Skip Navigation LinksHome > August 2001 - Volume 95 - Issue 2 > Propofol Dosing Regimens for ICU Sedation Based upon an Inte...
Anesthesiology:
Clinical Investigations

Propofol Dosing Regimens for ICU Sedation Based upon an Integrated Pharmacokinetic– Pharmacodynamic Model

Barr, Juliana M.D.*; Egan, Talmage D. M.D.†; Sandoval, Nancy F. M.D.‡; Zomorodi, Katayoun Ph.D.§; Cohane, Carol R.N.§; Gambus, Pedro L. M.D.‖‖; Shafer, Steven L. M.D.#

Free Access
Supplemental Author Material
Article Outline
Collapse Box

Author Information

Collapse Box

Abstract

Background: The pharmacology of propofol infusions administered for long-term sedation of intensive care unit (ICU) patients has not been fully characterized. The aim of the study was to develop propofol dosing guidelines for ICU sedation based on an integrated pharmacokinetic–pharmacodynamic model of propofol infusions in ICU patients.
Methods: With Institutional Review Board approval, 30 adult male medical and surgical ICU patients were given target-controlled infusions of propofol for sedation, adjusted to maintain a Ramsay sedation scale score of 2–5. Propofol administration in the first 20 subjects was based on a previously derived pharmacokinetic model for propofol. The last 10 subjects were given propofol based on a pharmacokinetic model derived from the first 20 subjects. Plasma propofol concentrations were measured, together with sedation score. Population pharmacokinetic and pharmacodynamic parameters were estimated by means of nonlinear regression analysis in the first 20 subjects, then prospectively tested in the last 10 subjects. An integrated pharmacokinetic–pharmacodynamic model was used to construct dosing regimens for light and deep sedation with propofol in ICU patients.
Results: The pharmacokinetics of propofol were described by a three-compartment model with lean body mass and fat body mass as covariates. The pharmacodynamics of propofol were described by a sigmoid model, relating the probability of sedation to plasma propofol concentration. The pharmacodynamic model for propofol predicted light and deep levels of sedation with 73% accuracy. Plasma propofol concentrations corresponding to the probability modes for sedation scores of 2, 3, 4, and 5 were 0.25, 0.6, 1.0, and 2.0 μg/ml. Predicted emergence times in a typical subject after 24 h, 72 h, 7 days, and 14 days of light sedation (sedation score = 3 → 2) with propofol were 13, 34, 198, and 203 min, respectively. Corresponding emergence times from deep sedation (sedation score = 5 → 2) with propofol were 25, 59, 71, and 74 h.
Conclusions: Emergence time from sedation with propofol in ICU patients varies with the depth of sedation, the duration of sedation, and the patient’s body habitus. Maintaining a light level of sedation ensures a rapid emergence from sedation with long-term propofol administration.
Back to Top | Article Outline

ArticlePlus

Click on the links below to access all the ArticlePlus for this article.
Please note that ArticlePlus files may launch a viewer application outside of your web browser.
* http://links.lww.com/ALN/A100
PROPOFOL is an intravenous sedative–hypnotic agent that is commonly administered for sedation of patients in the intensive care unit (ICU) who are being treated with tracheal intubation and mechanical ventilation. The pharmacokinetics of propofol in critically ill patients being given continuous intravenous infusions for sedation 1–4 differ significantly from the pharmacokinetics of propofol in healthy surgical patients being given intravenous boluses or short-term infusions of propofol for anesthesia. 5–7 Studies assessing the dose–response relationship of propofol in ICU patients have also shown significant variations in the mean time to emergence and extubation following discontinuation of propofol infusions. 8–12 To date, the exact relationship between the pharmacokinetics, depth of sedation, and propofol dosing in ICU patients has not been fully characterized. The purposes of this study were (1) to develop an integrated pharmacokinetic–pharmacodynamic model of propofol infusions in ICU patients; (2) to test this model prospectively in a second group of ICU patients; and (3) to develop rational dosing guidelines for propofol sedation in ICU patients based on the integrated pharmacokinetic–pharmacodynamic model for propofol.
Back to Top | Article Outline

Materials and Methods

Study Design
After institutional review board approval (Stanford University School of Medicine, Stanford, CA), written informed consent was obtained from 30 adult male medical or surgical ICU patients (age range, 21–80 yr) requiring endotracheal intubation and mechanical ventilation with sedation for more than 24 h. Individuals were excluded from the study if they had severe hepatic or renal insufficiency, significant hemodynamic instability, primary hyperlipidemia, pancreatitis, neurologic impairment, or a known allergy to eggs or propofol at the time of enrollment. Eligible individuals received no propofol within 30 days of enrollment into the study.
All subjects were given 10 mg/ml undiluted open-label intravenous propofol (Diprivan; AstraZeneca International, Wilmington, DE) for sedation. Propofol was administered to all subjects by means of a target-controlled infusion (TCI) to achieve predefined propofol plasma concentrations. Appropriate precautions were taken to prevent microbial contamination of the propofol infusion. The TCI system consisted of an 80306-20 laptop computer (Everex, Inc., Fremont, CA) with an MS-DOS operating system (Microsoft, Inc., Redmond, WA) running STANPUMP software. ** This computer was connected to an infusion pump (Harvard Pump 22; Harvard Apparatus, Inc., South Natick, MA) through a serial interface. The STANPUMP software controlled the infusion pump rate to target a specific plasma propofol concentration using a previously derived pharmacokinetic model for propofol. The first 20 subjects (i.e., learning group) were given propofol through the TCI system using a pharmacokinetic model for propofol derived from healthy surgical patients being given short-term propofol infusions for anesthesia (J. B. Dyck, M.D., Department of Anesthesia, Stanford University, Stanford, CA, written communication, February 1991). The last 10 subjects (i.e., test group) were given propofol through the TCI system using a pharmacokinetic model for propofol derived from the learning group. Subjects were given intravenous or epidural infusions of fentanyl (up to 200 μg/h) as needed for analgesia.
Table 1
Table 1
Image Tools
Fig. 1
Fig. 1
Image Tools
Subjects were allowed to emerge from the residual effects of general anesthesia (surgical patients) or previously administered sedative agents (medical patients) before the administration of propofol. An intravenous infusion of propofol was initiated at a target plasma propofol concentration of 0.5 μg/ml. This target concentration was increased every 5 min by 0.25–0.5 μg/ml until a sedation score (SS) of 5 or 6 was achieved as defined by the modified Ramsay Sedation Scale (table 1). 13 This level of sedation was maintained as long as subjects remained endotracheally intubated and mechanically ventilated except for daily neurologic assessments, when the target concentration was decreased by 0.25–0.5 μg/ml every 10 min until an SS of 2 was achieved. After the neurologic assessment, the target concentration was increased until the subject’s SS was again 5 or 6 (fig. 1). If a subject became agitated during the study, the propofol target concentration was incrementally increased to maintain an SS of 5 or 6. If a subject became hypotensive during the study, the propofol infusion was temporarily suspended until the subject was hemodynamically stable. Once subjects were ready to be weaned from mechanical ventilation, the propofol target concentration was decreased by 0.25–0.5 μg/ml every 10 min until an SS of 2 was achieved. This level of sedation was maintained until subjects were ready for tracheal extubation, at which point the propofol infusion was discontinued. Subjects were withdrawn from the study if they developed significant hemodynamic instability or hypertriglyceridemia (serum triglyceride concentration > 500 mg/dl) or if they required neuromuscular blockade or a surgical procedure requiring general anesthesia.
Plasma propofol assays were performed on 3-ml arterial blood samples obtained from subjects at the following times: at baseline; immediately before any changes made in the propofol target concentration; every 4 h during maintenance propofol infusion periods; and every 4 h for up to 5 days after discontinuation of the propofol infusion. Venous samples were obtained in lieu of arterial samples during the postinfusion period if a subject no longer had an indwelling arterial catheter. Blood samples were collected in 7-ml heparinized glass tubes and immediately placed on ice. Samples were centrifuged at 2,000 rpm for 15 min, and the plasma fraction was transferred to a 3-ml polypropylene tube and frozen at 4°C until assayed. Propofol assays were performed by ICI Pharmaceuticals Group (currently AstraZeneca International) using a modification of the whole-blood method of Plummer 14 (ICI Pharmaceuticals Group method 8P-03 and 8P-05). Plasma propofol concentrations were determined using liquid–liquid extraction followed by reverse-phase high-pressure liquid chromatography with fluorescence detection. Two different assay sensitivity ranges were used. The high-sensitivity range covered the standard from 2 to 200 ng/ml, and the low-sensitivity range covered the standard from 0.05 to 10 μg/ml. The limit of quantitation was 2 ng/ml. The use of target-controlled infusions, together with high-resolution sampling of plasma propofol concentrations and SS measurements, resulted in a highly accurate data set from which to derive pharmacologic models. 15
Back to Top | Article Outline
Statistical Analyses
All statistical analyses were performed by members of the Department of Anesthesia, Stanford University School of Medicine (Stanford, CA). The demographics of the learning group (n = 20) and the test group (n = 10) were compared using the two-tailed t test with the summary results expressed as mean (SD). The propofol infusion data for the learning group were compared to those of the test group using the Wilcoxon rank test with the summary results expressed as median (range). The value P < 0.05 was considered to be statistically significant in both cases.
Multiple nonlinear logistic regression analyses, using both naïve pooled data and mixed-effects modeling approaches, were performed to characterize the pharmacokinetic and pharmacodynamic models for propofol in the learning group. Then, these models were prospectively tested in the test group. Model performance was assessed both numerically and graphically in both groups. A detailed summary of the pharmacokinetic and pharmacodynamic analyses can be found in Appendix 1 (Web Enhancement). The newly derived pharmacokinetic and pharmacodynamic models for propofol were integrated to construct dosing regimens for light and deep sedation with propofol in ICU patients.
Back to Top | Article Outline

Results

Table 2
Table 2
Image Tools
Table 3
Table 3
Image Tools
The demographic profiles of subjects in the learning group (n = 20) and the test group (n = 10) are summarized in table 2. There were no significant differences between the two groups in age, body habitus, or severity of illness. The propofol administration profiles for each group are summarized in table 3. There were no significant differences between the two groups in median duration of infusion, total propofol dose, or steady-state infusion rates. There was significant variation within both groups in infusion duration and total propofol dose.
Table 4
Table 4
Image Tools
Reasons for discontinuing the propofol infusions are summarized for all subjects in table 4. Nineteen subjects (63%) had their propofol infusions discontinued in preparation for extubation. In 18 of these subjects, extubation was successful, including 15 subjects who had extubation within 45 min of stopping the propofol infusion. Extubation was significantly delayed (> 24 h) in two subjects after discontinuation of the propofol infusion. One subject with a cervical myelopathy developed acute respiratory failure during weaning, and another subject had prolonged respiratory depression attributable to epidural morphine (respiratory depression attributable to propofol in the latter subject was ruled out on the basis of subclinical plasma propofol concentrations). Five subjects (17%) had persistent hemodynamic instability requiring discontinuation of the propofol infusion. One subject developed significant hypertriglyceridemia (peak serum triglyceride concentration = 1,148 mg/dl) while receiving propofol in conjunction with parenteral lipids for nutrition. His serum triglyceride concentrations returned to normal within 48 h of discontinuing both the propofol and lipid infusions.
Three subjects were noted to have mild disorientation to place and time lasting 3–5 days after discontinuing their propofol infusions. All of these subjects had been given propofol for greater than 7 days and had been given large cumulative doses of propofol ranging from 308 to 1,421 mg/kg. A fourth subject became agitated and paranoid within 24 h of discontinuing his propofol infusion. This subject had a history of extensive ethanol use preoperatively and was given propofol for less than 48 h after major vascular surgery. He was treated with benzodiazepines and haloperidol for presumed ethanol withdrawal, and his mental status changes subsequently resolved.
Back to Top | Article Outline
Pharmacokinetics and Pharmacodynamics
Table 5
Table 5
Image Tools
The revised pharmacokinetic model for propofol was derived from 1,006 observations (93%) obtained from 19 of the 20 subjects in the learning group. One subject in the learning group was excluded from the pharmacokinetic analysis altogether, because of insufficient data. The data were best described both numerically and graphically by a three-compartment mammillary model using a naïve pooled data approach with lean body mass and fat body mass as covariates (table 5). This revised model differs significantly from the original model both numerically and in terms of its superior ability to predict plasma propofol concentrations. A detailed comparison of the original and revised pharmacokinetic models for propofol is summarized in Appendix 2 (Web Enhancement).
Table 6
Table 6
Image Tools
Fig. 2
Fig. 2
Image Tools
Fig. 3
Fig. 3
Image Tools
The revised pharmacokinetic model for propofol was prospectively applied to the test group (n = 10). The performance of the revised model was similar in both the learning group and the test group (table 6). The performance variability of the revised model in the test group is reflected in the differences between the residual error plots for all subjects in the learning and test groups (figs. 2A and B). Figures 3A and B demonstrate comparable individual performances of the revised model in both groups.
Table 7
Table 7
Image Tools
The pharmacodynamic model for propofol sedation was derived from 643 observations (100%) obtained from all 20 subjects in the learning group. The number of pharmacodynamic observations is less than the number of pharmacokinetic observations because SS measurements were suspended during the postinfusion period once the SS was 1 or 2, whereas plasma propofol concentrations were measured for up to 5 days after infusion. The results of the pharmacodynamic analyses are summarized in table 7. A mixed-effects model, relating the probability of sedation to plasma propofol concentration, best described the pharmacodynamic data as follows: where P(Sedation ≥ SS) is the probability that the sedation score is ≥ N (where N = 2, 3, . . .6), C is the plasma propofol concentration, C50,SS is the plasma propofol concentration at which P(Sedation ≥ SS) = 50%, and γ is the slope of the probability curve.
Fig. 4
Fig. 4
Image Tools
Although the percentage of correct (observed SS = predicted SS) and close (observed SS = predicted SS ± 1) predictions of sedation in both the learning and test groups are similar for the naïve pooled data and mixed-effects modeling approaches, the mixed-effects analysis yields a more accurate pharmacodynamic model in terms of minimizing the objective function. Figure 4 demonstrates that the mixed-effects approach also provides a better graphic description of the probability of sedation. On this basis, the mixed-effects model was chosen as the final pharmacodynamic model.
Equation 1
Equation 1
Image Tools
Equation U2
Equation U2
Image Tools
Equation 1 describes the probability of being at or deeper than a given level of sedation. For clinical purposes, it is more useful to know the probability of being at a specific or discrete level of sedation for a given propofol concentration. Therefore, the probability of being at a discrete sedation score is defined in as follows:MATH
Fig. 5
Fig. 5
Image Tools
Table 8
Table 8
Image Tools
The probability curves for discrete levels of sedation are depicted in figure 5. With the exception of the curves for SS = 1 and SS = 6, the remaining probability curves are asymmetrically distributed. The maximal probability of SS = 1 (i.e., no sedative effect) approaches 1 as the plasma propofol concentration approaches zero. The maximal probability of SS = 6 (deeply sedated, unresponsive to any stimuli) approaches 1 as the plasma propofol concentration approaches infinity. Because of their asymmetric distribution, the plasma propofol concentrations corresponding to the peak probabilities (i.e., probability modes) for SS = 2, 3, 4, and 5 differ from the C50,SS for each probability curve (table 8). The pharmacodynamic model derived for propofol using the mixed-effects modeling approach predicts light (SS = 3 ± 1) and deep (SS = 5 ± 1) levels of sedation in the test group with 73% accuracy (table 7).
Back to Top | Article Outline
Dosing Regimens for Propofol Sedation
Table 9
Table 9
Image Tools
Fig. 6
Fig. 6
Image Tools
By integrating the results of the pharmacokinetic and pharmacodynamic analyses, we were able to develop dosing regimens for propofol in ICU patients targeting specific levels of sedation over time. Table 9 summarizes the propofol infusion regimens necessary to maintain either light (SS = 3) or deep (SS = 5) levels of seda-tion in a typical ICU patient (i.e., 61-yr-old man; weight, 81 kg; height, 176 cm) for up to 14 days. The plasma propofol concentrations corresponding to the probability modes for SS = 3 and SS = 5 probability curves were used as target plasma propofol concentrations for light and deep sedation, respectively. The emergence times from light sedation (i.e., the time it takes for the SS to decrease from 3 to 2) remained fairly rapid (i.e., < 35 min) for propofol infusions lasting 3 days or less. For infusions of longer duration, the emergence time from light sedation continued to increase, but a plateau was reached at approximately 3.5 h for 14-day infusions. By contrast, the emergence times from deep sedation with propofol (i.e., the time required for SS to decrease from 5 to 2) rapidly increased with longer propofol infusions. After a 24-h infusion, the time to emergence from deep sedation with propofol was 25 h. The emergence time from continuous deep sedation with propofol for 7–14 days was approximately 3 days. The differences in emergence times from light versus deep sedation as a function of infusion duration is depicted graphically in figure 6. A 58% decrease in the plasma propofol concentration (from 0.6 to 0.25 μg/ml) was required for emergence from light sedation (SS = 3 → 2) with a steady-state emergence time of approximately 3.5 h. An 88% decrease in the plasma propofol concentration (from 2 to 0.25 μg/ml) was required for emergence from deep sedation (SS = 5 → 2) with a steady-state emergence time of approximately 75 h.
Back to Top | Article Outline

Discussion

Table 10
Table 10
Image Tools
Table 11
Table 11
Image Tools
Propofol is routinely administered as a continuous intravenous infusion for sedation of patients in the ICU. The unique lipophilic properties of propofol enable it to cross the blood–brain barrier quickly, resulting in a rapid onset of sedation. The high metabolic clearance rate of propofol and its rapid redistribution into peripheral tissues account for the rapid emergence from sedation with short-term infusions with propofol, even though the elimination half-life of propofol is quite long (table 10). 1–4 The reported observed emergence times from propofol sedation in ICU patients is highly variable (table 11). 8–12 Previous studies of propofol sedation in ICU patients have focused on either the pharmacokinetics or dose–response relationships of propofol infusions. The principal purpose of this study was to develop a prospectively tested, integrated pharmacokinetic–pharmacodynamic model of propofol infusions in ICU patients. This integrated model was then used to simulate propofol infusion regimens in a typical ICU patient with predicted patterns of sedation and emergence times. The results of this study demonstrate that the emergence time from propofol sedation varies considerably and is a function of the depth of sedation, the duration of the infusion, and patient size.
Back to Top | Article Outline
Observed Side Effects of Propofol Infusions
Five subjects (17%) enrolled in this study developed significant hypotension requiring discontinuation of their propofol infusions. Although hypotension attributable to systemic vasodilation is a known side effect of propofol, 16 the incidence of significant hypotension in this study was higher than reported in previous propofol studies. 12,17 This is probably the result of using target-controlled infusions in the present study, which typically deliver an initial bolus dose of propofol with each increase in the target plasma propofol concentration. Bolus dosing of propofol significantly increases the risk of hypotension in critically ill patients and is not recommended for the routine management of ICU patients being given propofol for sedation.
One subject developed significant hypertriglyceridemia while being given propofol. Mild hypertriglyceridemia occurs commonly with propofol infusions, because of its lipid carrier, and is of little clinical consequence. Severe hypertriglyceridemia (i.e., serum triglyceride concentrations > 1,000 mg/dl) in ICU patients receiving propofol infusions occurs rarely and is typically associated with high propofol infusion rates, concurrent administration of parenteral lipids for nutrition, or baseline hypertriglyceridemia. 18,19 The one subject in the present study who developed significant hypertriglyceridemia had normal baseline serum triglyceride concentrations. His hypertriglyceridemia quickly resolved once his parenteral lipid and propofol infusions were discontinued.
Three subjects had mild confusion lasting several days after discontinuation of their propofol infusions. Although each subject was cooperative and able to follow commands, the subjects were intermittently disoriented to place and time. These symptoms resolved completely after 3–5 days in all cases. This confusion was attributed to persistent effects of propofol because all three subjects had been given propofol for greater than 7 days and had detectable concentrations of propofol in their plasma for up to 5 days after infusion. A fourth subject became acutely agitated after discontinuation of his propofol infusion. Acute withdrawal syndrome has been reported in ICU patients after prolonged sedation with propofol. 20,21 In this case, the subject’s agitation was attributed to acute ethanol withdrawal rather than withdrawal from propofol because the subject had a history of ethanol abuse and had been given propofol for only 48 h. There was no evidence of withdrawal from propofol in any of the subjects who were given prolonged infusions of propofol in the current study.
Back to Top | Article Outline
Pharmacokinetics and Pharmacodynamics
The pharmacokinetics of intravenous propofol infusions in the current study were best described by a three-compartment model with lean body mass and fat body mass as covariates. The addition of lean and fat body masses as model covariates significantly improved the accuracy of the model, which was preserved when prospectively tested in a similar group of ICU patients being given propofol infusions for sedation. This list of covariates is by no means complete, and a larger study including ICU patients with a wider degree of illness would potentially yield additional pharmacokinetic model covariates. The pharmacokinetic model derived in this study differs significantly from the simple three-compartment models for propofol infusions previously described for ICU patients (table 10). 1–4 Although the metabolic clearance rate of propofol estimated in the present study is comparable to clearance rate estimates for propofol in previous ICU studies, the estimated volume of distribution (Vdss) is three to nine times larger than previous estimates of Vdss in ICU patients. This larger Vdss results from the longer duration of propofol administration, together with a longer plasma propofol sampling period (5 days vs. ≤ 72 h) compared with previous studies of propofol infusions in ICU patients. The variability of the Vdss estimated in the current study is explained by the lipophilic properties of propofol and the significant influence of fat body mass on its Vdss. The clinical significance of this large Vdss is that with long-term propofol administration, significant drug accumulation and saturation of peripheral tissues occur, especially in obese patients. With increasing peripheral tissue saturation, the rate at which plasma propofol concentrations decrease after discontinuation of the propofol infusion becomes less dependent on redistribution and more dependent on metabolic clearance. This results in a much slower rate of decrease in plasma propofol concentration over time, which potentially increases the emergence time from sedation in obese patients.
The pharmacodynamic model derived in the current study relating the probability of sedation to plasma propofol concentration was based on a sigmoid model and was best described using a mixed-effects modeling approach. The accuracy of this pharmacodynamic model, like the pharmacokinetic model, was preserved when prospectively tested in a similar group of ICU patients. The derived pharmacodynamic model does not include the potential effects of epidural or intravenous fentanyl on propofol sedation because the effect of fentanyl cannot be incorporated into this model without an accurate fentanyl infusion history or known fentanyl plasma or cerebrospinal fluid fentanyl concentrations. Eleven subjects in the learning group and nine subjects in the test group were given either intravenous or epidural fentanyl infusions together with propofol. There were no differences in the observed relationship between depth of sedation and plasma propofol concentrations in these subjects when compared with subjects who were given propofol alone, suggesting that the effect of fentanyl on sedation was minimal in these patients. In a more diverse group of ICU patients (e.g., those with hepatic failure, renal failure, higher Apache II scores) or in patients being given higher doses of opioids for analgesia, the synergistic sedative effect of opioids on propofol sedation might become significant. Although tolerance to propofol has been previously reported, 22 there was no evidence of tolerance in subjects being given prolonged infusions of propofol in the current study.
Back to Top | Article Outline
Developing Dosing Regimens for Propofol Sedation
Integrating the derived pharmacokinetic and pharmacodynamic models for propofol infusions in ICU patients enables us to simulate various propofol infusion regimens, the corresponding patterns of sedation, and the predicted times to emergence from sedation in these patients. As shown in table 9, propofol infusion rates and the resulting times to emergence from propofol sedation differ considerably for light and deep levels of sedation. In addition, the observed differences between emergence times for light and deep sedation increase significantly as the duration of propofol sedation increases. Propofol retains its short-acting properties in patients who are lightly sedated. The estimated emergence time in a typical patient ranges from 13 min to 3.5 h for infusions lasting longer than 24 h. Patients who are deeply sedated are given larger total doses of propofol, resulting in significant drug accumulation and slower decreases in plasma propofol concentrations after discontinuation of the infusion. Combined with the greater required decrease in plasma propofol concentration to achieve emergence from sedation (figure 6), emergence times from deep sedation with propofol are much longer, ranging from 24 to 72 h for propofol infusions lasting more than 24 h in a typical patient. In morbidly obese patients, the predicted emergence times from both light and deep sedation with propofol would be expected to be even longer, because of the larger Vdss for propofol in these patients. Regardless of a patient’s body habitus, to maintain a constant level of sedation, propofol infusion rates must be decreased over time to account for this cumulative drug effect.
None of the subjects in the current study had significant delays in emergence from sedation with propofol. This is attributable to the fact that all subjects had their propofol infusions frequently titrated to a specific level of sedation and were allowed to emerge to a light level of sedation before being weaned from mechanical ventilation. The variability in observed emergence times from propofol sedation reported in previous studies of ICU patients can be explained by the differences in the duration of infusion and the depth of sedation maintained (table 11). Subjects who were lightly sedated with propofol for 12 h–4 days had an observed sedation emergence time of 5–90 min, which is consistent with the emergence times predicted by the integrated model in the current study. 8,12 In contrast, subjects in the study of Barrientos-Vega et al.9 were more deeply sedated with propofol for an average of 6 days and had an average propofol emergence time of 35 h, which is also consistent with the results of the current study.
Propofol is a unique sedative–hypnotic agent with a rapid onset and offset of sedation with short-term administration. In critically ill patients being given continuous intravenous infusions of propofol for sedation, the offset of sedation varies considerably and is a function of the depth of sedation maintained, the duration of the infusion, and the patient’s size and body composition. Emergence times from sedation with propofol in ICU patients can be minimized by employing the following propofol sedation strategies: (1) Titrate propofol infusion rates to maintain a light level of sedation in ICU patients at all times (i.e., patient is asleep but responds to simple commands); (2) frequently reassess the patient’s depth of sedation and adjust the propofol infusion rate every 3–6 h for the first 24 h, then daily thereafter, to minimize propofol accumulation and decrease the risk of oversedation; (3) patients requiring deep sedation with propofol should have their propofol infusions suspended on a daily basis to allow them to emerge to a lighter level of sedation, and the propofol infusion should then be resumed at the minimal infusion rate required to maintain deep sedation; and (4) propofol dosing in morbidly obese patients should be based on their ideal body weight rather than their actual body weight and titrated to the desired level of sedation to prevent significant drug accumulation and oversedation.
The authors thank Eran Geller, M.D., M.S., Medical Director, Intensive Care Unit Service, VA Palo Alto Health Care System, Palo Alto, California, and Professor of Anesthesia, Stanford University, Stanford, California, and the Medical and Surgical Intensive Care Unit nursing staff at the VA Palo Alto Health Care System for their assistance and support during this study.
Back to Top | Article Outline

FOOTNOTES

** STANPUMP is available at the following Web site: http://pkpd.icon.palo-alto.med.va.gov. Cited Here...
Back to Top | Article Outline

References

1. Albanese J, Martin C, Lacarelle B, Saux P, Durand A, Gouin F: Pharmacokinetics of long-term propofol infusions used for sedation in ICU patients. A nesthesiology 1990; 73: 214–7

2. McMurray TJ, Collier PS, Carson IW, Lyons SM, Elliott P: Propofol sedation after open hear surgery: A clinical and pharmacokinetic study. Anaesthesia 1990; 45: 322–6

3. Bailie GR, Cockshott ID, Douglas EJ, Bowles BJ: Pharmacokinetics of propofol during and after long-term continuous infusion for maintenance of sedation in ICU patients. Br J Anaesth 1992; 68: 486–91

4. Frenkel C, Schuttler J, Ihmsen H, Heye H, Rommelsheim K: Pharmacokinetics and pharmacodynamics of propofol/alfentanil infusion for sedation in ICU patients. Intensive Care Med 1995; 21: 981–8

5. Shafer A, Doze VA, Shafer SL, White PF: Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. A nesthesiology 1988; 69: 348–56

6. Schuttler J, Stoeckel H, Schwilden H: Pharmacokinetic and pharmacodynamic modeling of propofol (‘Diprivan’) in volunteers and surgical patients. Postgrad Med J 1985; 61: 53–4

7. Gepts E, Camu F, Cockshott ID: Disposition of propofol administered as a constant-rate infusion in humans. Anesth Analg 1987; 66: 1256–63

8. Beller JP, Pottecher T, Lugnier A, Mangin P, Otteni JC: Prolonged sedation with propofol in ICU patients: Recovery and blood concentration changes during periodic interruptions in infusion. Br J Anaesth 1988; 61: 583–8

9. Barrientos-Vega R, Sanchez-Soria MM, Morales-Garcia C, Robas-Gomez A, Cuena-Boy R, Ayensa-Rincon A: Prolonged sedation of critically ill patients with midazolam or propofol: Impact on weaning and costs. Crit Care Med 1997; 25: 33–40

10. Chamorro C, deLatorre FJ, Montero A, Sanchez-Izquierdo JA, Jareno A, Moreno JA, Gonzalez E, Barrio M, Carpintero JL, Martin-Santos F, Otero B, Ginestal R: Comparative study of propofol versus midazolam in the sedation of critically ill patients: Results of a prospective, randomized, multicenter trial. Crit Care Med 1996; 24: 932–9

11. Weinbroum AA, Halpern P, Rudick V, Sorkine P, Freedman M, Geller E: Midazolam versus propofol for long-term sedation in the ICU: A randomized prospective comparison. Intensive Care Med 1997; 23: 1258–63

12. Ronan KP, Gallagher JT, George B, Hamby B: Comparison of propofol and midazolam for sedation in intensive care unit patients. Crit Care Med 1995; 23: 286–93

13. Ramsay MAE, Savege TM, Simpson BRJ, Goodwin R: Controlled sedation with alphaxalone-alphadolone. Br Med J 1974; 2: 656–9

14. Plummer GF: Improved method for the determination of propofol in blood by high performance liquid chromatography with fluorescein detection. J Chromatogr 1987; 421: 171–6

15. Gustafsson LL, Ebling WF, Osaki E, Harapat S, Stanski DR, Shafer SL: Plasma concentration clamping in the rat using a computer-controlled infusion pump. Pharm Res 1992; 9: 800–7

16. Robinson BJ, Ebert TJ, O’Brien TJ, Conlinco MD, Muzi M: Mechanisms whereby propofol mediates peripheral vasodilation in humans. A nesthesiology 1997; 86: 64–72

17. Higgins TL, Vared J, Estafanous FG, Coyle JP, Haumei KK, Goodale DB: Propofol versus midazolam for intensive care unit sedation after coronary artery bypass grafting. Crit Care Med 1994; 22: 1415–23

18. Lowrey TS, Dunlap AW, Brown RO, Dickerson RN: Pharmacologic influence on nutrition support therapy: Use of propofol in a patient receiving combined enteral and parenteral nutrition support. Nutr Clin Pract 1996; 11: 147–9

19. Eddleston JM, Shelly MP: The effect on serum lipid concentrations of a prolonged infusion of propofol–hypertriglyceridaemia associated with propofol administration. Intensive Care Med 1991; 17: 424–6

20. Valente JF, Anderson GL, Branson RD, Johnson DJ, Davis K, Porembka DT: Disadvantages of prolonged propofol sedation in the critical care unit. Crit Care Med 1994; 22: 710–2

21. Cammarano WB, Pittet J, Weitz S, Schlobohm RM, Marks JD: Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients. Crit Care Med 1998; 26: 676–84

22. Buckley PM: Propofol in patients needing long-term sedation in intensive care: An assessment of the development of tolerance. Intensive Care Med 1997; 23: 969–74

Cited By:

This article has been cited 38 time(s).

Indian Journal of Otolaryngology and Head & Neck Surgery
Recovery profile of patients undergoing nasal surgical procedures: a comparison between sevoflurane and propofol
Haq, AU; Aqil, M; Rasheed, A; Ahmed, RA
Indian Journal of Otolaryngology and Head & Neck Surgery, 60(2): 123-127.

Pediatrics
Continuous propofol infusion in 142 critically ill children
Cornfield, DN; Tegtmeyer, K; Nelson, MD; Milla, CE; Sweeney, M
Pediatrics, 110(6): 1177-1181.

Pharmaceutical Research
Population dose-response model for tadalafil in the treatment of male erectile dysfunction
Staab, A; Tillmann, C; Forgue, ST; Mackie, A; Allerheiligen, SRB; Rapado, J; Troconiz, IF
Pharmaceutical Research, 21(8): 1463-1470.

Clinics in Chest Medicine
Management of agitation in the intensive care unit
Siegel, MD
Clinics in Chest Medicine, 24(4): 713-+.
10.1016/S0272-5231(03)00104-7
CrossRef
International Journal on Artificial Intelligence Tools
Sedation of simulated ICU patients using reinforcement learning based control
Sinzinger, ED; Moore, B
International Journal on Artificial Intelligence Tools, 14(): 137-156.

Annales Francaises D Anesthesie Et De Reanimation
Target-controlled infusion with propofol for neuro-anesthesia
Debailleul, AM; Fichten, A; Krivosic-Horber, R
Annales Francaises D Anesthesie Et De Reanimation, 23(4): 375-382.
10.1016/j.annfar.2004.02.038
CrossRef
Swiss Medical Weekly
Analgesia and sedation in critically ill patients
Walder, B; Tramer, MR
Swiss Medical Weekly, 134(): 333-346.

Current Drug Targets
Sedation in PACU: The role of propofol
De Cosmo, G; Congedo, E; Clemente, A; Aceto, P
Current Drug Targets, 6(7): 741-744.

Journal of Clinical Neuroscience
Delayed awakening in dystonia patients undergoing deep brain stimulation surgery
Trombetta, C; Deogaonkar, A; Deogaonkar, M; Ebrahim, Z; Rezai, A; Machado, A; Farag, E
Journal of Clinical Neuroscience, 17(7): 865-868.
10.1016/j.jocn.2009.11.026
CrossRef
Journal of Pharmacokinetics and Pharmacodynamics
Assessing circadian rhythms in propofol PK and PD during prolonged infusion in ICU patients
Bienert, A; Kusza, K; Wawrzyniak, K; Grzeskowiak, E; Kokot, ZJ; Matysiak, J; Grabowski, T; Wolc, A; Wiczling, P; Regulski, M
Journal of Pharmacokinetics and Pharmacodynamics, 37(3): 289-304.
10.1007/s10928-010-9161-5
CrossRef
Anaesthesia
Propofol sedation using Diprifusor (TM) target-controlled infusion in adult intensive care unit patients
McMurray, TJ; Johnston, JR; Milligan, KR; Grant, IS; Mackenzie, SJ; Servin, F; Janvier, G; Glen, JB
Anaesthesia, 59(7): 636-641.

Anesthesia and Analgesia
A retrospective analysis of a remifentanil/propofol general anesthetic for craniotomy before awake functional brain mapping
Keifer, JC; Dentchev, D; Little, K; Warner, DS; Friedman, AH; Borel, CO
Anesthesia and Analgesia, 101(2): 502-508.
10.1213/01.ANE.0000160533.51420.44
CrossRef
Expert Opinion on Pharmacotherapy
Economic evaluation of sustained sedation/analgesia in the intensive care unit
MacLaren, R; Sullivan, PW
Expert Opinion on Pharmacotherapy, 7(): 2047-2068.
10.1517/14656566.7.15.2047
CrossRef
Clinical Pharmacology & Therapeutics
Disease severity is a major determinant for the pharmacodynamics of propofol in critically ill patients
Peeters, MMM; Bras, LJ; DeJongh, J; Wesselink, RMJ; Aarts, LPHJ; Danhof, M; Knibbe, CAJ
Clinical Pharmacology & Therapeutics, 83(3): 443-451.
10.1038/sj.clpt.6100309
CrossRef
Critical Care
Medications for analgesia and sedation in the intensive care unit: an overview
Gommers, D; Bakker, J
Critical Care, 12(): -.
ARTN S4
CrossRef
Annales Francaises D Anesthesie Et De Reanimation
Agents for sedation and analgesia in the intensive care unit
Sztark, F; Lagneau, F
Annales Francaises D Anesthesie Et De Reanimation, 27(): 560-566.
10.1016/j.annfar.2008.04.008
CrossRef
Drugs
Postoperative analgesia and sedation in the adult intensive care unit
Liu, LL; Gropper, MA
Drugs, 63(8): 755-767.

Anesthesia and Analgesia
Tolerance to propofol's sedative effect in mechanically ventilated rabbits
Ypsilantis, P; Mikroulis, D; Politou, M; Tsoukali, H; Pitiakoudis, M; Didilis, V; Theodoridis, G; Bougioukas, G; Simopoulos, C
Anesthesia and Analgesia, 103(2): 359-365.
10.1213/01.ane.0000223684.76783.bf
CrossRef
Neurocritical Care
Vasopressors and Propofol Infusion Syndrome in Severe Head Trauma
Smith, H; Sinson, G; Varelas, P
Neurocritical Care, 10(2): 166-172.
10.1007/s12028-008-9163-y
CrossRef
Anaesthesia and Intensive Care
A comparison of parametric and non-parametric approaches to target-controlled infusion of propofol
Crankshaw, DP; Brown, MJ; Bjorksten, AR
Anaesthesia and Intensive Care, 38(3): 437-444.

Minerva Anestesiologica
SIAARTI recommendations for analgo-sedation in intensive care unit
Mattia, C; Savoia, G; Paoletti, F; Piazza, O; Albanese, D; Amantea, B; Ambrosio, F; Belfiore, B; Berti, N; Bertini, L; Bruno, E; Carassiti, M; Celleno, D; Coluzzt, F; Consales, G; Costantini, A; Cuppini, F; De Gaudio, RA; Farnia, A; Niariconda, G; Martorano, PP; Medtati, R; Mercieri, M; Mondello, E; Oggioni, R; Iiaoliccht, A; Pelagalli, L; Perrotta, D; Petrini, F; Piacevoli, Q; Pirozzi, N; Santangelo, E; Stliottt, R; Stoppa, F; Tulli, G; Tufano, R
Minerva Anestesiologica, 72(): 769-805.

Clinics in Chest Medicine
Sedation and Analgesia for the Mechanically Ventilated Patient
Brush, DR; Kress, JP
Clinics in Chest Medicine, 30(1): 131-+.
10.1016/j.ccm.2008.09.001
CrossRef
Pharmacotherapy
Pharmacoeconomic modeling of lorazepam, midazolam, and propofol for continuous sedation in critically ill patients
MacLaren, R; Sullivan, PW
Pharmacotherapy, 25(): 1319-1328.

Anesthesia and Analgesia
Measuring depth of sedation with auditory evoked potentials during controlled infusion of propofol and remifentanil in healthy volunteers
Haenggi, M; Ypparila, H; Takala, J; Korhonen, I; Luginbuhl, M; Petersen-Felix, S; Jakob, SM
Anesthesia and Analgesia, 99(6): 1728-1736.
10.1213/01.ANE.0000135634.46493.0A
CrossRef
Critical Care Clinics
Pharmacology of Commonly Used Analgesics and Sedatives in the ICU: Benzodiazepines, Propofol, and Opioids
Devlin, JW; Roberts, RJ
Critical Care Clinics, 25(3): 431-+.
10.1016/j.ccc.2009.03.003
CrossRef
Cns Drugs
Propofol - A review of its use in intensive care sedation of adults
McKeage, K; Perry, CM
Cns Drugs, 17(4): 235-272.

Respiratory Care
Sedation and Paralysis
Piriyapatsom, A; Bittner, EA; Hines, J; Schmidt, UH
Respiratory Care, 58(6): 1024-1035.
10.4187/respcare.02232
CrossRef
Asian Journal of Control
Clinical Decision Support and Closed-Loop Control for Intensive Care Unit Sedation
Haddad, WM; Bailey, JM; Gholami, B; Tannenbaum, AR
Asian Journal of Control, 15(2): 317-339.
10.1002/asjc.701
CrossRef
Optimal Control Applications & Methods
Optimal drug dosing control for intensive care unit sedation by using a hybrid deterministic-stochastic pharmacokinetic and pharmacodynamic model
Gholami, B; Haddad, WM; Bailey, JM; Tannenbaum, AR
Optimal Control Applications & Methods, 34(5): 547-561.
10.1002/oca.2038
CrossRef
Journal of the Korean Medical Association
Pharmacokinetics and pharmacodynamics of drugs for sedation
Lee, YS
Journal of the Korean Medical Association, 56(4): 279-284.
10.5124/jkma.2013.56.4.279
CrossRef
Anesthesiology
Variability of Target-controlled Infusion Is Less Than the Variability after Bolus Injection
Hu, C; Horstman, DJ; Shafer, SL
Anesthesiology, 102(3): 639-645.

PDF (399)
Anesthesiology
AQUAVAN(R) Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN(R) (Part 1): Pharmacokinetics: Retracted
Gibiansky, E; Struys, MM; Gibiansky, L; Vanluchene, AL; Vornov, J; Mortier, EP; Burak, E; Van Bortel, L
Anesthesiology, 103(4): 718-729.

PDF (2152)
Anesthesiology
Modeling of the Sedative and Airway Obstruction Effects of Propofol in Patients with Parkinson Disease undergoing Stereotactic Surgery
Fábregas, N; Rapado, J; Gambús, PL; Valero, R; Carrero, E; Salvador, L; Nalda-Felipe, MA; Trocóniz, IF
Anesthesiology, 97(6): 1378-1386.

PDF (509)
Critical Care Medicine
Dose-dependent influence of barbiturates but not of propofol on human leukocyte phagocytosis of viable Staphylococcus aureus
Ploppa, A; Kiefer, R; Nohé, B; Haeberle, HA; Dieterich, H; Unertl, KE; Krueger, WA
Critical Care Medicine, 34(2): 478-483.
10.1097/01.CCM.0000199067.71968.6E
PDF (493) | CrossRef
The Clinical Journal of Pain
Ketamine Does Not Reduce Postoperative Morphine Consumption After Tonsillectomy in Children
Abu-Shahwan, I
The Clinical Journal of Pain, 24(5): 395-398.
10.1097/AJP.0b013e3181668aad
PDF (86) | CrossRef
European Journal of Anaesthesiology (EJA)
Total intravenous anaesthesia to obese patients: largely guesswork?
Coetzee, JF
European Journal of Anaesthesiology (EJA), 26(5): 359-361.
10.1097/EJA.0b013e328329c6e2
PDF (91) | CrossRef
Journal of Trauma and Acute Care Surgery
Closed-Loop Strategies for Patient Care Systems
Pauldine, R; Beck, G; Salinas, J; Kaczka, DW
Journal of Trauma and Acute Care Surgery, 64(4): S289-S294.
10.1097/TA.0b013e31816bce43
PDF (314) | CrossRef
Journal of Trauma and Acute Care Surgery
Too Much of a Good Thing? Tracing the History of the Propofol Infusion Syndrome
Rosen, DJ; Nicoara, A; Koshy, N; Wedderburn, RV
Journal of Trauma and Acute Care Surgery, 63(2): 443-447.
10.1097/TA.0b013e31809fe910
PDF (760) | CrossRef
Back to Top | Article Outline

Supplemental Digital Content

Back to Top | Article Outline

© 2001 American Society of Anesthesiologists, Inc.

Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.
Login

Article Tools

Images

Share