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A Prospective Evaluation of the Incidence of Adverse Events in Nurse-Administered Moderate Sedation Guided by Sedation Scores or Bispectral Index

Yang, Katie S. BS*; Habib, Ashraf S. MBBCh, MSc, MHSc, FRCA; Lu, Minyi MD, PhD; Branch, M. S. MD§; Muir, Holly MD; Manberg, Paul PhD; Sigl, Jeffrey C. PhD; Gan, Tong J. MB, MD, MHS, FRCA

doi: 10.1213/ANE.0b013e3182a125c3
Ambulatory Anesthesiology: Research Report

BACKGROUND: Moderate sedation is routinely performed in patients undergoing minor therapeutic and diagnostic procedures outside the operating room. The level of sedation is often monitored by sedation nurses using clinical criteria, such as sedation scores. The Bispectral Index (BIS) is derived from changes in the electroencephalograph profile that may provide an objective measure of the level of sedation. In this prospective observational study, we investigated whether using BIS values to guide sedative drug administration influences the level of sedation and the incidence of adverse events compared with using Ramsay sedation scale (RSS) only in nurse-administered moderate sedation. We hypothesized that both depth of sedation and the incidence of adverse events related to oversedation would decrease when sedation nurses used BIS values to help guide sedative drug administration.

METHODS: Sedation care was provided by trained sedation nurses under the supervision of a physician performing the procedure. The sedation regimen was initiated with IV midazolam 1 to 2 mg and fentanyl 50 mcg or hydromorphone 0.2 mg. Additional small boluses of midazolam, fentanyl, or hydromorphone were administered to maintain an RSS of 2 to 3 (cooperative, oriented, and responding to verbal command). Propofol was not used. Information including patient demographics, type of procedure, medication administered, RSS, and rates of adverse events was recorded by the sedation nurses for each patient on a computer-readable form. The study was divided into 3 phases. In phase 1 (baseline, 6 months’ duration), baseline data on sedation practice were prospectively collected. There was no change from standard of care for all patients except that each patient had a BIS sensor attached, but the monitor was covered and nurses were blinded to the BIS values. In phase 2 (training, 3 months), the sedation nurses received comprehensive education on the use of BIS to guide sedative drug administration, pharmacology of commonly used drugs, and methods for rescue from oversedation. The recommended BIS range for moderate sedation was 75 to 90. Adequate training of all sedation nurses on the use of BIS was documented. In phase 3 (implementation, 6 months), the BIS values were used to guide drug administration.

RESULTS: Data were available on 1766 patients (999 and 767 patients in phases 1 and 3, respectively). Most of the procedures were colonoscopies, upper gastrointestinal endoscopies, examinations under anesthesia, endoscopic retrograde cholangiopancreatography, and central venous access catheter placements. No differences in the demographics between the 2 groups were observed. The RSS was inversely associated with the BIS value, r = −0.16 (95% confidence interval, −0.19 to −0.12; P < 0.00001). An RSS of 2 to 3 was maintained in 94% of patients in phase 1 and 96% of patients in phase 3 The mean (±SD) BIS values were 80.9 ± 6.8 in phase 1 and 80.4 ± 6.5 in phase 3. The number of sedation-related adverse events was lower in our sample when BIS was used, with an odds ratio of 0.41 (95% confidence interval, 0.28–0.62; P < 0.0001), and patients with restlessness had a lower BIS value than those without this symptom (P < 0.0001). No serious adverse events or deaths were reported.

CONCLUSIONS: Nurse-administered moderate sedation using midazolam and fentanyl was usually associated with appropriate levels of sedation as assessed by both the RSS and BIS with an overall low incidence of adverse events. The use of BIS did not change the mean level of sedation significantly, although the number of sedation-related adverse events appears to be lower when BIS was used.

Published ahead of print January 9, 2014

From the *School of Medicine and the Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina; Healthcare Economics & Outcomes Research, Covidien, Inc., Mansfield, Massachusetts; §Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina; Corolla Clin/Reg Consulting, Corolla, North Carolina; and Advanced Research Group, Covidien, Mansfield, Massachusetts.

Accepted for publication June 9, 2013.

Published ahead of print January 9, 2014

Funding: Funding for this study was provided by Covidien, Inc. The first author was supported by the Foundation for Anesthesia Education and Research (FAER) Medical Student Anesthesia Research Fellowship.

This report was previously presented, in part, at the ASA Meeting in 2010.

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

Reprints will not be available from the authors.

Address correspondence to Tong J. Gan, MD, MHS, FRCA, Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710. Address e-mail to tjgan@duke.edu.

Moderate sedation is a common practice during minor therapeutic or diagnostic procedures. This level of sedation, as defined by the American Society of Anesthesiologists,1 consists of depressed consciousness with purposeful response to verbal or tactile stimulation. No assistance is required to maintain a patent airway, and spontaneous ventilation and cardiovascular function are generally maintained.a Despite the growing importance of moderate sedation with the emergence of new minimally invasive surgical techniques, there is a paucity of prospective data on sedation practice and complications because data from previous studies have mostly been obtained from retrospective quality improvement databases.2,3 Maintaining the proper level of sedation is important, as oversedation can lead to sedation-related adverse events, including cardiovascular and respiratory compromise. In practice, however, depth of sedation is difficult to gauge precisely. Tools such as the Observer’s Assessment of Alertness/Sedation Scale and the Ramsay Sedation Scale (RSS) have been demonstrated to be valid and reliable by various studies4–6; however, their descriptive nature could introduce some variability among observers.

The Bispectral Index (BIS) is an electroencephalogram parameter commonly used in patients receiving general anesthesia and deep sedation to estimate depth of sedation. BIS values range from 0 to 100, with 0 signifying no brain activity and 100 signifying a fully awake patient. This measure has been extensively validated against clinical assessment tools and has been shown to reduce anesthetic drug use, expedite wake up from general anesthesia, and decrease postoperative recovery time.1,7,8 BIS values of 40 to 60 are associated with a hypnotic state appropriate for general anesthesia,9 while values of 70 to 90 (or near 82) have been demonstrated to be appropriate for moderate sedation.10 Although many studies have found BIS values to closely reflect clinical assessment scores in patients undergoing moderate sedation,10–13 others have found BIS values to be unreliable in predicting sedation levels in this setting.14,15 A few small studies have examined the effect of BIS monitoring on sedation levels with conflicting results,16,17 and no large-scale outcome study has been performed for this application.

There were 2 goals for the present study: the first was to determine the practice pattern of procedural sedation by trained sedation nurses and the incidence of adverse events in a large tertiary teaching institution; the second was to study in a large-scale clinical setting how introduction of BIS monitoring to guide sedative drug administration influences the level of sedation and the incidence of adverse events compared with using RSS alone. We hypothesized that both depth of sedation and the incidence of adverse events related to oversedation would decrease when sedation nurses used BIS values to help guide sedative drug administration.

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METHODS

IRB approval and oral patient consent were obtained. Data were collected from patients undergoing procedures requiring sedation in high-volume locations outside the operating room, including the emergency room, gastrointestinal endoscopy suite, infertility suite, cardiac catheterization lab, and radiology suite. Sedation care was provided by trained sedation nurses under the supervision of a physician performing the procedure. This study was divided into 3 phases:

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Phase 1—Pretraining Baseline Phase (6 Months)

All patients received IV midazolam 1 to 2 mg and fentanyl 50 mcg or hydromorphone 0.2 mg. Additional small boluses of midazolam, fentanyl, or hydromorphone were administered to maintain an RSS of 2 to 3 (cooperative, oriented, and responds to verbal command). Propofol was not used. Information including patient demographics, type of procedure, comorbidities, medication administered, duration of sedation, RSS, and rates of adverse events was recorded by the sedation nurses for each patient on a computer-readable form. Recorded adverse events included apnea, arterial oxygen saturation (SaO2)<90%, airway obstruction, inability to arouse, loss of consciousness, heart rate >100 or <50 bpm, arterial blood pressure ≥20% above or below baseline, restlessness, and excessive, moderate, and mild pain. Baseline data on sedation practice were prospectively collected. Each patient had a BIS sensor applied to his/her forehead per protocol, but the monitor was covered and nurses were blinded to the BIS values. Sedation management was otherwise unchanged from standard of care.

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Phase 2—Training (3 Months)

The sedation nurses received a formalized, comprehensive education on the use of BIS to guide sedative drug administration, pharmacology of drugs commonly used, proper patient selection and assessment, and methods for rescue from oversedation. Education was provided by faculty and education nurses. The recommended BIS range for moderate sedation was 70 to 90.b Adequate training of all sedation nurses on the use of BIS and sedation education was documented.

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Phase 3—Implementation (6 Months)

After the training phase, the BIS values were used to help guide drug administration. Data collection was implemented as in phase 1, but BIS values were now visible to the sedation nurses. Nurses were instructed to target a BIS range of 70 to 90 as a goal to guide drug administration. Inadequate sedation or BIS >90 was treated with bolus doses of midazolam 1 mg. Fentanyl 25 mcg or hydromorphone 0.2 mg was administered to achieve adequate analgesia.

BIS values were recorded in real time in the internal monitor (Model A-2000, Aspect Medical Systems, Inc., Mansfield, MA) memory files. Data were downloaded at periodic intervals and matched to other procedure data based on time and location identifiers. The mean BIS value for the duration of the procedure for each patient was calculated based on the average minute by minute BIS value downloaded from the monitor.

Before the study, the proportion of overall adverse events was estimated to be 0.1 based on our database in phase 1 (baseline) and a decrease to 0.05 was postulated in phase 3. Using these estimates, group sample sizes of 999 in phase 1 and 767 in phase 3 were calculated to achieve 98% power to detect a difference of adverse events between the group proportions of 0.05. The test statistic used is the 2-sided Z test. The significance level of the test was 0.05.

The statistical analysis was performed by using IBM SPSS (V16; IBM, Somers, NY). The descriptive statistics such as mean and 95% confidence interval (CI) were reported. Mean BIS and other continuous variables were compared between 2 study phases using Student 2-group t tests. Pearson χ2 test was applied to compare the proportion of adverse events and other discrete variables between phases. Fisher exact test was used if the number in any of the cells of a contingency table was <5. The runs test was performed on age variable to determine the observations were independent. The significance level was set at 0.05.

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RESULTS

Data were available on 1766 patients, with 999 evaluable patients in phase 1 and 767 patients in phase 3. All patients receiving care during both phases were included. The most common procedures included colonoscopy, upper gastrointestinal endoscopy, examination under sedation, endoscopic retrograde cholangiopancreatography, and central venous catheter placement. No differences in the demographics between the 2 groups were observed (Table 1). The RSS was inversely associated with the BIS value, r = −0.16 (95% CI, −0.19 to −0.12; P < 0.00001), and an RSS of 2 to 3 was maintained in 94% of patients in phase 1 and 96% of patients in phase 3. In both groups, 7% of patients reached BIS values between 45 and 60 at some point during the procedure (67 in phase 1 and 52 in phase 3), below the recommended range of 70 to 90. Seven patients in phase 1 and 5 patients in phase 3 reached BIS values <45. In addition, the overall mean BIS values for the entire case were similar in the 2 groups, 80.9 ± 6.8 in phase 1 and 80.4 ± 6.5 in phase 3 (Table 2). Figure 1 presents typical BIS values for a patient during a procedure with a range between 70 and 90.

Table 1

Table 1

Table 2

Table 2

Figure 1

Figure 1

Although the number of adverse events was low for both groups, there were fewer adverse events reported when BIS monitoring was used, with an odds ratio of 0.41 (95% CI, 0.28–0.62; P < 0.0001). Differences were statistically significant (P < 0.0001) for significant desaturation (SaO2 <90%), but not for apnea, loss of consciousness, airway obstruction, inability to arouse, pain, tachycardia, bradycardia, hypertension, hypotension, or restlessness (Table 2). However, the incidence of all adverse events combined was found to be significantly lower in phase 3 (P < 0.0001). Patients with restlessness reported during the case had a lower BIS value than those without this symptom (P < 0.0001). The runs test on age variable showed that the observations were independent (P = 0.764). As such, we performed a before/after analysis by pooling the data together. Within each phase, there was no trend over time of the presence of adverse events. No serious adverse events or deaths were reported.

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DISCUSSION

In this prospective observational study, we sought to determine the practice pattern of moderate sedation at a large tertiary care facility and investigate the influence of introducing routine BIS monitoring on the depth of sedation and the incidence of adverse events. Nurse-administered moderate sedation using midazolam and fentanyl was usually associated with appropriate levels of sedation as assessed by both the RSS and BIS with an overall infrequent incidence of adverse events. There was a significantly lower incidence of all types of adverse events combined in phase 3, but differences did not reach statistical significance for each individual event type except for desaturation <90%.

The use of BIS monitoring has been studied extensively in general anesthesia1,7,8 and has been validated by several studies against clinical assessment tools like RSS in intensive care unit settings,2–4 but has not been well studied in procedural sedation. A small number of studies have examined practice trends in the technique. A 2007 study examined anesthesia records of 42 patients undergoing awake craniotomy with fentanyl and propofol infusion. Both anesthetic drug use and adverse event incidence were found to be significantly lower in patients monitored with BIS than without. However, this study has limitations in its small sample size and retrospective design.18 There are few prospective analyses on the subject. There are also very little data on the incidence of adverse events during BIS-guided procedural sedation. Although some studies have examined the relationships between BIS monitoring and depth of sedation, sample sizes have been small and findings inconsistent. A 2009 randomized controlled trial of 90 patients undergoing deep sedation for endoscopic retrograde cholangiopancreatography found that mean BIS values [SD] were higher when they were visible to the anesthesia provider compared with sedation with BIS values not available to providers (61.68 [7.5] and 56.93 [4.77] for BIS-visible and control groups, respectively, P = 0.001).16 However, a similar study of 102 patients undergoing moderate sedation for colonoscopy found no significant difference in these values when BIS values were visible (mean BIS value 59.3 [9.9] and 59.9 [10.1], P = 0.82, for BIS-visible and control groups, respectively).17 To further complicate matters, deeper sedation levels have been associated with higher BIS value variability.11

This is one of the largest reported prospective observational studies (1767 patients) that systematically collected information on sedation practice and incidence of adverse events related to procedural sedation as well as the impact of BIS-guided sedative drug administration. There were a number of limitations to the study. First, our data were collected exclusively from 1 center. Our findings thus may not reflect the practice trends of other centers. Nevertheless, our sedation practice model and drug choices mirror those of many other institutions across the United States.19 Second, our study was not randomized; patients were assigned to phase 1 and phase 3 groups based on scheduled procedure date, as phase 3 took place after the conclusion of phases 1 and 2. In addition, sedation nurses were not blinded to the sequential phases of the study. While lack of randomization and blinding may introduce bias, it is important to note that the sedation staff in phase 3 consisted of the same individuals as in phase 1, but had been trained in BIS-guided sedative administration in the training phase of the study. It is also notable that despite phase 2 nurse education, our assumption that the nurses changed their sedation practices between phases 1 and 3 could not be confirmed. It was not possible to adequately determine whether nurses followed the protocol or simply continued to titrate based on RSS in phase 3. There were at least 10 sedation nurses each day. However, we did not have specific information about nurses being fired, terminated, or relieved during the study period. There was no indication such issues existed. Importantly, however, this study design allows us to examine differences after a coordinated practice change; the systematic collection of data before and after the training phase allows us to realistically predict the consequences if such a change were to be implemented on an even larger scale. There is evidence that different sedative drug regimens may give rise to similar BIS values, but different sedation depths.20,21 Findings from this study thus may not apply for patients receiving different drugs than the regimen administered here. Midazolam was used in this study due to the well-validated correlation between BIS values and sedation levels in patients receiving this drug.22–24 Propofol was not used at our institution for nonanesthesia personnel-monitored sedation. In addition, this study was not sufficiently powered to determine any differences in the incidence of serious adverse events.

In conclusion, sedation provided by trained nurses was largely associated with appropriate levels of sedation, as measured by RSS and BIS values. Use of BIS monitoring to guide anesthetic drug administration did not significantly change sedation levels. RSS and BIS were found to have a significant inverse correlation suggesting that BIS is a reliable monitor for measuring sedation depth for moderate sedation with midazolam, fentanyl, and hydromorphone. There were fewer adverse events when BIS values were visible to sedation nurses, but the overall incidence of adverse events was too low to establish a relationship.

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DISCLOSURES

Name: Katie Yang, BS.

Contribution: This author helped in preparation of the manuscript.

Attestation: Katie Yang approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Ashraf S. Habib, MBBCh, MSc, MHSc, FRCA.

Contribution: This author helped conduct the study and preparation of the manuscript.

Attestation: Ashraf S. Habib approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Minyi Lu, MD, PhD.

Contribution: This author helped analyze the data and preparation of the manuscript.

Attestation: Minyi Lu approved the final manuscript.

Conflicts of Interest: Minyi Lu is an employee of Covidien.

Name: M. S. Branch, MD.

Contribution: This author helped design the study and preparation of the manuscript.

Attestation: M. S. Branch approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Holly Muir, MD.

Contribution: This author helped design and preparation of the manuscript.

Attestation: Holly Muir approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Paul Manberg, PhD.

Contribution: This author helped design the study and preparation of the manuscript.

Attestation: Paul Manberg approved the final manuscript.

Conflicts of Interest: Paul Manberg was an employee and stockholder of Aspect Medical Systems (now Covidien) at the time when this study was conducted.

Name: Jeff C. Sigl, PhD.

Contribution: This author helped analyze the data and preparation of the manuscript.

Attestation: Jeff Sigl approved the final manuscript.

Conflicts of Interest: Jeff Sigl is an employee of Covidien.

Name: Tong J. Gan, MB, MD, MHS, FRCA.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Tong J. Gan has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Tong J. Gan receive research funding from Covidien.

This manuscript was handled by: Peter S. A. Glass, MB, ChB.

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ACKNOWLEDGMENTS

We would like to thank Rhonda Spell RN, Kelly Monses RN, the sedation nurses, and care providers for their participation in this study.

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FOOTNOTES

a Continuum of Depth of Sedation: Definition of General Anesthesia and Levels of Sedation/Analgesia. Available at: http://www.asahq.org/For-Members/~/media/For%20Members/documents/Standards%20Guidelines%20Stmts/Continuum%20of%20Depth%20of%20Sedation.ashx. Accessed December 28, 2012.
Cited Here...

b BIS range recommendations. Available at: http://www.covidien.com/pace/pages.aspx?page=ClinicalEducation/Event/246147. Accessed December 28, 2012.
Cited Here...

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