A Prospective Randomized Controlled Trial of Two Different Sedation Sequences for Third Molar Removal in Adults

ANESTHESIA/FACIAL PAIN

A Prospective Randomized Controlled Trial of Two Different Sedation Sequences for Third Molar Removal in Adults Ruba Khader, BDS,* Daniel Oreadi, DMD,y Matthew Finkelman, PhD,z Marcin Jarmoc, DMD,x Sanjeet Chaudhary, DMD,k Roman Schumann, MD,{ and Morton Rosenberg, DMD# Purpose:

In oral and maxillofacial outpatient surgery, sedation techniques are an important component in patient management for a wide variety of surgical procedures. Fentanyl and midazolam are commonly used sedatives with different mechanisms of action and specific analgesic or amnestic properties. This study examined whether the order of their administration would affect a patient’s pain perception or procedural vital signs.

Materials and Methods:

After institutional review board approval and written informed consent, a prospective, randomized, parallel-group clinical trial was conducted in patients who planned to undergo removal of at least 2 third molars under intravenous moderate sedation. Patients were randomly assigned to 1 of 2 groups. The fentanyl-first group received fentanyl and then midazolam; the midazolam-first group received midazolam and then fentanyl. Recollection of the intraoperative pain score was assessed 24 hours after surgery using the Wong-Baker FACES pain scale. The MannWhitney U test was used to assess for the presence of a statistically significant difference between the 2 groups. Statistically significant differences in procedural vital sign fluctuations were examined using the t test. Patients’ satisfaction with the procedure was assessed and intergroup comparisons were made. Results:

Sixty-six patients were enrolled, 1 of whom did not complete the study. Recollected procedural pain scores at 24 hours after surgery were not statistically different between groups. Median scores on the Wong-Baker FACES pain scale for the 2 groups were 2.0 (interquartile range, 3.1) for the fentanyl-first group and 1.5 (interquartile range, 2.5) for the midazolam-first group (P = .333). There was no statistical difference in the change in vital signs from baseline to 2 surgical end points in the 2 groups. In addition, patient satisfaction with the procedure did not statistically differ between the 2 groups.

Conclusions: In this study, selective sequencing of midazolam or fentanyl during an intravenous moderate-sedation procedure did not result in a measurable difference of recollected procedural pain scores at 24 hours after third molar extraction. The choice of the sedation agents and the order of their

*Assistant Professor, Division of Oral and Maxillofacial Surgery,

of Academic Affairs, Department of Anesthesiology, Tufts Medical

Medical College of Wisconsin, Milwaukee, WI. yAssistant Professor, Department of Oral and Maxillofacial

Center; Professor, Tufts University School of Medicine, Boston, MA. #Professor, Department of Oral and Maxillofacial Surgery; Head,

Surgery, Tufts University School of Dental Medicine, Boston, MA.

Division of Anesthesia and Pain Control, Tufts University School of

zTufts Clinical and Translational Science Institute, Tufts

Dental

University, Boston, MA; Institute for Clinical Research and Health

Medicine;

Associate

Professor,

Department

of

Anesthesiology, Tufts University School of Medicine, Boston, MA.

Policy Studies, Tufts Medical Center, Boston, MA.

Address correspondence and reprint requests to Prof Khader:

xClinical Instructor, Department of Oral and Maxillofacial

Oral and Maxillofacial Surgery, Froedtert and the Medical College

Surgery, Tufts University School of Dental Medicine, Boston, MA;

of Wisconsin, Milwaukee, WI 53226; e-mail: [email protected]

Oral and Maxillofacial Surgeon, Northern Star Dental Group, Danvers, MA.

Received May 9 2014 Accepted August 24 2014

kResident, Department of Oral and Maxillofacial Surgery, Tufts

Ó 2015 American Association of Oral and Maxillofacial Surgeons

University School of Dental Medicine, Boston, MA.

0278-2391/14/01405-0

{Professor, Vice Chair of Academic Affairs, Department of

http://dx.doi.org/10.1016/j.joms.2014.08.033

Anesthesiology, Tufts Medical Center; Vice-Chair, Tufts University Health Sciences Institutional Review Board; Professor, Vice Chair

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administration should be tailored to the patient’s needs, type of surgical procedure, and surgeon preference. Ó 2015 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 73:224-231, 2015 Sedation is a vital component of patient management for a wide variety of surgical procedures in oral and maxillofacial surgery (OMS) outpatient practices. The choice of sedation technique is made according to the patient’s needs and health status, type of surgical procedure to be performed, and surgeon preference. The ideal sedation agent used in outpatient practices should provide a rapid onset of action and stable operating conditions, it should be easily reversed, it should ensure a fast and a predictable recovery, and it should carry very few side effects.1 Midazolam (a benzodiazepine) and fentanyl (an opioid) are 2 sedation agents that satisfy these requirements; therefore, they are 2 of the most commonly used drugs for intravenous moderate sedation in outpatient OMS practices.2 Surgeons in the Department of OMS at Tufts University (Boston, MA) use midazolam or the combination of midazolam and fentanyl for most of their intravenous moderate-sedation procedures. The efficacy and safety of midazolam, fentanyl, and their combination in outpatient intravenous moderate sedations have been well established in the literature.3-15 The choice of the order in which these medications are administered is left primarily up to the practitioners’ preference; the effect of the order in which these medications are administered on patient outcomes has not been scientifically studied. Although every patient encounter should be individualized and there is not one universal technique that will be suitable for all patients, the authors approached this issue with a fixed-dose study protocol to determine whether the difference in the order of administration of these medications in healthy patients for routine OMS procedures would produce clinically important results.16 This study examined the effect of the order in which intravenous midazolam and fentanyl are administered during an outpatient OMS procedure (ie, fentanyl and then midazolam and vice versa) on patient outcomes. To explore patient outcomes related to the alteration of the order in which intravenous sedation medications are administered, a double-blinded, randomized, clinical trial of patients undergoing outpatient surgical removal of third molars was conducted. The primary endpoint of this study was the recollection of intraoperative pain. In addition, the authors explored the effect of the alteration of the sequence of the order in which intravenous medica-

tions are administered on intraoperative vital signs. This was an exploratory study aimed at gathering preliminary data. The results from this study will be the first documentation of the effect of altering the sequence of administration of intravenous sedation medications on intraoperative pain perception. The purposes of this study were to: 1. explore the effect of the order in which intravenous sedation medications are administered (midazolam and fentanyl) on intraoperative pain perception 2. compare the effect of the order in which intravenous sedation medications are administered on patient satisfaction with the sedation procedure 3. compare the effect of the order in which intravenous sedation medications are administered on clinical outcomes (including fluctuations of vital signs)

Materials and Methods A prospective, randomized, parallel-group clinical trial was conducted in 66 patients who planned to undergo removal of at least 2 third molars under intravenous moderate sedation at the Department of OMS at the Tufts University School of Dental Medicine. The study was approved by the institutional review board and is in accordance with the Declaration of Helsinki. Potential subjects underwent a screening process at which point an informed consent was obtained. The surgeons explained to the participants the proposed surgical procedure, risks and benefits of the procedure, and the study protocol. Routine physical and radiographic examinations were completed. All patients had to meet the inclusion criteria listed in Table 1. Patients who requested general anesthesia or a deeper level of sedation were excluded (according to the exclusion criteria listed in Table 1). Recruited patients were consecutively assigned a participant number (from 1 through 66) and were scheduled for their surgical procedure. A computergenerated randomization scheme was produced assigning numbers 1 through 66 into 2 groups. The fentanyl-first group would receive fentanyl first in the sedation sequence, and the midazolam-first group would receive midazolam first in the sedation sequence. The key connecting the patient number with the assigned group was locked at the principal investigator’s office and was accessed by the surgeons immediately before commencing the surgical

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SEDATION FOR THIRD MOLAR REMOVAL IN ADULTS

Table 1. INCLUSION AND EXCLUSION CRITERIA

Inclusion criteria 1 2 3 4

Exclusion criteria 1

2 3 4

5 6

18-64 yr of age American Society of Anesthesiologists physical classification status I or II free of any major illness that would increase surgical risk surgical removal of $2 third molars ($1 third molar on right side $ 1 on left side) American Society of Anesthesiologists physical classification status at least III psychiatric disorders requiring >1 chronic medication any pregnant or nursing patient chronic benzodiazepine and opioid medication use before and up to day of surgery Mallampati classification III or IV any patient requesting deep sedation or general anesthesia

Khader et al. Sedation for Third Molar Removal in Adults. J Oral Maxillofac Surg 2015.

procedure. No other research personnel had access to the randomization scheme or the key. Two OMS residents performed all surgical procedures. The surgical procedures were performed under direct supervision of faculty members. All team members other than the operating surgical resident (and the supervising faculty) were blinded to the order in which sedation medications were administered. A blinded observer recorded the patients’ vital signs at baseline and every 5 minutes afterward. The patient’s medical history was reviewed, and the nothing-by-mouth status was confirmed before commencing the surgical procedure. Standard physiologic monitoring devices were used, including a 3-lead electrocardiographic monitor, a noninvasive blood pressure (BP) monitor, and a pulse oximeter. In addition, a transcutaneous carbon dioxide (tcpCO2) monitor (SenTec Digital Monitor, SenTec, Therwil, Switzerland) and a bispecteral index (BIS) monitoring device were used. The surgical team administered the sedation medications at 2 different time points during the procedure. Each administered dose preceded the surgical removal of third molars in 1 side of the oral cavity. All participants received intravenous midazolam and fentanyl to achieve moderate sedation. The order in which the patients received these medications differed according to their assigned

group. Nevertheless, the order was consistent throughout the procedure. Baseline recordings of BP, oxygen saturation measured by pulse oximetry, heart rate (HR), tcpCO2, and BIS were taken before administration of any medications (time point 0). Afterward, the fentanyl-first group received fentanyl 25 mg over 30 seconds and 60 seconds later received midazolam 2.5 mg over 30 seconds. The opposite sequence was used for the midazolam-first group (midazolam 2.5 mg over 30 seconds and 60 seconds later fentanyl 25 mg over 30 seconds). Then, local anesthesia was administered using 2% lidocaine with 1:100,000 epinephrine. No other local anesthetics were used in this study. A bite block and a throat shield were used during the entire procedure. One side of the oral cavity was addressed at a time. The necessary surgical procedure was performed to remove the third molar. This could have included using elevators and forceps, reflecting a surgical flap, removal of bone, or sectioning of the tooth according to the condition of the third molar. Copious irrigation was performed for all patients during the surgical procedure, all granulation tissue was removed, and the surgical site was closed using 3-0 chromic gut sutures. Hemostasis was observed before moving to the contralateral side of the oral cavity. The conclusion of the procedure on the first side of the oral cavity corresponded to time point 1. BP, SpO2, HR, tcpCO2, and BIS were recorded at that point. The same procedure was performed on the contralateral side after midazolam and fentanyl were administered; the order in which these were administered was consistent with the group assignment and with the order they were administered in the first part of the surgical procedure. Recordings of BP, SpO2, HR, tcpCO2, and BIS were taken at the conclusion of the second half of the procedure. This time point was referred to as time point 2. A blinded research team member contacted all participants by telephone 24 hours after the procedure. The research team member conducted a questionnaire that consisted of 8 items (Fig 1). The items addressed recollection of pain, overall experience, and nausea and vomiting after the procedure.

OUTCOME MEASUREMENTS

The primary outcome of the study was the recollection of intraoperative pain measured by the validated Wong-Baker FACES 10-point pain scale.17 The primary outcome was measured 24 hours after surgery by answering the second item in the questionnaire (Fig 1): ‘‘According to the pain scale given to you by

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1.) According to the following pressure scale, how would you rate your perception of pressure during the surgical procedure? 1 – No pressure 2 – Mild pressure but tolerable 3 – Moderate pressure but tolerable 4 – Severe pressure but tolerable 5 – Severe pressure not controlled by local anesthesia supplemented with conscious sedation 2.) “According to the pain scale given to you by the surgeon, how would you rate your perception of pain during the surgical procedure?”

3.) “In the evening immediately following the surgery, did you experience any nausea or vomiting?” (Yes/No) 4.) “Do you remember when the IV was started in your arm?” (Yes/No) 5.) “Do you remember local anesthesia injections in your mouth?” (Yes/No) 6.) “Do you remember being told postoperative instructions for after the procedure?” (Yes/No) 7.) “Would you like to have this same sedation again” (Yes/No) 8.) “Overall, how would you rate your sedation experience?” 1 – Unacceptable 2 – Poor 3 – Satisfactory 4 – Good 5 - Excellent FIGURE 1. Questionnaire administered to patients during follow-up telephone call conducted at least 24 hours after surgery. Khader et al. Sedation for Third Molar Removal in Adults. J Oral Maxillofac Surg 2015.

the surgeon, how would you rate your perception of pain during the surgical procedure?’’ Two secondary outcome measurements were measured: 1. The change (D) in vital signs (systolic BP [SBP], diastolic BP [DBP], and HR) from baseline was determined at 2 different time points during the surgical procedure. The calculation of the change in all vital signs was performed by simply sub-

tracting the baseline value (time 0) from the values at time points 1 and 2 (eg, DSBP at time point 1 = SBP at time 1  SBP at time 0). 2. The change in the BIS and tcpCO2 from baseline was determined at 2 different time points during the surgical procedure. The calculation of the change in these readings followed the same equation used for the remainder of the vital signs (eg, DBIS at time point 1 = BIS at time 1  BIS at time 0).

228 Additional secondary outcomes included satisfaction with the procedure (measured on a 5-point scale), recollection of key portions of the procedure, recollection of pressure during the procedure, and nausea and vomiting after the procedure. These additional secondary outcomes were measured 24 hours after surgery while answering the questionnaire (Fig 1). SAMPLE SIZE CALCULATION

A power calculation was conducted using nQuery Advisor 7.0 (Statistical Solutions, Boston, MA). The authors assumed a common within-group standard deviation of 1.32 points on a 10-point scale, which corresponds to the standard deviation of 13.2 on a 100-point scale found by Ong et al.10 Under this assumption, a sample size of at least 31 per study group was adequate to obtain a type I error rate of 5% and a power of just over 80% to detect a mean difference of 1 point on the 10-point Wong-Baker FACES scale. STATISTICAL ANALYSIS

Statistical analysis was performed using SPSS 19 (SPSS, Inc, Chicago, IL). The Mann-Whitney U test was used for comparison of the primary outcome measurement (recollection of intraoperative pain) between the 2 groups. DSBP, DDBP, DHR, DBIS, and DtcpCO2 comparisons between the 2 groups were tested using the independent-samples t test. The Mann-Whitney U test was used for statistical analysis of questionnaire items with ordinal outcomes (namely questions 1 and 8), and the Fisher exact test was used for statistical analysis of questionnaire items with dichotomous outcomes (namely questions 3, 5, 6, and 7). Differences were considered significant at a P value less than .05. Statistical analysis was not possible for questionnaire item 4 because no patient in either group provided a negative response (see Table 2 for details).

Results Sixty-six patients were enrolled in the study. All enrolled patients underwent the planned surgical procedure. One patient was uncomfortable during the procedure and requested a deeper level of sedation. The procedure was completed under general anesthesia, and he was excluded from the study. All remaining 65 patients underwent the surgical procedure and responded to the follow-up questionnaire telephone call. The demographics of the groups are presented in Table 3. The 2 groups’ baseline vital signs were compared. The results are presented in Table 4. The SBP at baseline was statistically significantly higher in the fentanyl-first group (P = .001). The mean SBP for the

SEDATION FOR THIRD MOLAR REMOVAL IN ADULTS

fentanyl-first group at baseline was 124.2, and the mean SBP for the midazolam-first group was 112.1. This difference (although important) was accounted for later by comparing the change in SBP in each group (from baseline) as opposed to comparing the SBP values between groups. Otherwise, all baseline values were comparable between the groups. Question 2 on the questionnaire provided the primary outcome measurement: ‘‘According to the pain scale given to you by the surgeon, how would you rate your perception of pain during the surgical procedure?’’ The results presented in Table 5 show that there was no statistical difference in the recollection of the perception of pain during the surgical procedure between the 2 groups. There was no statistical difference in the change in vital signs (SBP, DBP, and HR) from baseline at the 2 different time points during the surgical procedure between the 2 groups (Table 6). In addition, there was no statistical difference in the change in the BIS and tcpCO2 from baseline at the 2 different time points during the surgical procedure (Table 6). Some recordings were illegible or were missing from the sedation sheet, resulting in different counts for different tests. The counts for the BIS and tcpCO2 recordings were smaller than the overall sample size because of the learning curve required for the 2 devices, tolerance of the patients to the application of the devices, and the time consumption in setting the machines and calibrating them to produce meaningful results (see Tables 4 and 6 for details of the different counts in different tests). None of the additional secondary outcomes measured using the questionnaire yielded a statistically important result. Table 2 lists the questionnaire items (1 and 3 through 8), results of the questionnaire items in the 2 groups, and the respective P values.

Discussion The fast-paced nature of outpatient OMS practices requires a regimen of sedation medications that is safe, effective, potent, and easily reversible. The regimen should provide good patient satisfaction and a fast and uneventful recovery. The combination of midazolam and fentanyl provides the oral and maxillofacial surgeon with all these qualities.2 Midazolam is a commonly used benzodiazepine in OMS practices. It provides anxiolysis, anterograde amnesia, and sedation. Fentanyl is an opioid analgesic that has a quicker onset of action, greater potency, and a shorter duration of action than morphine, making it an excellent choice for intraoperative analgesia. Combining fentanyl with midazolam produces a synergistic effect on the sedation action produced by midazolam. Therefore, the dose of midazolam that is

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Table 2. QUESTIONNAIRE RESULTS (ITEMS 1 AND 3 THROUGH 8)

Questions

Fentanyl-First Group

1. According to the following pressure scale, how would you rate your perception of pressure during the surgical procedure? n 1 No pressure 2 Mild pressure but tolerable 3 Moderate pressure but tolerable 4 Severe pressure but tolerable 5 Severe pressure not controlled by local anesthesia supplemented with conscious sedation 3. In the evening immediately after surgery, did you experience any nausea or vomiting? n 1 Yes 2 No 4. Do you remember when the IV was started in your arm? n 1 Yes 2 No 5. Do you remember local anesthesia injections in your mouth? n 1 Yes 2 No 6. Do you remember being told postoperative instructions for after the procedure? n 1 Yes 2 No 7. Would you like to have this same sedation again? n 1 Yes 2 No 8. Overall, how would you rate your sedation experience? n 1 Unacceptable 2 Poor 3 Satisfactory 4 Good 5 Excellent

Midazolam-First Group

P Value .711*

34 5 (14.7%) 15 (44.1%) 10 (29.4%) 4 (11.8%) 0

31 8 (25.8%) 10 (32.3%) 7 (22.6%) 5 (16.1%) 0z .799y

34 14 (41.2%) 20 (58.8%)

31 11 (35.5%) 20 (64.5%)

34 34 (100%) 0

31 31 (100%) 0

34 18 (52.9%) 16 (47.1%)

31 18 (58.1%) 13 (41.9%)

34 27 (79.4%) 7 (20.6%)

31 26 (83.9%) 5 (16.1%)

34 32 (94.1%) 2 (5.9%)

31 30 (96.8%) 1 (3.2%)

x

.804y

.754y

1.00y

.438* 34 0 1 (2.9%) 1 (2.9%) 13 (38.2%) 18 (52.9%)k

31 0 1 (3.2%) 1 (3.2%) 9 (29.0%) 20 (64.5%)

Abbreviation: IV, intravenous drip. * By Mann-Whitney U test. y By Fisher exact test. z One patient (3.2%) answered 2.5. x Test could not be performed because all patients responded yes to this question. k One patient answered 4.5. Khader et al. Sedation for Third Molar Removal in Adults. J Oral Maxillofac Surg 2015.

required to produce a given level of sedation is lower when combined with fentanyl.2 No studies have been performed to test the effect of the order in which fentanyl and midazolam are admin-

istered on the patients’ sedation experience. The purpose of the present study was to explore the effects of the order in which midazolam and fentanyl are administered on the patient’s pain perception

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SEDATION FOR THIRD MOLAR REMOVAL IN ADULTS

Table 3. DETAILED DEMOGRAPHICS OF STUDY POPULATION

Study Sample N Age, mean (SD) Gender, n Male Female

Fentanyl-First Group

Midazolam-First Group

34 26.1 (5.6)

31 25.5 (6.7)

13 21

8 23

65 25.8 (6.1) 21 44

P Value

.697* .304y

Abbreviation: SD, standard deviation. * By independent-samples t test. y By Fisher exact test. Khader et al. Sedation for Third Molar Removal in Adults. J Oral Maxillofac Surg 2015.

intraoperatively. In addition, the present study explored the effect of the order in which the sedation medications are administered on vital sign fluctuations intraoperatively. The order of administration of the intravenous sedation medications (midazolam and fentanyl) did not produce any statistical differences in pain perception between the groups. In addition, there were no statistical differences in the fluctuations of vital signs between the 2 groups. Neither order of medication administration proved to be superior to the other. Safety and patient satisfaction were maintained in the 2 groups. Table 4. COMPARATIVE BASELINE VALUES FOR FENTANYL-FIRST AND MIDAZOLAM-FIRST GROUPS FOR SBP, DBP, HR, TCPCO2, AND BIS

Fentanyl-First Midazolam-First P Group Group Value Baseline SBP Mean (SD) n Baseline DBP Mean (SD) n Baseline HR Mean (SD) n Baseline tcpCO2 Mean (SD) n Baseline BIS Mean (SD) n

.001* 124.2 (13.7) 34

112.1 (14.3) 31

76.0 (10.2) 34

73.8 (13.8) 31

77.0 (13.3) 34

75.8 (15.4) 31

36.5 (5.9) 10

34.6 (10.1) 13

94.7 (4.7) 32

95.0 (5.7) 29

.471*

LIMITATIONS

The selected patients had a variable degree of case complexity (from a routine third molar extraction to a complicated full bony impacted third molar removal). Accounting for the confounding effect of complexity will require a considerably larger sample. The present method of recording vital signs was manual recording every 5 minutes. This method is the standard followed at the Tufts University School of Dental Medicine. For this study, an automated digital recording might have yielded a more sensitive record of the patient’s vital signs. The digital record would represent the fluctuations related to administration of medications more accurately. For future studies, the use of intravenous pumps and automated digital records of vital signs will be considered. Pain threshold differs among patients. The variability will lead to inherent variability in patients’ responses to the Wong-Baker FACES pain scale. This confounder was recognized during the study and is is very difficult to account for in sample size calculation and randomization. Table 5. COMPARISON BETWEEN FENTANYL-FIRST GROUP AND MIDAZOLAM-FIRST GROUP IN RECOLLECTION OF PAIN PERCEPTION

.739*

Group

n

Answer to Question 2 Answer on Wong-Baker FACES Scale (Scale, 0-10), Median

Fentanylfirst group Midazolamfirst group

34

2.0

3.1

31

1.5

2.5

.615* .386y

Interquartile Range

P Value* .330

Abbreviations: BIS, bispecteral index; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure; SD, standard deviation; tcpCO2, transcutaneous carbon dioxide. * By independent-samples t test. y By Mann-Whitney U test.

* By Mann-Whitney U test.

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Table 6. CHANGE IN HR, SBP, DBP, TCPCO2, AND BIS MEAN VALUES AT TIME POINTS 1 AND 2

Variable and Group Time point 1 DHR fentanyl-first group DHR midazolam-first group DSBP fentanyl-first group DSBP midazolam-first group DDBP fentanyl-first group DDBP midazolam-first group DBIS fentanyl-first group DBIS midazolam-first group DtcpCO2 fentanyl-first group DtcpCO2 midazolam-first group Time point 2 DHR fentanyl-first group DHR midazolam-first group DSBP fentanyl-first group DSBP midazolam-first group DDBP fentanyl-first group DDBP midazolam-first group DBIS fentanyl-first group DBIS midazolam-first group DtcpCO2 fentanyl-first group DtcpCO2 midazolam-first group

n Mean (SD)* P Valuey

33 31 34 31 34 31 32 29 10 13

9.6 (11.8) 12.2 (14.0) 2.1 (8.4) 5.2 (12.3) 6.1 (9.9) 3.7 (9.0) 6.5 (6.2) 5.3 (8.2) 5.6 (3.0) 4.1 (12.1)

.415

33 31 33 31 33 31 32 29 9 11

6.6 (11.3) 11.2 (16.9) 0.7 (10.0) 3.1 (11.8) 7.5 (10.0) 5.0 (9.1) 9.8 (8.9) 7.6 (7.1) 7.7 (4.7) 3.5 (16.0)

.194

.236 .330 .526 .712

.166 .302 .302 .454

Abbreviations: BIS, bispecteral index; D, change; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure; SD, standard deviation; tcpCO2, transcutaneous carbon dioxide. * A mean with a negative sign indicates a decrease from baseline, whereas a mean with a positive sign indicates an increase from baseline. For example, the mean HR increased from baseline at time point 1 for the fentanyl-first group, resulting in a positive value for the mean DHR. Conversely, the mean BIS reading for the midazolam-first group decreased from baseline at time point 1, resulting in a negative value for the mean DBIS. y By independent-samples t test. Khader et al. Sedation for Third Molar Removal in Adults. J Oral Maxillofac Surg 2015.

The present results did not show the superiority of one sedation sequence over the other. There was insufficient evidence that administration of fentanyl first as opposed to midazolam first in the

sedation sequence alters the perception of pain by the patient.

References 1. Lacombe GF, Leake JL, Clokie CML, et al: Comparison of remifentanil with fentanyl for deep sedation in oral surgery. J Oral Maxillofac Surg 64:215, 2006 2. Moore PA, Finder RL, Jackson DL: Multidrug intravenous sedation: Determinants of the sedative dose of midazolam. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:5, 1997 3. Bennett CR: A clinical evaluation of fentanyl for outpatient sedation in dentistry. Oral Surg Oral Med Oral Pathol 34:880, 1972 4. Bennett CR: Conscious sedation: An alternative to general anesthesia. J Dent Res 63:832, 1984 5. Dionne RA, Gift HC: Drugs used for parenteral sedation in dental practice. Anesth Prog 35:199, 1988 6. Driscoll EJ, Smilack ZH, Lighbody PM, et al: Sedation with intravenous diazepam. J Oral Surg 30:332, 1972 7. Everett GB, Allen GD: Simultaneous evaluation of cardiorespiratory and analgesic effects of intravenous analgesia in combination with local anesthesia. J Am Dent Assoc 81:926, 1970 8. Frolich MA, Burchfield DJ, Euliano TY, et al: A single dose of fentanyl and midazolam prior to Cesarean section have no adverse neonatal effects. Can J Anaesth 53:79, 2006 9. Hempenstall PD, Campbell JP, Bajurnow AT, et al: Cardiovascular, biochemical, and hormonal responses to intravenous sedation with local analgesia versus general anesthesia in patients undergoing oral surgery. J Oral Maxillofac Surg 44:441, 1986 10. Ong KS, Seymour RA, Tan J: Sedation with midazolam leads to reduced pain after dental surgery. Anesth Analg 98:1289, 2004 11. Ong KS, Seymour RA, Yeo JF, et al: The efficacy of preoperative versus postoperative rofecoxib for preventing acute postoperative dental pain: A prospective randomized crossover study using bilateral symmetrical oral surgery. Clin J Pain 21:536, 2005 12. Shane SM, Carrel R, Vandenberge J: Intravenous amnesia: An appraisal after seven years and 10,500 administrations. Anesth Prog 21:36, 1974 13. Kelly P, Higgins A, Cunningham J: Fentanyl and midazolam combination for endoscopy sedation is safe and effective. Gastroenterology 114:A22, 1998 14. Gilman RB, Rowe WA: Combination midazolam and fentanyl is more cost effective than combination midazolam and meperidine for endoscopic procedures. Gastrointest Endosc 43:312, 1996 15. Mamula P: Safety of intravenous midazolam and fentanyl for pediatric GI endoscopy: Prospective study of 1578 endoscopies. Gastrointest Endosc 65:203, 2007 16. Weaver J: The narcotic of the benzodiazepine—Which should be given first for IV conscious sedation? Anesth Prog 48:123, 2001 17. Wong DL, Baker CM: Pain in children: Comparison of assessment scales. Okla Nurse 33:8, 1988