Propofol in an Emulsion of Long- and Medium-Chain Triglycerides: The Effect on Pain (2001)

Propofol is formulated as a 1% solution in a fat emulsion (Intralipid®; KabiVitrum, Stockholm, Sweden) containing 10% soybean oil (long-chain triglycerides). On injection with propofol, 32% to 67% of patients experience moderate to severe pain (1). In previous studies, larger concentrations of free propofol in the aqueous phase of an emulsion were associated with more pain on injection (2,3). A mixture of long-chain and medium-chain triglycerides in the carrier emulsion was associated with an infrequent incidence of moderate or severe pain on bolus injection, without change in the pharmacokinetics and pharmacodynamics in volunteers (4). This prospective, randomized, double-blinded study was designed to compare the incidence and intensity of pain on injection of Lipofundin® MCT 10% (B. Braun, Melsungen, Germany) or Diprivan® 1% (AstraZeneca, Germany) in patients undergoing elective surgical procedures. Methods After approval by our IRB, 152 ASA physical status I-III patients provided written informed consent and were enrolled in this study. Patients were older than 18 yr and were scheduled for elective surgical procedures. Excluded from the study were breast-feeding mothers and patients with a history of neurologic disease, preexisting renal or hepatic insufficiency or a positive pregnancy test. The patients were randomly assigned to receive Diprivan® 1% or Lipofundin® MCT 10%. The investigators and patients were blinded to the preparations. The vials and the color of the formulations were identical. Premedication was with 1–2 mg lorazepam orally 1–2 h before induction of anesthesia. Standard monitoring devices were applied in the operating room. The pain caused by insertion of an 18-gauge venous cannula into a dorsal vein of the hand was measured with a 100-mm visual analog scale (VAS) 5 min after insertion was completed. Anesthesia was induced with propofol 20 mL/min until loss of eyelash reflex. During the injection, patients were asked to describe their sensations. After loss of consciousness, fentanyl and atracurium were administered IV at the discretion of the anesthesiologist before tracheal intubation. The lungs were ventilated with oxygen and air; propofol was used for maintenance continuously at the discretion of the anesthesiologist. One hour after tracheal extubation, patients were again asked to describe on the VAS their sensation during the initial injection of propofol. These data were analyzed by χ2 and Fisher’s exact test or by the Wilcoxon’s Mann-Whitney U-test. Results Patient characteristics, surgical duration, and pain 5 min after cannula insertion did not differ between groups. Mean induction dose, time until loss of eyelash reflex, and dose of propofol for maintenance of anesthesia were similar in both groups. All three variables were statistically equivalent between groups. The overall frequency of side effects (breath holding, excitement, cough) did not vary between groups. With Lipofundin® MCT 10%, 2 patients (2.7%) and with Diprivan® 1%, 11 patients (14.7%) complained spontaneously of discomfort during injection (P ≤ 0.005). The intensity of discomfort was less severe in the Lipofundin® MCT 10% group than in the Diprivan® group (Table 1). According to subjective ratings of pain on the VAS, Lipofundin® MCT 10% was associated with significantly less pain (P = 0.0007) than was Diprivan® 1%. Fewer patients (10.8% vs 26%) complained during induction about episodes of pain on injection of Lipofundin® MCT 10%. The pain intensity ratings given on the VAS 1 h after tracheal extubation were significantly lower with the new formulation (median, 2 mm vs 11.5 mm). The results of the VAS ratings are summarized in Table 2.Table 1: Incidence and Severity of Pain at Injection SiteTable 2: Assessment of Pain on a Visual Analog ScaleDiscussion Pain during IV bolus injection of propofol preparations is a known and common problem (1). Many strategies have been developed to diminish the pain associated with propofol injections, including the previous injection of lidocaine or mixing the two medications (1,5–7). Because lidocaine is absorbed by the fat emulsion, however, a lidocaine-propofol mixture must be used quickly after preparation to ensure the anesthetic effect of lidocaine in the vein (1,5,7). For slow infusion, propofol also may be diluted in a 5% glucose solution (8). Injection of cold (4°C) isotonic saline before propofol reduced the incidence of pain from 75% to 22%(8). Adding 5% glucose to propofol reduced the concentration of free propofol in the aqueous phase by only 6.4% as measured by in vitro dialysis over 24 hours (2). However, mixing 20 mL of the original propofol preparation with 10 mL Lipofundin® MCT 10% reduced the concentration of free propofol in the aqueous phase by 39.9%(2) and decreased pain on injection. On the basis of these results, we hypothesized that pain on injection of propofol is correlated with the amount of propofol in the aqueous phase of the emulsion. Diluting the propofol emulsion currently available to reduce pain has the disadvantage of requiring additional manipulation and the risk of contamination of the diluted preparation (9). The concentration of free propofol in the aqueous phase of a 1% propofol preparation in a 10% emulsion of medium- and long-chain triglycerides was 14.0 ± 0.5 μg/mL compared with 18.6 ± 0.6 μg/mL in Diprivan® 1%, a reduction of 25%(2). The new propofol preparation of 10 mg/mL (Lipofundin® MCT 10%) is manufactured by direct emulsification by B. Braun. In a previous study with 24 healthy volunteers, the 1% formulation of propofol was associated with significantly less pain on injection. The pharmacokinetic variables for the new preparation of propofol in medium- and long-chain triglycerides were similar to those reported in studies with the standard formulation currently available (4,10). Using Lipofundin® MCT 10% for induction of anesthesia in patients of ASA physical status I-III was associated with less pain on injection. Lipofundin® MCT 10% was not associated with changes from Diprivan® in hypnotic action or other pharmacodynamics of clinical importance.