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* Division of Pediatric Emergency Medicine, LeBonheur Children’s Medical Center, Memphis, Tennessee
Child Development Center, Vanderbilt University, Nashville, Tennessee
Division of Pediatric Emergency Medicine, Kosair Children’s Hospital, Louisville, Kentucky
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Methods. We conducted a prospective, partially-blinded controlled comparative trial comparing intravenous P/F with K/M in a convenience sample of 113 patients aged 3 to 18 years old undergoing orthopedic procedural sedation. All medications were administered by the intermittent intravenous bolus method. An independent sedation nurse recorded total sedation time and RT. Effectiveness was measured using 6 parameters: 1) patient distress as assessed by independent blinded observers after videotape review using the OSBD-r; 2) orthopedic satisfaction score (Likert scale 1–5); 3) sedation nurse satisfaction score (Likert 1–5); 4) parental perception of procedural pain using a 0 to 100 mm Visual Analog Scale with the upper limit being "most pain"; 5) patient recall of the procedure; and 6) 1 to 3 week follow-up.
Results. RT and total sedation time were significantly less in the P/F group than in the K/M group (33.4 minutes vs 23.2 minutes). The mean OSBD-r scores during manipulation were 0.084 and 0.278 for the K/M and P/F groups, respectively. Although this difference was statistically significant (95% confidence interval for the mean difference –0.34 to –0.048), both regimens were successful in keeping the scores low. There was no statistical difference between the groups in the other measures of effectiveness. There was a statistically significant difference between the groups in the occurrence of desaturation and late side effects.
Conclusions. RT with P/F is shorter than with K/M. P/F is comparable to K/M in reducing procedural distress associated with painful orthopedic procedures in the pediatric emergency department. Although propofol has a greater potential of respiratory depression and airway obstruction as compared with ketamine, it offers some unique advantages including a quicker offset and smoother recovery profile.
Key Words: propofol • fentanyl • ketamine • midazolam • procedural sedation
Abbreviations: PSA, procedural sedation and analgesia • P/F, propofol/fentanyl • K/M, ketamine/midazolam • RT, recovery time • OSBD-r, Observational Score of Behavioral Distress-revised • PED, pediatric emergency department • ED, emergency department • ASA, American Society of Anesthesia • TST, total sedation time • IV, intravenous • VAS, Visual Analog Scale • NPO, nil per os
Procedural sedation and analgesia (PSA) is an important component of pediatric emergency care. The ideal agent for PSA for a brief painful orthopedic procedure would be safe and easy to administer, provide adequate amnesia and muscle relaxation, and have a rapid onset and offset.
Currently, ketamine is a popular choice for PSA.1–5 It has intrinsic analgesic and amnestic properties, protects airway reflexes, and can be administered by multiple routes of administration. However, it has the potential for undesirable side effects that include unpleasant emergence hallucinations and emesis.1,2,5–11 Ketamine is also relatively contraindicated in patients with hypertension, increased intracranial pressure, respiratory tract infection, or underlying neuropsychiatric comorbidities such as seizures or psychoses.7
Propofol is an intravenous (IV) sedative-hypnotic agent with amnestic properties that causes loss of consciousness reliably and rapidly. It is structurally unrelated to other hypnotics such as barbiturates and benzodiazepines and represents a new class of sedative hypnotics called diisopropylphenols. It has been shown to have synergistic hypnotic effects when used in conjunction with other classes of analgesic/sedative agents as barbiturates, benzodiazepines, opioids, and ketamine.12–14 Because it is a poor analgesic, propofol usually requires the use of an adjunctive analgesic agent. Propofol is uniquely titratable and unlike ketamine, it has intrinsic anti-emetic properties.15 It provides for a smooth recovery without dysphoria. Its adverse effects include respiratory depression, airway obstruction, and pain at the site of injection. Multiple studies in the adult population have compared propofol to midazolam.16,17 Propofol’s use is increasing in pediatric emergency departments (PEDs) across the country. Numerous uncontrolled studies, in the intensive care unit and operating room setting, have documented the efficacy of propofol for sedation in children.13,18–22 We are not aware of any previous studies performed in the PED setting that have compared the use of propofol to ketamine for sedation during procedures. Prior data comparing these 2 agents has been from trials performed in the pediatric critical care unit.23,24
In a recent randomized double blind prospective trial in children, propofol was noted to induce sedation as effectively as midazolam. Propofol had a shorter time of onset and recovery, with an equivalent safety profile.22 Similar results were noted when propofol was compared with the barbiturates in children undergoing sedation for magnetic resonance imaging.25
We elected to examine the combination of propofol and fentanyl to ketamine and midazolam for the purpose of PSA for brief orthopedic manipulation in the PED with attention to the outcomes of recovery time (RT) and procedure-related distress.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Design
This was a prospective, partially-blinded, controlled comparative trial conducted in the emergency department (ED) of LeBonheur Children’s Medical Center, which is a regional referral tertiary care center and the designated Comprehensive Regional Pediatric Center for West Tennessee with an annual ED census of 65 000 patients. This study was approved by the Institutional Review Boards at LeBonheur Children’s Medical Center and the University of Tennessee.
We included children aged 3 years to 18 years that required PSA for emergency orthopedic procedures. Exclusion criteria were American Society of Anesthesia (ASA) class III or greater, fractures >24 hours old, and known allergy to any of the study medications or eggs. According to our institutional policy, all patients were fasting for at least 4 hours before the procedure. A convenience sample of eligible patents was recruited by 1 of 2 investigators (J.P. and S.A.G.).
Based on the results of previously published studies, we assumed that the mean RT with propofol would be 14.9 ± 11.1 minutes22 and that the mean OSBD-r score would be 1.08 ± 1.12 for PED procedures with ketamine and midazolam.5 To detect a difference in mean OSBD-r score of 1.05 and a 10-minute difference in RT, 50 subjects (25 in each group) were needed for an 
of 0.05 and power of 90%. We recruited patients for 10 months (September 2000 to June 2001) to capture the variety of seasonal sports injuries.
Protocol
Patients were enrolled in the study after caregiver consent and patient assent, when deemed appropriate, were obtained. A total of 140 patients were approached for participation, and 113 consented to participate in the study (Fig 1). Patients were assigned to P/F on odd days and K/M on even enrollment days. An odd or even day was defined as starting at 7 AM and ending at 7 AM on the following day. Children received narcotic analgesia at the treating physician’s discretion. The subjects and their parents were unaware of the patient-to-drug assignment protocol. In case of multiple attempts at reduction, only the initial attempt was included in the study. The design was based on intent-to-treat analysis.
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Quantification of Distress and Satisfaction
The procedure was videotaped for independent review of outcomes. One or both investigators were present for all sedations. Ketamine is known to produce a characteristic dissociative state with nystagmus and a vacant gaze. To mask these "tell tale" facies from the reviewer, patients wore dark goggles (sunglasses) for the duration of the video recording. The patients, their parents, and the reviewers of the tapes were blinded to the type of medication administered. All medications and tubing were covered from view of the video camera and the parents (or legal guardians). Both investigators reviewed all the tapes continuously to ensure that the protocol was followed. In anticipation of a greater frequency of airway repositioning maneuvers during propofol use, random mock jaw thrusts were performed to reduce bias on the part of the reviewers. Equal numbers of jaw thrusts, both actual and mock, were recorded for both medication groups.
The independent blinded reviewers assessed the tapes in random order for patient’s behavioral distress as measured by the previously validated pain scale know as the OSBD-r.26,27 This scale records the occurrence of 11 behaviors at distinct time points within a medical procedure. The scores range from a minimal distress score of 0 to a maximal distress score of 23.5. The behaviors are weighted according to the amount of anxiety or distress that they represent. Intensity ratings vary along a 1- to 4-point scale in which 4 indicates maximal anxiety or pain. The behaviors measured are cry, scream, physical restraint, verbal resistance, request for emotional support, muscular rigidity, verbal pain expression, flail, nervous behavior, and information seeking. The OSBD-r scores were measured at 15-second intervals for 3-minute periods during the presedation period (before the administration of sedative medications) and during orthopedic manipulation. Reviewers were encouraged to record the point when the patient had the most distress during the 2 periods and the highest OSBD-r scores were included in the tabulations. One of our reviewers was a child psychologist and the other a pediatric registered nurse.
We ensured that each reviewer had a complete understanding of the scale with assistance of a personal communication with Dr. Susan Jay, who originally devised and validated the scale in children.26,27 We then went through a trial of 5 patient tapes (not part of the study subject population) with the reviewers to ensure familiarity with the anticipated behaviors during the painful procedure as measured by the scale.
After completion of the procedure, the parents that chose to be in the room were asked to rate the degree of pain they perceived their child had experienced during the procedure, using the Visual Analog Scale (VAS).31 This scale, which ranges from 0 mm or no pain to 100 mm or maximal pain, has been previously validated.32,33 The orthopedic surgeon and the sedation nurse were asked to complete a 5-point Likert scale (with 1 representing the least and 5 the highest level of satisfaction with the PSA). On return to baseline status, patients were asked if they recalled the procedure.
Patients and their families were then contacted by telephone by either J.P. or S.A.G., the primary investigators, 1 to 3 weeks following their ED visit, to assess their level of satisfaction with the medication regimen that they had received using a standard questionnaire. The script was consistent and followed the questions prepared before initiating the study. Any adverse effects noted were recorded.
Statistical Analysis
Dichotomous variables like yes/no responses were analyzed using the 
2 test and Fisher exact test if needed. Using the Student t test and Wilcoxon rank-sum test, we assessed RT and TST data. Similarly, the parental VAS and satisfaction scores were analyzed using the Student t test and Mann-Whitney U test. Because the results of these tests were comparable, the Student t test was used for reporting all continuous variables. Interrater reliability for all reviewed tapes was assessed during orthopedic manipulation using the Spearman correlation coefficient and an intraclass correlation coefficient.34 SPSS (SPSS, Chicago, IL), Statview (SAS Institute, Cary, NC), and Prism (GraphPad, San Diego, CA) software were used in the analyses.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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) the intraclass coefficient, demonstrated good interrater reliability ( = 0.75 and intraclass coefficient (3,k) = 0.86).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Although the mean OSBD-r scores were greater in the P/F group, both groups of medications were successful in keeping the distress scores low during the procedures. The difference between the K/M and P/F groups OSBD-r scores, although statistically significant, are clinically insignificant. In each instance, the mean score was <1, indicating very minimal distress. The mean scores in both groups were lower than previously reported in the literature.5,35 Wathen et al35 reported mean OSBD-r scores of slightly <1 during the procedure with 1 mg/kg of ketamine. Kennedy et al5 administered a mean dose of 1.76 mg/kg of ketamine in their study subjects. The mean OSBD-r scores were 1.08. We speculate that the slightly lower scores in our subjects who received K/M may be attributable to a greater mean dose of ketamine (1.99 ± 0.58 mg/kg). However, K/M produced consistently effective conditions, whereas P/F had at least some unsatisfactory and/or borderline sedation conditions.
There are currently no published studies comparing propofol and ketamine during procedural sedation. Havel et al22 prospectively compared propofol and midazolam during orthopedic procedural sedation. They concluded that propofol was comparable to midazolam in efficacy and had a shorter RT. Our study results were similar and reflect the unique pharmacokinetic profile of propofol. Moreover, time from initial administration to manipulation was greater in the P/F group when compared with K/M.
At the completion of our study, an open-ended, formal survey was conducted. The 10 orthopedic surgeons that had participated in the study were mailed a brief questionnaire. Six completed questionnaires were returned. When asked which medication regimen they preferred most, 3 of the surveys indicated K/M and the other 3 indicated P/F. P/F was preferred during difficult reductions that required greater muscle relaxation. Because the turnaround time with P/F was shorter, the latter was also preferred when they had multiple patients in the department that required PSA. In accordance with our departmental policy, only 1 PSA can be performed at any given time. In settings where multiple patients can be sedated at any given time in the ED, this may not be the case. Those orthopedic surgeons that preferred K/M pointed out its ease of use related to the decreased time to onset of optimum conditions for fracture manipulation.
Our study had several limitations. The decision to use a convenience sample was based on the availability of the 2 principal investigators. Patient recruitment was also in the context of a busy ED. High census or acuity in the department did not permit subject recruitment. We recognize that this was a limitation of the study. However, we believe it closely reflects the nature of clinical practice in our busy urban pediatric ED. The odd/even day allocation was not the ideal method of randomization. However, an examination of our patient demographics revealed that our patient populations were closely matched for the multitude of characteristics that we examined.
The dose of each individual medication was intentionally not standardized. The sedative medications were carefully titrated to attain patient comfort as well as to facilitate manipulation of the injured extremity by the orthopedist. The actual dose administered was dependent on several factors. Some of these included the type of orthopedic injury, degree of pain, timing and dose of premedication, and individual patient characteristics. It was particularly difficult to control for analgesic premedication because many patients in our practice were referred to our center from outlying EDs.
Although this study was blinded for evaluation of efficacy, the sedation nurse, investigator, and orthopedic surgeon were not blinded to the medication administered. The sedation nurse recorded the various time points during PSA. This had the potential for bias on the part of the recorder. However, in accordance with our hospital sedation policy, the role of this independent sedation nurse is to be solely responsible for documentation and monitoring of the patient, until they reach their presedation baseline.
Moreover, our study occurred at a single site involving only 2 investigators. By limiting the number of providers involved with PSA, we believe this led to a stricter adherence to the protocol and uniformity of clinical practice by the nursing and ancillary staff. The results, particularly as they pertain to RT and TST, however, need to be validated at other centers.
Although our study was not powered for comparison of adverse effects between the 2 regimens, the incidence of airway obstruction and hypoxemia in the P/F group is consistent with other studies using propofol.16,19,20,22 Propofol can cause respiratory depression with loss of airway tone, necessitating airway interventions. No patient in our study had apnea or required the use of assisted ventilation. The routine use of an anti-sialogogue could have reduced our incidence of adverse respiratory events.
Another potential limitation was that we did not objectively measure the depth of sedation. Our study experience suggests that to achieve a relatively motionless state during painful orthopedic procedures requires deep sedation.36 None of the study patients experienced an aspiration event, nor did they require assisted ventilation. We believe that our presedation screening for potential airway problems, vigilant monitoring for early signs of airway obstruction, and strict adherence to the hospital sedation policy, based on the guidelines outlined by the American Academy of Pediatrics and ASA Committees on Sedation, was responsible for the relative lack of significant adverse events or escalation of care.28,30 This appears to be consistent with the experience at other similar institutions. Strict adherence to a generalized risk assessment tool reduced the rate of adverse events even with deep sedation at the Children’s Hospital of Wisconsin.37 We did not include end-tidal carbon dioxide monitoring during our sedations. Its use may add to the safety of procedural sedation by detecting hypoventilation earlier than with clinical assessment and pulse oximetry.38
The rates of dysphoric reactions and emesis with the use of K/M are consistent with the incidence reported in other studies.4,8,35 It could be argued that the addition of midazolam may have prolonged the RTs with ketamine. At the time of this study, we felt that adjunctive midazolam would mitigate the ketamine-induced dysphoria experienced especially by older children and teenagers. Since then, 2 large studies have examined the role of midazolam in conjunction with ketamine. The results are not conclusive. Emesis is an important adverse event that can occur during or after procedural sedation. The incidence of emesis in conjunction with PSA needs to examined further. Macario et al39 described that in postoperative adult patients, avoiding nausea and vomiting was a high priority. In Sherwin et al,8 the incidence of emesis was 2% in the K/M group and 12% in the ketamine/placebo group. In Wathen et al,35 a decreased incidence of emesis was observed when midazolam was given in conjunction with ketamine, 19.4% versus 9.6%, respectively. Moreover, the mean age of the ketamine only group was <7 years.8,35 Additionally, as suggested by Kennedy and MacAllister,40 there is limited data about the medium to long-term sequelae of ketamine sedation.
Because the caller during our telephone surveys after the sedation was not blinded to the medication administered, the validity of the results concerning the increased incidence of nightmares seen with K/M are in question.
It can be argued that the injured patient has delayed gastric emptying time and the conventional preoperative NPO guidelines are inadequate to reduce aspiration risk. Based on recent reviews of ED sedations, the risk of clinically significant aspiration syndrome is negligible. Failure to adhere to the NPO guidelines may not increase this risk.37,41 We speculate that propofol use in the ED setting may actually decrease this risk because of its intrinsic anti-emetic properties.15 Nonetheless, our NPO times were in accordance with our hospital policy. The latter was consistent with the above-mentioned ASA fasting guidelines for sedation. As indicated in Table 1, the mean NPO time was over 8 hours for both groups. None of the study subjects experienced a clinically significant aspiration event.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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We thank Steven Buckingham, Camilla Forsythe, Barry Gilmore, Martin Herman, Jerry Vile, and Joseph Weinberg for their critical reading of this manuscript and feedback. Jim Wan was invaluable for his assistance with the statistical analysis. We thank Susan Jay for her advice on how to use the OSBD-r and Elizabeth Meals for assistance with the figures. This study was made possible by the support and camaraderie of the staff of the LeBonheur Children’s Hospital ED.
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FOOTNOTES |
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Address correspondence to Sandip A. Godambe, MD, PhD, Division of Pediatric Emergency Medicine, University of Louisville, 571 S Floyd St, Suite 300, Louisville, KY 40202. E-mail: sandip.godambe{at}louisville.edu
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This article has been cited by other articles:
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  L. G. Yamamoto Initiating a Hospital-Wide Pediatric Sedation Service Provided by Emergency Physicians Clinical Pediatrics, February 1, 2008; 47(1): 37 - 48. [Abstract] [PDF]
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 M. Vespasiano, M. Finkelstein, and S. Kurachek Propofol Sedation: Intensivists' Experience With 7304 Cases in a Children's Hospital Pediatrics, December 1, 2007; 120(6): e1411 - e1417. [Abstract] [Full Text] [PDF]
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N. M. Tofil, M. A. Buckmaster, M. K. Winkler, B. H. Callans, M. P. Islam, and A. K. Percy Deep Sedation With Propofol in Patients With Rett Syndrome J Child Neurol, March 1, 2006; 21(3): 210 - 214. [Abstract] [PDF]
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L Symington and S Thakore A review of the use of propofol for procedural sedation in the emergency department Emerg. Med. J., February 1, 2006; 23(2): 89 - 93. [Abstract] [Full Text] [PDF]
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 Is Propofol Advantageous for Brief Pediatric Procedural Sedation? Journal Watch Emergency Medicine, August 27, 2003; 2003(827): 3 - 3. [Full Text]
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