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1.  Conscious Sedation and Emergency Department Length of Stay: A Comparison of Propofol, Ketamine, and Fentanyl/Versed 
Study Objectives:
Three of the most commonly used agents for conscious sedation in the Emergency Department (ED) are ketamine, fentanyl/versed, and propofol. In this study, we measured and compared the total times spent in the ED with each of these agents. Our objective was to determine whether the use of propofol for conscious sedation was associated with a shorter length of ED stay as compared to the other two agents.
This was a consecutive case series. All patients who required procedural conscious sedation who presented to the ED at University of California, Irvine Medical Center from January 2003 through April 2004 were included in the study. The attending ED physician evaluated the patient and determined which medication(s) would be administered. All patients underwent procedural sedation according to the ED’s standardized sedation protocol. The times and dosages of administered medications and the sedation/consciousness level (SCL) scores were recorded by ED nurses at 3–5 minute intervals. Data was abstracted prospectively. The time to sedation (first dose of agent to SCL score of 2 or less) and time to recovery (last dose of agent to SCL score of 4) of the different regimens were then analyzed and compared.
Thirty-eight patients received propofol, 38 received ketamine, and 14 received fentanyl/versed. The mean times to sedation (minutes) were: propofol 4.5 (95% CI: 3.3–5.7), ketamine 10.6 (95% CI: 5.8–15.4), fentanyl/versed 11.5 (95% CI: 3.5–19.4). The mean times to recovery were: propofol 21.6 (95% CI: 16.1–27.1), ketamine 55.4 (95% CI: 46.2–64.5), fentanyl/versed 59.9 (95% CI: 20.3–99.5). Propofol had a statistically significant shorter time to sedation than both ketamine (p<.001) and fentanyl/versed (p=.022). Propofol also produced shorter recovery times than both ketamine (p<.001) and fentanyl/versed (p=.002).
In this study, sedation and recovery times were shorter with propofol than with ketamine or fentanyl/versed. The use of propofol for conscious sedation in this non-randomized study was associated with a shorter ED length of stay.
PMCID: PMC2872520  PMID: 20505814
2.  Ketamine and midazolam sedation for pediatric gastrointestinal endoscopy in the Arab world 
AIM: To evaluate the safety and effectiveness of intravenous ketamine-midazolam sedation during pediatric endoscopy in the Arab world.
METHODS: A retrospective cohort study of all pediatric endoscopic procedures performed between 2002-2008 at the shared endoscopy suite of King Abdullah University Hospital, Jordan University of Science & Technology, Jordan was conducted. All children were > 1 year old and weighed > 10 kg with American Society of Anesthesiologists class 1 or 2. Analysis was performed in terms of sedation-related complications (desaturation, respiratory distress, apnea, bradycardia, cardiac arrest, emergence reactions), adequacy of sedation, need for sedation reversal, or failure to complete the procedure.
RESULTS: A total of 301 patients (including 160 males) with a mean age of 9.26 years (range, 1-18 years) were included. All were premedicated with atropine; and 79.4% (239/301) had effective and uneventful sedation. And 248 (82.4%) of the 301 patients received a mean dose of 0.16 mg/kg (range, 0.07-0.39) midazolam and 1.06 mg/kg (range, 0.31-2.67) ketamine, respectively within the recommended dosage guidelines. Recommended maximum midazolam dose was exceeded in 17.6% patients [34 female (F):19 male (M), P = 0.003] and ketamine in 2.7% (3 M:5 F). Maximum midazolam dose was more likely to be exceeded than ketamine (P < 0.001). Desaturation occurred in 37 (12.3%) patients, and was reversible by supplemental oxygen in all except 4 who continue to have desaturation despite supplemental oxygen. Four (1.3%) patients had respiratory distress and 6 (2%) were difficult to sedate and required a 3rd sedative; 12 (4%) required reversal and 7 (2.3%) failed to complete the procedure. None developed apnea, bradycardia, arrest, or emergence reactions.
CONCLUSION: Ketamine-midazolam sedation appears safe and effective for diagnostic pediatric gastrointestinal endoscopy in the Arab world for children aged > 1 year and weighing > 10 kg without co-morbidities.
PMCID: PMC3180020  PMID: 21987610
Pediatric endoscopy; Sedation; Ketamine; Arab
3.  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.
PMCID: PMC3683682  PMID: 23801836
Endoscopy; Deep sedation; Anesthetic administration; Anesthetic dose; Adverse effects
4.  Intravenous ketamine plus midazolam is superior to intranasal midazolam for emergency paediatric procedural sedation 
Objectives—This study compared intranasal midazolam (INM) with a combination of intravenous ketamine and intravenous midazolam (IVKM) for sedation of children requiring minor procedures in the emergency department.
Method—A single blinded randomised clinical trial was conducted in the emergency department of a major urban paediatric hospital. Subjects requiring sedation for minor procedures were randomised to receive either INM (0.4 mg/kg) or intravenous ketamine (1 mg/kg) plus intravenous midazolam (0.1 mg/kg). Physiological variables and two independent measures of sedation (Sedation Score and Visual Analogue Sedation Scale) were recorded before sedation and at regular intervals during the procedure and recovery period. Times to adequate level of sedation and to discharge were compared.
Results—Fifty three patients were enrolled over a 10 month period. Sedation was sufficient to complete the procedures in all children receiving IVKM and in 24 of the 26 receiving INM. Onset of sedation was an average of 5.3 minutes quicker with IVKM than with INM (95%CI 3.2, 7.4 minutes, p<0.001). Children given INM were discharged an average of 19 minutes earlier than those given IVKM (95%CI 4, 33 minutes, p=0.02). Mean Sedation Scores and Visual Analogue Sedation Scale scores for the 30 minutes after drug administration were significantly better in children given IVKM compared with INM (2.4 and 1.8 versus 3.5 and 3.8, respectively). Both doctors and parents were more satisfied with sedation by intravenous ketamine and midazolam.
Conclusions—Intravenous ketamine plus midazolam used in an appropriate setting by experienced personnel provides an excellent means of achieving sedation suitable for most non-painful minor procedures for children in the emergency department. This combination is superior to INM in terms of speed of onset and consistency of effect. INM delivered via aerosol spray has a more variable effect but may still be adequate for the completion of many of these procedures.
PMCID: PMC1725505  PMID: 11310461
5.  Adverse Events Associated With Procedural Sedation in Pediatric Patients in the Emergency Department 
Hospital Pharmacy  2013;48(2):134-142.
To determine the agents used by emergency medicine (EM) physicians in pediatric procedural sedation and the associated adverse events (AEs) and to provide recommendations for optimizing drug therapy in pediatric patients.
We conducted a prospective study at Stanford Hospital’s pediatric emergency department (ED) from April 2007 to April 2008 to determine the medications most frequently used in pediatric procedural sedation as well as their effectiveness and AEs. Patients, 18 years old or younger, who required procedural sedation in the pediatric ED were eligible for the study. The data collected included medical record number, sex, age, height, weight, procedure type and length, physician, and agents used. For each agent, the dose, route, time from administration to onset of sedation, duration of sedation, AEs, and sedation score were recorded. Use of supplemental oxygen and interventions during procedural sedation were also recorded.
We found that in a convenience sample of 196 children (202 procedures) receiving procedural sedation in a university-based ED, 8 different medications were used (ketamine, etomidate, fentanyl, hydromorphone, methohexital, midazolam, pentobarbital, and thiopental). Ketamine was the most frequently used medication (88%), regardless of the procedure. Only twice in the study was the medication that was initially used for procedural sedation changed completely. Fracture reduction was the most frequently performed procedure (41%), followed by laceration/suture repair (32%). There were no serious AEs reported.
EM-trained physicians can safely perform pediatric procedural sedation in the ED. In the pediatric ED, the most common procedure requiring conscious sedation is fracture reduction, with ketamine as the preferred agent.
PMCID: PMC3839476  PMID: 24421451
adverse events; emergency department; ketamine; pediatric patients; procedural sedation
6.  Comparison of nasal Midazolam with Ketamine versus nasal Midazolam as a premedication in children 
Saudi Journal of Anaesthesia  2014;8(1):17-21.
This study was done to compare effects of intranasal midazolam and intranasal midazolam with ketamine for premedication of children aged 1-12 yrs undergoing intermediate and major surgeries.
Midazolam and Ketamine have already been used as premedicants in children. Our aim was to find out advantage of combination of midazolam with ketamine over midazolam by nasal route.
Sixty children of age group 1-12 yrs of American Society of Anesthesiologists (ASA) grade 1 and 2 were selected. Group A- midazolam (0.2 mg/kg), Group B- midazolam (0.15 mg/kg + ketamine 1 mg/kg). Both groups received drug intranasally 30 min before surgery in recovery room with monitored anesthesia care. Onset of sedation, sedation score, emotional reaction, intravenous cannula acceptance, and mask acceptance were studied.
Statistical Analysis:
Unpaired t test and chi square test.
Sedation score, anxiolysis, attitude, reaction to intravenous cannulation, face mask acceptance, and emotional reaction were significantly better in midazolam with ketamine group. Intra operatively, in both groups, pulse rate, oxygen saturation, and respiratory rate had no significant difference; also, post operatively, no significant difference was observed in above parameters, post operative analgesia was significantly better in midazolam with ketamine group.
Intra nasal premedication allows rapid and predictable sedation in children. Midazolam as well as combination of Midazolam with ketamine gives good level of sedation and comfort. But quality of sedation, analgesia, and comfort is significantly better in midazolam with ketamine group. No significant side effects were observed in both groups.
PMCID: PMC3950446  PMID: 24665234
Intranasal; Ketamine; midazolam; pediatric anesthesia
7.  Sedation for children requiring wound repair: a randomised controlled double blind comparison of oral midazolam and oral ketamine 
Objective—To compare the efficacy of oral ketamine (10 mg/kg) with oral midazolam (0.7 mg/kg) in providing sedation for suturing of lacerations.
Method—Prospective, randomised, double blinded trial with consecutive, concealed recruitment of 59 children aged 1 to 7 with wounds requiring local anaesthetic (LA) injection or topical LA with an anxiety score greater than one.
Results—Tolerance to LA injection was better with ketamine (p=0.029) and tolerance to procedure after LA injection showed a trend towards being improved with ketamine (p=0.067). There was no difference in tolerance to LA application or procedure in children receiving topical LA. Time to reach a sedation score of less than four was faster with ketamine (medians 20 versus 43 minutes, p=0.001) but times from dosing to discharge (medians 105 and 110 minutes) were similar. Inconsolable agitation was reported with midazolam in six cases. Dysphoria was not noted with ketamine. Vomiting was more common with ketamine but not significantly so (six versus two, p = 0.14). Oxygen desaturations were noted in both groups. Ataxia after discharge was seen in four patients, two in each group. Thirty six per cent of children showed new behavioural disturbances in the two weeks after discharge, more commonly in the midazolam group (p=0.048).
Conclusions—At these doses tolerance to LA injection was better in children receiving ketamine, with fewer behavioural changes noted in the first two weeks. Midazolam at this dose caused dysphoric reactions, which may have affected the results. Continuous pulse oximetry monitoring is required when using these drugs. Vomiting and prolonged ataxia occurred in a few patients.
PMCID: PMC1725528  PMID: 11310459
8.  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.
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.
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.
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.
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)
PMCID: PMC3607964  PMID: 23170921
Balanced propofol sedation; Alfentanil; Fentanyl; Deep sedation; Diagnostic endoscopy; Cost benefit
9.  Preoperative anxiolysis in pediatric population: A comparative study between oral midazolam and oral ketamine 
Preoperative anxiety is synonymous with pediatric surgery. Anxiolysis is of crucial importance and poses a significant challenge to the pediatric anesthesiologist. Orally administered midazolam and ketamine can be used as anxiolytic premedication in children.
To compare the efficacy of orally administered midazolam and ketamine for preoperative sedation and anxiolysis in children and determine the minimum interval required between premedication and parental separation.
Setting and Design:
Prospective, randomized, double-blind study.
Materials and Methods:
A total of 70 children aged 2-8 years, belonging to ASA grade 1 and 2, scheduled to undergo elective infraumbilical and peripheral surgeries were randomized into two groups of 35 each to receive either midazolam (0.5 mg/kg) or ketamine (5 mg/kg) orally. They were assessed at an interval of 5 minutes up to 40 minutes, at the time of parental separation, intravenous cannulation, and application of face mask for ventilation. Sedation was noted according to Ramsay Sedation Scale and anxiolysis was noted according to Anxiolysis Scores used in previous published studies.
Statistical Analysis Used:
Skewed data between groups were analyzed by Mann Whitney U Test. Data within a group were analyzed using Friedman's Analysis of variance and a post hoc test.
No statistically significant difference in sedation and anxiolysis scores were obtained between the groups at any point of time. Maximum sedation score was achieved at 20 minutes in both the groups, with no statistically significant difference with scores obtained thereafter. Statistically significant difference occurred in anxiolysis score at study points in group receiving midazolam.
The study documents the rapid achievement of preoperative sedation and anxiolysis in children with orally administered midazolam or ketamine, with the latter producing a superior quality of anxiolysis. An interval of 20 minutes is sufficient between premedication and parental separation.
PMCID: PMC4173508
Anxiolysis; ketamine; midazolam; oral; sedation
10.  Comparison of effects of ketamine, ketamine-dexmedetomidine and ketamine-midazolam on dressing changes of burn patients 
The aim of this randomized, controlled study was to compare the sedoanalgesic effects of ketamine-dexmedetomidine and ketamine-midazolam on dressing changes of burn patients.
Materials and Methods:
Following Ethics Committee approval and informed patient consent, 90 ASA physical statuses I and II adult burn patients were included in the study. Patients were randomly divided into three groups. Ten minutes before dressing change, the dexmedetomidine group (group KD) (n = 30) received a continuous infusion of dexmedetomidine at a rate of 1 μg kg-1, the midazolam group (group KM) (n = 30) received a continuous infusion of midazolam at a rate of 0.05 mg kg-1 and the saline group (group KS) (n = 30) received a continuous infusion of saline intravenously. One minute before dressing change, each patient was administered 1 mg kg-1 ketamine intravenously. Hemodynamic variables, pain and sedation scores, the number of patients requiring additional ketamine, time to dressing change and recovery time were recorded.
Systolic blood pressure (SBP) values were significantly lower at, before and after ketamine administration; and 5, 10 and 15 minutes after the procedure in group KD in comparison with the other groups (P <0.05). There was no significant difference in pain scores among the groups during the study period. Sedation scores were significantly higher in group KD than in groups KM and KS at the end of the first hour (P <0.05). Time to dressing change and recovery time were similar in all the groups
In burn patients undergoing dressing changes, although both combinations ketamine-dexmedetomidine and ketamine-midazolam offered an effective sedoanalgesia without causing any significant side effect, the former resulted in higher sedation and lower hemodynamic discrepancy.
PMCID: PMC3127303  PMID: 21772684
Burn; dexmedetomidine; dressing changes; ketamine; midazolam
11.  Impact of the United States propofol ban on emergency providers’ procedural sedation agent choice and patient length of stay 
In the recent past, propofol was temporarily removed from the emergency department (ED) for use in procedural sedation. We sought to determine which agents replaced it in clinical practice and the impact this change had on turnaround times (TAT) for sedated patients.
This study is a retrospective chart review at a level one trauma center. Patients receiving sedative agents (propofol, ketamine, midazolam, and etomidate) were identified by pharmacy codes, and their charts were then reviewed for demographics and TAT. Propofol was unavailable in the emergency department (ED) between May 2010 and February 2011. The study period extended from May 2009 until May 2011. Patients receiving sedation by non-emergency medicine physicians and those receiving sedation related to intubation were excluded.
In total 2466 charts were reviewed and 209 met inclusion criteria. When propofol was available, the most commonly used sedative agent was etomidate (40%), followed by propofol (28%), ketamine (20%), and midazolam (6%). When propofol was unavailable, etomidate remained the most commonly used agent (43%), followed by ketamine (41%), and midazolam (11%). When propofol was available, the median TAT for sedated patients was 163 minutes compared to 178 minutes when propofol was unavailable (P=0.83). When propofol was the primary sedative agent used, the median TAT was 166 minutes as compared with a median TAT of 172 minutes for all other sedative agents combined (P=0.87).
When propofol was unavailable, ketamine became a preferred ED sedation agent. Removal of propofol from the sedation armamentarium did not affect ED TAT.
PMCID: PMC4129780  PMID: 25215059
Procedural sedation; Turnaround time; Propofol; Ketamine; Etomidate; Midazolam
12.  Safety and efficacy of analgesia-based sedation with remifentanil versus standard hypnotic-based regimens in intensive care unit patients with brain injuries: a randomised, controlled trial [ISRCTN50308308] 
Critical Care  2004;8(4):R268-R280.
This randomised, open-label, observational, multicentre, parallel group study assessed the safety and efficacy of analgesia-based sedation using remifentanil in the neuro-intensive care unit.
Patients aged 18–80 years admitted to the intensive care unit within the previous 24 hours, with acute brain injury or after neurosurgery, intubated, expected to require mechanical ventilation for 1–5 days and requiring daily downward titration of sedation for assessment of neurological function were studied. Patients received one of two treatment regimens. Regimen one consisted of analgesia-based sedation, in which remifentanil (initial rate 9 μg kg-1 h-1) was titrated before the addition of a hypnotic agent (propofol [0.5 mg kg-1 h-1] during days 1–3, midazolam [0.03 mg kg-1 h-1] during days 4 and 5) (n = 84). Regimen two consisted of hypnotic-based sedation: hypnotic agent (propofol days 1–3; midazolam days 4 and 5) and fentanyl (n = 37) or morphine (n = 40) according to routine clinical practice. For each regimen, agents were titrated to achieve optimal sedation (Sedation–Agitation Scale score 1–3) and analgesia (Pain Intensity score 1–2).
Overall, between-patient variability around the time of neurological assessment was statistically significantly smaller when using remifentanil (remifentanil 0.44 versus fentanyl 0.86 [P = 0.024] versus morphine 0.98 [P = 0.006]. Overall, mean neurological assessment times were significantly shorter when using remifentanil (remifentanil 0.41 hour versus fentanyl 0.71 hour [P = 0.001] versus morphine 0.82 hour [P < 0.001]). Patients receiving the remifentanil-based regimen were extubated significantly faster than those treated with morphine (1.0 hour versus 1.93 hour, P = 0.001) but there was no difference between remifentanil and fentanyl. Remifentanil was effective, well tolerated and provided comparable haemodynamic stability to that of the hypnotic-based regimen. Over three times as many users rated analgesia-based sedation with remifentanil as very good or excellent in facilitating assessment of neurological function compared with the hypnotic-based regimen.
Analgesia-based sedation with remifentanil permitted significantly faster and more predictable awakening for neurological assessment. Analgesia-based sedation with remifentanil was very effective, well tolerated and had a similar adverse event and haemodynamic profile to those of hypnotic-based regimens when used in critically ill neuro-intensive care unit patients for up to 5 days.
PMCID: PMC522854  PMID: 15312228
analgesia-based sedation; fentanyl; intensive care; morphine; remifentanil
13.  A comparison of ketamine-midazolam and ketamine-propofol combinations used for sedation in the endobronchial ultrasound-guided transbronchial needle aspiration: a prospective, single-blind, randomized study 
Journal of Thoracic Disease  2014;6(6):742-751.
We aimed to compare the effectiveness and safety of ketamine-midazolam and ketamine-propofol combinations for procedural sedation in endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA).
Sixty patients who were undergoing EBUS-TBNA were included in this study. Patients were randomly divided into two groups. Group 1 was given 0.25 mg/kg intravenous (iv) ketamine, 2 min later than 0.05 mg/kg iv midazolam. Group 2 received 0.125 mg/kg ketamine-propofol mixture (ketofol), 2 min subsequent to injection of 0.25 mg/kg each. Sedation was maintained with additional doses of ketamine 0.25 mg/kg, and ketofol 0.125 mg/kg each in Group 1 and Group 2, respectively. Blood pressure, heart rate (HR), peripheral oxygen saturation, respiratory rate (RR), Ramsay Sedation Score (RSS), and severity of cough were recorded prior to and after administration of sedation agent in the beginning of fiberoptic bronchoscopy (FOB) and every 5 min of the procedure. The consumption of the agents, the satisfactions of the bronchoscopist and the patients, and the recovery time were also recorded.
HR in the 10th min and RSS value in the 35th min of induction in Group 1 were higher than the other group (P<0.05). The recovery time in Group 1 was statistically longer than Group 2 (P<0.05). There was no statistically significant difference between groups with respect to other parameters (P>0.05).
It was concluded that both ketamine-midazolam and ketamine-propofol combinations for sedation during EBUS-TBNA were similarly effective and safe without remarkable side effects.
PMCID: PMC4073394  PMID: 24976998
Transbronchial needle aspiration (TBNA); sedation; ketamine; midazolam; propofol
14.  A comparative study on monitored anesthesia care 
The aim of this study is to compare the effectiveness, hemodynamic changes and duration of sedation and analgesia between combinations of fortwin-phenergan-midazolam (FPM) and ketamine - midazolam (KM) along with local anesthesia for the surgeries done under the umbrella of monitored anesthesia care.
Materials and Methods:
A total of 50 patients undergoing surgeries as tympanoplasty, septoplasty, lip repair, dacrocystectomy and cataract under local anesthesia, randomly received either intravenous (IV) fortwin 0.3 mg/kg over 1 min followed by IV midazolam 0.04 mg/kg plus IV phenergan 12.5 mg (Group FPM) or IV ketamine 0.3 mg/kg over 1 min plus IV midazolam 0.04 mg/kg (Group KM). Sedation was titrated to Ramsay sedation score (RSS) of 3. Patients’ mean arterial pressure (MAP), heart rate (HR), saturation peripheral pulse, duration of sedation and need for intraoperative rescue sedation/analgesic were recorded and compared. Satisfaction of patients (using a 1-7 point Likert verbal rating scale) and readiness for discharge towards (time to Aldrete score of 10) were also determined.
Group KM had significant rise in HR (20-25%) and MAP (25-30%) from 30 min after the bolus dose given until the end of the surgery in contrast to Group FPM. The target sedation level (RSS ≥ 3) was higher in Group FPM (n = 23 [92%]) as compared with Group KM (n = 12 [48%]). Time until need for rescue sedation was 66.96 ± 17.19 min in FPM and 32.80 ± 8.90 min in KM group. The patient satisfaction (Likert scale) is more with the FPM group (6.12 ± 0.83 vs. 4.40 ± 1.20).
We found that the combination of FPM is superior to the KM combination as per the hemodynamic changes, duration of analgesia, patients’ satisfaction and efficacy of the drugs are concerned.
PMCID: PMC4258969
Fortwin; ketamine; local anesthesia; midazolam; monitored anesthesia; phenergan; sedation
15.  Safety of midazolam for sedation of HIV-positive patients undergoing colonoscopy 
HIV medicine  2013;14(6):379-384.
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.
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.
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.
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.
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.
PMCID: PMC4120820  PMID: 23332038
Midazolam; HIV; antiretrovirals; colonoscopy; sedation
16.  Is atropine needed with ketamine sedation? A prospective, randomised, double blind study 
Emergency Medicine Journal : EMJ  2006;23(3):206-209.
To compare atropine with placebo as an adjunct to ketamine sedation in children undergoing minor painful procedures. Outcome measures included hypersalivation, side effect profile, parental/patient satisfaction, and procedural success rate.
Children aged between 1 and 16 years of age requiring ketamine procedural sedation in a tertiary emergency department were randomised to receive 0.01 mg/kg of atropine or placebo. All received 4 mg/kg of intramuscular ketamine. Tolerance and sedation scores were recorded throughout the procedure. Side effects were recorded from the start of sedation until discharge. Parental and patient satisfaction scores were obtained at discharge and three to five days after the procedure, with the opportunity to report side effects encountered at home.
A total of 83 patients aged 13 months to 14.5 years (median age 3.4 years) were enrolled over a 16 month period. Hypersalivation occurred in 11.4% of patients given atropine compared with 30.8% given placebo (odds ratio (OR) 0.29, 95% confidence interval (CI) 0.09 to 0.91). A transient rash was observed in 22.7% of the atropine group compared with 5.1% of the placebo group (OR 5.44, 95% CI 1.11 to 26.6). Vomiting during recovery occurred in 9.1% of atropine patients compared with 25.6% of placebo patients (OR 0.29, 95% CI 0.09 to 1.02). There was a trend towards better tolerance in the placebo group. No patient experienced serious side effects.
Ketamine sedation was successful and well tolerated in all cases. The use of atropine as an adjunct for intramuscular ketamine sedation in children significantly reduces hypersalivation and may lower the incidence of post‐procedural vomiting. Atropine is associated with a higher incidence of a transient rash. No serious adverse events were noted.
PMCID: PMC2464444  PMID: 16498158
ketamine; atropine; child; sedation; hypersalivation
17.  Utility of intranasal Ketamine and Midazolam to perform gastric aspirates in children: a double-blind, placebo controlled, randomized study 
BMC Pediatrics  2014;14:67.
We performed a prospective, randomized, placebo-controlled study aimed to evaluate the efficacy and safety of a sedation protocol based on intranasal Ketamine and Midazolam (INKM) administered by a mucosal atomizer device in uncooperative children undergoing gastric aspirates for suspected tuberculosis. Primary outcome: evaluation of Modified Objective Pain Score (MOPS) reduction in children undergoing INKM compared to the placebo group. Secondary outcomes: evaluation of safety of INKM protocol, start time sedation effect, duration of sedation and evaluation of parents and doctors’ satisfaction about the procedure.
In the sedation group, 19 children, mean age 41.5 months, received intranasal Midazolam (0.5 mg/kg) and Ketamine (2 mg/kg). In the placebo group, 17 children received normal saline solution twice in each nostril. The child’s degree of sedation was scored using the MOPS. A questionnaire was designed to evaluate the parents’ and doctors’ opinions on the procedures of both groups.
Fifty-seven gastric washings were performed in the sedation-group, while in the placebo-group we performed 51 gastric aspirates. The degree of sedation achieved by INMK enabled all procedures to be completed without additional drugs. The mean duration of sedation was 71.5 min. Mean MOPS was 3.5 (range 1-8) in the sedation-group, 7.2 (range 4-9) in the placebo-group (p <0.0001). The questionnaire revealed high levels of satisfaction by both doctors and parents in the sedation-group compared to the placebo-group. The only side effect registered was post-sedation agitation in 6 procedures in the sedation group (10.5%).
Our experience suggests that atomized INKM makes gastric aspirates more acceptable and easy to perform in children.
Trial registration
Unique trial Number: UMIN000010623; Receipt Number: R000012422.
PMCID: PMC3974003  PMID: 24598046
Intranasal sedation; Midazolam; Ketamine; Tuberculosis; Gastric washings
18.  A prospective, randomized, double blinded comparison of intranasal dexmedetomodine vs intranasal ketamine in combination with intravenous midazolam for procedural sedation in school aged children undergoing MRI 
For optimum magnetic resonance imaging (MRI) image quality and to ensure precise diagnosis, patients have to remain motionless. We studied the effects of intranasal dexmedetomidine and ketamine with intravenous midazolam for pre-procedural and procedural sedation in school aged children.
Patients and Methods:
Children were randomly allocated to one of two groups: (Group D) received intranasal dexmedetomidine 3 μg kg–1 and (Group K) received intranasal ketamine 7 mg kg–1. Sedation levels 10, 20 and 30 min after drug instillation were evaluated using a Modified Ramsay sedation scale. A 4-point score was used to evaluate patients when they were separated from their parents and their response to intravenous cannulation.
The two groups were comparable in terms of the child's anxiety at presentation (P = 0.245). We observed that Group K achieved faster sedation at 10 min point with P < 0.05. A comparable sedation score at 20 and 30 min were noted. The two groups were comparable regarding to the child's acceptance of nasal administration (P = 0.65). The sedation failure rate was insignificantly differ between groups (13.7% vs. 20.6% for Group D and K respectively). Heart rate and systolic blood pressure showed a significant difference between the two groups starting from the point of 20 min.
Intranasal dexmedetomidine 3 μg kg–1 or ketamine 7 mg kg–1 can be used safely and effectively to induce a state of moderate conscious sedation and to facilitate parents’ separation and IV cannulation. Addition of midazolam in a dose not sufficient alone to produce the target sedation achieved our goal of deep level of sedation suitable for MRI procedure.
PMCID: PMC4173611
Dexmedetomidine; ketamine; intranasal pediatric sedation; MRI
19.  Effect of ketamine pretreatment for anaesthesia in patients undergoing percutaneous transluminal balloon angioplasty with continuous remifentanil infusion 
Korean Journal of Anesthesiology  2011;61(4):308-314.
An appropriate level of sedation and pharmacological assist are essential during percutaneous transluminal balloon angioplasty (PTA). Ketamine provides good analgesia while preserving airway patency, ventilation, and cardiovascular stability with an opioid sparing effect suggesting that it would be ideal in combination with remifentanil and midazolam in spontaneously breathing patients. We evaluated the effect of a small dose of ketamine added to midazolam and remifentanil on analgesia/sedation for PTA procedures.
Sixty-four patients receiving PTA were enrolled. The Control group received midazolam 1.0 mg i.v. and continuous infusion of remifentanil 0.05 µg/kg/min. The Ketamine group received, in addition, an intravenous bolus of 0.5 mg/kg ketamine. Patients' haemodynamic data were monitored before remifentanil infusion, 5 min after remifentanil infusion, at 1, 3, 5, 30 min after incision, and at admission to the recovery room. Verbal numerical rating scales (VNRS) and sedation [OAA/S (Observer's Assessment of Alertness/Sedation)] scores were also recorded.
The VNRS values at 1, 3, and 5 min after incision and OAA/S scores at 5 min after remifentanil infusion, and 1, 3, and 5 min after incision were lower in the Ketamine group than in the Control group. In the Control group, the VNRS value at 1 min after incision significantly increased and OAA/S values at 3, 5, and 30 min after incision significantly decreased compared to baseline values, while there were no significant changes in the ketamine group.
A small dose of ketamine as an adjunct sedative to the combination of midazolam and remifentanil produced a better quality of sedation and analgesia than without ketamine and provided stable respiration without cardiopulmonary deterioration.
PMCID: PMC3219777  PMID: 22110884
Ketamine; Pain scale; Remifentanil; Sedation
20.  Comparison of Propofol-Remifentanil Versus Propofol-Ketamine Deep Sedation for Third Molar Surgery 
Anesthesia Progress  2012;59(3):107-117.
This study aimed to compare continuous intravenous infusion combinations of propofol-remifentanil and propofol-ketamine for deep sedation for surgical extraction of all 4 third molars. In a prospective, randomized, double-blinded controlled study, participants received 1 of 2 sedative combinations for deep sedation for the surgery. Both groups initially received midazolam 0.03 mg/kg for baseline sedation. The control group then received a combination of propofol-remifentanil in a ratio of 10 mg propofol to 5 μg of remifentanil per milliliter, and the experimental group received a combination of propofol-ketamine in a ratio of 10 mg of propofol to 2.5 mg of ketamine per milliliter; both were given at an initial propofol infusion rate of 100 μg/kg/min. Each group received an induction loading bolus of 500 μg/kg of the assigned propofol combination along with the appropriate continuous infusion combination . Measured outcomes included emergence and recovery times, various sedation parameters, hemodynamic and respiratory stability, patient and surgeon satisfaction, postoperative course, and associated drug costs. Thirty-seven participants were enrolled in the study. Both groups demonstrated similar sedation parameters and hemodynamic and respiratory stability; however, the ketamine group had prolonged emergence (13.6 ± 6.6 versus 7.1 ± 3.7 minutes, P = .0009) and recovery (42.9 ± 18.7 versus 24.7 ± 7.6 minutes, P = .0004) times. The prolonged recovery profile of continuously infused propofol-ketamine may limit its effectiveness as an alternative to propofol-remifentanil for deep sedation for third molar extraction and perhaps other short oral surgical procedures, especially in the ambulatory dental setting.
PMCID: PMC3468288  PMID: 23050750
Propofol; Ketamine; Remifentanil; Deep sedation; TIVA
21.  Effectiveness of Oral Ketamine, Midazolam, and Atropine Cocktail Versus Oral Diphenhydramine for Pediatric Sedation in the Emergency Department 
Sedation is a condition of reduced level of consciousness (LOC) for a patient that is created to decrease irritability, anxiety, and restlessness.
In this study, we compared the sedative effect of oral administration of ketamine, midazolam, and atropine cocktail with diphenhydramine in the referent children to the emergency department.
Patients and Methods:
Based on the double-blind randomized clinical trial in this investigation, 80 children, who needed to repair their wounds with suture were randomly divided into two groups: group 1 and group 2, who have received oral diphenhydramine and oral ketamine, midazolam, and atropine cocktail, respectively. Behavioral changes were collected and recorded before, during intervention and two weeks after intervention. Statistical data were analyzed by SPSS-16 software and chi-square and Mann-Whitney U tests were employed to study the relations among variables. P < 0.05 was considered statistically significant.
There was no significant difference between two groups in terms of drug acceptance and anxiety degree in children before intervention. Group 2 had achieved better and deeper sedation than group 1 during 45-minute post-medication (P < 0.05, P = 0.01). Regarding pediatric general behavior such as crying or interruptive moves, there was also a significant statistical difference between group 2 and group 1 (P = 0.009) based on Houpt Classification. The mean recovery times in groups 1 and 2 were 34.37 ± 14.23 min and 27.25 ± 5.14 min, respectively (P = 0.003). In terms of behavioral changes, the rate of cumulative frequency was computed for behavioral changes two weeks after the discharge from emergency department in which there were less behavioral changes in group 2 than in group 1 (P = 0.04).
Oral administration of ketamine, midazolam, and atropine cocktail induces better sedation than diphenhydramine with respect to its limited mood changes in children, who need a medical procedure at emergency department.
PMCID: PMC4270670  PMID: 25593736
Conscious Sedation; Children; Emergency Service; Oral Drug Administrations
22.  Assessment of the effects of ketamine-fentanyl combination versus propofol-remifentanil combination for sedation during endoscopic retrograde cholangiopancreatography 
Endoscopic retrograde cholangiopancreatography (ERCP) as a diagnostic and treatment procedure is used in most biliary tract and pancreatic. Either sedation or general anesthesia could be considered for this procedure. Combining a sedative with an opioid agent can provide effective moderate sedation. This study compared the impact of ketamine-fentanyl (KF) versus propofol-remifentanil (PR) on sedation scale in patients undergoing ERCP.
Materials and Methods:
As a double-blinded randomized clinical trial, 80 patients selected by convenient sampling, allocated randomly into two groups. KF group received ketamine 0.5 mg/kg body weight intravenously over 60 s and then fentanyl 1 mcg/kg body weight intravenously. PR group received propofol l mg/kg body weight intravenously over 60 s and then remifentanil 0.05 mcg/kg body weight/min intravenously. Intravenous (IV) infusion of propofol was maintained by 50 mcg/kg body weight/min throughout ERCP. Ramsay Sedation Score, vital signs, oxygen saturation (SpO2), recovery score (modified Aldrete score) and visual analog scales of pain intensity, and endoscopist's satisfaction were considered as measured outcomes. All analysis were analyzed by SPSS Statistics version 22 and using t-test, Chi-square and repeated measured ANOVA and Mann-Whitney tests for data analysis.
Respiratory rate and SpO2 level during the time intervals were lower in PR group (P < 0.001). Sedation score at intervals was not significantly different (P = 0.07). The frequency of apnea in PR group was significantly higher than the KF group (P = 0.003). The percentage of need to supplemental oxygen in PR group was 35.1% that was also significantly higher than 8.8% in the KF group (P = 0.008), but the dosage frequency was significantly higher in KF group (P < 0.001). The KF and PR groups average length of stay in the recovery room were 50.71 standard deviation (SD = 9.99) and 42.57 (SD = 11.99) minutes, respectively, indicating a significant difference (P = 0.003). The mean severity of nausea in KF and PR groups was, respectively, 2.74 confidence interval (CI = 1.68-3.81) and 0.43 (CI = 0.11-0.75), that was significantly higher in KF group (P < 0.001). The average score of surgeon satisfaction in both KF and PR groups were 7.69 (CI = 7.16-8.21) and 8.65 (CI = 8.25-9.05), respectively, which was higher in KF group (P = 0.004), but the average level of patients satisfaction in KF group was 8.86 (CI = 8.53-9.19) and in PR group was 8.95 (CI - 8.54-9.35) that were not significantly different (P = 0.074).
There is no statistically significant difference between KF and PR combinations in sedation score, but PR combination provides better pain control, with less nausea and shorter recovery time while causing more respiratory side effects, that is, apnea and need to oxygen.
PMCID: PMC4268195  PMID: 25535501
Endoscopic retrograde cholangiopancreatography; fentanyl; ketamine; propofol; remifentanil
23.  A prospective randomized double-blind study comparing dexmedetomidine vs. combination of midazolam-fentanyl for tympanoplasty surgery under monitored anesthesia care 
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.
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.
Dexmedetomidine is comparable to midazolam-fentanyl for sedation and analgesia in tympanoplasty with better surgeon and patient satisfaction. Hemodynamics need to be closely monitored.
PMCID: PMC3713662  PMID: 23878436
Dexmedetomidine; sedation; midazolam fentanyl sedation; monitored anesthesia care; satisfaction scores; surgery; otological
24.  Investigation of the potentiation of the analgesic effects of fentanyl by ketamine in humans: a double-blinded, randomised, placebo controlled, crossover study of experimental pain[ISRCTN83088383] 
BMC Anesthesiology  2005;5:2.
Despite preclinical evidence suggesting a synergistic interaction between ketamine and opioids promoting analgesia, several clinical trials have not identified dosing regimens capable of eliciting a benefit in the co-administration of ketamine with opioids.
Ten healthy volunteers participated in a double blinded, randomised, placebo controlled, crossover laboratory study in order to determine whether a low dose of ketamine potentiated the antinociceptive effect of fentanyl without causing an increase in sedative effects. A battery of tests was used to assess both nociception and sedation including electrical current, pressure, thermal stimuli, psychometric tests, and both subjective and objective scores of sedation. Target controlled infusions of the study drugs were used. Ketamine and fentanyl were administered alone and in combination in a double-blinded randomised crossover design. Saline was used as the control, and propofol was used to validate the tests of sedation. Cardiovascular and respiratory parameters were also assessed.
The electrical current pain threshold dose response curve of fentanyl combined with ketamine was markedly steeper than the dose response curve of fentanyl alone. While a ketamine serum concentration of 30 ng/ml did not result in a change in electrical pain threshold when administered alone, when it was added to fentanyl, the combination resulted in greater increase in pain threshold than that of fentanyl administered alone. When nociception was assessed using heat and pressure stimuli, ketamine did not potentiate the anti-nociceptive effect of fentanyl. There was no difference between the sedative effect of fentanyl and fentanyl in combination with ketamine as assessed by both subjective and objective measures of sedation. Cardiovascular and respiratory parameters were unaffected by the study drugs at the doses given.
A serum concentration of ketamine that did not alter indices of sedation potentiated the antinociceptive effect of fentanyl. This potentiation of antinociception occurred without an increase in sedation suggesting that low steady doses of ketamine (30–120 ng/ml) might be combined with μ opioid agonists to improve their analgesic effect in a clinical setting. (296 words)
PMCID: PMC1084341  PMID: 15804361
25.  Comparison of the effects of ketamine or lidocaine on fentanyl-induced cough in patients undergoing surgery: A prospective, double-blind, randomized, placebo-controlled study 
Background: Fentanyl-induced cough is common but has not been viewed as a serious anesthetic problem. However, the cough may be explosive at times, may require immediate intervention, and may be associated with undesirable increases in intracranial, intraocular, and intra-abdominal pressures. Prevention of fentanylinduced cough in such situations is of paramount importance. Ketamine, at concentrations achieved with standard clinical doses, has a direct relaxant effect on airway smooth muscle.
Objective: This study was designed to assess the effects of ketamine or lidocaine on fentanyl-induced cough.
Methods: This double-blind, randomized, placebo-controlled study was conducted at the Erciyes University Medical School, Kayseri, Turkey. Consecutive adult patients aged 18 to 65 years and classified as American Society of Anesthesiologists physical status I or II who were undergoing elective surgery with general anesthesia were enrolled. Patients were randomly allocated equally into 3 groups to receive lidocaine 1 mg/kg, ketamine 0.5 μg/kg, or placebo intravenously 1 minute before fentanyl administration. Following intravenous fentanyl (1.5 μg/kg over 2 seconds) injection, an observer, unaware of the type of medication given to the patients, recorded the number of episodes of coughing, if any. Any episode of cough was classified as coughing and graded by investigators blinded to treatment as mild (1–2 coughs), moderate (3–4), or severe (≥5). Blood pressure, heart rate, pulse oximetry oxygen saturation (SpO2), and adverse effects (AEs) were recorded.
Results: A total of 368 patients were approached for inclusion; 300 patients met the inclusion criteria and were enrolled in the study. No patients in the ketamine group had cough. The frequency of cough was significantly lower in the lidocaine (11/100 [11%]; P = 0.024) and ketamine (0/100; P = 0.001) groups compared with the placebo group (23/100 [23%]). The intensity of cough was significantly lower in the lidocaine (mild, 7/100 [7%]; moderate, 4/100 [4%]; P = 0.037) and ketamine (0/100; P < 0.001) groups compared with the placebo group (mild, 10/100 [10%]; moderate, 12/100 [12%]; severe, 1/100 [1%]). Severe cough (≥5) was observed in 1 patient in the placebo group. Incidence and intensity of cough were significantly decreased in the ketamine group compared with the lidocaine group (incidence, P = 0.001; intensity, P = 0.003). There were no significant differences between groups with respect to systolic blood pressure, diastolic blood pressure, heart rate, SpO2, and AEs.
Conclusion: Intravenous ketamine (0.5 mg/kg) significantly reduced the reflex cough induced by fentanyl compared with lidocaine and placebo, and was well tolerated.
PMCID: PMC3969624  PMID: 24688150
fentanyl; coughing; ketamine; lidocaine

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