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Anesth Analg 2002;95:923-929
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Propofol in a Medium- and Long-Chain Triglyceride Emulsion: Pharmacological Characteristics and Potential Beneficial Effects

Hermann J. Theilen, MD*, Sigrid Adam, MD{dagger}, Michael D. Albrecht, PhD*, and Maximilian Ragaller, MD*

*Department of Anesthesiology and Intensive Care Medicine, University Hospital of the Technical University of Dresden, Dresden, Germany; and {dagger}Department of Anesthesiology, University Hospital of the Erasmus University Rotterdam, Rotterdam, The Netherlands

Address correspondence and reprint requests to Hermann J. Theilen, MD, Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Anästhesiologie und Intensivtherapie, der Technischen Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany. Address e-mail to theilen{at}rcs.urz.tu-dresden.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Hypertriglyceridemia is a possible unwanted effect during long-term propofol sedation while using a formulation containing long-chain triglycerides (LCT) from soybean oil. The use of propofol formulated in a solvent consisting of medium-chain triglycerides (MCT) and LCT might reduce the risk. Because a new solvent may affect the pharmacological profile of propofol, in this prospective, randomized, controlled, and double-blinded study we compared the pharmacodynamic and kinetic characteristics of propofol diluted in MCT/LCT fat solution with those of propofol formulated in LCT fat emulsion. In addition, serum triglyceride levels were measured during and after the administration of both drugs. Thirty patients likely to require mechanical ventilation over at least 48 h were randomized to receive either propofol 2% MCT/LCT (Group 1) or propofol 2% LCT (Group 2). Infusion rates of propofol (2.34 ± 0.83 mg · kg-1 · h-1 in Group 1 versus 2.31 ± 0.6 mg · kg-1 · h-1 in Group 2), the plasma propofol concentrations during infusion (0.95 ± 0.53 versus 0.98 ± 0.32 µg/mL), and the concentrations and arousal behavior after discontinuation of the drug did not show significant differences. Plasma triglyceride concentrations during sedation did not differ between the groups, whereas there was a tendency toward a more rapid triglyceride elimination in Group 1 after termination of the propofol administration.

IMPLICATIONS: Propofol diluted in an emulsion of medium- and long chain-triglycerides shows equivalent pharmacological properties during long-term sedation compared with its hitherto well known formulation containing long-chain triglycerides only. In addition, potential favorable effects on the plasma triglyceride profile could be found.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
In the past decade, propofol (2-6-diisopropylphenol) has become an increasingly popular sedative drug for patients needing mechanical ventilation in the intensive care unit (ICU) (1,2). Although it is equally as effective as midazolam or lorazepam (3,4), propofol was associated with a shorter weaning time after prolonged administration, resulting in a favorable economic profile (5,6). Regarding potential risks related to propofol, however, an increase in serum triglyceride levels has been described repeatedly, particularly after long-lasting application (6,7). This effect can be ascribed to the hitherto commonly used formulation of propofol in a fat emulsion consisting of soybean oil long-chain triglyceride (LCT) emulsions. In critically ill patients presenting with deranged metabolic or enzymatic systems, prolonged propofol administration might result in an excessive fat load with ensuing pancreatitis, which is a well known complication of hypertriglyceridemia (8,9).

In parenteral nutrition the replacement of LCT fat solution by medium-chain triglyceride (MCT)- and LCT-enriched fat emulsions resulted in lower serum triglyceride plasma levels during lipid infusion and faster elimination of triglycerides after completion of administration (10,11). Hence, the use of a propofol formulation containing MCT/LCT emulsion instead of the most commonly used LCT emulsion could reduce the risk of a hypertriglyceridemia attributed to propofol application. A new propofol solution containing MCT/LCT was recently introduced into clinical practice (B. Braun AG, Melsungen, Germany). Any new formulation, however, implies the possibility of changed pharmacological properties (12,13). Therefore, this study was performed to compare the pharmacological characteristics of propofol MCT/LCT with those of propofol formulated in an LCT fat emulsion. In addition, serum triglyceride levels during and after the administration of both drugs were assessed.


   Methods
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 Introduction
 Methods
Results
 Discussion
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The study protocol was approved by the local ethics committee. From patients scheduled for elective surgery of the upper respiratory tract because of tumors of the oral cavity or the pharyngeal or laryngeal tract, written informed consent to participate in this study was obtained. After the operation, prolonged sedation was performed to enable sufficient mechanical ventilation for airway management during the period of potential local swelling in the operated field. The expected duration of sedation required for mechanical ventilation after surgery had to be at least 48 h. The study group comprised 30 patients (7 women and 23 men). They ranged in age from 22 to 61 yr (48 ± 11 yr) and were classified as ASA physical status II or III.

This prospective, randomized, controlled, double-blinded study was conducted in a 13-bed surgical ICU at a university hospital. Anesthesia for surgery consisted of an IV induction with thiopental, fentanyl, and rocuronium continued by means of isoflurane/N2O/fentanyl. To ensure adequate sedation during the subsequent transport to the ICU, a dose of up to 10 mg of midazolam and 0.1 mg of fentanyl given IV was allowed. On arrival, the patients were already sedated but not paralyzed and were thus able to tolerate transportation while being intubated and mechanically ventilated. In the ICU, the patients were monitored by electrocardiogram (ECG), invasive measurement of blood pressure by arterial cannulation, and pulse oximetry.

The patients were randomly allocated to receive either propofol 2% MCT/LCT (Propofol-Lipuro® 2%; B. Braun AG) or propofol 2% LCT (Disoprivan® 2%; Astra-Zeneca GmbH, Wedel, Germany) by means of a computer-generated random code (Rancode+ Version 3.1; IDV, München-Gauting, Germany). Indistinguishable propofol emulsions were delivered by B. Braun AG. Any other sedative or fat-containing drug other than those previously described were not allowed during the study period. In addition, neither enteral nor parenteral nutrition, including dextrose infusions, was administered.

Before starting sedation with propofol, venous blood samples were taken to quantify plasma concentrations of liver enzymes (aspartate aminotransferase [ASAT], alanine aminotransferase, and {gamma}-glutamyl transpeptidase [{gamma}-GT]; measurements with standard laboratory assays from Beckman Coulter, Inc., Fullerton, CA) and glycerin-glycerides. Because glycerol is a component of both propofol preparations, which cannot be separated while using an automatic analyzer for the measurement of the plasma triglyceride concentration, the computation of triglycerides was performed by subtracting free plasma glycerin (WAK-FG-100; WAK Chemie Medical GmbH, Bad Homburg, Germany) from total plasma glycerin (GPO-PAP No. 701912; Boehringer, Mannheim, Germany) to assess glycerin-glyceride as a measure of triglycerides.

After baseline vital signs and laboratory tests were obtained (mean arterial blood pressure, heart rate, arterial pH, arterial standard bicarbonate) and the clinical level of sedation with the Ramsay scale (14) was documented, sedation was started by using either propofol 2% MCT/LCT or propofol 2% LCT (2–4 mg · kg-1 · h-1). In addition, fentanyl (0.15–0.25 µg · kg-1 · h-1) was allowed for analgesia. Sedation was continued for at least 48 h and up to 120 h, until airway compression by postoperative edema could be excluded and extubation was indicated. The depth of sedation was assessed hourly by a physician and rated according to the Ramsay scale. The current dosage and any change in propofol administration were recorded. If the depth of sedation was considered inadequate, the dose rate of propofol was either increased or decreased to achieve a sedation score of 3 on the Ramsay scale (drowsy, easily responding to verbal commands).

Venous blood samples were taken to measure the plasma propofol concentration starting at Hour 6 after the commencement of the sedation and afterward every 12 h. Determination of propofol plasma concentration was performed by high-performance liquid chromatography, as described by Chan and So (15). In addition, at Hours 12, 36, 60, 84, and 108 (depending on the duration of sedation), the plasma concentrations of triglycerides and liver enzymes were measured. Five minutes before cessation of the propofol administration, another blood sample was obtained to assess the end-of-infusion plasma concentration of propofol and glycerin-glyceride.

Additional blood samples were obtained 20, 40, 60, 120, and 240 min after terminating the propofol delivery to assess the plasma concentration of glycerin-glyceride. Furthermore, in 17 randomly assigned patients (8 patients receiving propofol 2% MCT/LCT versus 9 patients receiving propofol 2% LCT) at 1, 3, 6, 20, and 40 min and at Hours 1, 2, 4, 6, and 24 after terminating the propofol infusion, further blood samples were drawn to measure the plasma propofol concentration to assess the plasma elimination kinetics of both propofol preparations.

When weaning from ventilation was clinically indicated, propofol and fentanyl infusions were discontinued, and the arousal behavior was recorded in all patients. The time of first spontaneous movements and, after extubation, the return of memory with regard to name and date of birth (personal orientation) and first calling the current location (local orientation) were documented. Because the procedure to perform extubation (ensuring free airways, evacuation of saliva from the laryngeal and pharyngeal tract) varies considerably, the time span between the cessation of drug infusion and extubation was not considered for the assessment of pharmacodynamic properties. Immediately after the extubation, no patient was able to provide correct information about the date of birth and the name.

Patients with a history of myocardial infarction in the 6 months before the planned intervention, cerebral abnormalities (seizures, history of brain trauma), renal (serum creatinine >100% of the upper limit of normal) and/or hepatic diseases (cirrhosis or ASAT, alanine aminotransferase, and/or {gamma}-GT >50% of the upper limit of normal), current drug or alcohol abuse, disorders of lipid metabolism, allergy to propofol or fentanyl, or obesity or cachexia (Broca’s index >50% or < 30% of normal), as well as pregnant women, were excluded from the study. Furthermore, patients who had been using long-acting sedative medication before surgery were not admitted to the study.

Sample size was determined by power analysis on the basis of the results of a previous study by Beller et al.(16), who examined the blood propofol concentrations in relation to recovery times in patients in the ICU sedated with propofol. Considering an equivalence range within 20%, and accepting a Type 1 error of 0.05 and a Type II error of 0.2, it was decided to enroll enough patients to obtain at least 12 complete data sets per group for this study. Taking into account 10% dropouts and a divergence of the target criterion from normally distributed data while comparing parallel groups, 2 x 15 patients were enrolled in the study.

Statistics were performed with Student’s t-tests to compare demographic data. Repeated-measures analysis of variance with Bonferroni corrections for multiple comparisons was performed to compare hemodynamic data, glycerin-glyceride values, the concentrations of liver enzymes, and propofol plasma concentrations. For all analyses, differences were rated significant at P < 0.05. All pharmacological calculations and statistical analyses were performed with SAS Version 6.12 (SAS Institute, Cary, NC).


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Thirty patients were admitted to the trial. One patient had to be excluded from the study because of withdrawal symptoms attributed to ethanol abuse. The patient did not volunteer his history of ethanol abuse during the preoperative visit. The symptoms could not be treated by propofol without inducing deep sedation. Thus, 15 patients in the propofol 2% MCT/LCT group (47.3 ± 13.3 yr, 70.6 ± 12.5 kg body weight) versus 14 patients in the propofol 2% LCT group (48.2 ± 8.6 yr, 70.4 ± 11.6 kg body weight) could be completely evaluated. The duration of the surgical procedure was similar in both groups (7.27 ± 7.2 h versus 7.21 ± 7.1 h).

No statistically significant differences concerning age or body weight between both groups of patients were computed. The duration of sedation in the propofol MCT/LCT group was significantly longer compared with the propofol LCT group (Table 1). However, the difference with regard to the total amount of propofol administered in both groups did not reach statistical significance. Hemodynamic, respiratory, and metabolic variables remained stable in all 29 patients during the whole study period (Table 2). A statistically significant decrease in the mean arterial blood pressure and {gamma}-GT plasma concentration after propofol sedation was found in both groups, although this change did not reach pathologic relevance. In addition, in the propofol LCT group, a significant increase in ASAT plasma concentration 36 h after commencing the propofol application was observed. The intended depth of sedation at a Ramsay score of 3 was reached in 83.4% of all hourly recordings.


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  		Table 1. Mean Infusion Rate for Propofol, Total Amount of Propofol, and Mean Infusion Rate of Fentanyl During the First 48 Hours and/or the Whole Study Period (*P < 0.05)
 

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  		Table 2. Safety Variables Before Sedation and After 36 Hours of Propofol Application Given for Both Groups, Separately
 
The amounts of propofol required to provide the target level of sedation of a Ramsay score of 3 were almost identical in both groups (Table 1). In addition, the required administration rates of fentanyl were very similar. When the propofol plasma concentration obtained within the first 42 h of sedation (Hours 6, 18, 30, and 42) was compared, no significant difference between both groups was found (Fig. 1). Calculating the mean propofol plasma concentration over the whole sedative period, similar values were obtained (propofol 2% MCT/LCT, 0.95 ± 0.53 µg/mL, versus propofol 2% LCT, 0.98 ± 0.32 µg/mL). Even the elimination kinetics of both propofol preparations after terminating the infusion showed equivalent characteristics ( Fig. 2).



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  		Figure 1. Plasma concentration of propofol (mean ± SD) measured after 6, 18, 30, and 42 h of sedation with either propofol 2% MCT/LCT (n = 15) or propofol 2% LCT (n = 14). MCT = medium-chain triglyceride; LCT = long-chain triglyceride.

 


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  		Figure 2. Plasma concentration of propofol (mean ± SD) after termination of the infusion in patients sedated either by propofol 2% MCT/LCT (n = 8) or propofol 2% LCT (n = 9). MCT = medium-chain triglyceride; LCT = long-chain triglyceride.

 
Glycerin-glyceride concentrations during the propofol sedation were similar in both groups. A small increase could be observed, although the mean values did not exceed the normal range during the first 36 h of the propofol application ( Fig. 3). Considering both groups during the first 36 h, only 3 of 58 glycerin-glyceride values exceeded the upper limit of the normal range. Glycerin-glyceride values after termination of propofol infusion (elimination kinetics) showed significantly different values at 240 min after cessation of the drug application. In contrast to propofol MCT/LCT, which showed a slight decrease, the levels generated by propofol LCT remained nearly constant during the following 240 min, thus resulting in a significant difference between both groups at this time point.



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  		Figure 3. Glycerin-glyceride plasma concentration (y axis) in patients sedated with propofol 2% LCT (n = 14; left graph) or propofol 2% MCT/LCT (n = 15; right graph). MCT = medium-chain triglyceride; LCT = long-chain triglyceride; control = value before commencement of propofol application; 12/36 h sedation = during propofol sedation; -5 min: values obtained 5 min before discontinuation of propofol sedation; 20/40/60/120/240 min = time points after discontinuation. Values are shown in boxplots (median, Q1/Q3 quartiles, minimum/maximum). Repeated-measures analysis of variance showed a statistically significant difference at 240 min (*P < 0.05).

 
Figure 4 illustrates the recovery characteristics observed with both propofol formulations. Similar values were obtained except for a significant difference in the time span between the cessation of the propofol infusion and the first moment of orientation with respect to place, which was significantly longer in the propofol 2% LCT group.



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  		Figure 4. Recovery times (mean ± SD) after termination of the propofol sedation by measuring the time points of the first spontaneous movements and, after extubation, while investigating the ability to call the name, the date of birth, and the current place of residence; *P < 0.05. MCT = medium-chain triglyceride; LCT = long-chain triglyceride.

 

   Discussion
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 Abstract
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 Methods
 Results
 Discussion
References
 
Most of the properties of propofol meet the demands of an ideal sedative drug for the ICU, such as rapid onset of action, being effective at providing adequate sedation, a lack of drug accumulation, ease of titration, and allowing rapid recovery (3–7). However, some adverse effects of the currently used propofol formulation call for restricted use, especially in prolonged sedation. Besides arterial hypotension, although with no major effects on whole-body oxygen transport (17), bradycardia (18), or bloodstream infection (19), the possibility of developing hypertriglyceridemia has been repeatedly stressed (6,20–23). The low water solubility of propofol necessitates its formulation in an oil-in-water emulsion. This emulsion presently contains soybean oil as the main component, consisting of LCT, which are generally considered responsible for the increase in the blood triglyceride concentration.

The use of propofol 2% instead of propofol 1% has reduced, although not eliminated, the occurrence of this adverse event substantially (23,24). As mentioned previously, the use of MCT/LCT instead of LCT fat emulsion as the solvent for propofol could further decrease the incidence of developing hypertriglyceridemia. Recently, a new propofol preparation was introduced containing this solvent (Propofol-Lipuro® 2%).

The use of a changed emulsion formulation, however, entails a new pharmacological study, because preparations using different formulations may result in varying pharmacodynamic and kinetic characteristics (12,13). This randomized, controlled, double-blinded, prospective study demonstrates that the pharmacological properties of propofol 2% diluted in an MCT/LCT solvent compared with propofol 2% LCT are indistinguishable. As shown in Table 1, the infusion rate of propofol during the whole sedation period was nearly identical in both groups. Accordingly, the total amount of propofol applied during the first 48 hours to generate a level of sedation corresponding to a Ramsay score of 3 and the plasma propofol concentration were almost equivalent. Moreover, both the elimination kinetics and the recovery times after cessation of drug delivery did not show any significant difference. The almost-identical supplementary fentanyl dosages given the patients to ensure analgesia in the two groups support the therapeutic equivalence of both propofol formulations in terms of sedative effects. The presented data are comparable to previously published data investigating the maintenance dosages of propofol in surgical patients while attaining a comparable depth of sedation (5,25,26).

There was one difference between the groups, in the propofol 2% MCT/LCT group the duration of sedation was significantly longer. This dissimilarity can be related to different surgical procedures. Despite proper randomization, in the propofol 2% MCT/LCT group, 10 patients were operated on in the Department of Otorhinolaryngology and 5 in the Department of Orthodontology, whereas in the propofol 2% LCT group, the corresponding allocation was 5 and 9. Surgical procedures in the otorhinolaryngological tract are often localized in areas that are predisposed to result in a more intense swelling postsurgery compared with orthodontological operations. Because sedation was stopped only after airway swelling could be definitely excluded, the longer sedation time could be attributed to this phenomenon.

In several studies the application of propofol has been associated with an increasing concentration of serum triglycerides (7,22,23,26), sometimes reaching hypertriglyceridemic levels (6,24). This phenomenon can be ascribed to its formulation, containing 10 mg/mL of oil-in-water emulsion, although the dosage of lipids infused together with the drug (0.27 g · kg-1 · d · -1) is far less than the maximum recommended dose of lipids in parenteral nutrition (2.4 g · kg-1 · d · -1) (27). As an alternative suggestion, McLeod et al. (22) hypothesized that changes in plasma lipids might be attributable to an interaction of propofol metabolism and proteins of the acute phase response of inflammatory processes. Thus, a positive correlation between triglyceride and C-reactive protein levels and an inverse correlation between cholesterol and C-reactive protein concentration was detected under propofol sedation. This contention might be of pathologic relevance for many critically ill patients. In five patients in our study presenting with hypertriglyceridemia, we found considerably increased C-reactive protein concentrations in the plasma, in contrast to patients showing normal triglyceride values, which could support the suggestion of McLeod et al. (22).

Regarding the plasma triglyceride concentrations observed in this study, two different phases must be distinguished. During sedation, both triglyceride levels were nearly identical. Subsequently, after discontinuation of propofol, a tendency of a more rapid decrease in triglyceride levels was found in the MCT/LCT group compared with the LCT group (Fig. 3), even though a significant difference was detected in the last value only. The similar triglyceride concentrations in both groups during propofol application were initially surprising. It should be taken into account, however, that the mean molecular weight of triglycerides in the MCT/LCT fat emulsion (containing 45% fatty acids of chain length C8 to C10 and 54% of chain length C16 and C18) amounts to 695, whereas triglycerides in the LCT emulsion (99% of C16 and C18) have a mean molecular weight of 850. Hence, to achieve equal amounts of fat in both formulations, more triglycerides have to be added to the MCT/LCT emulsion than to the LCT emulsion. This may influence the molar plasma triglyceride concentration as measured by the method used in this study. A gravimetric analysis, although exhibiting technical limitations, measuring the weight per volume concentration of the plasma triglycerides, would probably have resulted in lower triglyceride values both during and after propofol administration and thus to a smaller lipid load of the propofol 2% MCT/LCT group compared with the propofol 2% LCT group.

In view of the fact that the total amount of propofol, and thus the amount of fat, in the propofol-MCT/LCT group (13,868.9 ± 10,233 mg) was distinctly larger than in the propofol-LCT group (8,880.1 ± 4,479.6 mg) because of the longer sedation time (Table 1), larger plasma triglyceride concentrations could be expected in the former group. Comparing the values five minutes before the termination of the drug application particularly, it could be assumed that a more than 50% larger amount of fat applied in the MCT/LCT group might indicate higher triglyceride values or at least delayed metabolism. The similar triglyceride concentrations at the end of the infusion in both groups, as well as the trend toward a more rapid decrease after discontinuation of propofol, could be associated with the well known characteristics of MCT/LCT, which are more readily hydrolyzed and more quickly eliminated from the circulation than are LCT. Nonetheless, only in 4 of 29 patients (2 patients in each group) in this study did the plasma triglyceride concentrations attain values of >2 mmol/L. These values were not associated with potential pathologic relevance. It should be taken into account, however, that preexisting metabolic derangement led to exclusion from the study. To further elucidate a clinical relevance and a possible advantage of propofol 2% MCT/LCT in contrast to propofol 2% LCT, additional studies are needed while using propofol 2% MCT/LCT in patients exhibiting an impaired oxidative metabolism (sepsis, trauma) or disturbed fat metabolism (diabetes, hyperlipoproteinemia, liver disease).


   Acknowledgments
 
Supported by a grant from B. Braun AG, Melsungen, Germany.

The authors thank all medical and nursing staff of the Department of Anesthesiology and Intensive Care for their excellent support in conducting this study.


   References
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 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 30, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press