Dig Dis Sci (2010) 55:2537–2544 DOI 10.1007/s10620-010-1308-0

ORIGINAL ARTICLE

Comparison of Propofol Deep Sedation Versus Moderate Sedation During Endosonography D. S. Nayar • W. G. Guthrie • A. Goodman Y. Lee • M. Feuerman • L. Scheinberg • F. G. Gress

•

Received: 10 January 2010 / Accepted: 14 June 2010 / Published online: 16 July 2010 Ó Springer Science+Business Media, LLC 2010

Abstract Background The purposes of this study are: (1) to prospectively evaluate clinically relevant outcomes including sedation-related complications for endoscopic ultrasound (EUS) procedures performed with the use of propofol deep sedation administered by monitored anesthesia care (MAC), and (2) to compare these results with a historical case–control cohort of EUS procedures performed using moderate sedation provided by the gastrointestinal (GI) endoscopist. Materials And Methods Patients referred for EUS between January 1, 2001 and December 31, 2002 were enrolled. Complication rates for EUS using MAC sedation were observed and also compared with a historical case– control cohort of EUS patients who received meperidine/ midazolam for moderate sedation, administered by the GI endoscopist. Logistic regression analysis was used to isolate possible predictors of complications. Results A total of 1,000 patients underwent EUS with propofol sedation during the period from January 1, 2001 through December 31, 2002 (mean age 64 years, 53%

female). The distribution of EUS indications based on the primary area of interest was: 170 gastroduodenal, 92 anorectal, 508 pancreaticohepatobiliary, 183 esophageal, and 47 mediastinal. The primary endpoint of the study was development of sedation-related complications occurring during a performed procedure. A total of six patients experienced complications: duodenal perforation (one), hypotension (one), aspiration pneumonia (one), and apnea requiring endotracheal intubation (three). The complication rate with propofol was 0.60%, compared with 1% for the historical case–control (meperidine/midazolam moderate sedation) group. Conclusions There does not appear to be a significant difference between complication rates for propofol deep sedation with MAC and meperidine/midazolam administered for moderate sedation. Keywords Endoscopic ultrasound
EUS
Propofol
Deep sedation
Complications

Introduction D. S. Nayar Gastroenterology Associates of Central Jersey, Edison, NJ, USA M. Feuerman Department of Biostatistics, Winthrop University Hospital, Mineola, NY, USA L. Scheinberg Department of Anesthesiology, Winthrop University Hospital, Mineola, NY, USA W. G. Guthrie (&)
A. Goodman
Y. Lee
F. G. Gress Division of Gastroenterology, SUNY-Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, USA e-mail: [email protected]

Propofol (2,6-diisopropylphenol) is a short-acting sedative hypnotic that provides clinically significant levels of amnesia [1]. Induction time of propofol deep sedation (PDS) depends on several patient factors but can be as short as 15–30 s. Similarly, recovery times after PDS are also rapid, often less than with typical narcotic and benzodiazepine regimens for conscious sedation [3]. For these reasons propofol continues to grow in popularity among gastrointestinal endoscopists [2, 4]. The general excitement regarding PDS has given rise to a paradigm shift in gastrointestinal endoscopy. In some cases, patients even ask for it by name.

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However, as with any innovative application, including medications, most endoscopists prefer to wait until investigations can demonstrate adequate safety data before changing their practice. At present, the literature is still expanding with regards to PDS safety during gastrointestinal endoscopy. However, numerous studies using PDS are now underway to study its use and experience at centers of excellence. PDS has been studied during basic gastrointestinal endoscopy. In fact, use of PDS during routine upper gastrointestinal endoscopy and colonoscopy has largely shifted from safety [5–9] to cost-effectiveness studies [10]. Some authors have used PDS in combination with other medications in an algorithmic fashion [10–12]. There is limited data regarding use of PDS for more complex, advanced endoscopic procedures such as endoscopic retrograde cholangiopancreatography (ERCP) or endoscopic ultrasonography (EUS) [7, 13, 14]. However, propofol may actually be well suited for use in this group of patients, due to the length of these relatively complex procedures compared with routine upper endoscopy and patient’s natural discomfort with an endoscope traversing the hypopharynx adjacent to the upper airway. Propofol typically provides much deeper levels of sedation than meperidine/midazolam administered for moderate sedation (MMMS), giving improved patient comfort during the procedure. In addition, due to its rapid onset of action and predictable dose effect, it can provide a consistent level of sedation during longer endoscopic procedures. There is also limited data comparing the safety of conscious sedation regimens versus PDS. Traditional moderate sedation utilizes benzodiazepines alone or in combination with an opiate analgesic. In general, this regimen is well tolerated. Its safety profile is reflected in its general acceptance as the standard regimen for sedation in general gastrointestinal endoscopy. Furthermore, this regimen is often used as the standard for comparison against novel sedative combinations or compounds being evaluated for use during endoscopy. However few comparisons exist for advanced endoscopic procedures [15, 16]. Very few large-scale trials comparing outcomes of PDS with those of moderate sedation during EUS have been performed. The purpose of this study is to collect and compare outcome data for MAC-assisted PDS including complications and compare these data with a cohort of patients who received meperidine/midazolam administered for moderate sedation (MMMS) during EUS procedures.

Patients and Methods The Winthrop University Hospital institutional review board approved our study protocol. The endoscopy unit at this institution maintains a prospective database of all

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endoscopic procedures including complications since 1996. We began using PDS with MAC for EUS procedures in January 2001; prior to this we used moderate sedation. We performed a search of this database for the first 1,000 consecutive patients having PDS during their EUS procedure and the last 1,000 consecutive patients receiving MMMS to December 31, 2000. Patient Selection The PDS subset included 1,000 consecutive patients referred for EUS procedures between January 1, 2001 and December 31, 2002. The MMMS group consisted of 1,000 consecutive patients referred to our institution between January 1, 1999 and December 31, 2000. Patients varied only by indication. If a decision was made to perform fineneedle aspiration (FNA) biopsy, then re-intubation with a curvilinear endoscope may have been required. All patients included in the study were consecutive adult (age [18 years) inpatients and outpatients able to provide informed consent. Patients were excluded if aged \18 years, pregnant, unable to provide verbal and written informed consent, or with history of sulfite, egg or soybean allergy. No patient was excluded based on American Society of Anesthesiologists (ASA) classification. Patient Assessment A brief assessment was administered by nursing staff in order to gather demographic data, medications, allergies, past medical history, and appropriate history regarding their present illness. The physician(s), including the endoscopist and anesthesiologist, involved in the case also repeated certain aspects of this interview and examined each patient prior to their procedure. Trained recoveryroom nurses provided all postendoscopy monitoring. Patient Monitoring Administration of PDS was performed by a board-certified anesthesiologist (MAC). MMMS was supervised by the endoscopist. In both types of sedation, vital sign monitoring was performed as follows: chest excursion, respiratory rate, and respiratory effort were monitored by the anesthesiologist for PDS or sedation nurse for MMMS; blood pressure was monitored using an automated blood pressure cuff (Datascope, Montvale, NJ). Supplemental oxygen was provided via nasal cannula (2–4 l/min). Oxygen saturation level was monitored continuously via pulse oximetry (Datascope, Montvale, NJ). Continuous electrocardiographic rhythm monitoring was also performed. Graphical assessment of electrical heart rhythm (three chest leads), heart rate, blood pressure, respiratory rate, and arterial

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waveform were monitored by the anesthesiologist for PDS and by the sedation nurse for MMMS. Baseline vital signs and pulse oximetry were monitored for a minimum of 3 min. Cardiopulmonary activity was recorded on an anesthesia flow sheet. Capnography monitoring was not used during our procedures. The goal of sedation was for patients to maintain their own airway without assistance, maintain spontaneous breathing, and remain ‘‘comfortable.’’ During moderate sedation cases using MMMS a sedation nurse dedicated to continuous monitoring of all vital signs was located at the head of the patient’s bed. A second nurse or technician provided procedural assistance and remained beside the primary endoscopist to provide any necessary accessories (catheters, needles, etc.) or assist with patient as needed (i.e., oropharyngeal suctioning). During the PDS procedures, a nurse or a technician was present, but usually not both. The anesthesiologist monitored the patient’s vital signs. A gastroenterology fellow usually performed the initial endosonographic study in the presence of the attending physician, prior to completion of the procedure by the attending physician. Recovery Monitoring After the procedure, patients were brought to the endoscopy unit recovery room for postprocedure monitoring. Since MAC-assisted procedures were being performed in our unit, recovery-room nurses were required to be trained similarly to postanesthesia care unit (PACU) nurses. This meant an additional cost outlay initially for the endoscopy unit in order to bring our nurses up to this standard. In addition, our recovery-room monitoring equipment had to be upgraded to PACU standards as well. Outcomes and Statistical Methods Variables are expressed as mean ± standard deviation (range). Examined outcomes included sedation time, procedure time, recovery time, mean dose, complications, and patient satisfaction as measured by visual analog scale (VAS, 1-worse to 10-best). Time to intubation was calculated as the difference between procedure start time and anesthesia start time. P-values were calculated for outcome data using Fisher’s exact test and unpaired t-tests. For the PDS arm, logistic regression analysis was used to determine whether age, sex, procedure time, propofol dose, area of study or performance of fine-needle aspiration biopsy were possible predictors of complications. The primary endpoint of the study was development of a sedationrelated complication during the procedure. A procedure was flagged as having a sedation-related complication if a cardiopulmonary event (desaturation \85%, respiratory

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rate \8/min, systolic blood pressure \90 mmHg, heart rate \50 bpm) was noted. Secondary endpoints were defined as postprocedure sedation-related complication [postprocedure hypoxia \85%, apnea defined as respiratory rate \8/min, hypotension defined as systolic blood pressure (SBP) \90 mmHg or bradycardia defined as heart rate \50 bpm] or occurrence of a procedure-related event (perforation, bleeding, aspiration). All patients were contacted by telephone by endoscopy nursing staff on the day after the procedure. This call was always made within 24 h after their EUS study. The purposes of the telephone call were to assess for adverse outcomes and compliance with postprocedure physician recommendations, and to answer any questions the patient may have had related to their recent procedure. Drug Regimens One of 18 board-certified anesthesiologists provided PDS. A 1% propofol injectable emulsion (Diprivan, Astra Zeneca, Wilmington, DE; or Propofol, Baxter, New Providence, NJ) was given via 0.5–1.0 mg/kg slow infusion over 3 min for induction. In patients with ASA class III or higher, lower-dose (0.1–0.4 mg/kg) slow infusion was administered for induction. Maintenance of MAC sedation was carried out using a variable-rate infusion method (from 25 to 75 mg/kg/min) in patients with ASA class III and higher, and 0.3–0.7 mg/kg slow injections in ASA class I and II patients. There were no set limits on total cumulative dose. In cases where moderate sedation was used prior to January 1, 2001, 50 mg meperidine/2 mg midazolam was the typical intravenous induction dose for moderate sedation, formerly referred to as conscious sedation. Increments of 25 mg meperidine and 1 mg midazolam were given as needed when patients exhibited symptoms of discomfort. Conversely, the goal in the PDS cohort was to achieve deep sedation, defined as a level of sedation whereby patients were unable to respond to tactile stimuli but were able to maintain their own airway without assistance and breathe spontaneously on their own [17, 18].

Postanesthesia Recovery Score A recovery scoring system was used to determine appropriateness for discharge from the recovery room. Patients were scored from 0 to 2 points for five distinct categories: 1. 2.

Activity (able to move all extremities, ability to move two limbs, not able to move extremities) Respiration (able to breathe deeply and cough, limited respiratory effort, apnea)

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3. 4.

5.

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Circulation (systolic blood pressure value compared with baseline prior to PDS or MMMS) Moderateness (fully alert, able to answer questions and acknowledge location, aroused to name, not responding) Color (normal appearance, pale or dusky, cyanotic)

Recovery-room nurses discharged patients once they achieved a 10 out of 10 score (full recovery). Time to full recovery was recorded for each patient.

Results Patient characteristics are summarized in Table 1. Patients were evenly matched with respect to age, gender, body mass index, ASA classification, and performance of FNA. Propofol Deep Sedation Group One thousand seventy-four patients undergoing PDS were eligible for the study. Of these, the first 1,000 patients eligible for inclusion were selected (Table 1). The remaining patients were excluded based on previously described exclusion criteria. Mean age was 64 years (range 32–90 years; 475 men, 525 women). A total of 42% of patients were classified as ASA class III, IV or V. A total of 36% of patients underwent EUS-guided FNA during their procedure. Meperidine/Midazolam Moderate Sedation Historical Cohort Group One thousand consecutive patients who underwent MMMS were selected (Table 1). Mean age was 65 years (range 28–89 years; 52 men, 48 women). A total of 31% of patients

Table 1 Patient characteristics

were classified as ASA class III or higher. A total of 32% of patients underwent EUS FNA. Procedure-related data indicated that patients in the PDS arm had shorter time to initial intubation, shorter procedure time, shorter recovery time, and greater patient satisfaction score. The differences in time measurements reached statistical significance. There was no statistically significant difference in complication rates. The mean propofol dose was 320 mg (range 60–620 mg). In the MMMS arm, mean meperidine dose was 84 mg (range 25–200 mg) and mean midazolam dose was 5.9 mg (range 2–10 mg) (Table 2). Five sedation-related complications and one proceduralrelated complication occurred in the PDS group. One postprocedure sedation-related complication occurred in the MMMS group (Table 3). There were no procedurerelated complications in the MMMS group. There were no intraprocedure sedation-related complications in the MMMS group. Age, gender, BMI, ASA class, indication, and performance of FNA were not shown to be predictors of complications (P [ 0.05) (Table 4). Complications Related to PDS A 73-year-old female had a history of gastroparesis and esophagectomy for esophageal adenocarcinoma. She underwent EUS to stage tumor recurrence. An initial upper endoscopy noted solid food in her stomach up to the esophageal remnant. She subsequently aspirated. She was treated with intravenous antibiotics and was discharged on hospital day 8. Three patients developed respiratory failure. All three were undergoing EUS through the upper gastrointestinal tract. Each patient required transient endotracheal intubation. However, no patient required overnight hospital stay, and each procedure was completed after endotracheal (ET)

PDS (N = 1,000)

MMMS (N = 1,000)

P value

Age, mean ± SD (range), years

64 ± 11 (32–90)

65 ± 4.5 (28–89)

0.37a

Gender (M/F, %)

47.5/52.5%

52/48%

0.40b

Body mass index (kg/m )

26.6 ± 6.2

26.9 ± 6.1

0.46a

ASA class I or II

578

690

ASA class III or higher

422

310

Anorectal

92

53

Pancreaticohepatobiliary Esophageal

508 183

485 138

Gastroduodenal

170

265

Mediastinal/non-GI

47

59

Performance of FNA

357

329

2

Indication

a

Student’s t-test; b Chi-square or Fisher’s exact test

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Dig Dis Sci (2010) 55:2537–2544 Table 2 Procedural data

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N

PDS 1,000

Dose, mean ± SD (range), mg

320 ± 50 (60–620)

MMMS 1,000

P value

84 ± 1.0 meperidine

N/A

(25–200) 5.9 ± 0.4 midazolam (2–10)

Table 3 Complication data

Sedation time, mean ± SD (range), min

3.1 ± 1.4 (1–5.5)

5.8 ± 2 (4–10)

Procedure time, mean ± SD (range), min

28 ± 15 (6–48)

61 ± 11 (22–120)

0.0001

Recovery time, mean ± SD (range), min

35 ± 10 (21–50)

70 ± 8 (30–120)

0.0001

Patient satisfaction, mean ± SD (range), (1–10)

9.5 ± 1.2 (8–10)

8.3 ± 1.5 (1–9)

0.0001

Complications

6 (1 perforation, 3 respiratory failure, 1 aspiration, 1 hypotensive event)

1 (prolonged lethargy)

0.49

Patient

Sedation type

Complication type

1

PDS

2

PDS

3

0.0001

Hospital admission

Hospital days required

Perforation

Yes

11

Aspiration

Yes

8

PDS

Apnea

No

0

4

PDS

Apnea

No

0

Total number of PDS cases analyzed: 1,000

5

PDS

Apnea

No

0

6

PDS

Hypotension

No

0

Total number of MMCS cases analyzed: 1,000

1

MMMS

Obtundation

No

0

Table 4 Patient characteristics as predictors of complications Patient

Age

Sex

BMI

ASA class

Indication

FNA

1

49

M

27.9

I

Gastroduodenal

No

2

73

F

25.2

III

Esophageal

No

3

56

M

25.1

II

Pancreaticohepatobiliary

Yes

4

40

M

28.4

II

Mediastinal/non-GI

No

5

85

F

23.3

I

Pancreaticohepatobiliary

Yes

6

59

F

24.8

IV

Gastroduodenal

Yes

1

67

M

22.1

III

Pancreaticohepatobiliary

No

intubation. The ET tube was removed immediately after the procedure was completed. Intravenous fluids were required for another patient whose systolic blood pressure fell by [50% of baseline (120 to 50 mmHg). The patient’s hemodynamics responded slowly to fluid resuscitation, and the procedure was abandoned for safety concerns. The patient recovered without further complications. There was one procedure-related complication. This involved a 49-year-old male who underwent outpatient EUS staging of a lesion in the duodenal bulb and

subsequently underwent endoscopic mucosal resection (EMR) of the same. The patient suffered a perforation during EMR, which was recognized immediately. The patient was ASA class I. A hospital stay of 7 days was required. The patient underwent exploratory laparotomy with repair of the perforation. Complications Related to MMMS One patient, undergoing EUS to evaluate his pancreas for chronic pancreatitis, reported prolonged somnolence lasting almost 24 h after the procedure. The patient denied that these adverse effects interfered with lifestyle or daily activities. No patient in this study group required reversal of sedation, and there were no procedure-related complications.

Discussion To our knowledge, there are very few studies comparing traditional MMMS versus PDS in patients undergoing EUS [14, 19–21]. Also, existing literature does not adequately

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study patients having outpatient endoscopy and classified as ASA class III, IV or V [22–25]. The results of our study confirmed that PDS provides effective sedation and allowed shorter procedure time (28 ± 15 min versus 61 ± 11 min), which may suggest better cost efficiency, although this point will need to be formally evaluated in future studies. The reasons for this shorter procedure time are not clear, although they may be related to a deeper, more consistent sedation with less patient movement and/ or discomfort, allowing more time-efficient examination to be performed. In this study, we evaluated use of PDS in 1,000 consecutive patients and compared clinical outcomes with 1,000 historical control patients who received MMMS. Time to intubation (sedation time), procedure time, recovery time, and patient satisfaction score were significantly better for the PDS group. Based on our institution’s experience, we did not observe significant differences in complication rates between the two groups. Various centers of excellence have instituted PDS administration by trained nurses or gastrointestinal endoscopists [2, 5, 20]. Previous published data regarding PDS during EUS are limited to small numbers of relatively ‘‘healthy’’ patients [4]. Many studies have been limited to ASA class I or II patients. Published data regarding nurseadministered PDS in patients of ASA class III or above is also limited. Furthermore, adequacy of sedation in this population is called into question in these studies [9]. Our institution’s guidelines mandate utilization of a board-certified anesthesiologist during PDS administration in the nonintubated patient. Therefore, no patient was denied PDS based on ASA class. Furthermore, ASA class (I though V) was not a predictor of potential complications during PDS in our study. This study establishes favorable safety data for anesthesiologist-administered PDS during EUS. While safety data is comparable for low-dose propofol sedation, it must be recognized that these studies involved patients suitable for basic endoscopic procedures, taking about 15–30 min to complete, as an outpatient, and in some cases office-based procedures. In this study, we were performing complex, advanced procedures, and in some cases these were performed on patients with multiple comorbid conditions, advanced ASA class, and tolerance to pain medication. The majority of these patients tolerated the procedure well under MAC-assisted propofol sedation. Although there were three episodes of respiratory failure in the PDS group, each patient was stabilized by the anesthesiologist and the study was then completed. Also noteworthy in our study is that the PDS group received only propofol as a single agent. PDS was not used in combination with another benzodiazepine and/or narcotic. The combination of propofol/narcotic or propofol/

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narcotic/benzodiazepine has been used in both basic and endoscopic procedures [6, 8]. These combinations may provide powerful synergistic effects, giving deep sedation. However, it is difficult to compare safety profiles when drugs are used in combination; therefore, we chose to use single agents in this study. Cost concerns relating to anesthesiologist-administered PDS need to be weighed against several other factors. Estimated costs at our institution for MMMS are US $25/ case, which includes the costs of the fentanyl and midazolam as the administration of the sedation is performed by the endoscopist and bundled into the endoscopist’s fee. In contrast, estimated costs at our institution for PDS are US $500 to US $900/case, which include the costs of not only the propofol (US $25/bottle) but also the costs of administration by the anesthesiologist. However, despite the incremental costs of providing PDS, one must also consider the overall savings to the endoscopy unit. These savings are based on the decrease in recovery time and the decrease in the time from procedure to discharge of the patient (Table 2). This improved efficiency provides for more cases to be performed in the same amount of time, somewhat offsetting this incremental cost. Furthermore, the need for less ancillary staff in the EUS room due to the ability to achieve deeper sedation and the presence of the anesthesiologist, although not formally evaluated in this study, was observed and potentially may offset some of the costs of anesthesiologist-administered sedation. Future studies are necessary to establish the true cost-effectiveness of this approach. However, our data suggest that patients were sedated faster than with MMMS (Table 2). The procedures were completed quickly and safely without a significant increase in complications. Patients also recovered in a more efficient manner than the moderate sedation group. Most importantly, the PDS group was, overall, more satisfied with their level of sedation and procedure experience. Given this information, it would be beneficial to study a differential cost-effectiveness ratio of propofol sedation versus traditional moderate sedation. An important limitation of our study is that we did not provide an objective measurement of endoscopist satisfaction. However, our subjective impression and the overall data including the patient’s satisfaction showed that PDS dramatically facilitated the examination. Prolonged sedation was possible during PDS, allowing for a sense of reassurance during difficult procedures. We found that relatively large doses of propofol were necessary in certain cases. Based on our study, PDS used alone, when administered by highly experienced physicians (i.e., anesthesiologists), did not seem to have such a ‘‘narrow’’ therapeutic window. Other important limitations involve the study design. We compared two historical cohorts over two time periods

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at the same institution. A prospective randomized trial would provide more powerful and compelling data if it did show a significant difference, as our study did between the two sedation types. However, enrolling patients in such a study may prove difficult given patient and endoscopist preference for deeper sedation. Secondly, a large portion of patient complications in the PDS group were related to apnea (Table 3). This is a concerning complication and, although it was not shown to be statistically significant in our study, may have been preventable. End-tidal CO2 capnography, now commonly used by anesthesiologists to monitor for apnea, was not available at the time our study was conducted. However, addition of this to our study design may have predicted and/or prevented these outcomes in our patients. Finally, inclusion of patients undergoing anorectal EUS in both sedation cohorts is somewhat controversial. Not all institutions use sedation for anorectal cases, or may only provide sedation in selected cases. However the policy at our institution is to provide sedation for all patients undergoing endoscopic procedures who request it, and the only sedation available is MAC-administered PDS. Furthermore a number of patients referred to our center for anorectal EUS have malignancies and, due to significant discomfort, request sedation. In conclusion, propofol sedation appears to be an effective method for providing deep sedation during endoscopic procedures. While several studies have reported on its efficacy when used in low doses in conjunction with nurse administration, these reports were mainly on patients receiving general endoscopic procedures [i.e., esophagogastroduodenoscopy (EGD) and colonoscopy]. The need for deep sedation during advanced procedures inspired this study. We hypothesized that presence of an anesthesiologist during the procedure, while adding costs, would not only be safe but also efficacious. Our data supports this hypothesis. The need for additional studies that look at the cost-effectiveness of this approach, a comparison of ‘‘lower dose’’ propofol use, and propofol administration by nonanesthesiology health care providers for advanced endoscopic procedures would be valuable.

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