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Anesth Analg 2004;98:687-691 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000103184.36451.D7
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Abstract |
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Using a randomized, double-blind protocol design, we compared a new lower-lipid emulsion of propofol (Ampofol®) containing propofol 1%, soybean oil 5%, and egg lecithin 0.6% with the most commonly used formulation of propofol (Diprivan®) with respect to onset of action and recovery profiles, as well as intraoperative efficacy, when administered for induction and maintenance of general anesthesia as part of a "balanced" anesthetic technique in 63 healthy outpatients. Anesthesia was induced with sufentanil 0.1 µg/kg (or fentanyl 1 µg/kg) and propofol 2 mg/kg IV and maintained with a variable-rate propofol infusion, 120–200 µg · kg-1 · min-1. Onset times to loss of the eyelash reflex and dropping a syringe were recorded. Severity of pain on injection, speed of induction, intraoperative hemodynamic variables, and electroencephalographic bispectral index values were assessed. Recovery times to opening eyes and orientation were noted. The results demonstrated that there were no significant differences between Ampofol® and Diprivan® with respect to onset times, speed of induction, anesthetic dose requirements, bispectral index values, hemodynamic variables, recovery variables, or patient satisfaction. However, the incidence of pain on injection was more frequent in the Ampofol® group (26% versus 6%, P < 0.05). We conclude that Ampofol® is equipotent to Diprivan® with respect to its anesthetic properties but was associated with a more frequent incidence of mild pain on injection.
IMPLICATIONS: The pharmacodynamic profile of a lower-lipid containing emulsion of propofol (Ampofol®) was compared with Diprivan® when administered for induction and maintenance of general anesthesia. This preliminary study demonstrated that the two formulations of propofol were equivalent with respect to their induction and maintenance properties. However, Ampofol® was associated with a more frequent incidence of pain on injection.
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Introduction |
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Propofol is the most commonly used IV anesthetic (1). Although propofol has an excellent recovery profile (e.g., fast and smooth emergence, infrequent incidence of postoperative nausea and vomiting), its use is associated with pain on injection, increased triglyceride levels, and the potential for microbial contamination (2–5). In recent years, efforts have been made to find alternative formulations of propofol that might minimize some of these adverse effects (6–8). Ampofol® (Amphastar Pharmaceuticals, Inc., Rancho Cucamonga, CA) is a new propofol formulation that contains 50% less soybean oil and egg lecithin emulsion than the currently marketed formulations of propofol, Diprivan® (AstraZeneca, Wilmington, DE) and generic propofol (Gensia Sicor, Irvine, CA).
Ampofol® contains 1% propofol, 5% soybean oil, and 0.6% egg lecithin. In addition, Ampofol® possesses intrinsic antimicrobial activity (9). Therefore, in contrast to Diprivan® and generic propofol, it does not require a preservative or microbial growth retardant. There have been no clinical studies comparing the pharmacodynamic profile of Ampofol® to the currently available propofol formulations.
We hypothesized that Ampofol® (1% propofol) would have a similar pharmacodynamic profile to the current "gold standard" propofol formulation (Diprivan®), which contains 1% propofol in 10% soybean oil and 1.2% egg lecithin. This randomized, double-blind study was designed to evaluate the comparability of these two propofol formulations when used as part of a "balanced" anesthetic technique to induce and maintain general anesthesia in outpatients undergoing elective surgery.
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Methods |
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After obtaining IRB approval and written informed consent, 65 ASA physical status I or II outpatients undergoing ambulatory ear, nose, or throat surgery received either Ampofol® or Diprivan® for induction and maintenance of general anesthesia according to a computer-generated random numbers table. Patients with neurologic, cardiovascular, or metabolic diseases, impaired renal or hepatic function, 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 or soybean oil allergies, were excluded from participating in this study.
All patients were premedicated with rofecoxib, 50 mg per os, and midazolam, 20 µg/kg IV, 30–45 min and 5–10 min before the induction of anesthesia, respectively. On arrival in the operating room, routine monitors were applied for recording heart rate (HR), mean arterial blood pressure (MAP), and oxygen saturation values. In addition, the one-channel electroencephalographic bispectral index (BIS) monitor (A-2000 BIS monitoring system with the XP platform; Aspect Medical System, Natick, MA) was used for recording perioperative BIS values.
Before induction of anesthesia, 1% lidocaine 0.5 mg/kg IV, was administered to reduce injection pain. Anesthesia was induced using a combination of sufentanil, 0.1 µg/kg or fentanyl 1 µg/kg IV (3 min before propofol administration), and propofol, 2 mg/kg IV (injected over 15–18 s through a 22-gauge cannula in a small vein on the dorsum of the hand). The propofol solution (either Diprivan® 1% or Ampofol® 1%) was prepared by the operating room pharmacist in unlabeled syringes according to the ran-domization table provided by the study sponsor (Amphastar Pharmaceuticals, Inc). As the physical appearance of Diprivan® and Ampofol® are identical, the anesthesia providers and the investigators recording these data were unaware of the propofol formulation. After loss of consciousness, rocuronium, 0.6 mg/kg IV, was administered to facilitate tracheal intubation. Anesthesia was initially maintained with a propofol infusion at a rate of 120 µg · kg-1 · min-1 in combination with nitrous oxide 67% in oxygen. Subsequently, the propofol infusion rate was varied between 120 and 200 µg · kg-1 · min-1 to maintain the MAP within 25% of the preanesthesia baseline values. All patients were mechanically ventilated to maintain an end-tidal carbon dioxide concentration of 32–36 mm Hg. Muscle relaxation was maintained with rocuronium, 0.15 mg/kg IV boluses. Supplemental boluses of sufentanil, 5–10 µg IV or fentanyl 50–100 µg, were administered at the discretion of the attending anesthesiologists to treat sustained increases in HR (more than 15% above baseline values). All patients received ondansetron, 4 mg IV, at the time of surgical closure for antiemetic prophylaxis. On completion of surgery, the combination of neostigmine, 2–5 mg IV and glycopyrrolate, 0.2–1 mg IV, was administered for reversal of residual neuromuscular blockade, and the propofol infusion and nitrous oxide were discontinued.
The MAP, HR, and BIS values were recorded at 1-min intervals throughout the induction period, and at 5-min intervals during the maintenance period. Pain on injection of propofol was assessed on a four-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe) every 5–10 s until the patient lost consciousness. Induction times were determined as the times to loss of response to the verbal command to open their eyes, loss of eyelash reflex, and dropping of a 20-mL syringe-like cylinder. The overall quality of induction was subjectively assessed by the anesthesiologist using a 3-point rating scale (i.e., poor, good, or excellent) immediately after tracheal intubation.
Recovery times were assessed at 1–5 min intervals from the time the propofol infusion was discontinued until the patients opened their eyes on command, were orientated to person, date, and place, ambulated, and were ready to be discharged home ("home ready") (7). In addition, maximal postoperative pain and nausea scores were assessed using an 11-point verbal rating scale (VRS) (0 = none, 10 = worst imaginable), and patients’ satisfaction with their overall anesthetic experience was evaluated on a 100-point VRS (1 = highly dissatisfied to 100 = highly satisfied) at the time of discharge home. Patients were also questioned regarding their recall of pain on injection of the study drug at the time of discharge. A follow-up telephone call was performed at 24 h after surgery to assess their degree of pain and nausea after discharge using the 11-point VRS, as well as their overall satisfaction with the anesthesia experience on the 100-point VRS.
Before initiating the study, a power analysis was performed to estimate the sample size. The calculation was based on the mean induction times for the two study groups. Assuming an induction time in the Diprivan® group of 58 s with a standard deviation of 20 s, a sample size of 29 patients for each group was determined to detect a 15-s prolongation in the time from injection of propofol to loss of consciousness, with a 
= 0.05 and ß = 0.2, using the software nQuery AdvisorTM (version 1.0, Janet D. Elashoff, 1995). Analysis of variance was used for comparison of all continuous variables between the groups. Kruskal-Wallis test and 
2 test were used for analysis of all nonparametric variables as appropriate. Data are expressed as mean values ± SD or median values ± interquartile ranges and P values of < 0.05 were considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Of the 65 outpatients enrolled in the study, 2 voluntarily withdrew before the study medication was administered. The two treatment groups were comparable with respect to their demographic characteristics (Table 1). Similarly, no differences were found in the duration of anesthesia, dosages of adjunctive anesthetic and analgesic medications, or in the amount of IV fluid administered during the perioperative period. The average maintenance infusion rate and total dosages of propofol administered were also identical in both groups.
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The induction time and quality of induction were similar in the two groups. However, the incidence of mild pain on injection was significantly more frequent in the Ampofol® group (Table 2). The overall incidence of pain on injection was 39% in the Ampofol® group compared with only 9% in the Diprivan® group. Although more patients in the Diprivan® group experienced transient decreases in MAP >25% from the baseline value during the initial 10-min period after propofol injection (Table 2), none of the patients required a therapeutic intervention, and this difference failed to achieve statistical significance. Furthermore, the MAP and HR values during the induction and maintenance period were similar with the two propofol emulsion formulations (Fig. 1). Of importance, the BIS values were also similar during both the induction and maintenance periods in both study groups (Table 3).
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–, Diprivan® group; –•–, Ampofol® group. No significant difference between the two study groups.
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During the recovery phase, there were no significant differences between the two groups with respect to recovery times, pain and nausea scores, and patient satisfaction with the anesthetic experience (Table 3). Although more pain on injection was observed in the Ampofol® (versus Diprivan®) group, none of these patients had recall of this pain when questioned at the time of discharge home (Table 2). There were also no differences in postdischarge side effects at the 24 h follow-up evaluation period.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Propofol is only minimally soluble in water and is therefore formulated in a soybean oil-based fat emulsion. Although the soybean oil and egg lecithin content of Ampofol® is reduced by 50% compared with the currently marketed 1% propofol emulsions, this does not appear to alter its anesthetic potency (i.e., dosage requirement). In addition, there are no preservatives or microbial growth retardants in Ampofol® because this formulation possesses intrinsic antimicrobial activity (9).
The pharmacodynamic profile of Ampofol® was similar to Diprivan® with respect to both onset and recovery times, as well as intraoperative BIS values. Both propofol formulations produced loss of consciousness within 40 s, which is the time for one arm-to-brain circulation (10). Emergence times from discontinuation of the propofol infusion to eye opening and orientation were also similar with the two propofol formulations. In a recent study comparing Diprivan® with a medium-chain triglyceride (MCT) emulsion of propofol (IDD-DTM), Ward et al. (6) reported that the MCT formulation of propofol was associated with a 14% delay in the induction time and a 5% delay in the emergence time.
In the current study, the reduction of soybean oil and egg lecithin in the propofol emulsion was associated with more pain on injection in contrast to the earlier study with the MCT formulation (6). Although 1% lidocaine was administered 1.5 min before injection of propofol, the overall incidence of pain in the Ampofol® group was still 39% (compared with only 9% in the Diprivan® group). Because pain-relieving drugs were administered at the start and throughout the study, the incidence and severity of the pain on injection could be even more significant with the new formulation when administered in the absence of any anesthetic adjuvants. The pH of Ampofol® is 5.5–7.0 compared with a pH of 7.0–8.5 for Diprivan®. Of interest, the lower pH of the currently used generic emulsion formulation of propofol was actually associated with a somewhat less frequent incidence of severe pain on injection than Diprivan® (7). Because the generic formulation contains the same lipid content as Diprivan®, the increased pain on injection of Ampofol® may be related to an increase in the free fraction of propofol as the lipid component of the emulsion formulation is reduced. In studies comparing MCT formulations of propofol with Diprivan® (2,6), less injection pain was reported with the MCT emulsion.
Given the similar intraoperative BIS index values at comparable intraoperative propofol infusion rates, these data suggest that the two formulations are equipotent and possess similar depressant effects on the central nervous system. The similar intraoperative hemodynamic profiles also suggest that changing the lipid content of propofol failed to significantly alter its cardiac and peripheral vascular effects (1). However, further studies involving the use of invasive cardiovascular monitors are necessary to confirm our preliminary pharmacodynamic findings.
This study can be criticized because the new formulation of propofol was administered in combination with other anesthetic adjuvants and the propofol infusion rate was titrated to maintain hemodynamic stability (rather than a specific BIS value) to reflect current clinical practice. A further limitation of this preliminary study relates to our failure to measure plasma triglyceride and propofol levels. It is possible that in the presence of a similar plasma concentration of propofol, the Ampofol® formulation would have significantly reduced the plasma triglyceride concentration compared with Diprivan®. However, this potential benefit of the new propofol formulation should be evaluated in situations in which larger dosages of propofol are administered for total IV anesthesia or for prolonged sedation in the intensive care unit. Unlike the MCT emulsion, generic propofol and Diprivan®, the Ampofol® formulation of propofol is not associated with the potential for octanoate toxicity, or allergic reactions to bisulfite or EDTA, respectively (6,11,12). Additional studies evaluating strategies for reducing Ampofol®-induced pain on injection are clearly needed.
In conclusion, this pharmacodynamic study demonstrates that the new Ampofol® formulation of propofol possesses equivalent anesthetic efficacy to Diprivan® in patients undergoing ambulatory surgery. Although Ampofol® was associated with a more frequent incidence of pain on injection, no patients had recall of the pain at the follow-up evaluation.
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Acknowledgments |
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Supported, in part, by a research grant from Amphastar Pharmaceuticals, Inc. (Rancho Cucamonga, California) and endowment funds from the Margaret Milam McDermott Distinguished Chair in Anesthesiology.
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References |
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- Smith I, White PF, Nathanson M, Gouldson R. Propofol: an update on its clinical use. Anesthesiology 1994; 8: 1005–43.
- Rau J, Roizen MF, Doenicke AW, et al. Propofol in an emulsion of long- and medium-chain triglycerides: the effect on pain. Anesth Analg 2001; 93: 382–4.
[Abstract/Free Full Text] - Redhead HM, Jones CB, Bobey DG. Pharmaceutical and antimicrobial differences between propofol products. Am J Health Syst Pharm 2000; 57: 1174, 1176–7.
- Sklar GE. Propofol and postoperative infections. Ann Pharmacother 1997; 31: 1521–3.[Abstract]
- El-Ebiary M, Torres A, Ramirez J, et al. Lipid deposition during the long-term infusion of propofol. Crit Care Med 1995; 23: 1928–30.[Medline]
- Ward DS, Norton JR, Guivarc’h PH, et al. Pharmacodynamics and pharmacokinetics of propofol in a medium-chain triglyceride emulsion. Anesthesiology 2002; 97: 1401–8.[Web of Science][Medline]
- Shao X, Li H, White PF, et al. Bisulfite-containing propofol: is it a cost-effective alternative to Diprivan for induction of anesthesia? Anesth Analg 2000; 91: 871–5.
[Abstract/Free Full Text] - Theilen HJ, Adam S, Albrecht MD, Ragaller M. Propofol in a medium- and long-chain triglyceride emulsion: pharmacological characteristics and potential beneficial effects. Anesth Analg 2002; 95: 923–9.
[Abstract/Free Full Text] - Zhang Y, Lou Z, Ding J, Zhou R. Comparison of microbial growth retardation of propofol formulations: Ampofol versus Diprivan with and without EDTA [abstract]. Anesthesiology 2003; 99: A57.
- Fulton B, Sorkin EM. Propofol: an overview of its pharmacology and a review of its clinical efficacy in intensive care sedation. Drugs 1995; 50: 636–57.[Web of Science][Medline]
- Doenicke AW, Roizen MF, Rau J, et al. Reducing pain during propofol injection: the role of the solvent. Anesth Analg 1996; 82: 472–4.[Abstract]
- Rabinowitz JL, Staeffen J, Aumonier P, et al. The effects of intravenous sodium octanoate on the rhesus monkey. Am J Gastroenterol 1978; 69: 187–90.[Medline]
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