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From the Division of Pediatric Critical Care, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Design. Multiphase clinical trial.
Setting. Outpatient treatment center of a university children's hospital.
Patients. Pediatric outpatients undergoing painful medical procedures.
Interventions. Patients were sedated with propofol for the procedures. Patients were monitored with a BIS monitor, and the BIS score was correlated with the patient's clinical level of sedation. The BIS score was then used as a guide to titrate propofol in the last phase of the study.
Measurements and Main Results. The study consisted of 3 phases. In a chart review of data for 154 children who underwent 212 procedures, propofol was found to be safe and effective, with consistent dosing among the intensivists administering the medication. The children received a mean bolus dose of propofol of 1.56 mg/kg, with a mean total dose of propofol of 0.33 mg/kg per minute for the duration of the procedure. In the second phase, 21 patients ranging in age from 27 weeks to 18 years, with normal neurologic function, were sedated with propofol. An observer who was blinded to the BIS scores recorded clinical levels of sedation and reactivity (with a modified Ramsay scale and reactivity score) every 1 to 3 minutes. Another observer recorded the BIS scores at the same times. A total of 275 data points were collected and evaluated. All data points from the times at which patients were considered to be sedated adequately were used to construct a normal distribution of BIS scores. The mean BIS score was 62. This distribution was used to predict that a maximal BIS score of 47 was needed to ensure adequate sedation for 90% of the population. In the third phase of the study, an algorithm was devised to determine the target BIS score necessary for adequate sedation of 95% of the patients. We chose an initial BIS score of 50 (at which 85% of the patients in phase 2 were sedated) because of the possibility of data from phase 2 being skewed toward oversedation. Propofol was administered by an intensivist in an attempt to maintain the target BIS score. A blinded observer noted the patient's clinical level of sedation. In this group, there were 2 failures, ie, patients were clinically uncomfortable despite a BIS score of 
50, representing only 90% success. Therefore, with the algorithm, propofol was titrated to sedate the next patients to a BIS score of 45. These patients required a mean bolus dose of 1.47 mg/kg and a mean total dose of 0.51 mg/kg per minute to maintain a BIS score of 45. They awakened in 12.75 minutes. All patients were sedated adequately, all procedures were successful, and no patients experienced complications from the sedation. To eliminate variability in the way propofol was dosed, the next 10 patients were given propofol according to a standardized protocol. These 10 children received an initial bolus of 1 mg/kg, with incremental bolus doses of 0.5 mg/kg per dose (maximum: 20 mg) to achieve and to maintain a BIS score of 45. With this protocol, all patients were sedated adequately and none experienced complications from the sedation. The patients required a mean bolus dose of 2.23 mg/kg and a mean dose of 0.52 mg/kg per minute to maintain a BIS score of 45. The mean time until awakening was 14.9 minutes. Regarding the total dose over time and the time until awakening, there was no statistical significance between this group and the group sedated to a BIS score of 45 without the dosing protocol.
Conclusion. The BIS monitor can be a useful monitoring guide for the titration of propofol by physicians who are competent in airway and hemodynamic management, to achieve deep sedation for children undergoing painful procedures.
Key Words: bispectral index monitor • propofol • deep sedation • pediatrics • outpatient procedures • painful procedures • procedural sedation
Abbreviations: BIS, bispectral index
The number of painful procedures necessary in the care of children is increasing. These procedures and the anxiety that surrounds them induce distress that is often viewed as worse than the disease itself, particularly for children who require repeated procedures.1,2 When 118 cancer centers throughout Europe and North America were surveyed (58% response rate), nearly one third of North American centers did not use deep sedation for bone marrow procedures. One fourth of those centers did not use any sedation. Many centers reported that the procedures were performed on conscious children either because of difficulties in obtaining anesthesia support or because the perceived risks for untoward effects were high.3
Propofol is often administered to children undergoing painful procedures.4–19 Intravenously administered, it has a rapid onset of action and dose-dependent sedative effect. It also has antiemetic and amnestic properties. McDowall et al15 reported a decreased incidence (0.5%) of vomiting and postanesthetic agitation with propofol, compared with sedation with ketamine or etomidate. Once administration is discontinued, patients recover rapidly, allowing shorter observation periods to discharge.8 Propofol in conjunction with local anesthetics not only eliminates discomfort for the children but also, by decreasing patient movement and reactivity, facilitates successful completion of the procedure.
Practitioners rely generally on imprecise measures of patient responsiveness to judge the depth of sedation. Although drug treatment is safe in experienced hands, there remains the potential for oversedation of patients. Oversedation makes adverse events, including respiratory depression, hypotension, loss of protective airway reflexes, and prolonged recovery times, more likely.
The bispectral index (BIS) system uses processed electroencephalographic signals to measure sedation on a unitless scale from 0 to 100 (with 0 indicating coma and 100 indicating normal). The BIS has been validated with children undergoing general anesthesia in the operating room.20–24 Outside the operating room, McDermott et al25 found the BIS monitor to correlate well with the University of Michigan Sedation Scale and to be a valid measure of the level of sedation. Agrawal et al26 and Aneja et al27 reported good correlation between BIS monitor results and Ramsay Sedation Scale results among children.26,27 However, Motas et al28 found a wide variation in the depth of sedation with the BIS monitor and the University of Michigan Sedation Scale, despite established dosing protocols with multiple medications.
Guenther et al10 used a dosing protocol to administer propofol for children undergoing lumbar punctures and bone marrow aspiration and biopsy in the emergency department setting. They found this protocol to be efficacious and safe but did not score the depth of sedation objectively.
Finally, 97% of parents surveyed by von Heijne et al12 preferred their child to receive sedation for invasive procedures on the pediatric oncology ward, rather than in the operating room. They reported the advantages of familiar doctors, nurses, and environment; shorter waiting times; faster recovery times; and parents and child remaining calmer. Therefore, we designed a 3-phase protocol with the ultimate aim of using the BIS monitor as a guide to administer propofol safely and effectively to children undergoing painful procedures. Data were analyzed with commercially available software (Excel for Windows; Microsoft, Redmond, WA).
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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All children received nothing by mouth, according to the current recommended dietary precautions of the American Academy of Pediatrics and the American Society of Anesthesiologists.29,30 Informed consent for the sedation and procedure was obtained from each child's parent or legal guardian. The child was examined before the procedure, with specific attention to the child's airway competency and cardiopulmonary status. Sedation was performed by a board-certified pediatric intensivist, whose only responsibility was to maintain the child's comfort and safety. Children were monitored with continuous pulse oximetry, noninvasive blood pressure measurements, and continuous electrocardiography when indicated. Most children received supplemental oxygen; many had indwelling central catheters. For those who required a peripheral intravenous line, the line was placed preferentially in a larger antecubital vein, to minimize pain with the infusion of propofol; some children received a small intravenous dose of lidocaine before propofol. The data were evaluated to determine the bolus and total doses of propofol for the procedure, the time from the end of the procedure until awakening, untoward effects, and differences in dose administration among the intensivists.
Phase 2: Correlation of BIS Index With Clinical Parameters of Sedation Among Children
A sample of 21 children with normal neurologic function, ranging in age from 27 weeks to 18 years, was recruited. The children underwent painful procedures, including bone marrow aspiration and biopsy, lumbar puncture, esophagogastroduodenoscopy, colonoscopy, and renal biopsy. Local anesthetic was administered over the puncture site once adequate sedation was achieved. Consent for the procedure and sedation was obtained in the usual manner. The requirement for informed consent for the observational study was waived by the university's institutional review board; all participants received an informational letter. In addition to continuous cardiac monitoring, continuous pulse oximetry, and noninvasive blood pressure monitoring, the BIS sensor probe was placed on the child's forehead and connected to the BIS monitor (model A-2000, XP platform; Aspect Medical Systems, Natick, MA). The BIS monitor was turned out of view of the intensivist administering the sedative. One of 4 board-certified pediatric intensivists administered propofol and/or other sedatives/analgesics on the basis of clinical signs of arousability, movement, heart rate, blood pressure, and respiratory rate. Intravenous fluids, emergency airway equipment, and emergency medications were immediately available. Vital signs, doses of medications, and clinical levels of sedation were recorded every 3 minutes and at all additional time points at which the procedure could elicit pain. The patients were monitored by the intensivist until they awakened and were then monitored by nurses until all effects of sedation had cleared. An intensivist who was blinded to the BIS score assigned a sedation score (0–5) based on a modified Ramsay scale and a reactivity score (0–4) based on a behavioral scale (Table 1). These scores were later correlated with each BIS score. A total of 275 data points were evaluated, to determine the maximal BIS score that could predict adequate sedation (defined as a sedation score of 5 and a reactivity score of 3 or 4).
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A sample of children ranging from newborn to 18 years of age, with normal neurologic function, who needed to undergo painful procedures were eligible for the study. Informed consent was obtained from each child's legal parent or guardian, with assent from the child when appropriate. In addition to the standard cardiac, blood pressure, and oxygen saturation monitors that are used for all children undergoing sedation, the BIS sensor was placed on the child's forehead. Emergency equipment was available, and monitoring was performed as described for phase 2. In this phase of the study, the intensivist administered propofol while observing the BIS score, titrating the medication to maintain a BIS score of 50. A single intensivist, who was blinded to the BIS score, assigned a sedation score and a reactivity score every 3 minutes for all patients. A student or nurse not involved in the procedure recorded the BIS score, vital signs, patient movements, the beginning and end of the procedures, and doses of propofol, while remaining blinded to the clinical sedation scores. With the limits of expectation of a Poisson distribution, the following algorithm was used to determine the ideal BIS score to maintain adequate sedation at the highest BIS level (Fig 1).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The mean length of time that the children were sedated was 23.3 minutes (range: 3–106 minutes). Data on the time until awakening were available for 126 encounters. The children had a mean time until awakening of 11.02 minutes (range: 2–30 minutes).
Four intensivists and 1 anesthesiologist provided sedation. In cases for which the total dose of propofol administered over time was available, 154 sedations were provided by the intensivists. There was no difference in the amount of propofol administered by the intensivists (P = .13).
Among the 212 sedations performed, no major adverse events related to propofol were recorded. Table 2 lists the minor complications encountered. Several children experienced desaturation, responding to standard airway maneuvers or, in 2 cases, brief, assisted, bag-valve-mask ventilation. One child developed bleeding of esophageal varices and subsequent hypotension. The child was intubated and received fluids and blood, and the sedation technique was changed to ketamine.
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According to the protocol, the target BIS score was decreased 10% to 45, and an additional 10 patients were recruited. All 10 of the patients who were sedated to a BIS score of 45 were sedated adequately.
To eliminate any potential variability in the way propofol was dosed, another 10 patients were given propofol according to a protocol designed to maintain a BIS score of 45. These 10 patients were initially given 1 mg/kg propofol. Propofol was then titrated until the BIS score was 45. For infants and young children (weight: <40 kg), this titration was performed with increments of 0.5 mg/kg propofol. Adolescents (weight: 
40 kg) received increments of 20 mg of propofol. Whenever the BIS score increased to 50, an additional bolus of 0.5 mg/kg or 20 mg (whichever was smaller) was administered. The clinical level of sedation was determined again by the same intensivist, who was blinded to the BIS score. The results were analyzed to determine whether the patients were sedated clinically (sedation score of 5 and reactivity score of 3 or 4) when the BIS score was 45. These sedations were also reviewed for any untoward effects, the total dose of propofol, and the length of time until awakening.
The first 10 patients who were sedated to a target BIS score of 45 required a mean bolus dose of propofol of 1.47 mg/kg (range: 0.49–2.44 mg/kg) and a mean dose of propofol of 0.39 mg/kg per minute (range: 0.25–0.66 mg/kg per minute) to maintain a BIS score of 45 throughout the procedure. Including the initial bolus dose, they required a mean total dose of propofol of 0.51 mg/kg per minute (range: 0.34–0.79 mg/kg per minute). The mean time until awakening was 12.75 minutes (range: 5–20 minutes). No children experienced any untoward effects during the sedations. The next 10 patients who received propofol with the dosing protocol ranged in age from 3 to 17 years (4 female patients and 6 male patents). These children all underwent either lumbar puncture or bone marrow aspiration. All patients were sedated adequately (sedation score of 5 and reactivity score of 3 or 4) throughout the procedure. All patients received subcutaneous lidocaine after being sedated adequately, before placement of the spinal or bone marrow needle. These 10 patients required a mean bolus dose of propofol of 2.23 mg/kg, to achieve a BIS score of 45 (range: 1.11–4.27 mg/kg). They required an additional mean dose of propofol of 0.32 mg/kg per minute (range: 0.12–0.62 mg/kg per minute) to maintain the goal BIS score. Including the bolus dose, they required a mean total dose of 0.52 mg/kg per minute (range: 0.26–1.00 mg/kg per minute). The mean time until awakening was 14.9 minutes (range: 4–27 minutes). No children had any untoward effects, and all procedures were successful.
Because there were no differences in the total dose of propofol (P = .94) and the time until awakening (P = .49) between these groups (Table 3), they were considered together in a comparison with the historical control group. When the 212 procedures from the chart reviews were compared with those for the patients sedated to a BIS score of 45, there was a significant difference in the total dose of propofol given over time (P = .000046), with the patients sedated to a BIS score of 45 receiving higher doses of propofol. The time until awakening in the 2 groups, however, was not different, ie, 11.02 minutes from the chart review and 13.89 minutes for patients sedated to a BIS score of 45 (P = .07) (Table 4).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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For the past 10 years, the pediatric intensivists at our institution have been providing deep sedation with propofol for outpatient children undergoing painful procedures outside the intensive care unit and operating room suites. We have found propofol to be a safe, effective medication. The incidence of adverse effects is quite low, but the nature of these uncommon occurrences requires a physician skilled in airway and hemodynamic management to be present during all sedations. We think that treatment rooms in outpatient clinics and radiology suites can be equipped for proper monitoring of these children during their sedations.
We first performed a representative chart review of data for 154 children who received propofol while undergoing 212 painful procedures. The dose of propofol, recovery times, and complications were similar to those found in the literature (Table 5). In addition to published studies,25–27 we validated the correlation of the BIS scores with the level of sedation with a modified Ramsay sedation scale and a reactivity score (Fig 2). In this phase of the study, we found a mean BIS score of 62 ± 12 for all times at which a patient was determined to be sedated adequately, with a Ramsay score of 5 and a reactivity score of 3 or 4. This agrees with the results reported by Aneja et al27 of a mean BIS score of 52 ± 14 when children were sedated deeply, with a Ramsay score of 4 or 5.
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During this phase of our study, we found that the mean total amount of propofol needed to achieve and maintain a BIS score of 45 was 0.51 mg/kg per minute. When reviewing our results, we noted that there was no standard amount of propofol given or timing to administer additional propofol on the basis of the increase in BIS scores. Therefore, we developed a protocol to standardize the administration of propofol and used this for the sedation of an additional 10 patients. With this dosing protocol, we found the mean total amount of propofol needed to achieve and maintain a BIS score of 45 to be 0.52 mg/kg per minute, which was not different (P = .94) from the amount required without a dosing protocol (Table 3).
In evaluating our results, we sought to compare our propofol dosing with that described previously. Unfortunately, most authors reported the total dose of propofol in milligrams per kilogram, without using time as a denominator. Because of the short half-life of propofol, reporting the total dose as milligrams per kilogram per minute is more relevant, because longer procedures require higher doses. Therefore, we reviewed the current literature and, with the data available, were able to derive the total dose in milligrams per kilogram per minute for many of the studies. This information is reported in Table 5. Where information was available, the range of mean total propofol doses administered was 0.16 to 0.41 mg/kg per minute. In the majority of studies in which propofol was administered for painful procedures, additional medications, such as opiates, benzodiazepines, or ketamine, were administered. Not surprisingly, lower doses of propofol were required, except in the study by Skokan et al,18 in which all patients received morphine or fentanyl before propofol, according to the protocol. These patients required a mean dose of propofol of 0.41 mg/kg per minute to be sedated adequately, as determined by the tolerance of noxious stimuli (60% underwent fracture reduction) without complaint.18 In studies in which patients underwent painful procedures (nonimaging only), the mean dose of propofol required was 0.27 to 0.37 mg/kg per minute. The total dose of 0.33 mg/kg per minute determined in our chart review of data for 212 patients was within this range.
With titration of propofol to a BIS score of 45, our patients required a mean total dose of 0.52 mg/kg per minute. This dose was significantly higher than the dose we recorded from our chart review, as well as from the review of the literature. This difference is not surprising, because the goal of the protocol was to ensure that 95% of the patients were sedated adequately. However, it may be unfair to compare our doses with those reported in the literature, because none of the other studies evaluated objectively the adequacy of sedation for their patients, with the exception of Vardi et al,8 who used a Ramsay scale, and Jayabose et al,7 who deemed sedation adequate if the patient did not require restraint. In addition, time intervals were not defined clearly in all studies. We used the time from the first dose of propofol until completion of the procedure as the denominator. If the procedure time included the time until complete recovery, then this would skew the data to a lower value. Finally, although statistically sound, our sample size was small.
In addition, it is very reasonable that this BIS-guided protocol could be used with a higher BIS level, with the appreciation that there could be a 10% to 15% failure rate. Because of the rapid onset of action of propofol, patients could then receive additional doses of propofol, titrating to a goal BIS score of 45.
The time until awakening, from completion of the protocol until eye opening, was 13.89 minutes with the protocol. This time is less than that reported in the literature (range: 14–28.8 minutes). Again, the time intervals were not defined clearly in all studies. When the time from the dose-guided protocol was compared with 11.02 minutes from the chart review, the difference was not statistically significant (P = .07). More importantly, however, an average difference in awakening of 2 minutes has little clinical significance, especially with no increase in the incidence of untoward effects or complications.
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CONCLUSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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FOOTNOTES |
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Address correspondence to Karen S. Powers, MD, Department of Pediatric Critical Care, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 667, Rochester, NY 14642. E-mail: karen_powers{at}urmc.rochester.edu
No conflict of interest declared.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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 S. E. Zgleszewski, D. Zurakowski, P. J. Fontaine, M. D'Angelo, and K. P. Mason Is Propofol a Safe Alternative to Pentobarbital for Sedation during Pediatric Diagnostic CT? Radiology, May 1, 2008; 247(2): 528 - 534. [Abstract] [Full Text] [PDF]
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