A phase 3, randomized, double blind study to assess the efficacy and safety of fospropofol disodium

Original Research INTERVENTIONAL PULMONOLOGY

A Phase 3, Randomized, Double-Blind Study To Assess the Efficacy and Safety of Fospropofol Disodium Injection for Moderate Sedation in Patients Undergoing Flexible Bronchoscopy* Gerard A. Silvestri, MD, FCCP; Brad D. Vincent, MD, FCCP; Momen M. Wahidi, MD, FCCP; Emory Robinette, MD, FCCP; James R. Hansbrough, MD, FCCP; and Gordon H. Downie, MD, PhD, FCCP

Background: Fospropofol disodium is a water-soluble prodrug of propofol with unique pharmacokinetic/pharmacodynamic properties. This randomized, double-blind, multicenter study evaluated the use of fospropofol in patients undergoing flexible bronchoscopy.

Methods: Patients > 18 years of age were randomized (2:3) to receive fospropofol, 2 mg/kg or 6.5 mg/kg, after pretreatment with fentanyl, 50 !g. Supplemental doses of each were given per protocol. The primary end point was sedation success, which was defined as follows: three consecutive Modified Observer’s Assessment of Alertness/Sedation scores of < 4 plus procedure completion without alternative sedative medication and/or mechanical ventilation. Other end points included treatment success, patient/physician satisfaction, and safety.

Results: Of 252 patients, 150 were randomized to receive 6.5 mg/kg fospropofol; 102 were randomized to receive 2 mg/kg fospropofol. Sedation success rates were 88.7% and 27.5%, respectively (p < 0.0001).

Treatment successes (91.3% vs 41.2%, respectively; p < 0.001), willingness to be treated again (94.6% vs 78.2%, respectively; p < 0.001), and absence of procedural recall (83.3% vs 55.4%, respectively; p < 0.001) were significantly better with the administration of 6.5 mg/kg fospropofol. The median time to full alertness was slightly longer for the 6.5 mg/kg dose (5.5 vs 3.0 min, respectively). The proportion of patients requiring supplemental therapy with analgesics (16.7% vs 37.3%, respectively) and the use of alternative sedative medications (8.0% vs 58.8%, respectively) were lower for patients in the 6.5 mg/kg dose group (all comparisons, p < 0.001). The most frequent adverse events (AEs) were transient and self-limited paresthesias and pruritus of mild-to-moderate severity. Hypoxemia (predominantly mild-to-moderate) was the most common sedation-related AE, and occurred in 15.4% and 12.6% of patients, respectively, in the 6.5 and 2 mg/kg fospropofol dose groups.

Conclusions: Fospropofol provided safe and effective sedation for patients undergoing flexible bronchoscopy.

Trial registration: Clinical Trials.gov Identifier: NCT00306722 (CHEST 2009; 135:41– 47) Key words: bronchoscopy; conscious sedation; fospropofol disodium Abbreviations: AE ! adverse event; ASA ! American Society of Anesthesiologists; HVLT-R ! Hopkins Verbal Learning Test-Revised; MOAA/S ! Modified Observer’s Assessment of Alertness/Sedation

ver 500,000 flexible bronchoscopies are perO formed yearly in the United States. Sedative 1

medications decrease bronchoscopy-related anxiety, For editorial comment see page 4

pain, oropharyngeal irritation, cough, and chest discomfort, thus increasing the tolerability of the procedure.2–6 Benzodiazepines combined with opioids are the most frequently used sedative agents.7,8 Benzodiazepines may produce prolonged sedation and cogni-

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tive impairment, particularly in elderly patients and those with hepatic/renal dysfunction.9 –11 In two randomized clinical trials,12,13 the time to full alertness following the administration of midazolam plus an opioid ranged from 19 to 120 min.

Midazolam is a selective substrate of CYP3A4 and CYP3A5, causing variability in metabolic activity (approximately fivefold) and numerous drug-drug interactions.14,15 The lipid emulsion propofol provides a rapid onset after delivery and fast recovery, but the potential hazards include cardiopulmonary depression, injection site pain, and microbial contamination.16,17 Fospropofol disodium (AQUAVAN Injection; MGI PHARMA, Inc; Bloomington, MN "a wholly owned subsidiary of Eisai Corporation of North America, Woodcliff Lake, NJ#) is a water-soluble prodrug of propofol with a unique pharmacokinetic and pharmacodynamic profile compared to lipid propofol.18 Propofol is liberated from fospropofol by tissue alkaline phosphatases with a predictable rise and decline in the plasma concentration of propofol compared to lipid propofol, which demonstrates a rapid increase in plasma levels following injection.18,19 Because of its unique pharmacokinetic properties, fospropofol can be titrated to provide moderate sedation and is not considered to be a general anesthetic. Prior studies20,21 in patients undergoing colonoscopy demonstrated that fospropofol had an acceptable safety profile. The primary objective of this study was to determine the efficacy and safety of fospropofol in patients undergoing flexible bronchoscopy.

*From the Division of Pulmonary and Critical Care Medicine (Drs. Silvestri and Vincent), Medical University of South Carolina, Charleston, SC; Duke University School of Medicine (Dr. Wahidi), Durham, NC; Pulmonary Research (Dr. Robinette), Johnston Memorial Hospital, Abingdon, VA; Graves-Gilbert Clinic (Dr. Hansbrough), Bowling Green, KY; and the Brody School of Medicine (Dr. Downie), East Carolina University, Greenville, NC. This study was funded by a grant from MGI PHARMA, Inc (Bloomington, MN).

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Manuscript received April 1, 2008; revision accepted June 18, 2008.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Gerard A. Silvestri, MD, FCCP, Department of Pulmonary and Critical Care Medicine Medical University of South Carolina, 171 Ashley Ave, Room 812-CSB, Charleston, SC 29425-2220; e-mail: silvestri@musc.edu DOI: 10.1378/chest.08-0623

Materials and Methods Study Design This was a phase 3, randomized, double-blind, dose-controlled study. The institutional review board at each study site approved the protocol. All patients provided oral and written informed consent.22 Patients Patients ! 18 years of age and with an American Society of Anesthesiologists (ASA) Physical Classification System status of P1 to P4 were eligible for study enrollment. Female patients of child-bearing age had to have a negative pregnancy test result and to have used an acceptable method of birth control for ! 1 month prior to study enrollment. Exclusion criteria included hypersensitivity to any anesthetic or opioid; failure to meet non per os status; an abnormal, clinically significant ECG finding; and participation in an investigational drug study within the previous month. Other exclusions were patients with a Mallampati classification score of IV, a Mallampati classification score of III and a thyromental distance of " 4 cm, or a difficult airway for any other reason as judged by the clinician.

Study Procedures Following the completion of preprocedural assessments, patients were randomly assigned to one of two treatment groups (fospropofol, 2 mg/kg, or fospropofol, 6.5 mg/kg) in a 2:3 allocation ratio, respectively. All patients received fentanyl, 50 $g, prior to the first dose of fospropofol and were given supplemental oxygen (4 L/min). Patients were monitored by continuous ECG, pulse oximetry, and BP monitoring until the time of hospital discharge. Lidocaine was administered topically for cough suppression.

Sedation was evaluated during the following two phases: initiation and maintenance. During the initiation phase, one bolus dose and up to three supplemental doses of fospropofol were administered to reach a Modified Observer’s Assessment of Alertness/Sedation (MOAA/S)23 score of " 4 (Table 1). Supplemental doses of fospropofol (at intervals of ! 4 min from the preceding dose) were 25% of the initial dose (ie, 0.5 mg/kg "range, 30 to 45 mg# for the 2 mg/kg group; 1.63 mg/kg "range, 97.5 to 146 mg# for the 6.5 mg/kg group). Patients ! 65 years of age and/or with an ASA Physical Classification System status of P4 (or P3, at the investigator’s discretion) had their doses reduced by 25%. The dosage was also limited by lower and upper weight bounds of 60 and 90 kg, respectively.

The procedure began after the first MOAA/S score of " 4. If the MOAA/S score was % 3, supplemental doses of fospropofol were required to maintain three consecutive MOAA/S scores of

Table 1—MOAA/S Scale Responsiveness

Score

Responds readily to name spoken in normal tone Lethargic response to name spoken in normal tone Responds only after name is called loudly and/or repeatedly Responds only after mild prodding or shaking Responds only after painful trapezius squeeze Does not respond to painful trapezius squeeze

5 (alert) 4 3

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Original Research

" 4, the patient was considered to have experienced sedation failure, and usual sedative medication was administered.

During the maintenance phase, supplemental doses could be administered at intervals of ! 4 min if the patient had a MOAA/S score of ! 4 and demonstrated purposeful movement. One additional 25-$g dose of fentanyl was permitted for the treatment of pain. Alternative sedative medication could be administered only to patients experiencing sedation failure. The patientâ&#x20AC;&#x2122;s level of sedation was assessed using the MOAA/S scale (Table 1) every 2 min from first dose of fospropofol until the patient was determined to be fully alert.

Study End Points Primary End Point: The primary efficacy end point was sedation success, which was defined as three consecutive MOAA/S scores of " 4 after fospropofol administration and completion of the procedure without requiring either alternative sedative or mechanical/manual ventilation.

Secondary End Points: Additional secondary efficacy parameters included treatment success (ie, completion of the procedure without requiring either alternative sedative or mechanical/ manual ventilation), and the proportion of patients who were willing to be retreated with fospropofol and who did not recall being awake during the procedure. Other efficacy end points included the proportion of patients requiring supplemental therapy with fentanyl, the number of supplemental fospropofol doses, the level of sedation, the time to sedation, and hospital discharge parameters.

Satisfaction: Physician satisfaction scores were collected at the end of the initiation phase and at the end of the procedure. When they were ready for hospital discharge (! 9 on the Aldrete discharge scale),24 patients rated aspects of the experience (ie, recall of insertion and/or removal of the bronchoscope), level of satisfaction, and comfort. A 10-point Likert scale (1, dissatisfied; 10, highly satisfied) was used for both.

Psychometric Performance: Psychometric performance was assessed using the Hopkins Verbal Learning Test-Revised (HVLT-R),25 a validated neurocognitive assessment of verbal learning and memory that has been used to evaluate the influence of benzodiazepines on short-term memory.26,27 The HVLT-R was performed at screening and during recovery.

Safety: Adverse events (AEs) were analyzed for frequency, severity, relationship to treatment, and outcome. Events were considered to be severe if they interfered with the patientâ&#x20AC;&#x2122;s daily functioning or, according to the investigator, if the symptom was of significant intensity. Sedation-related AEs included apnea (lack of spontaneous breathing for % 30 s), hypoxemia (oxygen saturation & 90% for % 30 s), bradycardia (heart rate & 50 beats/min and requiring intervention), and hypotension (systolic BP & 90 mm Hg and requiring intervention). The need for airway assistance was also considered to be a sedation-related AE. Statistical Analysis Results for the two populations are presented. The modified intent-to-treat population included all randomized patients who received one or more doses of fospropofol and had undergone one or more postdose clinical assessments. The safety population included randomized patients who had received one or more doses of fospropofol.

The number and proportion of patients achieving the primary and secondary end points were calculated. The Fisher exact test was used to compare the two treatment groups. Other end points and safety variables were reported descriptively. Based on previous data,28 this sample size gave % 90% power to detect the primary and secondary end point differences between the two dosing groups (' ! 0.05).

Results Patients Twenty-four centers screened 290 patients, and 256 patients were randomized (Fig 1). Centers enrolled between 1 and 35 patients (mean, 11 patients). Four patients were eliminated from the study prior to drug administration due to abnormal laboratory test results, pharmacy delays, invalid consent, or bronchoscopy cancellation (each category, n ! 1). Thus, 252 patients were included in the modified intent-to-treat population. Demographic and baseline characteristics were similar between the treatment groups (Table 2).

Efficacy Sedation Success: The rates were significantly higher in the 6.5 mg/kg group than in the 2 mg/kg group for sedation success (88.7% vs 27.5%, respectively; p & 0.001) and for treatment success (91.3% vs 41.2%, respectively; p & 0.001).

With the 6.5 mg/kg group, 89.3% of procedures could be initiated after two or fewer supplemental doses vs 33.3% for the 2 mg/kg group. The mean (( SD) number of supplemental doses of fospropofol required to initiate and complete the procedure was lower in the 6.5 mg/kg group (Table 3). Over half of the patients (56%) in the 6.5 mg/kg group needed no supplemental doses compared with 7% of those in the 2 mg/kg group. Eight percent of the patients in the 6.5 mg/kg group required alternative sedative medication vs 58.8% in the 2 mg/kg group. All patients received midazolam as the alternative sedative; one patient in the 2 mg/kg group also received propofol. Fewer patients in the 6.5 mg/kg group required supplemental treatment with fentanyl (16.7% vs 37.3%, respectively).

Depth and Duration of Sedation and Other Secondary End Points: The mean percentage of time spent at a MOAA/S score of 0 to 1 from the first dose of fospropofol to full alertness was 3.7 ( 10.4% in the 6.5 mg/kg group and 1.5 ( 7.0% in the 2 mg/kg group. When evaluating patients who went to deep sedation (MOAA/S score, 0 or 1), 13 of 24 patients (54.2%) experienced a sedation-related AE (eg, apnea, hypoxemia, and hypotension) compared to 17 of 125 patients (13.6%; p & 0.0001) for those who remained in a state of minimal-to-moderate sedation (MOAA/S score, 2 to 5). The single patient who required manually assisted ventilation experienced deep sedation (MOAA/S scores, 0 and 1).

The median time to sedation was shorter for the 6.5 mg/kg group than for the 2 mg/kg group (4.0 vs 18.0 min, respectively). For the 6.5 mg/kg group, the median time to full alertness from the beginning of the procedure was 16.0 min, and the median time to

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Assessed for eligibility (n = 290)

Excluded (n = 34) Withdrawn consent (n = 11) Did not meet inclusion criteria (n = 7) Investigator’s discretion (n = 5) Adverse event (n = 1) Other reasons (n = 10)

Randomized (n = 256)

Fospropofol 2 mg/kg (n = 103) Received study drug (n = 102) Did not receive (n = 1)

Fospropofol 6.5 mg/kg (n = 153) Received study drug (n = 150) Did not receive (n = 3)

Lost to follow up (n = 0)

Lost to follow up (n = 0)

mITT population (n = 150) Safety population (n = 149)

mITT population (n = 102) Safety population (n = 103)

(n = 1 randomized to 6.5mg/kg dose but instead received 2.0 mg/kg dose; remains in ITT 6.5 mg but in Safety 2.0 mg)

Figure 1. Patient disposition. mITT ! modified intention to treat.

full alertness from the end of procedure was 5.5 min (2.0 mg/kg group, 14.5 and 3.0 min, respectively).

The median time to readiness for hospital discharge from the end of procedure for the 6.5 mg/kg group was slightly longer than that for the 2.0 mg/kg group (8.5 vs 8.0 min, respectively), but this was not statistically significant. Psychometric performance (determined by the HVLT-R) was similar for patients in the 2 and 6.5 mg/kg groups at baseline (93.5% vs 94.6%, respectively) and recovery (63.6% vs 64.2%, respectively).

Table 2—Demographics and Baseline Characteristics* Fospropofol Groups Characteristics Age, yr Elderly (age ! 65 yr) Female gender Weight group & 60 kg 60 to & 90 kg ! 90 kg ASA Physical Classification System status P1 P2 P3 P4 History of sedation without an AE

2 mg/kg (n ! 102)

6.5 mg/kg (n ! 150)

60.1 (22–84) 42 (41.2) 48 (47.1)

60.8 (25–83) 61 (40.7) 64 (42.7)

19 (18.6) 51 (50.0) 32 (31.4)

27 (18.0) 81 (54.0) 42 (28.0)

6 (5.9) 58 (56.9) 31 (30.4) 7 (6.9) 96 (94.1)

7 (4.7) 74 (49.3) 61 (40.7) 8 (5.3) 145 (96.7)

*Values are given as the mean (range) or No. (%).

Satisfaction The mean physician satisfaction scores were higher in the 6.5 mg/kg group than in the 2 mg/kg group at the end of sedation (8.0 vs 3.9, respectively) and at the end of the procedure (8.3 vs 5.0, respectively). Patients receiving 6.5 mg/kg fospropofol gave mean satisfaction scores of 9.5 compared to 8.7 for patients receiving 2 mg/kg fospropofol. The proportion of patients willing to be retreated with fospropofol was higher in the 6.5 mg/kg group (94.6% vs 78.2%, respectively; p & 0.001), as was the proportion of patients who did not recall being awake during the procedure (83.3% vs 55.4%, respectively; p & 0.001) "Table 4#.

Table 3—Number of Supplemental Doses of Study Sedative Medication* Fospropofol Groups Sedation Period

2 mg/kg (n ! 102)

6.5 mg/kg (n ! 150)

Initiation phase Maintenance phase Total combined 0 1 2 3 4 5 %5 Mean

2.4 ( 0.9 1.0 ( 1.3

0.9 ( 1.0 0.9 ( 1.3

2 (2) 5 (4.9) 13 (12.7) 69 (67.6) 9 (8.8) 2 (2) 2 (2) 2.9 ( 0.9

38 (25.3) 46 (30.7) 25 (16.7) 23 (15.3) 6 (4.0) 5 (3.3) 7 (4.7) 1.7 ( 1.6†

*Values are given as the mean (( SD) or No. (%). †p & 0.001 (vs fospropofol, 2 mg/kg).

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Table 4 —Patient Satisfaction* Fospropofol Groups Parameters Patient ratings Remembers being awake during scope insertion Remembers being awake during procedure Remembers having scope removed Agrees to use sedative again Overall satisfaction with entire procedure‡ 1–5 6–8 9–10 Overall comfort level during procedure§ 1–5 6–8 9–10

2 mg/kg (n ! 102)

6.5 mg/kg (n ! 150)

47 (46.5)

19 (12.7)

45 (44.6)

25 (16.7)†

40 (39.6) 79 (78.2)

16 (10.7) 141 (94.6)†

8 (7.9) 22 (21.8) 71 (70.3)

1 (0.7) 21 (14.1) 127 (85.2)

11 (10.9) 24 (23.8) 66 (65.3)

7 (4.7) 13 (8.7) 130 (86.7)

*Values are given as No. (%). †p & 0.01 (vs fospropofol, 2 mg/kg). ‡Satisfaction scale ranged from 1 (dissatisfied) through 10 (highly satisfied). §Comfort scale ranged from 1 (least comfortable) though 10 (most comfortable).

Safety Of the 256 patients who were randomized, 252 received one or more doses of fospropofol and were included in the safety population. No treatmentrelated AEs led to study discontinuation or death.

AEs: Most AEs were self-limited, transient, and mild to moderate in severity. These AEs included paresthesia (47.6%) and pruritus (14.7%). Twentytwo patients (14.8%) in the 6.5 mg/kg group and 13 patients (12.6%) in the 2 mg/kg group experienced severe AEs during the study. Eight patients in the 6.5 mg/kg group (paresthesia, n ! 5; hypoxemia, n ! 2; and pruritus, n ! 1) and two patients in the 2 mg/kg group (paresthesia, n ! 1; pruritus, n ! 1) experienced severe AEs that were considered to be related to fospropofol. Only one of these AEs (paresthesia, which resolved within 6 min) led to the discontinuation of fospropofol therapy.

The most common cardiopulmonary AEs were hypoxemia (14.3%) and hypotension (3.2%). All instances of hypotension (n ! 8) occurred in the 6.5 mg/kg group, with two patients requiring IV fluid bolus during their return to a normal BP. Sedation-Related AEs in Subgroup Populations: When sedation-related AEs were evaluated in relation to age, there was an increased incidence in patients ! 65 years of age (14 of 61 patients; 23%) compared to patients & 65 years of age (16 of 88

patients; 18.2%), but this did not reach statistical significance (p " 0.5355). There was no difference in the incidence of sedation-related AEs when evaluated by patient weight (& 60 kg, 6 of 27 patients "22.2%#; 60 to 90 kg, 15 of 80 patients "18.8%#; and ! 90 kg, 9 of 42 patients "21.4%#; p ! 0.7804) or ASA status (ASA Physical Classification System status, P1/P2 "17 of 80 patients; 21.3%#; ASA Physical Classification System status, P3/P4 "13 of 69 patients; 18.8%; p ! 0.8283#).

Airway Assistance: Sedation with fospropofol, 6.5 mg/kg, was associated with a higher frequency of hypoxemia vs sedation with fospropofol, 2.0 mg/kg (15.4% vs 12.6%, respectively). Airway assistance events are summarized in Table 5. Overall, 46 patients (18.3%) required some form of airway assistance, most commonly increased oxygen flow (15.9%). There were two instances of severe hypoxemia, both in the 6.5 mg/kg group. The first instance was a 78-year-old patient with a history of severe COPD, congestive heart failure, recurrent pneumonia, and home oxygen therapy (4 L/min). The patient’s oxygen saturation at hospital admission was 92% and fell to as low as 72% approximately 32 min after receiving fospropofol, 6.5 mg/kg (17 min after withdrawal of the bronchoscope). The patient recovered without incident. The second patient recovered with repositioning, suction, increased oxygen flow, and verbal stimulation. In the 6.5 mg/kg group, there was a single occurrence of apnea/hypopnea lasting for 3.1 min at 14 min after the first fospropofol dose.

This resolved following chin lifting and tactile stimulation. There were no episodes of bradycardia.

Discussion Most guidelines in the United States8,29 and Europe30 recommend the sedation of patients when Table 5—Airway Assistance* Fospropofol Groups Events Patients requiring any type of airway assistance Increased oxygen flow Verbal stimulation Chin lift Jaw thrust Tactile stimulation Patient repositioning Suction Face mask (100% oxygen) Manual ventilation (bag-valve mask)

2 mg/kg (n ! 103)

6.5 mg/kg (n ! 149)

14 (13.6)

33 (21.5)

12 (11.7) 2 (1.9) 1 (1.0) 3 (2.9) 1 (1.0) 0 (0) 0 (0) 1 (1.0) 0 (0)

28 (18.8) 6 (4.0) 5 (3.4) 2 (1.3) 4 (2.7) 3 (2.0) 3 (2.0) 1 (0.7) 1 (0.7)

*Values are given as No. (%). Individual patients may be counted in more than one event category.

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undergoing bronchoscopy. An ideal sedative should be easy to use and have a rapid onset, short duration, and quick recovery with a rapid return of cognition, as well as a predictable pharmacokinetic/pharmacodynamic profile. The most commonly used agents (benzodiazepines and opioids) have some of these properties, but each has limitations. Fospropofol may have certain advantages when compared to lipid propofol. Since propofol is not released from the prodrug until it comes in contact with endogenous enzymes, the plasma concentration profile produced by fospropofol is characterized by lower peak concentrations and a more gradual decline compared to the lipid formulation.18,19 Since the cardiopulmonary effects associated with propofol are related with the concentration,17 the pharmacokinetics of fospropofol should theoretically produce less cardiopulmonary depression due to its less variable peak concentration (ie, wider therapeutic index).

This study demonstrated that fospropofol was titratable to a moderate depth and duration of sedation with a favorable safety profile. For the primary end point (sedation success rate), the difference between the two dose groups was both statistically significant and clinically meaningful. Secondary end points (ie, treatment success, willingness to be treated again, and not recalling being awake during the procedure) also favored the 6.5 mg/kg group. While no direct comparison has yet been made between fospropofol and the commonly used midazolam/fentanyl combination, previous studies12,13 have reported that the time to full alertness ranged from 20 to 120 min with the use of midazolam/ opioids, compared with 16 min with the use of fospropofol. This may be significant since prolonged sedation might lead to longer recovery times and decreased throughput. The use of fospropofol, 6.5 mg/kg, significantly reduced the need for alternative sedation regimens, thus avoiding the potential synergism associated with the use of multiple medications.31 The major safety concern with sedative regimens is excessive depth and duration of sedation causing apnea, hypoxemia, hypotension, and bradycardia.

The safety profile of fospropofol was similar to that of commonly used sedation medications in a similar population.12,32 Most AEs were of mild-to-moderate intensity and resolved with minimal intervention.

Patients in this study were frequently elderly (41% were ! 65 years of age) with significant comorbid illnesses (43% were considered to have an ASA Physical Classification System status of 3 or 4).

Hypoxemia was the most common sedation-related event (14.3%) but resolved in the majority of patients with an increase in oxygen flow. The rate of hypoxemia here is similar to that in other studies12,31–33

with a similar patient population using midazolam and fentanyl (reported rates of 24 to 32%).

The side-effect profile of lipid propofol has caused some hospitals to require anesthesiology supervision for use outside the ICU. Since this drug is not a general anesthetic but a medication to be used for moderate sedation, the study was performed by pulmonologists without anesthesia supervision and had an acceptable safety profile.

There are two limitations of this study worth noting. First, this study was not designed to compare fospropofol with established sedative regimens (eg, midazolam or opioids). Thus, the relative efficacy and safety of fospropofol was inferred but not directly determined, and will require prospective comparative trials. The second limitation is the possible additive effect of the single preprocedure dose of fentanyl in combination with fospropofol. To avoid this, future studies could be performed in the absence of fentanyl.

The strengths of this study include the robust study design (prospective, blinded, randomized, and multicentered), a population of patients who frequently undergo bronchoscopy, and the number of relevant end points that explore benefits to the patient, physician, and practice. To date, we are unaware of any study evaluating the efficacy and safety of a moderate sedation regimen for bronchoscopy that has collected data in this extensive a manner. The data collection instruments used in this study may provide the basis for the evaluation of both currently used sedative medications as well as those that are in development.

In summary, fospropofol is an effective sedative regimen that results in predictable moderate sedation with an acceptable safety profile in patients undergoing flexible bronchoscopy. This is the first new drug in % 2 decades that has been evaluated for use in conscious sedation during fiberoptic bronchoscopy. Future trials should focus on directly comparing fospropofol and the current sedative regimens used for this commonly performed procedure.

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Anaesthesia 1988; 43:281–284 14 Floyd MD, Gervasini G, Masica AL, et al. Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women. Pharmacogenetics 2003; 13:595– 606 15 Rogers JF, Rocci ML Jr, Haughey DB, et al. An evaluation of the suitability of intravenous midazolam as an in vivo marker for hepatic cytochrome P4503A activity. Clin Pharmacol Ther 2003; 73:153–158 16 Gan TJ. Pharmacokinetic and pharmacodynamic characteristics of medications used for moderate sedation. Clin Pharmacokinet 2006; 45:855– 869 17 Kanto J, Gepts E. Pharmacokinetic implications for the clinical use of propofol. Clin Pharmacokinet 1989; 17:308 – 326 18 Shah A, Fechner J, Struys M, et. al. Differential PK/PD of propofol after intravenous fospropofol and diprivan in healthy subjects. Anesthesiology 2007; 107:A46 19 Fechner J, Ihmsen H, Hatterscheid D, et al. Pharmacokinetics and clinical pharmacodynamics of the new propofol prodrug GPI 15715 in volunteers. Anesthesiology 2003; 99: 303–313 20 Cohen LB, Wang C, Jones JB. AQUAVAN is safe and

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