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A Randomized, Open-Label Study of the Safety and Tolerability of Fospropofol for Patients Requiring Intubation and Mechanical Ventilation in the Intensive Care Unit

Candiotti, Keith A., MD*; Gan, Tong J., MD, FRCA; Young, Christopher, MD; Bekker, Alex, MD, PhD; Sum-Ping, S. T. John, MB, ChB, FRCA§; Kahn, Richard, MD; Lebowitz, Philip, MD; Littman, Jeffrey J., MD, MS**

doi: 10.1213/ANE.0b013e31821d7faf
Critical Care, Trauma, and Resuscitation: Research Reports

BACKGROUND: Current drugs for induction and maintenance of sedation in mechanically ventilated patients in the intensive care unit have limitations. Fospropofol, a prodrug of propofol, has not been studied as a sedative in the ICU setting.

METHODS: In this randomized, open-label pilot study, patients received 1 of 3 regimens with a goal of maintaining a Ramsay Sedation Score of 2 to 5: (1) fospropofol IV infusion with a bolus and increased infusion rate for agitation events (infusion/bolus); (2) fospropofol IV infusion with an increased infusion rate for agitation events (infusion only); or (3) propofol IV infusion with an increased infusion rate for agitation events.

RESULTS: Sixty patients received study drug and were included in the safety and efficacy analyses. Because incidence rates for adverse events were similar between fospropofol groups, and because the study was not powered to determine significant differences between treatment groups for safety variables, adverse events for both fospropofol groups were combined. In the fospropofol groups, 28 out of 38 patients (74%) experienced treatment-emergent adverse events in comparison with 14 out of 22 patients (64%) in the propofol group. The most common treatment-emergent adverse events with fospropofol were procedural pain (21.1%) and nausea (13.2%). Two patients (1 each in the fospropofol infusion/bolus and the propofol groups) experienced hypotension during the study as a potential sedation-related adverse event. Mean plasma formate levels were not significantly different among groups. Patients in all 3 treatment groups maintained Ramsay Sedation Scores of 2 to 5 for >90% of the time they were sedated.

CONCLUSION: This pilot study suggests that fospropofol, administered in either an infusion/bolus or infusion-only regimen, is tolerable and effective for short-term induction and maintenance of sedation in mechanically ventilated intensive care unit patients.

Published ahead of print May 19, 2011

From the *Department of Anesthesiology, University of Miami, Miami, FL; Department of Anesthesiology, Duke University Medical Center, Durham, NC; Department of Anesthesiology, New York University School of Medicine, New York, NY; §University of Texas Southwestern Medical Center and Department of Veterans Affairs, North Texas Health Care System, Dallas, TX; Central Maine Pulmonary Associates, Auburn, ME; Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY; **Department of Anesthesiology, Cooper University Hospital, Camden, NJ.

Funding: This study was supported by Eisai Inc. (formerly MGI Pharma Inc.).

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Keith A. Candiotti, MD, Department of Anesthesiology, University of Miami/Jackson Memorial Hospital, R-C370, 1611 NW 12th Avenue, Miami, FL 33101. Address e-mail to

Accepted March 23, 2011

Published ahead of print May 19, 2011

Patients who are tracheally intubated and their lungs mechanically ventilated in the intensive care unit (ICU) usually require sedation to avoid agitation and excessive stress responses.1 In this setting, short-acting sedatives/hypnotics, such as propofol and midazolam, are typically used for sedation.24 The pharmacodynamic profile of propofol provides a rapid onset of action and recovery from sedation.5,6 However, lipid-related adverse effects and bacterial contamination may occur and become more significant with prolonged administration.7 The disadvantages of midazolam include a slower onset of sedation and the potential for drug accumulation that can result in oversedation and prolonged recovery.810 Thus, a short-acting sedative available as a nonlipid (aqueous) formulation may be desirable for this patient population.

Fospropofol disodium is a water-soluble prodrug of propofol suitable for IV administration.7 When given as a bolus, fospropofol produces a gradual increase in therapeutic plasma propofol concentrations followed by a gradual decrease over time, resulting in the patient spending more time within the therapeutic range versus a standard propofol bolus.10 These properties may be useful in clinical conditions that do not require an immediate onset of action but rather a more prolonged effect over time.

The use of fospropofol for sedation in an ICU setting has not been reported. The primary objective of this pilot study was to assess the safety and tolerability of IV infusions of fospropofol versus propofol at sedative doses administered over periods of 2 to 12 hours in patients requiring sedation in the ICU. Secondary objectives were to evaluate fospropofol for maintaining sedation and managing patient agitation.

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Study Design

This randomized, open-label study was conducted at 10 clinical sites in the United States in compliance with the Declaration of Helsinki and in accordance with the International Conference on Harmonization Good Clinical Practice guidelines (registered as NCT00125398 at The protocol, amendments, and informed consent forms were reviewed and approved by appropriate IRBs. Each participant was required to provide written informed consent before enrollment in the study.

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Eligible adult patients (≥18 to ≤80 years of age) met ASA physical classification system status 1 to 4 and were expected to require mechanical ventilation for 2 to 12 hours with sedation in an ICU setting. Women were required to be surgically sterile, postmenopausal, or not pregnant or lactating, and to be using an acceptable method of birth control, with a negative serum and urine pregnancy test result at screening and baseline.

Patients were excluded for a history of allergic reaction or hypersensitivity to any anesthetic drug, narcotic, or benzodiazepine; for prior exposure to fospropofol; or for participation in an investigational drug study within 1 month before this study. Patients also were excluded if they had a central nervous system injury that would interfere with the assessment of sedation; required emergency surgery; had one or more conditions that, in the opinion of the principal investigator, could interfere with appropriate airway management or adequate assessment of funduscopic changes; or required use of neuromuscular blocking drugs during sedation in the ICU setting.

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Study Procedures

For surgical patients, study drug was administered after admission to the ICU. For nonsurgical conditions, the study drug was initiated after baseline evaluation and determination of eligibility. If the anesthetic effects from a surgical procedure or sedative effects from prior drugs used for a nonsurgical condition were still present upon patient admission to the ICU, the investigator could delay initiation of study drug until medically appropriate.

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Patients were randomly assigned to 1 of 3 treatment groups in a 1:1:1 allocation ratio stratified by study site. In group 1 (fospropofol infusion/bolus group), sedation was induced with a continuous IV infusion of fospropofol (25 μg/kg/min) with increases or decreases of 25 μg/kg/min at 5-minute intervals to maintain a Ramsay Sedation Score (RSS) of 2 to 5. Agitation in this group was treated with a 100-mg bolus dose of fospropofol, followed by a 25-μg/kg/min increase in the infusion rate every 5 minutes. Group 2 (fospropofol infusion-only group) received the same fospropofol dose for the induction and maintenance of sedation, but agitation was treated only with an increase in the infusion rate (i.e., 25-μg/kg/min increase every 5 minutes). In group 3 (propofol group), sedation was induced with a continuous infusion of propofol at a dose of 25 μg/kg/min and maintained by adjusting the infusion rate from 5 to 50 μg/kg/min to maintain an RSS of 2 to 5. Agitation in the propofol group was treated by increasing the infusion rate by 5 to 10 μg/kg/min every 5 minutes. Patients were transitioned to an alternative sedative medication if agitation did not resolve (i.e., RSS level ≥2 not achieved) after 4 successive dosage increases of the study drug. All treatment groups received morphine sulfate, fentanyl citrate, or hydromorphone as needed for analgesia. Each patient received a multivitamin containing folic acid and vitamin B12 to ensure complete metabolism of formate and minimize the risk of any potential adverse effects. Enrollment, randomization, and allocation sequence were determined by investigators at each study site in accordance with study protocol.

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Safety and Tolerability

Safety was assessed by monitoring treatment-emergent adverse events (TEAEs), arterial blood pressure, heart rate, respiratory rate, echocardiography, oxygen saturation, concomitant medications, and funduscopy, and by evaluating central nervous system function. Laboratory assessments included plasma formate concentrations, serum chemistry, hematology, serum electrolytes, and urinalysis. Safety assessments were conducted at baseline, during the observation period, at day 1 and day 3 after sedation, and for up to 30 days after the observation period.

The nature, frequency, severity, seriousness, suspected relationship to treatment, and outcome of all TEAEs were recorded. Potential sedation-related adverse events (SRAEs) were bradycardia (heart rate <50 beats per minute (bpm) and requiring medical intervention) and hypotension (systolic blood pressure <90 mm Hg and requiring medical intervention). Because all patients in this study were tracheally intubated and their lungs mechanically ventilated for the duration of the sedation period, hypoxemia and apnea were not considered SRAEs.

The RSS was used to assess the level of sedation on a scale of 1 to 6.11 The evaluator determined the RSS score immediately before the start of study drug, at 5-minute intervals for the initial 60 minutes after the start of study drug, and at 15-minute intervals thereafter until the patient was extubated (or had completed 12 hours of study drug treatment). If the patient experienced inadequate sedation, the RSS score was assessed at 5-minute intervals until adequate sedation was achieved.

The following variables were calculated at 2-hour intervals after sedation: the percentage of time spent at each RSS during the dosing period, the percentage of agitated patients at any time during the study, the percentage of agitated patients requiring alternative sedative medication, and the average infusion rate. After completion of the observation period (2 hours after discontinuation of study treatment), a designated ICU staff member who had monitored sedation completed a survey, in consultation with the investigator, to assess perceived comfort, anxiety and agitation, and cooperation with study medication. Both were asked to respond to questions on a 10-point scale (10 being the highest score) regarding their satisfaction with the time to sedation, the sedation levels, and the recovery process.

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Statistical Analysis

All data were reported using the modified intent-to-treat population, which included all randomized patients who received at least 1 dose of either fospropofol or propofol and had at least 1 postdose clinical assessment. The safety population included all patients who received at least 1 dose of study drug. For this study, the modified intent-to-treat and safety populations were the same. The planned sample sizes were approximately 20 patients in each of the 3 treatment groups. Assuming 75% of patients in the fospropofol group would develop agitation during the study, and further assuming that no failure was observed in agitated patients treated with either fospropofol regimen, the study had 80% power to detect that the treatment failure rate with fospropofol was <0.05.

For continuous variables, data were summarized by treatment group as mean, standard deviation (SD), and median. For categorical variables, data were tabulated by treatment group as the number and proportion of patients in each category. The average number of agitation events was summarized by treatment group.

Plasma formate concentrations from the 2 fospropofol groups were combined. Data from fospropofol and propofol groups were summarized by the time of collection (before versus after dosing) using descriptive statistics. Predose and postdose formate concentrations were compared within groups and between fospropofol and propofol groups. For comparisons we used a 2-sample t test, and all comparisons were based on 2-sided tests with α = 0.05.

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Of the 96 patients screened (Fig. 1), 18 were not included for administrative reasons (n = 6), consent withdrawal (n = 9), or failure to meet selection criteria (n = 3). Of the 78 patients randomized, 18 were discontinued before drug administration (1 had an adverse complication from surgery, 2 withdrew consent, 1 died of intraoperative bleeding, and 14 were withdrawn for other reasons, including patient extubation [n = 8], investigator discretion [n = 4], or administrative reasons [n = 2]). Withdrawals due to investigator discretion were similar in the fospropofol infusion/bolus (n = 1), fospropofol infusion-only (n = 1), and propofol (n = 2) groups. One patient in the fospropofol infusion-only group was discontinued after study drug administration because of an insufficient response. At baseline, patients randomized to the fospropofol infusion/bolus group tended to be older, exhibited more racial diversity, and included more individuals weighing ≥80 kg in comparison with the propofol and fospropofol infusion-only groups (Table 1).

Figure 1

Figure 1

Table 1

Table 1

The mean total amount of fospropofol administered to patients in the fospropofol infusion/bolus group was 2365.8 mg (range: 252.0 to 6981.0) in comparison with 1383.1 mg (range: 155.3 to 4835.6) for the fospropofol infusion-only group. The increased total dose in the infusion/bolus group was related to a longer median duration of dosing in comparison with the infusion-only group (5.46 hours [range 2.0 to 12.0] vs 3.71 hours [range 1.5 to 12.2]) and to the use of bolus doses. In the propofol group, patients received a mean total amount of 948.5 mg (range: 69.7 to 3153.5). The median dosing period for the propofol group was 6.38 hours (range 1.75 to 16.67). Mean infusion rates are given in Table 2.

Table 2

Table 2

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Tolerability and Safety

Incidence rates for TEAEs are summarized in Table 3. No TEAEs led to discontinuation of study medication or discontinuation from the study. The frequency of TEAEs was similar between the 2 fospropofol dosing groups, with the exception of procedural pain (33.3% vs 5.0%; infusion/bolus and infusion only). Because the study was not powered to determine statistically significant differences between treatment groups in safety variables, the adverse events for both fospropofol groups were combined. The most frequently occurring TEAEs in the fospropofol and propofol groups, respectively, were procedural pain (18.4% vs 9.1%), infusion-site pain (5.3% vs 13.6%), hyperglycemia (5.3% vs 13.6%), and nausea (10.5% vs 4.5%).

Table 3

Table 3

Two patients (1 each in the fospropofol infusion/bolus group and the propofol group) experienced hypotension during the study, which was initially reported as a potential SRAE. The fospropofol patient had an event lasting 11 minutes during the administration of study medication and received IV fluids. The patient receiving propofol had an event 1 day after receiving study drug and did not require additional therapy to treat the hypotension. Both events were considered mild in severity and unrelated to study drug, and both patients recovered fully.

Five deaths (severe gastrointestinal bleed [1], cardiopulmonary arrest [1], septic shock [1], and acute respiratory failure [2]) occurred during the study: 4 in the fospropofol groups and 1 in the propofol group. The gastrointestinal bleed–related death occurred in the propofol group, and the cardiopulmonary arrest occurred in the infusion/bolus group. Both instances of acute respiratory failure occurred in the fospropofol infusion-only group. The death from septic shock occurred 1 day after administration of study drug (fospropofol infusion only). The other 4 deaths occurred between 3 and 31 days after receiving study drug. All 5 deaths were not considered related to study medication.

Serious TEAEs occurred in 13 patients: 10 out of 38 (26.3%) patients treated with fospropofol and 3 of 22 (13.6%) patients treated with propofol. Four of the 13 serious TEAEs were classified as infections in the fospropofol infusion-only group (1 each of postoperative infection, septic shock, Serratia sepsis, and wound infection). However, these events were not considered related to study medication. The only serious adverse event considered possibly related to study medication was brief (5 to 10 seconds), nonsustained ventricular tachycardia experienced by 1 patient in the fospropofol infusion-only group. This single episode was treated with IV magnesium and potassium because of low-normal serum levels before the event and was considered mild in severity. Fospropofol was continued for another 8 hours and 5 minutes, with no further episodes of ventricular tachycardia or other types of cardiac arrhythmia observed.

Modest changes in mean phosphorus levels were observed from baseline to the end of the observation period, with increases of 0.04 mg/dL and 0.64 mg/dL in the infusion/bolus and infusion-only fospropofol groups and a decrease of −0.32 mg/dL in the propofol group. Treatment duration did not appear to influence phosphorous levels for any of the treatment groups. When patients were categorized according to the duration of dosing, there did not appear to be any meaningful difference in mean phosphorous levels between patients who received short-term sedation and those receiving longer-term sedation in any of the treatment groups (Fig. 2). Mean triglyceride concentrations decreased by 6.1 mg/dL in the combined fospropofol groups and increased by 31.4 mg/dL in the propofol group. No other clinically relevant laboratory abnormalities, electrocardiogram changes, or changes in other safety variables were observed.

Figure 2

Figure 2

No significant differences (P > 0.05) were observed between predose and postdose formate plasma concentrations within the 3 groups or between the combined fospropofol and propofol groups (Fig. 3). Higher plasma formate concentrations were observed in 3 patients. In the fospropofol infusion/bolus group, one 36-year-old patient exhibited a substantial increase from a predose value of 66.3 μg/mL to 212 μg/mL at the end of the infusion. However, this patient had severe hepatic and renal dysfunction and did not receive hemodialysis during the study. He had no adverse events and minimal changes in vital signs. A second patient in the same group showed a slight decline from 101 μg/mL predose to 88.8 μg/mL at the end of dosing. In the propofol group, a third patient had a slight increase in concentration from 63.6 μg/mL predose to 86.0 μg/mL at the end of the infusion. No adverse events (typically either toxic effects on the optic nerve [as assessed by fundoscopy] or allergic skin reactions) were reported in association with any of these higher formate levels.

Figure 3

Figure 3

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Effect on Sedation and Agitation

Mean (SD) RSSs were 3.5 (1.1) in the fospropofol infusion/bolus group, 3.3 (0.8) in the fospropofol infusion-only group, and 3.2 (0.9) in the propofol group. Mean percentages of time during which RSSs were between 2 and 5 were 91.6% for fospropofol infusion/bolus, 95.5% for fospropofol infusion only, and 93.4% for propofol. The mean percentage of time spent at each RSS during the dosing period for each treatment group was generally comparable. Agitation events occurred in 6 patients (33.3%) in the fospropofol infusion/bolus group, 7 (35.0%) in the fospropofol infusion-only group, and 5 (22.7%) in the propofol group. The mean (SD) numbers of agitation events during the dosing period were 0.9 (2.1) with fospropofol infusion/bolus, 1.6 (3.6) with fospropofol infusion only, and 0.9 (2.2) with propofol. Only 1 patient (fospropofol infusion-only group) required alternative sedation medication during the dosing period.

Results from the satisfaction survey showed that physicians were satisfied with the sedative medications for the majority of patients in the study. Mean (SD) survey scores were 8.3 (1.6) for fospropofol infusion/bolus, 8.1 (1.5) for fospropofol infusion only, and 8.4 (1.3) for propofol. The large majority of physicians indicated that they would be willing to use fospropofol infusion/bolus (94.4%), fospropofol infusion only (94.7%), and propofol (100%) again.

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This pilot study was designed to evaluate the safety and efficacy of 2 dosage regimens of fospropofol versus propofol for sedation in ICU patients requiring mechanical ventilation. The results suggest that both fospropofol regimens were acceptable for sedation of intubated patients in the ICU with mostly mild TEAEs and only 1 serious adverse event, which was judged to be related to study medication. The types of TEAEs differed somewhat among treatment groups, with procedural pain (21.1%) and nausea (13.2%) the most frequent events for fospropofol and infusion-site pain (13.6%) and hyperglycemia (13.6%) the most common events for propofol. The high incidence of TEAEs overall was probably not unexpected in an ICU population because of the presence of comorbid and potentially life-threatening conditions.

Fospropofol is rapidly and completely metabolized by alkaline phosphatase to yield the active metabolite (propofol), formaldehyde, and phosphate.12 Evidence suggests that phosphate, formaldehyde, and formate (which is formed from the conversion of formaldehyde) do not accumulate during administration of fospropofol.13 The analyses of predose and postdose formate and phosphorus levels in this study suggest that accumulation of formate or phosphorus with fospropofol administration is unlikely to occur during relatively short-term ICU sedation.

Patients in each treatment group achieved the goal of attaining and maintaining an RSS of 2 to 5 for >90% of the time under sedation. Previous studies showed attainment of adequate sedation in the ICU in 40% to 97% of patients with propofol or midazolam.5,14,15 ICU staff were satisfied with each of the sedative regimens and would consider using the sedative again in >90% of the patients in the present study. The majority of patients were sedated adequately without experiencing agitation. However, the reported incidence of agitation was approximately 33%, which is considerably below the planned 75%. Thus, no definitive conclusions can be drawn regarding the relative efficacy of the infusion/bolus and infusion-only regimens for the management of agitation in these patients. Nevertheless, the primary objective of the study, to assess the safety of fospropofol to manage patient sedation in the ICU, was not influenced by the analysis of agitation. Collectively, these data suggest that both the infusion/bolus and infusion-only regimens are feasible methods of administering fospropofol ICU sedation.

Two reports in the literature have identified a high frequency of deep sedation in mechanically ventilated patients in the ICU.8,9 A prospective, observational study of 1381 adult ICU patients who were mechanically ventilated reported oversedation in 40%–50% of patients with the use of midazolam and propofol.8 A review of sedation practices in mechanically ventilated patients reported that benzodiazepines were associated with more oversedation than were propofol or other drugs.9 It was concluded that use of benzodiazepines in mechanically ventilated patients should be limited to those with a specific need, e.g., for anxiety or seizures.9 Deep sedation was uncommon in the current study, with only 5.5%, 0.2%, and 3.4% of time spent at an RSS of 6 in the infusion/bolus, infusion-only, and propofol groups, respectively.

Propofol may be a better alternative than midazolam for ICU sedation because of its more rapid onset and recovery. However, propofol is associated with hyperlipidemia,1619 an increased risk of bacterial contamination,2023 and propofol-related infusion syndrome,2426 properties that limit its use for ICU sedation. Currently, it is unclear whether fospropofol can also cause propofol-related infusion syndrome. In the current study, fospropofol was associated with a slight decrease in mean triglyceride levels (−6.1 mg/dL), whereas propofol was associated with a modest increase (+31.4 mg/dL).

Limitations of the current study are the lack of blinding to study treatment, the small number of patients included, and limited comparative efficacy. In addition, a propofol bolus/infusion regimen was not included for comparison.

In summary, this is the first study assessing the use of fospropofol in a mechanically ventilated ICU population, and the results show that fospropofol was tolerable and effective for up to 12 hours when used for sedation, administered as either an infusion/bolus or an infusion-only regimen. Further studies are warranted to establish the safety and efficacy of fospropofol for this indication and to determine whether the aqueous formulation has advantages over the propofol lipid emulsion formulation.

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Name: Keith A. Candiotti, MD.

Contribution: Data analysis, conduct of study, manuscript preparation.

Conflict of Interest: Dr. Keith Candiotti has received research funding, is a member of a speaker's bureau, and has received consulting fees.

Name: Tong J. Gan, MD, FRCA.

Contribution: Study design, conduct of study, manuscript preparation.

Conflict of Interest: Dr. Gan has received research funding, is a member of a speaker's bureau, and has received consulting fees.

Name: Christopher Young, MD.

Contribution: Study design, conduct of study, manuscript preparation.

Conflict of Interest: Dr. Young has no conflict of interest to report.

Name: Alex Bekker, MD, PhD.

Contribution: Conduct of study, manuscript preparation.

Conflict of Interest: Dr. Alex Bekker has received research funding and is a member of a speaker's bureau.

Name: S. T. John Sum-Ping, MB, ChB, FRCA.

Contribution: Conduct of study, manuscript preparation.

Conflict of Interest: Dr. S. T. John Sum-Ping has received research funding.

Name: Richard Kahn, MD.

Contribution: Conduct of study.

Conflict of Interest: Dr. Kahn has no conflict of interest to report.

Name: Philip Lebowitz, MD.

Contribution: Conduct of study.

Conflict of Interest: Dr. Lebowitz has no conflict of interest to report.

Name: Jeffrey J. Littman, MD, MS.

Contribution: Conduct of study.

Conflict of Interest: Dr. Jeffrey J. Littman has received research funding.

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The authors would like to acknowledge the contributions of the investigators and study personnel at each study site: James Berry, MD, Vanderbilt University, Nashville, TN; John White, MD, Advocate Lutheran General Hospital, Park Ridge, IL; Ruben Avocar, MD, Boston Medical Center, Boston, MA; David Bowton, MD, Wake Forest University Health Sciences, Winston-Salem, NC; Robert Brewer, MD, Henry Ford Hospital Heart and Vascular Institute, Detroit, MI; Jane Fitch, MD, Oklahoma University Medical Center, Oklahoma City, OK; Anthony Manasia, MD, Mount Sinai School of Medicine, New York, NY; Kent Pearson, MD, University of Iowa Hospital and Clinics, Iowa City, IA; Cordelia Sharma, MD, Long Island–Jewish Medical Center, New Hyde Park, NY; and G. Bruce Waldon, MD, St. Mary's Hospital, Rogers, AK. The authors also would like to acknowledge the editorial assistance of Richard S. Perry, PharmD, in the preparation of this manuscript.

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1. Ostermann ME, Keenan SP, Seiferling RA, Sibbald WJ. Sedation in the intensive care unit: a systematic review. JAMA 2000;283:1451–9
2. Gehlbach BK, Kress JP. Sedation in the intensive care unit. Curr Opin Crit Care 2002;8:290–8
3. Young CC, Prielipp RC. Benzodiazepines in the intensive care unit. Crit Care Clin 2001;17:843–62
4. Ho KM, Ng JY. The use of propofol for medium and long-term sedation in critically ill adult patients: a meta-analysis. Intensive Care Med 2008;34:1969–79
5. McKeage K, Perry CM. Propofol: a review of its use in intensive care sedation of adults. CNS Drugs 2003;17:235–72
6. Barr J, Egan TD, Sandoval NF, Zomorodi K, Cohane C, Gambus PL, Shafer SL. Propofol dosing regimens for ICU sedation based upon an integrated pharmacokinetic–pharmacodynamic model. Anesthesiology 2001;95:324–33
7. Levitzky BE, Vargo JJ. Fospropofol disodium injection for the sedation of patients undergoing colonoscopy. Ther Clin Risk Manag 2008;4:1–6
8. Payen JF, Chanques G, Mantz J, Hercule C, Auriant I, Leguillou JL. Binhas M, Genty C, Rolland C, Bosson JL. Current practices in sedation and analgesia for mechanically ventilated critically ill patients: a prospective multicenter patient-based study. Anesthesiology 2007;106:687–95
9. Devlin JW. The pharmacology of oversedation in mechanically ventilated adults. Curr Opin Crit Care 2008;14:403–7
10. Shafer A. Complications of sedation with midazolam in the intensive care unit and a comparison with other sedative regimens. Crit Care Med 1998;26:947–56
11. Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone–alphadolone. BMJ 1974;2:656–9
12. Shah A, Fechner J, Struys M, Mistry B. Differential PK/PD of propofol after intravenous fospropofol and Diprivan® in healthy subjects. American Society of Anesthesiologists Annual Meeting; October 13–17, 2007; San Francisco, CA
13. Fechner J, Ihmsen H, Hatterscheid D, Schiessel C, Vornov JJ, Burak E, Schwilden H, Schuttler J. Pharmacokinetics and clinical pharmacodynamics of the new propofol prodrug GPI 15715 in volunteers. Anesthesiology 2003;99:303–13
14. Hall RI, Sandham D, Cardinal P, Tweeddale M, Moher D, Wang X, Anis AN, Study Investigators. Propofol vs midazolam for ICU sedation: a Can multicenter randomized trial. Chest 2001;119:1151–9
15. Searle NR, Côté S, Taillefer J, Carrier JM, Gagnon L, Roy M, Lusser D. Propofol or midazolam for sedation and early extubation following cardiac surgery. Can J Anaesth 1997;44:629–35
16. Eddleston JM, Shelly MP. The effect on serum lipid concentrations of a prolonged infusion of propofol: hypertriglyceridemia associated with propofol administration. Intensive Care Med 1991;17:424–6
17. Mateu J, Barrachina F. Hypertriglyceridaemia associated with propofol sedation in critically ill patients. Intensive Care Med 1996;22:834–5
18. McLeod G, Dick J, Wallis C, Patterson A, Cox C, Colvin J. Propofol 2% in critically ill patients: effects on lipids. Crit Care Med 1997;25:1976–81
19. Devlin JW, Lau AK, Tanios MA. Propofol-associated hypertriglyceridemia and pancreatitis in the intensive care unit: an analysis of frequency and risk factors. Pharmacotherapy 2005;25:1348–52
20. Arduino MJ, Bland LA, McAllister SK, Aguero SM, Villarino ME, McNeil MM, Jarvis WR, Favero MS. Microbial growth and endotoxin production in the intravenous anesthetic propofol. Infect Control Hosp Epidemiol 1991;12:535–9
21. Tessler M, Dascal A, Gioseffini S, Miller M, Mendelson J. Growth curves of Staphylococcus aureus, Candida albicans, and Moraxella osloensis in propofol and other media. Can J Anaesth 1992;39:509–11
22. Bennett SN, McNeil MM, Bland LA, Arduino MJ, Villarino ME, Perrotta DM, Burwen DR, Welbel SF, Pegues DA, Stroud L, Zeitz PS, Jarvis WR. Postoperative infections traced to contamination of an intravenous anesthetic, propofol. N Engl J Med 1995;333:147–54
23. McHugh GJ, Roper GM. Propofol emulsion and bacterial contamination. Can J Anaesth 1995;42:801–4
24. Kam PC, Cardone D. Propofol infusion syndrome. Anaesthesia 2007;62:690–701
25. Sabsovich I, Rehman Z, Yunen J, Coritsidis G. Propofol infusion syndrome: a case of increasing morbidity with traumatic brain injury. Am J Crit Care 2007;16:82–5
26. Zaccheo MM, Bucher DH. Propofol infusion syndrome: a rare complication with potentially fatal results. Crit Care Nurse 2008;28:18–26
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