg lecithin, soybean, or sulfite allergies from participation. However, none of the potential study patients were excluded on the basis of these exclusionary criteria. Of interest, none of the patients in either propofol treatment group manifested signs or symptoms of an allergic-type drug reaction. According to the manufacturer of generic propofol (R. Trillo, Baxter PPI, oral communication, March 2000), more than five million patients have received this formulation for the induction of anesthesia to date, and no allergic-type reactions have been reported.

In conclusion, the new generic formulation of propofol containing sodium bisulfite is equally effective but causes less pain on IV injection than the original commercial formulation of propofol. Given that the bisulfite-containing formation is less costly, generic propofol would appear to be a cost-effective alternative to Diprivan^TM for the induction of general anesthesia in the outpatient setting.

	References

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