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1.  Deep sedation during gastrointestinal endoscopy: Propofol-fentanyl and midazolam-fentanyl regimens 
AIM: To compare deep sedation with propofol-fentanyl and midazolam-fentanyl regimens during upper gastrointestinal endoscopy.
METHODS: After obtaining approval of the research ethics committee and informed consent, 200 patients were evaluated and referred for upper gastrointestinal endoscopy. Patients were randomized to receive propofol-fentanyl or midazolam-fentanyl (n = 100/group). We assessed the level of sedation using the observer’s assessment of alertness/sedation (OAA/S) score and bispectral index (BIS). We evaluated patient and physician satisfaction, as well as the recovery time and complication rates. The statistical analysis was performed using SPSS statistical software and included the Mann-Whitney test, χ2 test, measurement of analysis of variance, and the κ statistic.
RESULTS: The times to induction of sedation, recovery, and discharge were shorter in the propofol-fentanyl group than the midazolam-fentanyl group. According to the OAA/S score, deep sedation events occurred in 25% of the propofol-fentanyl group and 11% of the midazolam-fentanyl group (P = 0.014). Additionally, deep sedation events occurred in 19% of the propofol-fentanyl group and 7% of the midazolam-fentanyl group according to the BIS scale (P = 0.039). There was good concordance between the OAA/S score and BIS for both groups (κ = 0.71 and κ = 0.63, respectively). Oxygen supplementation was required in 42% of the propofol-fentanyl group and 26% of the midazolam-fentanyl group (P = 0.025). The mean time to recovery was 28.82 and 44.13 min in the propofol-fentanyl and midazolam-fentanyl groups, respectively (P < 0.001). There were no severe complications in either group. Although patients were equally satisfied with both drug combinations, physicians were more satisfied with the propofol-fentanyl combination.
CONCLUSION: Deep sedation occurred with propofol-fentanyl and midazolam-fentanyl, but was more frequent in the former. Recovery was faster in the propofol-fentanyl group.
doi:10.3748/wjg.v19.i22.3439
PMCID: PMC3683682  PMID: 23801836
Endoscopy; Deep sedation; Anesthetic administration; Anesthetic dose; Adverse effects
2.  A Comparison of Fospropofol to Midazolam for Moderate Sedation During Outpatient Dental Procedures 
Anesthesia Progress  2013;60(4):162-177.
Moderate intravenous (IV) sedation combined with local anesthesia is common for outpatient oral surgery procedures. An ideal sedative agent must be safe and well tolerated by patients and practitioners. This study evaluated fospropofol, a relatively new sedative/hypnotic, in comparison to midazolam, a commonly used benzodiazepine, for IV moderate sedation during oral and maxillofacial surgery. Sixty patients were randomly assigned to either the fospropofol or the midazolam group. Each participant received 1 μg/kg of fentanyl prior to administration of the selected sedative. Those in the fospropofol group received an initial dose of 6.5 mg/kg, with 1.6 mg/kg supplemental doses as needed. Those in the midazolam group received initial doses of 0.05 mg/kg, followed by 0.02 mg/kg supplemental doses. The quality of sedation in each patient was evaluated with regard to (a) onset of sedation, maintenance, and recovery profile; (b) patient and surgeon satisfaction; and (c) hemodynamic stability and adverse effects. The fospropofol group demonstrated shorter physical recovery times than midazolam patients, taking a mean of 11.6 minutes versus 18.4 minutes for physical recovery (P = .007). Cognitive recovery comparison did not find any difference with a mean of 7.5 minutes versus 8.8 minutes between the 2 drug groups (P = .123). The fospropofol group had a higher rate of local anesthetic injection recall (90.5 vs 44.4%, P = .004). Other parameters of recall were comparable. Two adverse effects demonstrated significance, with more patients in the midazolam group experiencing tachycardia (48.2 vs 9.4%, P = .001), and more patients in the fospropofol group experiencing perineal discomfort (40.6 vs 0, P < .001). No significant difference was found in any other measures of sedation safety, maintenance, or satisfaction. Fospropofol, when administered intravenously by a dentist anesthesiologist at the indicated dose in this study, appears to be a safe, well-tolerated alternative to midazolam for intravenous moderate sedation during minor oral surgery procedures.
doi:10.2344/0003-3006-60.4.162
PMCID: PMC3891457  PMID: 24423419
Fospropofol; Midazolam; Moderate sedation; Outpatient surgery; IV conscious sedation; Benzodiazepine; Propofol
3.  A comparison of diazepam and midazolam as endoscopy premedication assessing changes in ventilation and oxygen saturation. 
1. One hundred and two consecutive patients undergoing upper gastrointestinal endoscopy were randomised to be sedated with either intravenous diazepam (Diazemuls-Kabi Vitrum) or intravenous midazolam (Hypnovel-Roche). It was assumed that midazolam was likely to be approximately twice as potent as diazepam on the basis of previous work. 2. All patients had an ear oximeter attached throughout the procedure to record continuously their level of oxygen saturation. 3. All 102 patients had pre-endoscopy respiratory function tests measured and 100 wore an induction plethysmograph vest to allow continuous estimation of respiratory rate and excursion. The plethysmograph was calibrated using a pneumotachygraph, so baseline, post-injection and post-endoscopy minute volumes could be estimated. 4. The age, sex ratio and pre-endoscopy respiratory function tests of the 51 patients given intravenous diazepam in a mean dose (s.d.) of 11.5 (5.8) mg over a mean of 3.4 (0.9) min) were similar to that of the 51 patients sedated with intravenous midazolam (mean dose 6.0 (2.8) mg over 3.3 (0.9) min. 5. Both drugs significantly reduced minute volume (P less than 0.001) and oxygen saturation (P less than 0.001). Midazolam appeared to produce slightly greater hypoxaemia with 57% having falls in oxygen saturation of greater than 2.5% compared with only 35% given an equivalent dose of diazepam. 6. Ventilation was still less than baseline when re-checked some minutes after removal of the gastroscope. The speed of recovery appeared faster after diazepam sedation which is in contrast to its longer pharmacological half-life.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1386637  PMID: 3061425
4.  Sedation in gastrointestinal endoscopy: Current issues 
Diagnostic and therapeutic endoscopy can successfully be performed by applying moderate (conscious) sedation. Moderate sedation, using midazolam and an opioid, is the standard method of sedation, although propofol is increasingly being used in many countries because the satisfaction of endoscopists with propofol sedation is greater compared with their satisfaction with conventional sedation. Moreover, the use of propofol is currently preferred for the endoscopic sedation of patients with advanced liver disease due to its short biologic half-life and, consequently, its low risk of inducing hepatic encephalopathy. In the future, propofol could become the preferred sedation agent, especially for routine colonoscopy. Midazolam is the benzodiazepine of choice because of its shorter duration of action and better pharmacokinetic profile compared with diazepam. Among opioids, pethidine and fentanyl are the most popular. A number of other substances have been tested in several clinical trials with promising results. Among them, newer opioids, such as remifentanil, enable a faster recovery. The controversy regarding the administration of sedation by an endoscopist or an experienced nurse, as well as the optimal staffing of endoscopy units, continues to be a matter of discussion. Safe sedation in special clinical circumstances, such as in the cases of obese, pregnant, and elderly individuals, as well as patients with chronic lung, renal or liver disease, requires modification of the dose of the drugs used for sedation. In the great majority of patients, sedation under the supervision of a properly trained endoscopist remains the standard practice worldwide. In this review, an overview of the current knowledge concerning sedation during digestive endoscopy will be provided based on the data in the current literature.
doi:10.3748/wjg.v19.i4.463
PMCID: PMC3558570  PMID: 23382625
Gastrointestinal endoscopy; Endoscopy; Sedation; Analgesia; Digestive system
5.  The effect of flumazenil on the recovery time of dental patients sedated with diazepam. 
Anesthesia Progress  1989;36(2):46-51.
Flumazenil is an imidazobenzodiazepine that binds specifically to the central benzodiazepine receptor and antagonizes the actions of diazepam and other benzodiazepines. Previous studies in Europe have shown flumazenil at doses of 2 to 30 mg IV to reverse sedation in patients sedated with flunitrazepam, midazolam, and diazepam when evaluated by subjective criteria. The purpose of this study was to determine if flumazenil at 0.015 mg/kg IV was efficacious in shortening the recovery time of young, healthy dental patients sedated with diazepam (0.15 mg/kg IV) and restoring their psychomotor function to presedation levels. A total of 21 patients were randomized to placebo or flumazenil, sedated with diazepam, underwent a restorative dental procedure, and were then administered the test drug. Evaluations of psychomotor function by the Trieger test, Digit-Symbol Substitution test, Romberg test, and nurse questioning were carried out before sedation and at 10-minute intervals after test drug. Observations by the patients and nurses were not significantly different before versus after test drug. The investigator, however, found that flumazenil resulted in more rapid awakening. Patients treated with placebo exhibited significantly greater deficits in the number of dots missed and sum of deviations on the Trieger test than flumazenil-treated patients. Similar time-related deficits were recorded for the Digit-Symbol Substitution test. Flumazenil, at a dose of 0.015 mg/kg, was found to be efficacious in reducing the recovery time after diazepam sedation in dental patients.
PMCID: PMC2148636  PMID: 2513741
6.  Safety of midazolam for sedation of HIV-positive patients undergoing colonoscopy 
HIV medicine  2013;14(6):379-384.
Summary
Concerns regarding possible interactions between midazolam and antiretroviral medicines have caused clinicians to use second-line sedatives, such as diazepam, instead. We demonstrated that patients who received midazolam during colonoscopy had similar clinical outcomes as those who received diazepam.
Background
Because of concerns regarding interactions between midazolam and antiretroviral therapy (ART), alternative sedatives are sometimes used during procedural sedation. Our objective was to compare outcomes in patients on ART who received intravenous (IV) midazolam versus IV diazepam, a second-line agent, during colonoscopy.
Methods
We conducted a retrospective analysis of adult HIV-infected patients who underwent colonoscopy over a 3.5-year period. Primary outcomes were sedation duration, nadir systolic blood pressure, nadir oxygen saturation, abnormal cardiac rhythm, and change in level of consciousness using a standardized scale. We calculated rates of adverse events according to benzodiazepine use and identified risk factors for complications using univariate and multivariate analyses.
Results
We identified 136 patients for this analysis: 70 received midazolam-based sedation and 66 received a diazepam-based regimen. There were no significant differences between the two groups with respect to sedation duration (48 versus 45.7 minutes, P = 0.68), nadir systolic blood pressure (97 versus 101.6 mmHg, P = 0.06), nadir oxygen saturation (94.6 versus 94.8%, P = 0.72), or rate of abnormal cardiac rhythm (11.4 versus 19.7%, P = 0.18). More patients in the midazolam group experienced a depressed level of consciousness (91 versus 74%, P = 0.0075), but no patient required reversal of sedation or became unresponsive.
Conclusions
Although IV midazolam interacts with ART, we did not find evidence that patients who received this agent for procedural sedation had clinical outcomes statistically different from those who received diazepam. These findings should be confirmed in prospective studies or in a randomized controlled trial.
doi:10.1111/hiv.12014
PMCID: PMC4120820  PMID: 23332038
Midazolam; HIV; antiretrovirals; colonoscopy; sedation
7.  A prospective randomized double-blind study comparing dexmedetomidine vs. combination of midazolam-fentanyl for tympanoplasty surgery under monitored anesthesia care 
Background:
Analgesia and sedation are usually required for the comfort of the patient and surgeon during tympanoplasty surgery done under local anesthesia. In this study, satisfaction scores and effectiveness of sedation and analgesia with dexmedetomidine were compared with a combination of midazolam-fentanyl.
Materials and Methods:
Ninety patients undergoing tympanoplasty under local anesthesia randomly received either IV dexmedetomidine 1 μg kg-1 over 10 min followed by 0.2 μg kg-1h-1 infusion (Group D) or IV midazolam 0.06 mg kg-1 plus IV fentanyl 1 μg kg-1 over 10 min (Group MF) followed by normal saline infusion at 0.2 ml kg-1h-1. Sedation was titrated to Ramsay sedation score (RSS) of three. Vital parameters, rescue analgesics (fentanyl 1 μg kg-1) and sedatives (midazolam 0.01 mg kg-1), patient and surgeon satisfaction scores were recorded.
Results:
Patient and surgeon satisfaction score was better in Group D than Group MF (median interquartile range (IQR) 9 (8-10) vs. 8 (6.5-9.5) and 9 (8.5-9.5) vs. 8 (6.75-9.25), P = 0.0001 for both). Intraoperative heart rate and mean arterial pressure in Group D were lower than the baseline values and the corresponding values in Group MF (P < 0.05). Percentage of patients requiring rescue fentanyl was higher in Group MF than Group D (40% vs. 11.1%, P = 0.01). One patient in Group D while four in Group MF (8.8%) required rescue sedation with midazolam (P > 0.17). Seven patients in Group D had dry mouth vs. none in Group MF (P = 0.006). One patient in Group D had bradycardia with hypotension which was effectively treated.
Conclusion:
Dexmedetomidine is comparable to midazolam-fentanyl for sedation and analgesia in tympanoplasty with better surgeon and patient satisfaction. Hemodynamics need to be closely monitored.
doi:10.4103/0970-9185.111671
PMCID: PMC3713662  PMID: 23878436
Dexmedetomidine; sedation; midazolam fentanyl sedation; monitored anesthesia care; satisfaction scores; surgery; otological
8.  Sedative Efficacy of Propofol in Patients Intubated/Ventilated after Coronary Artery Bypass Graft Surgery 
Background:
Sedation after open heart surgery is important in preventing stress on the heart. The unique sedative features of propofol prompted us to evaluate its potential clinical role in the sedation of post-CABG patients.
Objectives:
To compare propofol-based sedation to midazolam-based sedation after coronary artery bypass graft (CABG) surgery in the intensive care unit (ICU).
Patients and Methods:
Fifty patients who were admitted to the ICU after CABG surgery was randomized into two groups to receive sedation with either midazolam or propofol infusions; and additional analgesia was administered if required. Inclusion criteria were as follows: patients 40-60 years old, hemodynamic stability, ejection fraction (EF) more than 40%; exclusion criteria included patients who required intra-aortic balloon pump or inotropic drugs post-bypass. The same protocol of anesthetic medications was used in both groups. Depth of sedation was monitored using the Ramsay sedation score (RSS). Invasive mean arterial pressure (MAP) and heart rate (HR), arterial blood gas (ABG) and ventilatory parameters were monitored continuously after the start of study drug and until the patients were extubated.
Results:
The depth of sedation was almost the same in the two groups (RSS=4.5 in midazolam group vs 4.7 in propofol group; P = 0.259) but the total dose of fentanyl in the midazolam group was significantly more than the propofol group (12.5 mg/hr vs 4 mg/hr) (P = 0.0039). No significant differences were found in MAP (P = 0.51) and HR (P = 0.41) between the groups. The mean extubation time in patients sedated with propofol was shorter than those sedated with midazolam (102 ± 27 min vs 245 ± 42 min, respectively; P < 0.05) but the ICU discharge time was not shorter (47.5 hr vs 36.3 hr, respectively; P = 0.24).
Conclusions:
Propofol provided a safe and acceptable sedation for post-CABG surgical patients, significantly reduced the requirement for analgesics, and allowed for more rapid tracheal extubation than midazolam but did not result in earlier ICU discharge.
doi:10.5812/aapm.17109
PMCID: PMC3961039  PMID: 24660162
Propofol; Analgesics; Coronary Artery Bypass; Deep Sedation; Midazolam; Airway Extubation; Length of Stay
9.  The Effect of Sedation During Upper Gastrointestinal Endoscopy 
Background/Aim:
We aimed to study whether sedation reduces discomfort during endoscopy and a comparison of longer-acting diazepam with shorter-acting midazolam.
Patients and Methods:
A prospective, randomized, single-blinded study was conducted at the Department of Medicine at Government Medical College and Hospital, Chandigarh, and was completed over a period of 6 months. The patients were randomized to receive either placebo or sedation with midazolam or diazepam before endoscopy. The endoscopist and the observer recording patient’s/physician’s responses were blinded to the drugs administered. Two hundred and fifty two consecutive patients undergoing diagnostic or therapeutic upper gastrointestinal endoscopy were recruited. The patient’s discomfort and the physician’s comfort during the procedure were recorded on a visual analogue scale rated from 1-10 with-in 10 minutes of the procedure by an independent observer. The Patient’s discomfort ratings were further divided into 3 groups, comfortable (score, 1-3), satisfactory (score, 4-7) and uncomfortable (a score of >7). Similarly the physician’s ease of performing the procedure was also recorded on the same scale. This was again divided into 3 groups: easy (score, 1-3), satisfactory (score, 4-7) and difficult (a score of >7).
Results:
Out of the total of 252 patients, 82 patients received no sedation (group I), 85 received diazepam (group II) and 85 received midazolam (group III). There was no statistical difference in the discomfort experienced by the patients during endoscopy when sedation was used (P=0.0754). Out of 252 patients, 49 underwent endoscopic procedures. Nineteen patients were included in group I, 18 in group II and 12 in group III. Only 10 (20%) patients undergoing endoscopic procedures complained of significant discomfort, but there was no difference in the ones undergoing interventions with or without sedation (P=0.854). The physicians were more comfortable in performing endoscopic procedure in sedated patients, however, the difference between patients in group II and group III was not statistically significant (P=0.0461). Both diazepam and midazolam fared equally well in increasing physician’s comfort (P=0.617).
Conclusion:
There was no difference in the patient’s discomfort with regard to the sedative used (midazolam or diazepam). Although endoscopy was easy or satisfactory in the majority of patients in the unsedated as well as the sedated groups, more often the endoscopist found it difficult to do endoscopy on the unsedated patients.
doi:10.4103/1319-3767.70616
PMCID: PMC2995098  PMID: 20871194
Endoscopic procedures; gastrointestinal endoscopy; patient’s perception; sedation
10.  Carbon dioxide accumulation during analgosedated colonoscopy: Comparison of propofol and midazolam 
AIM: To characterize the profiles of alveolar hypoventilation during colonoscopies performed under sedoanalgesia with a combination of alfentanil and either midazolam or propofol.
METHODS: Consecutive patients undergoing routine colonoscopy were randomly assigned to sedation with either propofol or midazolam in an open-labeled design using a titration scheme. All patients received 4 μg/kg per body weight alfentanil for analgesia and 3 L of supplemental oxygen. Oxygen saturation (SpO2) was measured by pulse oximetry (POX), and capnography (PcCO2) was continuously measured using a combined dedicated sensor at the ear lobe. Instances of apnea resulting in measures such as stimulation of the patient, a chin lift, a mask maneuver, or withholding of sedation were recorded. PcCO2 values (as a parameter of sedation-induced hypoventilation) were compared between groups at the following distinct time points: baseline, maximal rise, termination of the procedure and 5 min after termination of the procedure. The number of patients in both study groups who regained baseline PcCO2 values (± 1.5 mmHg) five minutes after the procedure was determined.
RESULTS: A total of 97 patients entered this study. The data from 14 patients were subsequently excluded for clinical procedure-related reasons or for technical problems. Therefore, 83 patients (mean age 62 ± 13 years) were successfully randomized to receive propofol (n = 42) or midazolam (n = 41) for sedation. Most of the patients were classified as American Society of Anesthesiologists (ASA) II [16 (38%) in the midazolam group and 15 (32%) in the propofol group] and ASA III [14 (33%) and 13 (32%) in the midazolam and propofol groups, respectively]. A mean dose of 5 (4-7) mg of IV midazolam and 131 (70-260) mg of IV propofol was used during the procedure in the corresponding study arms. The mean SpO2 at baseline (%) was 99 ± 1 for the midazolam group and 99 ± 1 for the propofol group. No cases of hypoxemia (SpO2 < 85%) or apnea were recorded. However, an increase in PcCO2 that indicated alveolar hypoventilation occurred in both groups after administration of the first drug and was not detected with pulse oximetry alone. The mean interval between the initiation of sedation and the time when the PcCO2 value increased to more than 2 mmHg was 2.8 ± 1.3 min for midazolam and 2.8 ± 1.1 min for propofol. The mean maximal rise was similar for both drugs: 8.6 ± 3.7 mmHg for midazolam and 7.4 ± 3.2 mmHg for propofol. Five minutes after the end of the procedure, the mean difference from the baseline values was significantly lower for the propofol treatment compared with midazolam (0.9 ± 3.0 mmHg vs 4.3 ± 3.7 mmHg, P = 0.0000169), and significantly more patients in the propofol group had regained their baseline value ± 1.5 mmHg (32 of 41 vs 12 of 42, P = 0.0004).
CONCLUSION: A significantly higher number of patients sedated with propofol had normalized PcCO2 values five minutes after sedation when compared with patients sedated with midazolam.
doi:10.3748/wjg.v18.i38.5389
PMCID: PMC3471107  PMID: 23082055
Colonoscopy; Deep sedation; Propofol; Hypoventilation; Blood gas monitoring; Transcutaneous
11.  Dexmedetomidine-ketamine versus Dexmedetomidine-midazolam-fentanyl for monitored anesthesia care during chemoport insertion: a Prospective Randomized Study 
BMC Anesthesiology  2016;16:49.
Background
Dexmedetomidine as a sole agent showed limited use for painful procedures due to its insufficient sedative/analgesic effect, pronounced hemodynamic instability and prolonged recovery. The aim of this study was to compare the effects of dexmedetomidine-ketamine (DK) versus dexmedetomidine-midazolam-fentanyl (DMF) combination on the quality of sedation/analgesia and recovery profiles for monitored anesthesia care (MAC).
Methods
Fifty six patients undergoing chemoport insertion were randomly assigned to group DK or DMF. All patients received 1 μg.kg−1 dexmedetomidine over 10 min followed by 0.2–1.0 μg.kg−1h−1 in order to maintain 3 or 4 of modified Observer's Assessment of Analgesia and Sedation score checked every 3 min. At the start of dexmedetomidine infusion, patients in group DK or DMF received 0.5 mg.kg−1 ketamine or 0.05 mg.kg−1 midazolam + 0.5 μg.kg−1 fentanyl intravenously, respectively. When required, rescue sedatives (0.5 mg.kg-1 of ketamine or 0.05 mg.kg-1 of midazolam) and analgesics (0.5 mg.kg-1 of ketamine or 0.5 μg.kg-1 of fentanyl) were given to the patients in DK or DMF group, respectively. The primary outcome of this study was the recovery parameters (time to spontaneous eye opening and the length of the recovery room stay). The secondary outcomes were parameters indicating quality of sedation/analgesia, cardiorespiratory variables, and satisfaction scores.
Results
There were no significant differences in the onset time, time to spontaneous eye opening, recovery room stay, the incidences of inadequate analgesia, hypotension and bradycardia between the two groups. Despite lower infusion rate of dexmedetomidine, more patients in the DMF group had bispectral index (BIS) < 60 than in the DK group and vice versa for need of rescue sedatives. The satisfaction scores of patients, surgeon, and anesthesiologist in the DMF group were significantly better than the DK group.
Conclusions
The DK and DMF groups showed comparable recovery time, onset time, cardiorespiratory variables, and analgesia. However, the DMF group showed a better sedation quality and satisfaction scores despite the lower infusion rate of dexmedetomidine, and a higher incidence of BIS < 60 than the DK group.
Trial registration
Clinical Trial Registry of Korea KCT0000951, registered 12/12/2013
doi:10.1186/s12871-016-0211-4
PMCID: PMC4970235  PMID: 27484227
Dexmedetomidine; Fentanyl; Ketamine; Midazolam; Monitored anesthesia care
12.  A Comparison between Sedative Effect of Propofol-Fentanyl and Propofol-Midazolam Combinations in Microlaryngeal Surgeries 
Considering the growing trend of laryngeal surgeries and the need to protect the airway during and after surgery, among several therapeutic regimens to induce sedation, two regimens of propofol-fentanyl and propofol-midazolam were compared in microlaryngeal surgeries.
Forty ASA I-II class patients undergoing microlaryngeal surgeries and referring routinely for postoperative visits were randomly recruited into two groups. For all the patients, 0.5 mg/Kg of propofol was used as bolus and then, 50 mcg/Kg/min of the drug was infused intravenously. For one group, 0.03 mg/Kg bolus of midazolam and for the other group, 2 mcg/Kg bolus of fentanyl was administered in combination with propofol. Ramsay system was used in order to evaluate the effect of the two drugs in inducing sedation. The need for additional dose, blood pressure, heart rate, arterial blood oxygen saturation, and also recovery time and adverse effects such as nausea/vomiting and recalling intra-operative memories, were assessed.
The patients in the two groups were not statistically different regarding the number of patients, age, sex, preoperative vital signs, the need for additional doses of propofol, systolic blood pressure and mean systolic blood pressure during laryngoscopy. However, mean systolic blood pressure 1 min after removal of laryngoscope returned faster to the baseline in midazolam group (p < 0.01). Mean heart rate returned sooner to the baseline in fentanyl group following removal of stimulation. Besides, heart rate showed a more reduction following administration of fentanyl (p < 0.02). Mean arterial blood oxygen saturation during laryngoscopy significantly decreased in fentanyl group (p < 0.05) compared to the other group. The time it took to achieve a full consciousness was shorter in midazolam group (p < 0.01). Nausea/vomiting was significantly more prevalent in fentanyl group while the patients in midazolam group apparently experienced more of amnesia, comparatively (p < 0.01).
Inducing laryngeal block and local anesthesia using propofol-midazolam regimen is not only associated with a more rapid recovery and less recalling of unpleasant memories, but also better in preventing reduction of arterial oxygen saturation during laryngoscopy compared with propofol-fentanyl regimen.
PMCID: PMC3813093  PMID: 24250451
Sedation; Microlaryngeal surgery; Propofol; Midazolam; Fentanyl
13.  A comparative study between oral melatonin and oral midazolam on preoperative anxiety, cognitive, and psychomotor functions 
Background & Aims:
Melatonin, a naturally occurring hormone in the human body, has been reported to cause preoperative anxiolysis and sedation without impairing orientation. The aim of the following study was to evaluate and to compare the effects of oral melatonin and oral midazolam on preoperative anxiety, sedation, psychomotor, and cognitive function.
Materials and Methods:
A study conducted on 120 patients aged 16-55 years, of American Society of Anesthesiologists Grade 1 and 2 posted for elective surgery, with each group of melatonin, midazolam, and placebo comprising 40 patients. Patients were given either 0.4 mg/kg oral melatonin or 0.2 mg/kg oral midazolam or a placebo 60-90 min before induction. Preoperative anxiety was studied before and 60-90 min after giving medications using visual analog scale (VAS) anxiety score, orientation score, and sedation score. Psychomotor and cognitive functions were studied using the digit symbol substitution test (DSST) and trail making test (TMT) tests. Data were analyzed using Chi-square test or Kruskal–Wallis analysis of variance and the value of P < 0.05 was considered as statistically significant.
Results:
Changes in VAS anxiety scores were significant when melatonin was compared with placebo (P = 0.0124) and when midazolam was compared with placebo (P = 0.0003). When melatonin was compared with midazolam, no significant difference (P = 0.49) in VAS anxiety scores was observed. Intergroup comparison of sedation scores showed melatonin (P = 0.0258) and midazolam (P = 0.0000) to be statistically significant when compared with placebo. No changes in orientation scores occurred in melatonin and placebo group. Change in DSST scores and TMT scores were seen to be significant only in midazolam group.
Conclusion:
Oral melatonin 0.4 mg/kg provides adequate anxiolysis comparable to that of oral midazolam. Unlike midazolam, oral melatonin 0.4 mg/kg does not impair the general cognitive and psychomotor function especially cognitive aspects such as working memory, memory retrieval, sustained attention, and flexibility of thinking.
doi:10.4103/0970-9185.150534
PMCID: PMC4353150  PMID: 25788771
Cognition; melatonin; midazolam; preoperative anxiety; psychomotor performance
14.  Dexmedetomidine use in the ICU: Are we there yet? 
Critical Care  2013;17(3):320.
Expanded abstract
Citation
Jakob SM, Ruokonen E, Grounds RM, Sarapohja T, Garratt C, Pocock SJ, Bratty JR, Takala J; Dexmedeto midine for Long-Term Sedation Investigators: Dexmedetomidine vesus midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 2012, 307:1151-1160.
Background
Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an alpha-2 agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.
Methods
Objective
The objective was to determine the efficacy of dexmedetomidine versus midazolam or propofol (preferred usual care) in maintaining sedation, reducing duration of mechanical ventilation, and improving patients' interaction with nursing care.
Design
Two phase 3 multicenter, randomized, double-blind trials were conducted.
Setting
The MIDEX (Midazolam vs. Dexmedetomidine) trial compared midazolam with dexmedetomidine in ICUs of 44 centers in nine European countries. The PRODEX (Propofol vs. Dexmedetomidine) trial compared propofol with dexmedetomidine in 31 centers in six European countries and two centers in Russia.
Subjects
The subjects were adult ICU patients who were receiving mechanical ventilation and who needed light to moderate sedation for more than 24 hours.
Intervention
After enrollment, 251 and 249 subjects were randomly assigned midazolam and dexmedetomidine, respectively, in the MIDEX trial, and 247 and 251 subjects were randomly assigned propofol and dexmedetomidine, respectively, in the PRODEX trial. Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials were employed.
Outcomes
For each trial, investigators tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were the ability of the patient to communicate pain (measured by using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol (midazolam, n = 233, versus dexmedetomidine, n = 227; propofol, n = 214, versus dexmedetomidine, n = 223) population.
Results
Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% confidence interval (CI) 0.97 to 1.18), and dexmedetomidine/propofol ratio in time at target sedation was 1.00 (95% CI 0.92 to 1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours, interquartile range (IQR) 67 to 337) versus midazolam (164 hours, IQR 92 to 380; P = 0.03) but not with dexmedetomidine (97 hours, IQR 45 to 257) versus propofol (118 hours, IQR 48 to 327; P = 0.24). Patient interaction (measured by using VAS) was improved with dexmedetomidine (estimated score difference versus midazolam 19.7, 95% CI 15.2 to 24.2; P <0.001; and versus propofol 11.2, 95% CI 6.4 to 15.9; P <0.001). Lengths of ICU and hospital stays and mortality rates were similar. Dexmedetomidine versus midazolam patients had more hypotension (51/247 [20.6%] versus 29/250 [11.6%]; P = 0.007) and bradycardia (35/247 [14.2%] versus 13/250 [5.2%]; P <0.001).
Conclusions
Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved the ability of patients to communicate pain compared with midazolam and propofol. Greater numbers of adverse effects were associated with dexmedetomidine.
doi:10.1186/cc12707
PMCID: PMC3706806  PMID: 23731973
15.  Arousal time from sedation during spinal anaesthesia for elective infraumbilical surgeries: Comparison between propofol and midazolam 
Indian Journal of Anaesthesia  2014;58(4):403-409.
Background and Aims:
Studies have already compared propofol and midazolam as sedatives during regional anaesthesia. A few studies have focused on recovery characteristics and very few have utilised both instrumental and clinical sedation monitoring for assessing recovery time. This study was designed primarily to compare arousal time from sedation using propofol with that of midazolam during spinal anaesthesia for infraumbilical surgeries, while depth of sedation was monitored continuously with bispectral index (BIS) monitor. The correlation between the BIS score and observer's assessment of awareness/sedation (OAA/S) score during recovery from sedation was also studied.
Methods:
A total of 110 patients were randomly assigned to receive either propofol (Group P, n = 55) or midazolam (Group M, n = 55). Patients in the Group P received bolus of propofol (1 mg/kg), followed by infusion at 3 mg/kg/h; Group M received bolus of midazolam (0.05 mg/kg), followed by infusion at 0.06 mg/kg/h and titration until BIS score 70 was achieved and maintained between 65 and 70. OAA/S score was noted at BIS 70 and again at BIS 90 during recovery. The time to achieve OAA/S score 5 was noted. Spearman's correlation was calculated between the arousal time from sedation and the time taken to reach an OAA/S score of 5 in both the study groups.
Results:
Arousal time from sedation was found lower for Group P compared to Group M (7.54 ± 3.70 vs. 15.54 ± 6.93 min, respectively, P = 0.000). The time taken to reach OAA/S score 5 was also found to be lower for Group P than Group M (6.81 ± 2.54 min vs. 13.51 ± 6.24 min, respectively, P = 0.000).
Conclusion:
A shorter arousal time from sedation during spinal anaesthesia can be achieved using propofol compared with midazolam, while depth of sedation was monitored with BIS monitor and OAA/S score. Both objective and clinical scoring correlate strongly during recovery from sedation.
doi:10.4103/0019-5049.138972
PMCID: PMC4155284  PMID: 25197107
Bispectral index monitoring; midazolam; propofol; sedation; spinal anaesthesia
16.  Sedation in the intensive care unit with remifentanil/propofol versus midazolam/fentanyl: a randomised, open-label, pharmacoeconomic trial 
Critical Care  2006;10(3):R91.
Introduction
Remifentanil is an opioid with a unique pharmacokinetic profile. Its organ-independent elimination and short context-sensitive half time of 3 to 4 minutes lead to a highly predictable offset of action. We tested the hypothesis that with an analgesia-based sedation regimen with remifentanil and propofol, patients after cardiac surgery reach predefined criteria for discharge from the intensive care unit (ICU) sooner, resulting in shorter duration of time spent in the ICU, compared to a conventional regimen consisting of midazolam and fentanyl. In addition, the two regimens were compared regarding their costs.
Methods
In this prospective, open-label, randomised, single-centre study, a total of 80 patients (18 to 75 years old), who had undergone cardiac surgery, were postoperatively assigned to one of two treatment regimens for sedation in the ICU for 12 to 72 hours. Patients in the remifentanil/propofol group received remifentanil (6- max. 60 μg kg-1 h-1; dose exceeds recommended labelling). Propofol (0.5 to 4.0 mg kg-1 h-1) was supplemented only in the case of insufficient sedation at maximal remifentanil dose. Patients in the midazolam/fentanyl group received midazolam (0.02 to 0.2 mg kg-1 h-1) and fentanyl (1.0 to 7.0 μg kg-1 h-1). For treatment of pain after extubation, both groups received morphine and/or non-opioid analgesics.
Results
The time intervals (mean values ± standard deviation) from arrival at the ICU until extubation (20.7 ± 5.2 hours versus 24.2 h ± 7.0 hours) and from arrival until eligible discharge from the ICU (46.1 ± 22.0 hours versus 62.4 ± 27.2 hours) were significantly (p < 0.05) shorter in the remifentanil/propofol group. Overall costs of the ICU stay per patient were equal (approximately €1,700 on average).
Conclusion
Compared with midazolam/fentanyl, a remifentanil-based regimen for analgesia and sedation supplemented with propofol significantly reduced the time on mechanical ventilation and allowed earlier discharge from the ICU, at equal overall costs.
doi:10.1186/cc4939
PMCID: PMC1550941  PMID: 16780597
17.  Comparitive Evaluation of Propofol and Midazolam as Conscious Sedatives in Minor Oral Surgery 
Objective
The objective of the study was to assess the efficacy of propofol and midazolam as an intravenous sedative agent in minor oral surgical procedures in terms of: (a) the onset of action, (b) heart rate, (c) oxygen saturation, (d) systolic and diastolic blood pressure, (e) respiratory rate, (f) pain during the injection of sedative agent, (g) recovery period, (h) side effects, (i) patient’s cooperation during the surgery.
Methodology
This was a double blind randomized study in which one group of 20 patients received propofol with the induction dose of 0.5 mg/kg and 50 μg/kg/min which was administered by syringe infusion pump as a maintenance dose and the other group received midazolam in a single dose of 75 μg/kg and no maintenance dose was given, instead 5 % dextrose was administered by syringe infusion pump at the rate of 50 μg/kg/min. Since propofol was milky white in colour, a green cloth was covered over the infusion pump in all cases. The surgeon, assistants and observers were blind about the medications which would be given to the patient for sedation. After the administration of the sedative, local anesthesia was achieved with 2 % lignocaine hydrochloride.
Results
The onset of action in propofol group was significant as onset of action was faster. The maximum increase in heart rate in propofol group was at 10 min intraoperatively (Mean ± 80.40 ± 12.73) and that in midazolam group was at 15 min intraoperatively (Mean 79.25 ± 13.44). Post operatively the heart rate decreased near to the baseline value in both the groups. The average oxygen saturation before induction in propofol group was 99.7 ± 0.73 % and that of midazolam group was 99.15 ± 01.31 P = 0.314. None of the patients in this study developed apnea. The systolic blood pressure (Mean ± SD) before induction in both the groups decreased from the baseline value after the administration of sedatives. The diastolic blood pressure (Mean ± SD) before induction in both the groups decreased from the baseline value after the administration of sedatives and the decreased diastolic blood pressure was maintained throughout the procedure. The respiratory rate (Mean ± SD) before induction in both the groups decreased from the baseline value after the administration of sedatives. The decreased respiratory rate remained throughout the surgical procedure. Pain during the injection of the sedatives was reported by nine patients (45 %) in the propofol group whereas none of the patients in midazolam group complained of pain during the injection. This is statistically significant (P = 0.001). The recovery time (Mean ± SD) in propofol group was 22.50 ± 3.04 (range 15–25 min) and that in midazolam group was 33.75 ± 3.93 (range 30–40 min), which was statistically significant (P < 0.001). Patients in the propofol group were significantly less co-operative than midazolam group at both 10 and 25 min intra operatively.
Conclusion
The design of the present study permitted qualitative assessment of propofol and midazolam as sedative agents in minor oral surgical procedures. The ideal anesthetic agent should provide rapid onset of action, profound intra operative amnesia while ensuring rapid recovery without much complications. There were no significant differences in either patient demographics or surgical characteristics between the two groups. The propofol group was less co-operative than midazolam group. Pain during the injection of sedative was a significant adverse effect in the propofol group. Cardiovascular parameters remained stable throughout the procedure in both study groups and no intervention was required. However recovery and onset of action was faster in the propofol group as compared with the midazolam group.
doi:10.1007/s12663-014-0676-y
PMCID: PMC4510082  PMID: 26225076
Propofol; Midazolam; Minor oral surgery; Day care surgery
18.  Role of Benzodiazepines in the management of agitation due to inappropriate use of naltrexone 
Background:
Agitation is an early symptom of the acute opioid withdrawal syndrome in addicts that may start by inappropriate use of naltrexone. The current drug interventions are not efficient or need critical care as well. This study compares the clinical role of midazolam and diazepam for the management of agitation due to inappropriate use of naltrexone.
Materials and Methods:
In this double-blind randomized controlled clinical trial, 44 agitated addicts, who did not use any type of benzodiazepine, not on systematic central nervous system depressant drugs, without any known hypersensitivity to diazepam, midazolam, or any other component of their formulation and had no evidence for the need of critical care, were enrolled. An i.v. stat dose of 0.1 mg/kg diazepam and 0.1 mg/kg stat dose of midazolam and a 0.1 mg/kg/h infusion of these drugs were administered for different groups of patients, respectively. Agitation scores were recorded at 30, 60, 120 min after the start of drug administration using Richmond Agitation Sedation Scale score.
Results:
A significant difference between the mean onset of agitation control in midazolam group (at 67 min) and diazepam group (at 81 min) was recorded. The difference of mean agitation score in the midazolam and diazepam group was only significant at 120 min. There was a negative correlation between agitation score and time elapsed from naltrexone administration to admission.
Conclusion:
Midazolam and diazepam may not be considered suitable and perfect pharmacologic agents for the initial controlling of agitation induced by naltrexone.
PMCID: PMC3703077  PMID: 23853649
Benzodiazepines; naltrexone; psychomotor agitation; substance withdrawal syndrome
19.  Comparison between the recovery time of alfentanil and fentanyl in balanced propofol sedation for gastrointestinal and colonoscopy: a prospective, randomized study 
BMC Gastroenterology  2012;12:164.
Background
There is increasing interest in balanced propofol sedation (BPS) titrated to moderate sedation (conscious sedation) for endoscopic procedures. However, few controlled studies on BPS targeted to deep sedation for diagnostic endoscopy were found. Alfentanil, a rapid and short-acting synthetic analog of fentanyl, appears to offer clinically significant advantages over fentanyl during outpatient anesthesia.
It is reasonable to hypothesize that low dose of alfentanil used in BPS might also result in more rapid recovery as compared with fentanyl.
Methods
A prospective, randomized and double-blinded clinical trial of alfentanil, midazolam and propofol versus fentanyl, midazolam and propofol in 272 outpatients undergoing diagnostic esophagogastroduodenal endoscopy (EGD) and colonoscopy for health examination were enrolled. Randomization was achieved by using the computer-generated random sequence. Each combination regimen was titrated to deep sedation. The recovery time, patient satisfaction, safety and the efficacy and cost benefit between groups were compared.
Results
260 participants were analyzed, 129 in alfentanil group and 131 in fentanyl group. There is no significant difference in sex, age, body weight, BMI and ASA distribution between two groups. Also, there is no significant difference in recovery time, satisfaction score from patients, propofol consumption, awake time from sedation, and sedation-related cardiopulmonary complications between two groups. Though deep sedation was targeted, all cardiopulmonary complications were minor and transient (10.8%, 28/260). No serious adverse events including the use of flumazenil, assisted ventilation, permanent injury or death, and temporary or permanent interruption of procedure were found in both groups. However, fentanyl is New Taiwan Dollar (NT$) 103 (approximate US$ 4) cheaper than alfentanil, leading to a significant difference in total cost between two groups.
Conclusions
This randomized, double-blinded clinical trial showed that there is no significant difference in the recovery time, satisfaction score from patients, propofol consumption, awake time from sedation, and sedation-related cardiopulmonary complications between the two most common sedation regimens for EGD and colonoscopy in our hospital. However, fentanyl is NT$103 (US$ 4) cheaper than alfentanil in each case.
Trial registration
Institutional Review Board of Buddhist Tzu Chi General Hospital (IRB097-18) and Chinese Clinical Trial Registry (ChiCTR-TRC-12002575)
doi:10.1186/1471-230X-12-164
PMCID: PMC3607964  PMID: 23170921
Balanced propofol sedation; Alfentanil; Fentanyl; Deep sedation; Diagnostic endoscopy; Cost benefit
20.  Variation in diurnal sedation in mechanically ventilated patients who are managed with a sedation protocol alone or a sedation protocol and daily interruption 
Critical Care  2016;20:233.
Background
Mechanically ventilated patients may receive more sedation during the night than during the day, potentially delaying extubation. We compared nighttime and daytime benzodiazepine and opioid administration in adult patients enrolled in a multicenter sedation trial comparing protocolized sedation alone or protocolized sedation combined with daily sedation interruption; and we evaluated whether nighttime and daytime doses were associated with liberation from mechanical ventilation.
Methods
This is a secondary analysis of a randomized trial which was conducted in 16 North American medical-surgical ICUs. In all 423 patients, nurses applied a validated sedation scale hourly to titrate benzodiazepine and opioid infusions to achieve a light level of sedation. Using fentanyl equivalents and midazolam equivalents, we compared dosages administered during night (19:00 to 07:00) and day (07:00 to 19:00) shifts. Using multivariable logistic regression we evaluated the association between nighttime and daytime opioid and sedative doses, and spontaneous breathing trial (SBT) conduct, SBT success, and extubation.
Results
Nighttime benzodiazepine and opioid doses were significantly higher than daytime doses (mean difference midazolam equivalents 23.3 mg, 95 % CI 12.9, 33.8, p < 0.0001; mean difference fentanyl equivalents 356 mcg, 95 % CI 130, 582, p = 0.0021). Mean Sedation Agitation Scale score was similar between night and day, and was at target (3.2 vs 3.3, 95 % CI −0.05, 0.02, p = 0.35). Self-reported nurse workload was similar during the night and day. Patients were more often restrained during day shifts (76.3 % vs 73.7 %, p < 0.0001), and there were more unintentional device removals during the day compared with night (15.9 % vs 9.1 %, p < 0.0001). Increases in nighttime drug doses were independently associated with failure to meet SBT screening criteria, SBT failure, and the decision not to extubate the patient despite successful SBT.
Conclusion
Patients received higher doses of opioids and benzodiazepines at night. Higher nighttime doses were associated with SBT failure and delayed extubation.
Trial registration
ClinicalTrials.gov NCT00675363. Registered 7 May 2008.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-016-1405-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-016-1405-3
PMCID: PMC4968433  PMID: 27480314
Sedation; Opioids; Mechanical ventilation; Protocols; Weaning; Diurnal rhythm; Intensive care unit
21.  Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study 
BMJ : British Medical Journal  2000;321(7253):83-86.
Objective
To compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with prolonged febrile seizures.
Design
Prospective randomised study.
Setting
Paediatric emergency department in a general hospital.
Subjects
47 children aged six months to five years with prolonged febrile seizure (at least 10 minutes) during a 12 month period.
Interventions
Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg).
Main outcome measures
Time from arrival at hospital to starting treatment and cessation of seizures.
Results
Intranasal midazolam and intravenous diazepam were equally effective. Overall, 23 of 26 seizures were controlled with midazolam and 24 out of 26 with diazepam. The mean time from arrival at hospital to starting treatment was significantly shorter in the midazolam group (3.5 (SD 1.8) minutes, 95% confidence interval 3.3 to 3.7) than the diazepam group (5.5 (2.0), 5.3 to 5.7). The mean time to control of seizures was significantly sooner (6.1 (3.6), 6.3 to 6.7) in the midazolam group than the diazepam group (8.0 (0.5), 7.9 to 8.3). No significant side effects were observed in either group.
Conclusion
Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. The overall time to cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam. The intranasal route can possibly be used not only in medical centres but in general practice and, with appropriate instructions, by families of children with recurrent febrile seizures at home.
PMCID: PMC27427  PMID: 10884257
22.  Preanesthetic medication in children: A comparison of intranasal dexmedetomidine versus oral midazolam 
Saudi Journal of Anaesthesia  2011;5(4):387-391.
Background:
Relieving preoperative anxiety is an important concern for the pediatric anesthesiologist. Midazolam has become the most frequently used premedication in children. However, new drugs such as the α2 -agonists have emerged as alternatives for premedication in pediatric anesthesia.
Methods:
One hundred and twenty children scheduled for adenotonsillectomy were enrolled in this prospective, double-blind, randomized study. The children were divided into two equal groups to receive either intranasal dexmedetomidine 1 μg/kg (group D), or oral midazolam 0.5 mg/kg (group M) at approximately 60 and 30 mins, respectively, before induction of anesthesia. Preoperative sedative effects, anxiety level changes, and the ease of child-parent separation were assessed. Also, the recovery profile and postoperative analgesic properties were assessed.
Results:
Children premedicated with intranasal dexmedetomidine achieved significantly lower sedation levels (P=0.042), lower anxiety levels (P=0.036), and easier child-parent separation (P=0.029) than children who received oral midazolam at the time of transferring the patients to the operating room. Postoperatively, the time to achieve an Aldrete score of 10 was similar in both the groups (P=0.067). Also, the number of children who required fentanyl as rescue analgesia medication was significantly less (P=0.027) in the dexmedetomidine group.
Conclusion:
Intranasal dexmedetomidine appears to be a better choice for preanesthetic medication than oral midazolam in our study. Dexmedetomidine was associated with lower sedation levels, lower anxiety levels, and easier child-parent separation at the time of transferring patients to the operating room than children who received oral midazolam. Moreover, intranasal dexmedetomidine has better analgesic property than oral midazolam with discharge time from postanesthetic care unit similar to oral midazolam.
doi:10.4103/1658-354X.87268
PMCID: PMC3227308  PMID: 22144926
Dexmedetomidine; midazolam; pediatric; sedation
23.  Comparison of Oral Midazolam and Promethazine with Oral Midazolam alone for Sedating Children during Computed Tomography  
Emergency  2015;3(3):109-113.
Introduction:
Both midazolam and promethazine are recommended to be used as sedatives in many studies but each have some side effects that limits their use. Combination therapy as an alternative method, may decreases these limitations. Therefore, this study aimed to compare midazolam with midazolam-promethazine regarding induction, maintenance, and recovery characteristics following pediatric procedural sedation and analgesia.
Methods:
Children under 7 years old who needed sedation for being CT scanned were included in this double-blind randomized clinical trial. The patients were randomly divided into 2 groups: one only received midazolam (0.5 mg/kg), while the other group received a combination of midazolam (0.5 mg/kg) and promethazine (1.25 mg/kg). University of Michigan Sedation Scale (UMSS) was used to assess sedation induction. In addition to demographic data, the child’s vital signs were evaluated before prescribing the drugs and after inducing sedation (reaching UMSS level 2). The primary outcomes in the present study were onset of action after administration and duration of the drugs’ effect.
Results:
107 patients were included in the study. Mean onset of action was 55.4±20.3 minutes for midazolam and 32.5±11.1 minutes for midazolam-promethazine combination (p<0.001). But duration of effect was not different between the 2 groups (p=0.36). 8 (7.5%) patients were unresponsive to the medication, all 8 of which were in the midazolam treated group (p=0.006). Also in 18 (16.8%) cases a rescue dose was prescribed, 14 (25.9%) were in the midazolam group and 4 (7.5%) were in the midazolam-promethazine group (p=0.02). Comparing systolic (p=0.20) and diastolic (p=0.34) blood pressure, heart rate (p=0.16), respiratory rate (p=0.17) and arterial oxygen saturation level (p=0.91) showed no significant difference between the 2 groups after intervention.
Conclusion:
Based on the findings of this study, it seems that using a combination of midazolam and promethazine not only speeds up the sedation induction, but also decreases unresponsiveness to the treatment and the need for a rescue dose.
PMCID: PMC4608335  PMID: 26495395
Promethazine; midazolam; anti-anxiety agents; conscious sedation
24.  Preemptive Oral Clonidine Provides Better Sedation Than Intravenous Midazolam in Brachial Plexus Nerve Blocks 
Background
Preemptive analgesia is the blocking of pain perception afferent pathways before noxious painful stimuli. Clonidine is an alpha agonist drug that is partially selective for α-2 adrenoreceptors. Clonidine is used as anti-anxiety medication and an, analgesic, and it prolongs the duration of the block in the brachial plexus block.
Objectives
To compare the effect of preemptive clonidine with midazolam on intraoperative sedation, duration of block, and postoperative pain scores.
Patients and Methods
In a randomized clinical trial, 80 patients with orthopedic fractures of an upper extremity who underwent supraclavicular nerve block were randomly assigned to receive 0.2 mg oral clonidine or 2 mg oral midazolam. Intraoperative sedation was measured at one hour after the start of urgery and again in the PACU (Post-Anesthesia Care Unit) using the Ramsay scale. The duration of sensory blockade was measured. Postoperative pain scores were measured using the VAS (Visual Analogue Scale) after entrance to recovery up to 2 hours.
Results
The percentages of patients in the calm and sedated scale were significantly higher in clonidine group (35 and 42.5%, respectively), compared to the midazolam group (17.5 and 17.5%, respectively) (P = 0.042, 0.029; respectively). Those administered fentanyl in the clonidine group 105 ± 30.8 was significantly lower than that for the midazolam group 165 ± 34.5 (P = 0.0018). The percentages of patients in the calm scale were significantly higher in the clonidine group (52.5), compared to the midazolam group (17.5) (P = 0.001) in the post-operative period. VAS scores were significantly lower at one (P = 0.01) and two hours (P = 0.001) after operation in the clonidine group, compared to the midazolam group.
Conclusions
Preemptive clonidine has many marvelous advantages over midazolam, including better sedation inside the operating room and then in the post-operative care unit, lower fentanyl doses are required during surgery, more stable heart rate and blood pressure are observed during the procedure, and patients report lower post-operative pain scores.
doi:10.5812/aapm.28768
PMCID: PMC5055753  PMID: 27761415
Clonidine; Midazolam; Preemptive Analgesia; Brachial Plexus Nerve Blocks
25.  The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity 
Aims
To examine the effects of an oral contraceptive containing ethinyloestradiol and norgestrel on intestinal and hepatic CYP3A activity using midazolam as a probe substrate.
Methods
In a nonblinded sequential study, nine healthy women received simultaneous doses of intravenous midazolam (0.05 mg kg−1) and oral 15N3-midazolam (3 mg) on days 0, 4, 6, 8, and 14. On study day 5, Ovral™ (50 µg ethinyloestradiol/500 µg norgestrel) was administered for 10 days. Serum and urine samples were assayed for midazolam, 15N3-midazolam and metabolites by liquid chromatography-mass spectrometry. A Digit Symbol Substitution Test (DSST) was used to assess changes in the pharmacodynamic activity of midazolam.
Results
Moderate (% CV 26–46) interindividual variability in the pharmacokinetics of midazolam were observed. Compared with baseline, AUC(0,∞)iv ratios (95% CIs) after 2, 4, and 10 days treatment with OC were 89% (79, 101), 96% (85, 109), and 88% (77, 99), respectively. The AUC(0,∞)oral ratios (95% CIs) were 101% (82, 125), 105% (85, 130), and 114% (92, 141), respectively, after 2, 4, and 10 days OC treatment compared with baseline. Concomitant administration of the oral contraceptive, Ovral™ for 2, 4 or 10 days did not significantly alter the area under the curve, clearance, or half-life of midazolam after either oral or intravenous administration. No alterations in pharmacodynamic effects of midazolam were observed between treatment days. Mean DSST scores strongly correlated with mean total midazolam blood concentrations (r = −0.936).
Conclusions
Administration of Ovral™ for 10 days had no impact on intestinal or hepatic CYP3A activity as determined by midazolam metabolism.
doi:10.1046/j.0306-5251.2001.01521.x
PMCID: PMC1874548  PMID: 11849197
CYP3A; ethinyloestradiol; midazolam; norgestrel

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