- Email: [email protected]
Can the bispectral index monitor the sedation adequacy of intubated ED adults?
Can the Bispectral Index Monitor the Sedation Adequacy of Intubated ED Adults? MICHELLE GILL, MD,* KORBIN HAYCOCK, MD,* STEVEN M. GREEN, MD,* AND BARUCH KRAUSS, MD, EDM† The Bispectral Index Monitor (BIS) is validated as a measure of sedation depth during general anesthesia, but its value otherwise remains unclear. We hypothesized that BIS scores would correlate with standard subjective measures of assessing sedation in intubated adult ED patients and that BIS would predict inadequate sedation. Sedation was assessed by recording clinical features and by having treating physicians complete a visual analog scale (VAS; rated “not sedated” to “completely sedated”) at 10, 30, and 60 minutes after intubation. Measurements of BIS were later paired with sedation assessments. Despite being statistically significant (p ⴝ .002), the correlation between BIS and VAS in our 147 paired readings was fair (Pearson’s rho ⴝ ⴚ0.37) and displayed wide variability. Receiver operating characteristic curve analysis of BIS demonstrated no discriminatory power in predicting sedation adequacy (area under curve 0.53). BIS is not associated with and did not predict standard measures of sedation adequacy in intubated adults. (Am J Emerg Med 2004;22:76-82. © 2004 Elsevier Inc. All rights reserved.)
There is currently no standard or reliable objective method for the assessment of the adequacy of sedation for intubated patients in the ED. As a result, EPs use clinical parameters, subjective sedation scales, and “gut instincts” to monitor sedation adequacy in these patients. The Bispectral Index Monitor (BIS) could potentially replace this deficit in the ED by providing an objective measurement of a patient’s level of consciousness while they are intubated, and is already being used by some intensivists for the continuous assessment of intubated patients in the intensive care unit (ICU) setting.1-3 The BIS, which is approved by the Food and Drug Administration for the assessment of patients’ level of consciousness during general anesthesia, has been found to decrease the likelihood of recall during surgery4-8 and to shorten postoperative recovery times.9,10 The bispectral analysis of an electroencephalogram (EEG) is represented as a unitless numerical value ranging from 0 to 100, with “0” representing patients with no brain activity and “100” representing patients who are fully
From the *Department of Emergency Medicine, Loma Linda University School of Medicine, Loma Linda, California; and the †Division of Emergency Medicine, Children’s Hospital and Harvard Medical School, Boston, Massachusetts. Presented as a poster at the American College of Emergency Physicians conference, Seattle, WA, October 8, 2002. Manuscript received December 1, 2002; accepted January 11, 2003. Address correspondence to Michelle Gill, MD, Loma Linda University Medical Center, 11234 Anderson St., P.O. Box 2000, Rm. A-108, Loma Linda, California 92354. Email: [email protected] Key Words: Bispectral Index Monitor, intubation, sedation, neuromuscular blockade © 2004 Elsevier Inc. All rights reserved. 0735-6757/04/2202-0003$30.00/0 doi:10.1016/j.ajem.2003.12.006
76
awake. The numbers between 0 and 100 represent a continuum of level of consciousness, with 60 or less reflecting a hypnotic state consistent with general anesthesia.4,5,7,11-14 If validated for use in the ED for the purpose of assessing intubated patients, the BIS could quickly alert staff when undersedation is present or being approached. Such a device could potentially allow for faster, more predictable patient assessment and precise titration of sedatives in this patient group. We hypothesized that BIS values would be associated with clinical assessments of unsatisfactory sedation (ie, lacrimation, mydriasis, increases in pulse and blood pressure) in intubated, mechanically ventilated adult ED patients, and that the BIS scores would correlate with visual analog scale (VAS) assessments of sedation adequacy completed by the treating physician. Our second study objective was to descriptively screen for BIS thresholds that might predict sedation adequacy in this patient population. METHODS Study Design This prospective observational study was approved by the hospital’s Institutional Review Board, which approved a waiver of informed consent through an expedited review process for this study. Study Setting and Population This study was performed in the ED of an integrated medical center and children’s hospital with an annual census of 44,000 patients per year. We studied a convenience sample of intubated, mechanically ventilated ED adults, including those intubated prehospital. We excluded patients with known or subsequently established abnormal baseline mental status (eg, dementia, mental retardation), ongoing seizure activity, severe ophthalmologic trauma (which might prevent assessment of lacrimation and mydriasis), or cardiac arrest. Study Protocol We entered patients into the study at the earliest possible time after intubation. Treating physicians (typically postgraduate year 3 EM residents) were asked to provide sedation in their usual manner. We asked them to grade sedation adequacy approximately 10, 30, and 60 minutes after enrollment using an unmarked 100-mm VAS labeled “not sedated” on the left and “completely sedated” on the right. To prevent reference to earlier measures, treating physicians were given different VAS cards at each assessment. Con-
GILL ET AL ■ BIS FOR INTUBATED ED PATIENTS
current with and blinded to each VAS measurement, investigators independently recorded the patient’s heart rate, blood pressure, pupil diameter, and the presence or absence of lacrimation. Before the first VAS measurement, the investigator applied a BIS sensor to the patient’s forehead using commercially available EEG pads (Zippeprep; Aspect Medical Systems, Natick, MA). The BIS Monitor (Aspect A-2000 Monitor System) screen was covered throughout data collection to maintain blinding of the investigator and treating physician. Immediately after each sedation assessment, investigators briefly uncovered the BIS Monitor and recorded the corresponding BIS value. We defined a priori criteria for inadequate sedation based on existing literature15-17 and our clinical experience. We defined “inadequate sedation” as the presence of any of the following: (1) lacrimation, (2) bilateral pupillary dilation of ⱖ2 mm over baseline or prior measure while sedated, or (3) heart rate or blood pressure increase of ⱖ15% over normotensive baseline or prior measure while sedated. Patients lacking these features were considered to be “adequately sedated.” These definitions were coded for each assessment point by a single investigator at a time nonconcurrent with patient care using study data forms and baseline values taken from the medical records. Treating physicians were unaware that the investigators were applying any specific definition for sedation adequacy. To assess the interrater agreement of our study measures, we had an additional EP (not an investigator or treating physician) independently complete a VAS assessment of sedation adequacy immediately before or after the corresponding treating physician assessment in a convenience sample of approximately 15% of readings. They concurrently recorded the pupil size and presence or absence of lacrimation at each time interval independently of the formal study assessment. To assess the interrater reliability of the study assessment of adequate versus inadequate sedation, a second investigator independently coded these findings using the same methodology as the first in a convenience sample of approximately 20% of readings. We were unable to perform a sample size calculation as a result of the unavailability of baseline reference measures for either BIS or sedation adequacy. Therefore, we chose to evaluate 52 subjects in accordance with sample sizes reported for other BIS pilot research.1,2,18,19 Data Analysis We assessed interrater reliability using the Pearson correlation for paired VAS measures and using the unweighted kappa for all other assessments. We plotted the BIS scores against the VAS and calculated the Pearson correlation coefficient. We compared the BIS distributions between patients who were adequately versus inadequately sedated. A receiver operating characteristic (ROC) curve was then constructed for prediction of sedation adequacy, and the area under this curve was measured. We then calculated the sensitivity and specificity of the most discriminatory BIS threshold. All analyses were performed using Stata 7 (Stata Corp., College Station, TX).
77
RESULTS Investigators screened 54 ED patients for enrollment and excluded 2 patients as a result of the presence of seizure activity before or during enrollment. No subjects were excluded as a result of inability to tolerate the BIS sensors or for any other study exclusion criteria. Thus, the study sample comprised 52 ED patients (32 males, 20 females) in whom 147 total readings were made. The median number of readings per patient was 3 (range, 1-4). The median subject age was 58.5 years (range, 21-91 years; Table 1). We assessed interrater reliability of subject measures in 21 (14%) of the study readings. Agreement was substantial for lacrimation (kappa ⫽ 0.69) and moderate for pupil size (kappa ⫽ 0.55).20 Agreement for VAS was only fair (kappa ⫽ 0.35). We assessed interrater reliability for the coding of adequate versus inadequate sedation in 29 (20%) of the study readings, and this rating was moderate to substantial (kappa ⫽ 0.60). Despite being statistically significant (P ⫽ .002), the correlation between the BIS scores and treating physician VAS assessments of sedation adequacy was only fair (Pearson r ⫽ ⫺0.37) and displayed wide variability (Fig 1). Distributions and medians of BIS scores were similar in those adequately sedated and those inadequately sedated (Fig 2). ROC curve analysis demonstrated essentially no discriminatory power in predicting sedation adequacy (Fig 3). Accordingly, we were unable to identify an optimal discriminatory BIS threshold suitable for calculating sensitivity and specificity. DISCUSSION In this first study comparing BIS with standard measures of sedation adequacy in intubated ED patients, we found no evidence of association or discriminatory value for this modality. These results do not show promise for the BIS in the ED for the purpose of monitoring intubated patients and conflict with results from similar studies conducted in ICU settings.1-3 Simmons compared the Sedation–Agitation Scale (SAS) with BIS in an ICU study and found that SAS correlated (Spearman’s r ⫽ 0.61, P ⬍ .001) with the average BIS values obtained on 63 intubated patients.1 Frenzel found that BIS correlated with five different sedation scores (Kendall’s ⬎0.5906, P ⬍ .0001) administered to intubated ICU patients.3 Riker compared the SAS, a VAS for sedation, and BIS in a third ICU study in 39 intubated patients, and found that BIS correlated moderately with SAS (Spearman’s r ⫽ 0.60, P ⬍ .001) and the VAS (Spearman’s r ⫽ 0.60, P ⬍ .001).2 All three of these studies excluded patients on continuous neuromuscular-blocking agents (NMBA) as a result of the inability to apply the subjective sedation scales when patients are chemically paralyzed. Neuromuscular-blocking agents were withheld from Riker’s subjects as part of their intubation-weaning protocol2 Simmons’ subjects were checked with train-of-four testing before inclusion1 and Frenzel’s subjects were tested for presence of NMBA using an acceleromyographic monitor.3 In contrast, Nasraway recently compared the SAS to BIS in 20 adult ICU patients with decreased levels of conscious-
AMERICAN JOURNAL OF EMERGENCY MEDICINE ■ Volume 22, Number 2 ■ March 2004
78
TABLE 1.
Study Subjects
Age(years)/Sex
BIS
Visual Analog Scale*
Adequate (A) v. Inadequate (I) Sedation
31/F
41 43 51 44 49 52 45 68 83 96 58 71 65 89 63 86 49 36 32 39 40 45 98 93 97 76 67 76 62 34 97 95 56 66 73 72 56 55 43 38 52 47 41 63 54 49 61 67 40 18 35 50 67 87 58 67 64 33 33 53 71 66 70
87 85 84 48 58 33 100 100 100 0 100 94 98 19 6 8 96 98 97 100 99 100 3 3 2 56 46 37 32 44 76 81 87 100 100 100 97 98 68 66 68 100 92 94 91 93 73 99 64 35 72 59 61 18 94 97 77 83 90 3 66 79 77
I I I A A I A I A A I I I I I I I I I I I A I I I I I I A A A A I A I I A I I I I A I A A A I A A A A I A I I A A A A A I A A
61/M
54/M
58/M 62/M 59/F
40/M
70/M
85/F
52/F
60/M 78/M
37/M
88/F 90/F 66/M 84/F
21/M
20/F
32/M
67/F
26/M
47/M
CT Findings
Diagnosis
N/A
Respiratory distress resulting from malignant pleural effusions
Normal
Closed head injury, ethanol intoxication
Normal
Flail chest, postblunt trauma
N/A Normal
Pulmonary embolism Closed head injury
Subarachnoid hemorrhage
Closed head injury
N/A
Congestive heart failure
Chronic atrophy
Pneumonia
N/A
Postcardiac arrest
Arteriovenous malformation ⫹ bleed N/A
Arteriovenous malformation
Intracranial hemorrhage
Spontaneous intracranial hemorrhage
Normal
Closed head injury
N/A
Congestive heart failure
N/A
Sepsis
N/A
Sepsis
Normal
Ruptured viscus ⫹ sepsis
N/A
Closed head injury
Subarachnoid hemorrhage
Closed head injury
Normal
Closed head injury
Normal
Narcotic overdose
N/A
Ethanol intoxication
N/A
Sepsis ⫹ cardiogenic shock
Pneumonia
GILL ET AL ■ BIS FOR INTUBATED ED PATIENTS
TABLE 1.
79
(Continued)
Age(years)/Sex
BIS
Visual Analog Scale*
Adequate (A) v. Inadequate (I) Sedation
71/M
40 54 44 98 94 95 51 43 62 41 35 40 98 98 76 98 84 89 55 67 62 63 56 67 48 47 71 44 47 41 51 58 56 64 68 47 62 61 58 57 63 41 29 61 41 21 60 57 57 57 66 70 67 67 73 64 66 78 48 35 27 37
69 94 94 94 99 97 74 100 96 56 61 93 87 82 93 84 77 86 62 13 10 70 62 16 88 83 85 100 100 100 88 89 100 30 54 40 97 95 98 100 100 98 81 100 81 92 93 70 100 80 82 70 14 92 90 96 34 98 92 100 71 100
A I A A I I I I I A I I I A A A I I A A I A A A I I A I I I I A A A I I I I I I I I I I A I A I A A A I I I A I A A A I I A
25/M
39/M
79/F
77/F
73/M
46/M
38/M
56/F
67/M
34/M
73/F
89/M
19/M 37/M
55/F
48/M
68/M
58/F
20/M
91/M
CT Findings
Diagnosis
N/A
Sepsis
N/A
Gunshot wound to chest ⫹ hemothorax
Normal
Closed head injury ⫹ ethanol intoxication
Intracranial hemorrhage
Coagulopathy
Normal
Postcardiac arrest
Cerebellar hemorrhage
Spontaneous intracranial hemorrhage
Intracranial hemorrhage
Hypertensive emergency
Normal
Multisubstance overdose
N/A
Narcotic overdose
Lacunar infarct
Undetermined toxicologic overdose
Normal
Narcotic overdose
Intracranial hemorrhage
Spontaneous intracranial hemorrhage
Subarachnoid hemorrhage
Spontaneous intracranial hemorrhage
N/A
Gunshot wound ⫹ pneumothorax
Intracranial hemorrhage
Spontaneous intracranial hemorrhage
N/A
Asthma exacerbation
Subarachnoid hemorrhage
Spontaneous intracranial hemorrhage
Intracranial hemorrhage
Closed head injury
N/A
Toxicologic overdose
N/A
Gunshot wound to face ⫹ respiratory distress
Subdural hemorrhage
Subdural hematoma
AMERICAN JOURNAL OF EMERGENCY MEDICINE ■ Volume 22, Number 2 ■ March 2004
80
TABLE 1.
(Continued)
Age(years)/Sex
BIS
Visual Analog Scale*
Adequate (A) v. Inadequate (I) Sedation
63/F
1 1 3 74 48 68 48 55 55 75 77 69 84 48 36 38 46 44 60 41 31 42
100 100 100 59 46 55 91 91 77 97 41 58 15 83 94 90 82 60 77 98 95 96
A A A I I I I I I I I I A A I I I I I I A A
82/F
55/M
44/M
50/M
65/F
42/M
30/M
CT Findings
Diagnosis
Subarachnoid hemorrhage
Spontaneous intracranial hemorrhage
N/A
Congestive heart failure
Subarachnoid hemorrhage
Spontaneous intracranial hemorrhage
Normal
Closed head injury
Normal
Toxicologic overdose
N/A
Gastrointestinal bleed
Normal
Heat stroke
Normal
Closed head injury
*Millimeters. Abbreviations: BIS, Bispectral Index Score; CT, computed tomography; N/A, not applicable.
ness and found that unarousable patients had BIS scores ranging from 23 to 97.21 The Spearman correlation between SAS and BIS in this study was r ⫽ 0.36 (P ⬍ .001) and similar to our study, does not support the discriminatory value of BIS for the assessment of the sedation status of intubated patients. Two other ED groups have reported pilot studies of BIS in intubated patients. Stephanides and Shaw noted that all of
23 such study subjects had BIS values greater than 80 (which is consistent with being in a “light hypnotic state” according to the manufacturer11,12) one-third of the total BIS monitored time.22 Miner et al applied BIS monitoring to 54 intubated ED patients and were able to interview 26 when they had recovered. Four of these 26 reported recollection of the intubation, with their BIS values being ⬎70 (n ⫽ 1) and ⬍70 (n ⫽ 3). In contrast, 10 of 13 patients with BIS ⬍70
FIGURE 1. Correlation between BIS and physician sedation assessments.* *Smoothing line generated by LOWESS locally weighted regression with bandwidth of 5. Pearson r ⫽ ⫺0.37, p ⫽ .002.
FIGURE 2. BIS scores stratified by sedation adequacy.* *The median (interquartile range) BIS score for adequately sedated patients was 58 (45-67), and 57 (44-69) for inadequately sedated patients.
GILL ET AL ■ BIS FOR INTUBATED ED PATIENTS
81
rameters most clinicians use in their clinical assessments of sedation adequacy. Second, even if our gold standard were only weakly associated with the reality of true sedation adequacy, we should observe at least a trend toward such association. CONCLUSIONS BIS is not associated with and did not predict standard measures of sedation adequacy in mechanically ventilated ED adults. The authors thank Ryan Arnold and Kristan Guenterberg for their assistance with entering patients into this study. Aspect Medical Systems loaned a Bispectral Index Monitor and printer for this study but provided no direct financial support.
REFERENCES FIGURE 3. ROC curve for BIS as predictor of sedation adequacy.* *Area under curve 0.53 (95%CI0.40,067)
and 12 of 13 patients with BIS ⬎70 denied any recollection of the intubation.23 Patients on NMBA were included in both of these ED studies. LIMITATIONS AND FUTURE QUESTIONS Studies of sedation adequacy in the intubated patient are generally limited by the inherent subjectivity of this clinical assessment. Although scales such as the SAS and Ramsay Sedation Scale have been shown to reliably monitor sedation in the ICU setting, these scales cannot be applied to patients on continuous NMBA as a result of their motor components.1-3,18 Because of the necessary inclusion of patients on NMBA into our study, we assessed sedation in a novel fashion (VAS for sedation adequacy and a priori clinical parameters) even though these techniques have not yet been specifically validated for this purpose. When we initiated the study, we assumed that each parameter would likely display a substantial degree of interrater reliability; however, we were disappointed at our observed levels of agreement for all measures. The poorest such measure was the one we originally projected to be the most accurate of all, the VAS rating of sedation adequacy by the treating physician (ie, the “gut instinct”). It is likely that these suboptimal findings do not reflect improper choice of assessment tools, but rather the overall subjectivity of these traditional techniques themselves. This observed clinical variance only underscores the desirability of ultimately identifying an objective measure of sedation adequacy. Given the suboptimal interrater agreement noted in this study, it will not be unreasonable for some to conjecture that perhaps BIS truly is a highly accurate measure of sedation adequacy, and our observed lack of association is only a result of the admittedly subjective gold standard of clinical assessment. Although such speculation cannot be definitively disproven, we believe it to be highly unlikely. First, our chosen clinical measures have substantial face validity for this application, because they represent the typical pa-
1. Simmons LE, Riker RR, Prato BS, Fraser GL: Assessing sedation during intensive care unit mechanical ventilation with the Bispectral Index and the Sedation–Agitation Scale. Crit Care Med 1999;27:1499-1504 2. Riker RR, Fraser GL, Simmons LE, Wilkins ML: Validating the Sedation–Agitation Scale with the Bispectral Index and Visual Analog Scale in adult ICU patients after cardiac surgery. Intensive Care Med 2001;27:853-858 3. Frenzel D, Greim C, Sommer C, Bauerle K, Roewer N: Is the Bispectral Index appropriate for monitoring the sedation level of mechanically ventilated surgical ICU patients? Intensive Care Med 2002;28:178-183 4. Flaishon R, Windsor A, Sigl J, Sebel PS: Recovery of consciousness after thiopental or propofol. Bispectral Index and isolated forearm technique. Anesthesiology 1997;86:613-619 5. Glass P, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P: Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997;86:836-847 6. McCann ME, Brustowicz RM, Bacsik J, Sullivan L, Aublc SG, Laussen PC: The Bispectral Index and explicit recall during the intraoperative wake-up test for scoliosis surgery. Anesth Analg 2002;94:1474-1478 7. Liu J, Singh H, White P: Electroencephalographic Bispectral Index correlates with intraoperative recall and depth of propofolinduced sedation. Anesth Analg 1997;84:185-189 8. Barr G, Anderson RE, Owall A, Jakobsson JG: Being awake intermittently during propofol-induced hypnosis: a study of BIS, explicit and implicit memory. Acta Anaesthesiol Scand 2001;45: 834-838 9. Song D, Joshi GP, White PF: Titration of volatile anesthetics using Bispectral Index facilitates recovery after ambulatory anesthesia. Anesthesiology 1997;87:842-848 10. Gan TJ, Glass PS, Windson A, et al: BIS Utility Study Group. Bispectral Index monitoring allows faster emergence and improved recovery from propofol, alfentil, and nitrous oxide anesthesia. Anesthesiology 1997;87:808-815 11. Critical Care: What is BIS? [Brochure on www.aspectms.com website] Available at: aspectms.com/downloads/pdf_documents/ product_resources_what_is_bis.pdf. Accessed September 2002 12. Using BIS: BIS Range Guidelines [Brochure on www.aspectms. com website] Available at: aspectms.com/downloads/proc_cards/or/ using_bis.html. Accessed September 2002 13. Katoh T, Suzuki A, Ikeda K: Electroencephalographic derivatives as a tool for predicting the depth of sedation and anesthesia induced by sevoflurane. Anesthesiology 1998;88:642-50 14. Driessen J, Harbers J, van Egmond J, Booij L: Evaluation of the electroencephalographic Bispectral Index during fentanyl–midazolam anaesthesia for cardiac surgery. Does it predict haemodynamic responses during endotracheal intubation and sternotomy? Eur J Anaesthesiol 1999;16:622-627 15. Sa Rego MM, White PF: Monitored anesthesia care, in Miller RD (ed): Anesthesia, 5th ed. Philadelphia, Churchill Livingstone, Inc, 2000, pp 1452-1469
82
AMERICAN JOURNAL OF EMERGENCY MEDICINE ■ Volume 22, Number 2 ■ March 2004
16. Shapiro BA, Warren J, Egol AB, et al: Practice parameters for sustained neuromuscular blockade in the adult critically ill patient: an executive summary. Crit Care Med 1995;23:1601-1605 17. Hansen-Flaschen JH, Brazinsky S, Basilc C, Lanken PN: Use of sedating drugs and neuromuscular blocking agents in patients requiring mechanical ventilation for respiratory failure. A national survey. JAMA 1991;266:2870-2875 18. Riker RR, Fraser GL: Monitoring sedation, agitation, analgesia, neuromuscular blockade, and delirium in adult ICU patients. Semin Resp Crit Care Med 2001;22:189-198 19. Shah N, Clack S, Chea F, Tayong M, Anderson C: Does Bispectral Index of EEG (BIS) correlate with Ramsay Sedation Score in ICU patients? Anesthesiology 1996;85:A469
20. Landis JR, Koch GG: The measurement of observer agreement for categorical data. Biometrics 1977;33:159-174 21. Nasraway SA, Wu EC, Kelleher RM, Yasuda CM, Donnelly AM: How reliable is the Bispectral Index in critically ill patients? A prospective, comparative, single-blinded observer study. Crit Care Med 2002;30:1483-1487 22. Stephanides S, Shaw G, Murphy M, Jauch E: Level of sedation as determined by Bispectral Index measurement in intubated emergency department patients. Ann Emerg Med 2001;38:S6 [Abstract] 23. Miner JR, Haug E, Fricwald S, Biros M: Evaluation of Bispectral EEG analysis and recall in paralyzed intubated patients. Acad Emerg Med 2002;9:405-406 [Abstract]
There is currently no standard or reliable objective method for the assessment of the adequacy of sedation for intubated patients in the ED. As a result, EPs use clinical parameters, subjective sedation scales, and “gut instincts” to monitor sedation adequacy in these patients. The Bispectral Index Monitor (BIS) could potentially replace this deficit in the ED by providing an objective measurement of a patient’s level of consciousness while they are intubated, and is already being used by some intensivists for the continuous assessment of intubated patients in the intensive care unit (ICU) setting.1-3 The BIS, which is approved by the Food and Drug Administration for the assessment of patients’ level of consciousness during general anesthesia, has been found to decrease the likelihood of recall during surgery4-8 and to shorten postoperative recovery times.9,10 The bispectral analysis of an electroencephalogram (EEG) is represented as a unitless numerical value ranging from 0 to 100, with “0” representing patients with no brain activity and “100” representing patients who are fully
From the *Department of Emergency Medicine, Loma Linda University School of Medicine, Loma Linda, California; and the †Division of Emergency Medicine, Children’s Hospital and Harvard Medical School, Boston, Massachusetts. Presented as a poster at the American College of Emergency Physicians conference, Seattle, WA, October 8, 2002. Manuscript received December 1, 2002; accepted January 11, 2003. Address correspondence to Michelle Gill, MD, Loma Linda University Medical Center, 11234 Anderson St., P.O. Box 2000, Rm. A-108, Loma Linda, California 92354. Email: [email protected] Key Words: Bispectral Index Monitor, intubation, sedation, neuromuscular blockade © 2004 Elsevier Inc. All rights reserved. 0735-6757/04/2202-0003$30.00/0 doi:10.1016/j.ajem.2003.12.006
76
awake. The numbers between 0 and 100 represent a continuum of level of consciousness, with 60 or less reflecting a hypnotic state consistent with general anesthesia.4,5,7,11-14 If validated for use in the ED for the purpose of assessing intubated patients, the BIS could quickly alert staff when undersedation is present or being approached. Such a device could potentially allow for faster, more predictable patient assessment and precise titration of sedatives in this patient group. We hypothesized that BIS values would be associated with clinical assessments of unsatisfactory sedation (ie, lacrimation, mydriasis, increases in pulse and blood pressure) in intubated, mechanically ventilated adult ED patients, and that the BIS scores would correlate with visual analog scale (VAS) assessments of sedation adequacy completed by the treating physician. Our second study objective was to descriptively screen for BIS thresholds that might predict sedation adequacy in this patient population. METHODS Study Design This prospective observational study was approved by the hospital’s Institutional Review Board, which approved a waiver of informed consent through an expedited review process for this study. Study Setting and Population This study was performed in the ED of an integrated medical center and children’s hospital with an annual census of 44,000 patients per year. We studied a convenience sample of intubated, mechanically ventilated ED adults, including those intubated prehospital. We excluded patients with known or subsequently established abnormal baseline mental status (eg, dementia, mental retardation), ongoing seizure activity, severe ophthalmologic trauma (which might prevent assessment of lacrimation and mydriasis), or cardiac arrest. Study Protocol We entered patients into the study at the earliest possible time after intubation. Treating physicians (typically postgraduate year 3 EM residents) were asked to provide sedation in their usual manner. We asked them to grade sedation adequacy approximately 10, 30, and 60 minutes after enrollment using an unmarked 100-mm VAS labeled “not sedated” on the left and “completely sedated” on the right. To prevent reference to earlier measures, treating physicians were given different VAS cards at each assessment. Con-
GILL ET AL ■ BIS FOR INTUBATED ED PATIENTS
current with and blinded to each VAS measurement, investigators independently recorded the patient’s heart rate, blood pressure, pupil diameter, and the presence or absence of lacrimation. Before the first VAS measurement, the investigator applied a BIS sensor to the patient’s forehead using commercially available EEG pads (Zippeprep; Aspect Medical Systems, Natick, MA). The BIS Monitor (Aspect A-2000 Monitor System) screen was covered throughout data collection to maintain blinding of the investigator and treating physician. Immediately after each sedation assessment, investigators briefly uncovered the BIS Monitor and recorded the corresponding BIS value. We defined a priori criteria for inadequate sedation based on existing literature15-17 and our clinical experience. We defined “inadequate sedation” as the presence of any of the following: (1) lacrimation, (2) bilateral pupillary dilation of ⱖ2 mm over baseline or prior measure while sedated, or (3) heart rate or blood pressure increase of ⱖ15% over normotensive baseline or prior measure while sedated. Patients lacking these features were considered to be “adequately sedated.” These definitions were coded for each assessment point by a single investigator at a time nonconcurrent with patient care using study data forms and baseline values taken from the medical records. Treating physicians were unaware that the investigators were applying any specific definition for sedation adequacy. To assess the interrater agreement of our study measures, we had an additional EP (not an investigator or treating physician) independently complete a VAS assessment of sedation adequacy immediately before or after the corresponding treating physician assessment in a convenience sample of approximately 15% of readings. They concurrently recorded the pupil size and presence or absence of lacrimation at each time interval independently of the formal study assessment. To assess the interrater reliability of the study assessment of adequate versus inadequate sedation, a second investigator independently coded these findings using the same methodology as the first in a convenience sample of approximately 20% of readings. We were unable to perform a sample size calculation as a result of the unavailability of baseline reference measures for either BIS or sedation adequacy. Therefore, we chose to evaluate 52 subjects in accordance with sample sizes reported for other BIS pilot research.1,2,18,19 Data Analysis We assessed interrater reliability using the Pearson correlation for paired VAS measures and using the unweighted kappa for all other assessments. We plotted the BIS scores against the VAS and calculated the Pearson correlation coefficient. We compared the BIS distributions between patients who were adequately versus inadequately sedated. A receiver operating characteristic (ROC) curve was then constructed for prediction of sedation adequacy, and the area under this curve was measured. We then calculated the sensitivity and specificity of the most discriminatory BIS threshold. All analyses were performed using Stata 7 (Stata Corp., College Station, TX).
77
RESULTS Investigators screened 54 ED patients for enrollment and excluded 2 patients as a result of the presence of seizure activity before or during enrollment. No subjects were excluded as a result of inability to tolerate the BIS sensors or for any other study exclusion criteria. Thus, the study sample comprised 52 ED patients (32 males, 20 females) in whom 147 total readings were made. The median number of readings per patient was 3 (range, 1-4). The median subject age was 58.5 years (range, 21-91 years; Table 1). We assessed interrater reliability of subject measures in 21 (14%) of the study readings. Agreement was substantial for lacrimation (kappa ⫽ 0.69) and moderate for pupil size (kappa ⫽ 0.55).20 Agreement for VAS was only fair (kappa ⫽ 0.35). We assessed interrater reliability for the coding of adequate versus inadequate sedation in 29 (20%) of the study readings, and this rating was moderate to substantial (kappa ⫽ 0.60). Despite being statistically significant (P ⫽ .002), the correlation between the BIS scores and treating physician VAS assessments of sedation adequacy was only fair (Pearson r ⫽ ⫺0.37) and displayed wide variability (Fig 1). Distributions and medians of BIS scores were similar in those adequately sedated and those inadequately sedated (Fig 2). ROC curve analysis demonstrated essentially no discriminatory power in predicting sedation adequacy (Fig 3). Accordingly, we were unable to identify an optimal discriminatory BIS threshold suitable for calculating sensitivity and specificity. DISCUSSION In this first study comparing BIS with standard measures of sedation adequacy in intubated ED patients, we found no evidence of association or discriminatory value for this modality. These results do not show promise for the BIS in the ED for the purpose of monitoring intubated patients and conflict with results from similar studies conducted in ICU settings.1-3 Simmons compared the Sedation–Agitation Scale (SAS) with BIS in an ICU study and found that SAS correlated (Spearman’s r ⫽ 0.61, P ⬍ .001) with the average BIS values obtained on 63 intubated patients.1 Frenzel found that BIS correlated with five different sedation scores (Kendall’s ⬎0.5906, P ⬍ .0001) administered to intubated ICU patients.3 Riker compared the SAS, a VAS for sedation, and BIS in a third ICU study in 39 intubated patients, and found that BIS correlated moderately with SAS (Spearman’s r ⫽ 0.60, P ⬍ .001) and the VAS (Spearman’s r ⫽ 0.60, P ⬍ .001).2 All three of these studies excluded patients on continuous neuromuscular-blocking agents (NMBA) as a result of the inability to apply the subjective sedation scales when patients are chemically paralyzed. Neuromuscular-blocking agents were withheld from Riker’s subjects as part of their intubation-weaning protocol2 Simmons’ subjects were checked with train-of-four testing before inclusion1 and Frenzel’s subjects were tested for presence of NMBA using an acceleromyographic monitor.3 In contrast, Nasraway recently compared the SAS to BIS in 20 adult ICU patients with decreased levels of conscious-
AMERICAN JOURNAL OF EMERGENCY MEDICINE ■ Volume 22, Number 2 ■ March 2004
78
TABLE 1.
Study Subjects
Age(years)/Sex
BIS
Visual Analog Scale*
Adequate (A) v. Inadequate (I) Sedation
31/F
41 43 51 44 49 52 45 68 83 96 58 71 65 89 63 86 49 36 32 39 40 45 98 93 97 76 67 76 62 34 97 95 56 66 73 72 56 55 43 38 52 47 41 63 54 49 61 67 40 18 35 50 67 87 58 67 64 33 33 53 71 66 70
87 85 84 48 58 33 100 100 100 0 100 94 98 19 6 8 96 98 97 100 99 100 3 3 2 56 46 37 32 44 76 81 87 100 100 100 97 98 68 66 68 100 92 94 91 93 73 99 64 35 72 59 61 18 94 97 77 83 90 3 66 79 77
I I I A A I A I A A I I I I I I I I I I I A I I I I I I A A A A I A I I A I I I I A I A A A I A A A A I A I I A A A A A I A A
61/M
54/M
58/M 62/M 59/F
40/M
70/M
85/F
52/F
60/M 78/M
37/M
88/F 90/F 66/M 84/F
21/M
20/F
32/M
67/F
26/M
47/M
CT Findings
Diagnosis
N/A
Respiratory distress resulting from malignant pleural effusions
Normal
Closed head injury, ethanol intoxication
Normal
Flail chest, postblunt trauma
N/A Normal
Pulmonary embolism Closed head injury
Subarachnoid hemorrhage
Closed head injury
N/A
Congestive heart failure
Chronic atrophy
Pneumonia
N/A
Postcardiac arrest
Arteriovenous malformation ⫹ bleed N/A
Arteriovenous malformation
Intracranial hemorrhage
Spontaneous intracranial hemorrhage
Normal
Closed head injury
N/A
Congestive heart failure
N/A
Sepsis
N/A
Sepsis
Normal
Ruptured viscus ⫹ sepsis
N/A
Closed head injury
Subarachnoid hemorrhage
Closed head injury
Normal
Closed head injury
Normal
Narcotic overdose
N/A
Ethanol intoxication
N/A
Sepsis ⫹ cardiogenic shock
Pneumonia
GILL ET AL ■ BIS FOR INTUBATED ED PATIENTS
TABLE 1.
79
(Continued)
Age(years)/Sex
BIS
Visual Analog Scale*
Adequate (A) v. Inadequate (I) Sedation
71/M
40 54 44 98 94 95 51 43 62 41 35 40 98 98 76 98 84 89 55 67 62 63 56 67 48 47 71 44 47 41 51 58 56 64 68 47 62 61 58 57 63 41 29 61 41 21 60 57 57 57 66 70 67 67 73 64 66 78 48 35 27 37
69 94 94 94 99 97 74 100 96 56 61 93 87 82 93 84 77 86 62 13 10 70 62 16 88 83 85 100 100 100 88 89 100 30 54 40 97 95 98 100 100 98 81 100 81 92 93 70 100 80 82 70 14 92 90 96 34 98 92 100 71 100
A I A A I I I I I A I I I A A A I I A A I A A A I I A I I I I A A A I I I I I I I I I I A I A I A A A I I I A I A A A I I A
25/M
39/M
79/F
77/F
73/M
46/M
38/M
56/F
67/M
34/M
73/F
89/M
19/M 37/M
55/F
48/M
68/M
58/F
20/M
91/M
CT Findings
Diagnosis
N/A
Sepsis
N/A
Gunshot wound to chest ⫹ hemothorax
Normal
Closed head injury ⫹ ethanol intoxication
Intracranial hemorrhage
Coagulopathy
Normal
Postcardiac arrest
Cerebellar hemorrhage
Spontaneous intracranial hemorrhage
Intracranial hemorrhage
Hypertensive emergency
Normal
Multisubstance overdose
N/A
Narcotic overdose
Lacunar infarct
Undetermined toxicologic overdose
Normal
Narcotic overdose
Intracranial hemorrhage
Spontaneous intracranial hemorrhage
Subarachnoid hemorrhage
Spontaneous intracranial hemorrhage
N/A
Gunshot wound ⫹ pneumothorax
Intracranial hemorrhage
Spontaneous intracranial hemorrhage
N/A
Asthma exacerbation
Subarachnoid hemorrhage
Spontaneous intracranial hemorrhage
Intracranial hemorrhage
Closed head injury
N/A
Toxicologic overdose
N/A
Gunshot wound to face ⫹ respiratory distress
Subdural hemorrhage
Subdural hematoma
AMERICAN JOURNAL OF EMERGENCY MEDICINE ■ Volume 22, Number 2 ■ March 2004
80
TABLE 1.
(Continued)
Age(years)/Sex
BIS
Visual Analog Scale*
Adequate (A) v. Inadequate (I) Sedation
63/F
1 1 3 74 48 68 48 55 55 75 77 69 84 48 36 38 46 44 60 41 31 42
100 100 100 59 46 55 91 91 77 97 41 58 15 83 94 90 82 60 77 98 95 96
A A A I I I I I I I I I A A I I I I I I A A
82/F
55/M
44/M
50/M
65/F
42/M
30/M
CT Findings
Diagnosis
Subarachnoid hemorrhage
Spontaneous intracranial hemorrhage
N/A
Congestive heart failure
Subarachnoid hemorrhage
Spontaneous intracranial hemorrhage
Normal
Closed head injury
Normal
Toxicologic overdose
N/A
Gastrointestinal bleed
Normal
Heat stroke
Normal
Closed head injury
*Millimeters. Abbreviations: BIS, Bispectral Index Score; CT, computed tomography; N/A, not applicable.
ness and found that unarousable patients had BIS scores ranging from 23 to 97.21 The Spearman correlation between SAS and BIS in this study was r ⫽ 0.36 (P ⬍ .001) and similar to our study, does not support the discriminatory value of BIS for the assessment of the sedation status of intubated patients. Two other ED groups have reported pilot studies of BIS in intubated patients. Stephanides and Shaw noted that all of
23 such study subjects had BIS values greater than 80 (which is consistent with being in a “light hypnotic state” according to the manufacturer11,12) one-third of the total BIS monitored time.22 Miner et al applied BIS monitoring to 54 intubated ED patients and were able to interview 26 when they had recovered. Four of these 26 reported recollection of the intubation, with their BIS values being ⬎70 (n ⫽ 1) and ⬍70 (n ⫽ 3). In contrast, 10 of 13 patients with BIS ⬍70
FIGURE 1. Correlation between BIS and physician sedation assessments.* *Smoothing line generated by LOWESS locally weighted regression with bandwidth of 5. Pearson r ⫽ ⫺0.37, p ⫽ .002.
FIGURE 2. BIS scores stratified by sedation adequacy.* *The median (interquartile range) BIS score for adequately sedated patients was 58 (45-67), and 57 (44-69) for inadequately sedated patients.
GILL ET AL ■ BIS FOR INTUBATED ED PATIENTS
81
rameters most clinicians use in their clinical assessments of sedation adequacy. Second, even if our gold standard were only weakly associated with the reality of true sedation adequacy, we should observe at least a trend toward such association. CONCLUSIONS BIS is not associated with and did not predict standard measures of sedation adequacy in mechanically ventilated ED adults. The authors thank Ryan Arnold and Kristan Guenterberg for their assistance with entering patients into this study. Aspect Medical Systems loaned a Bispectral Index Monitor and printer for this study but provided no direct financial support.
REFERENCES FIGURE 3. ROC curve for BIS as predictor of sedation adequacy.* *Area under curve 0.53 (95%CI0.40,067)
and 12 of 13 patients with BIS ⬎70 denied any recollection of the intubation.23 Patients on NMBA were included in both of these ED studies. LIMITATIONS AND FUTURE QUESTIONS Studies of sedation adequacy in the intubated patient are generally limited by the inherent subjectivity of this clinical assessment. Although scales such as the SAS and Ramsay Sedation Scale have been shown to reliably monitor sedation in the ICU setting, these scales cannot be applied to patients on continuous NMBA as a result of their motor components.1-3,18 Because of the necessary inclusion of patients on NMBA into our study, we assessed sedation in a novel fashion (VAS for sedation adequacy and a priori clinical parameters) even though these techniques have not yet been specifically validated for this purpose. When we initiated the study, we assumed that each parameter would likely display a substantial degree of interrater reliability; however, we were disappointed at our observed levels of agreement for all measures. The poorest such measure was the one we originally projected to be the most accurate of all, the VAS rating of sedation adequacy by the treating physician (ie, the “gut instinct”). It is likely that these suboptimal findings do not reflect improper choice of assessment tools, but rather the overall subjectivity of these traditional techniques themselves. This observed clinical variance only underscores the desirability of ultimately identifying an objective measure of sedation adequacy. Given the suboptimal interrater agreement noted in this study, it will not be unreasonable for some to conjecture that perhaps BIS truly is a highly accurate measure of sedation adequacy, and our observed lack of association is only a result of the admittedly subjective gold standard of clinical assessment. Although such speculation cannot be definitively disproven, we believe it to be highly unlikely. First, our chosen clinical measures have substantial face validity for this application, because they represent the typical pa-
1. Simmons LE, Riker RR, Prato BS, Fraser GL: Assessing sedation during intensive care unit mechanical ventilation with the Bispectral Index and the Sedation–Agitation Scale. Crit Care Med 1999;27:1499-1504 2. Riker RR, Fraser GL, Simmons LE, Wilkins ML: Validating the Sedation–Agitation Scale with the Bispectral Index and Visual Analog Scale in adult ICU patients after cardiac surgery. Intensive Care Med 2001;27:853-858 3. Frenzel D, Greim C, Sommer C, Bauerle K, Roewer N: Is the Bispectral Index appropriate for monitoring the sedation level of mechanically ventilated surgical ICU patients? Intensive Care Med 2002;28:178-183 4. Flaishon R, Windsor A, Sigl J, Sebel PS: Recovery of consciousness after thiopental or propofol. Bispectral Index and isolated forearm technique. Anesthesiology 1997;86:613-619 5. Glass P, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P: Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997;86:836-847 6. McCann ME, Brustowicz RM, Bacsik J, Sullivan L, Aublc SG, Laussen PC: The Bispectral Index and explicit recall during the intraoperative wake-up test for scoliosis surgery. Anesth Analg 2002;94:1474-1478 7. Liu J, Singh H, White P: Electroencephalographic Bispectral Index correlates with intraoperative recall and depth of propofolinduced sedation. Anesth Analg 1997;84:185-189 8. Barr G, Anderson RE, Owall A, Jakobsson JG: Being awake intermittently during propofol-induced hypnosis: a study of BIS, explicit and implicit memory. Acta Anaesthesiol Scand 2001;45: 834-838 9. Song D, Joshi GP, White PF: Titration of volatile anesthetics using Bispectral Index facilitates recovery after ambulatory anesthesia. Anesthesiology 1997;87:842-848 10. Gan TJ, Glass PS, Windson A, et al: BIS Utility Study Group. Bispectral Index monitoring allows faster emergence and improved recovery from propofol, alfentil, and nitrous oxide anesthesia. Anesthesiology 1997;87:808-815 11. Critical Care: What is BIS? [Brochure on www.aspectms.com website] Available at: aspectms.com/downloads/pdf_documents/ product_resources_what_is_bis.pdf. Accessed September 2002 12. Using BIS: BIS Range Guidelines [Brochure on www.aspectms. com website] Available at: aspectms.com/downloads/proc_cards/or/ using_bis.html. Accessed September 2002 13. Katoh T, Suzuki A, Ikeda K: Electroencephalographic derivatives as a tool for predicting the depth of sedation and anesthesia induced by sevoflurane. Anesthesiology 1998;88:642-50 14. Driessen J, Harbers J, van Egmond J, Booij L: Evaluation of the electroencephalographic Bispectral Index during fentanyl–midazolam anaesthesia for cardiac surgery. Does it predict haemodynamic responses during endotracheal intubation and sternotomy? Eur J Anaesthesiol 1999;16:622-627 15. Sa Rego MM, White PF: Monitored anesthesia care, in Miller RD (ed): Anesthesia, 5th ed. Philadelphia, Churchill Livingstone, Inc, 2000, pp 1452-1469
82
AMERICAN JOURNAL OF EMERGENCY MEDICINE ■ Volume 22, Number 2 ■ March 2004
16. Shapiro BA, Warren J, Egol AB, et al: Practice parameters for sustained neuromuscular blockade in the adult critically ill patient: an executive summary. Crit Care Med 1995;23:1601-1605 17. Hansen-Flaschen JH, Brazinsky S, Basilc C, Lanken PN: Use of sedating drugs and neuromuscular blocking agents in patients requiring mechanical ventilation for respiratory failure. A national survey. JAMA 1991;266:2870-2875 18. Riker RR, Fraser GL: Monitoring sedation, agitation, analgesia, neuromuscular blockade, and delirium in adult ICU patients. Semin Resp Crit Care Med 2001;22:189-198 19. Shah N, Clack S, Chea F, Tayong M, Anderson C: Does Bispectral Index of EEG (BIS) correlate with Ramsay Sedation Score in ICU patients? Anesthesiology 1996;85:A469
20. Landis JR, Koch GG: The measurement of observer agreement for categorical data. Biometrics 1977;33:159-174 21. Nasraway SA, Wu EC, Kelleher RM, Yasuda CM, Donnelly AM: How reliable is the Bispectral Index in critically ill patients? A prospective, comparative, single-blinded observer study. Crit Care Med 2002;30:1483-1487 22. Stephanides S, Shaw G, Murphy M, Jauch E: Level of sedation as determined by Bispectral Index measurement in intubated emergency department patients. Ann Emerg Med 2001;38:S6 [Abstract] 23. Miner JR, Haug E, Fricwald S, Biros M: Evaluation of Bispectral EEG analysis and recall in paralyzed intubated patients. Acad Emerg Med 2002;9:405-406 [Abstract]