The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study.
ABSTRACT: OBJECTIVES:Ketamine is a well-known analgesic and dose-dependent anesthetic used in emergency and disaster medicine. Recently, a new formulation of S-ketamine, as an intranasal spray, was developed and tested in our institution in healthy volunteers. The authors investigated the effect of intranasal S-ketamine spray combined with midazolam intranasal spray in postoperative spinal surgery patients. MATERIALS AND METHODS:In this prospective, computer-randomized, double-blinded noninferiority study in spinal surgery patients, the effects of intranasal S-ketamine and midazolam were compared with standard morphine patient-controlled analgesia (PCA). The primary end point was the numeric rating scale pain score 24 hours after surgery. RESULTS:Twenty-two patients finished this study, eleven in each group. There were similar numeric rating scale scores in the morphine PCA and the S-ketamine-PCA groups at 1, 2, 4, 24, 48, and 72 hours after surgery during rest as well as in motion. There were no differences in the satisfaction scores at any time between the groups. The number of bolus demands and deliveries was not significantly different. DISCUSSION:In our study, we found that an S-ketamine intranasal spray combined with intra-nasal midazolam was similar in effectiveness, satisfaction, number of demands/deliveries of S-ketamine and morphine, and number/severity of adverse events compared with standard intravenous PCA with morphine. S-ketamine can be regarded as an effective alternative for a traditional intravenous morphine PCA in the postoperative setting.
Project description:PURPOSE:The optimal sedative regime that provides the greatest comfort and the lowest risk for procedural sedation in young children remains to be determined. The aim of this randomized, blinded, controlled, parallel-design trial was to evaluate the efficacy of intranasal ketamine and midazolam as the main component of the behavioral guidance approach for preschoolers during dental treatment. MATERIALS AND METHODS:Children under seven years of age, with caries and non-cooperative behavior, were randomized into three groups: (KMIN) intranasal ketamine and midazolam; (KMO) oral ketamine and midazolam; or (MO) oral midazolam. The dental sedation appointments were videotaped, and the videos were analyzed using the Ohio State University Behavioral Rating Scale (OSUBRS) to determine the success of the sedation in each group. Intra- and postoperative adverse events were recorded. Data analysis involved descriptive statistics and non-parametric tests (P < 0.05, IBM SPSS). RESULTS:Participants were 84 children (28 per group; 43 boys), with a mean age of 3.1 years (SD 1.2). Children's baseline and the dental sedation session characteristics were balanced among groups. The success of the treatment as assessed by the dichotomous variable 'quiet behavior for at least 60% of the session length' was: KMIN 50.0% (n = 14; OR 2.10, 95% CI 0.71 to 6.30), KMO 46.4% (n = 13; OR 1.80, 95% CI 0.62 to 5.40), MO 32.1% (n = 9) (P = 0.360). Adverse events were minor, occurred in 37 of 84 children (44.0%), and did not differ among groups (P = 0.462). CONCLUSION:All three regimens provided moderate dental sedation with minor adverse events, with marked variability in the behavior of children during dental treatment. The potential benefit of the ketamine-midazolam combination should be further investigated in studies with larger samples. TRIAL REGISTRATION:ClinicalTrials.gov, identifier: NCT02447289. Registered on 11 May 2015, named "Midazolam and Ketamine Effect Administered Through the Nose for Sedation of Children for Dental Treatment (NASO)."
Project description:Uncooperative children may need to receive dental treatment under sedation, which is indicated when nonpharmacological behavior guidance is unsuccessful. There are randomized controlled trials (RCTs) comparing different sedative protocols for dental procedures; however, the evidence for superiority of one form over another is weak. The primary aim of this study is to investigate the efficacy of intranasally administered ketamine plus midazolam for the dental treatment of children.We have designed a three-armed, parallel RCT to assess intranasal sedation using ketamine/midazolam in terms of the following measures: efficacy, safety, and cost-effectiveness. Two- to 6-year-old healthy children, referred for dental treatment in a dental sedation center in Brazil due to uncooperative behavior and requiring restorative dental procedures, will be recruited. Each child will be randomly assigned to one of the three groups: A - Intranasal administration of ketamine (4.0 mg/kg, maximum 100 mg) and midazolam (0.2 mg/kg, maximum 5.0 mg); B - Oral administration of ketamine (4.0 mg/kg, maximum 100 mg) and midazolam (0.5 mg/kg, maximum 20 mg); and C - Oral administration of midazolam (1.0 mg/kg, maximum 20 mg). The primary outcome is the child's behavior assessed through an observational scale using digital videos of the restorative dental treatment under sedation. The secondary outcomes are as follows: acceptance of sedative administration; memory of intraoperative events; the child's stress; adverse events; the child's pain during the procedure; the parent's, dentists', and child's perceptions of sedation; and economic analysis. Measures will be taken at baseline and drug administration and during and after the dental procedure. The necessary sample size was estimated to be 84 children after a blinded interim analysis of the first 30 cases.This study will provide data that can substantially add to science and pediatric dentistry as it examines the effect of sedative regimes from different perspectives (outcomes).ClinicalTrials.gov, identifier: NCT02447289 . Registered on 11 May 2015, named "Midazolam and Ketamine Effect Administered Through the Nose for Sedation of Children for Dental Treatment (NASO)."
Project description:<h4>Background and aims</h4>Patient-controlled analgesia (PCA) with morphine is commonly used to provide analgesia following major surgery, but is not sufficient as a monotherapy strategy. This study aimed to compare the adjunctive analgesic effect of ketamine versus tramadol on postoperative analgesia provided via PCA-morphine in patients undergoing major upper abdominal surgeries.<h4>Methods</h4>Forty-two patients undergoing elective major upper abdominal surgery under general anesthesia were allocated to receive either ketamine (load dose of 0.5 mg kg<sup>-1</sup> followed by a continuous infusion of 0.12 mg kg<sup>-1</sup> h<sup>-1</sup> up to 48 postoperative hours; ketamine group, n = 21) or tramadol (load dose of 1 mg kg<sup>-1</sup> followed by a continuous infusion of 0.2 mg kg<sup>-1</sup> h<sup>-1</sup> up to 48 postoperative hours; tramadol group, n = 21) in addition to their standard postoperative analgesia with PCA-morphine. Postoperative data included morphine consumption, visual analog scale (VAS) scores, and side effects during the first 48 postoperative hours after PCA-morphine initiation.<h4>Results</h4>There were no significant differences in patient demographic and intraoperative data between the two groups. Tramadol group had significantly less total morphine consumption during the first 48 postoperative hours (28.905 [16.504] vs 54.524 [20.846] mg [p < 0.001]) and presented significantly lower VAS scores at rest and mobilization (p < 0.05) than the ketamine group. No statistical difference was recorded between the two groups (p > 0.05) regarding postoperative cough, sedation, hallucinations, pruritus, urine retention, and postoperative nausea and vomiting. However, patients in the ketamine group reported dry mouth more frequently than patients in the tramadol group (p = 0.032).<h4>Conclusions</h4>Postoperative administration of tramadol was superior to ketamine due to significantly reduced opioid consumption and better pain scores in patients receiving PCA-morphine after major upper abdominal surgery.
Project description:Aim. A double-blind, randomized, placebo-controlled trial was designed to evaluate the efficacy of continuous intraoperative infusion of S(+)-ketamine under intravenous anesthesia with target-controlled infusion of remifentanil and propofol for postoperative pain control. Methods. Forty-eight patients undergoing laparoscopic cholecystectomy were assigned to receive continuous S(+)-ketamine infusion at a rate of 0.3?mg·kg(-1)·h(-1) (n = 24, intervention group) or an equivalent volume of saline at the same rate (n = 24, placebo group). The same target-controlled intravenous anesthesia was induced in both groups. Pain was assessed using a 0 to 10 verbal numeric rating scale during the first 12 postoperative hours. Pain scores and morphine consumption were recorded in the postanesthesia care unit (PACU) and at 4 and 12 hours after surgery. Results. Pain scores were lower in the intervention group at all time points. Morphine consumption did not differ significantly between groups during PACU stay, but it was significantly lower in the intervention group at each time point after PACU discharge (P = 0.0061). At 12 hours after surgery, cumulative morphine consumption was also lower in the intervention group (5.200 ± 2.707) than in the placebo group (7.525 ± 1.872). Conclusions. Continuous S(+)-ketamine infusion during laparoscopic cholecystectomy under target-controlled intravenous anesthesia provided better postoperative pain control than placebo, reducing morphine requirement. Trial Registration. This trial is registered with ClinicalTrials.gov NCT02421913.
Project description:We determine whether aerosolized intranasal or buccal midazolam reduces the distress of pediatric laceration repair compared with oral midazolam.Children aged 0.5 to 7 years and needing nonparenteral sedation for laceration repair were randomized to receive oral, aerosolized intranasal, or aerosolized buccal midazolam. Patient distress was rated by blinded review of videotapes, using the Children's Hospital of Eastern Ontario Pain Score. Secondary outcomes included activity scores, sedation adequacy, sedation onset, satisfaction, and adverse events.For the 169 subjects (median age 3.1 years) evaluated for the primary outcome, we found significantly less distress in the buccal midazolam group compared with the oral route group (P=.04; difference -2; 95% confidence interval -4 to 0) and a corresponding nonsignificant trend for the intranasal route (P=.08; difference -1; 95% confidence interval -3 to 1). Secondary outcomes (177 subjects) favored the intranasal group, including a greater proportion of patients with an optimal activity score (74%), a greater proportion of parents wanting this sedation in the future, and faster sedation onset. Intranasal was the route least tolerated at administration. Adverse events were similar between groups.When comparing the administration of midazolam by 3 routes to facilitate pediatric laceration repair, we observed slightly less distress in the aerosolized buccal group. The intranasal route demonstrated a greater proportion of patients with optimal activity scores, greater proportions of parents wanting similar sedation in the future, and faster onset but was also the most poorly tolerated at administration. Aerosolized buccal or intranasal midazolam represents an effective and useful alternative to oral midazolam for sedation for laceration repair.
Project description:BACKGROUND:We assessed the effects of low-dose IV ketamine-midazolam versus morphine on pain control in patients with closed limb fracture(s); and also compared the incidence of adverse events (cardio-pulmonary) between two groups. MATERIALS AND METHODS:This prospective, single-blind, non-inferiority trial randomized consecutive emergency department (ED) patients aged 18-60 years to two groups: Receiving 300-500 mcg/kg ketamine plus 0.03 mg/kg midazolam, or 0.05-0.1 mg/kg morphine. Visual analogue score (VAS) and adverse events were verified during an interval of 30 minutes. RESULTS:Two hundred and thirty - six patients were selected, among whom 207 were males (87.3%). The average age was 29 ± 2, (range, 18-60 years). The VAS score at T30 (i.e., 30 minutes after initial analgesic dose) was significantly decreased compared with VAS score at T0, in both groups. No statistically significant difference, however, was observed between the two groups (-6.1 ± 1.1 versus -6.2 ± 1.0; P = 0.16). With regard to systolic blood pressure and respiratory rate, however, a meaningful difference was noted between the two groups (1.5 ± 6.4 versus -2.1 ± 6.6; P = 0.000 for SBP, and -0.2 ± 1.1 versus -1.1 ± 6.1; P = 0.048 for RR). CONCLUSION:Low-dose intravenous ketamine plus midazolam has the same analgesic effects as morphine on pain control in trauma patients with closed limb fracture(s), in addition to less respiratory adverse events.
Project description:<h4>Objective</h4>Pain and distress associated with intranasal midazolam administration can be decreased by administering lidocaine before intranasal midazolam (preadministered lidocaine) or combining lidocaine with midazolam in a single solution (coadministered lidocaine). We hypothesized coadministered lidocaine is non-inferior to preadministered lidocaine for decreasing pain and distress associated with intranasal midazolam administration.<h4>Methods</h4>Randomized, outcome assessor-blinded, noninferiority trial. Children aged 6 months to 7 years undergoing laceration repair received intranasal midazolam with preadministered or coadministered lidocaine. Pain and distress were evaluated with the Observational Scale of Behavioral Distress-Revised (OSBD-R) (primary outcome; non-inferiority margin 1.8 units) and the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and Faces, Legs, Activity, Cry, Consolability (FLACC) scales and cry duration (secondary outcomes). Secondary outcomes also included adverse events, clinician and caregiver satisfaction, and pain and distress associated with intranasal lidocaine administration.<h4>Results</h4>Fifty-one patients were analyzed. Mean OSBD-R scores associated with intranasal midazolam administration were 6.4 (95% confidence interval [CI] 5, 7.8) and 7 (95% CI 5.2, 8.9) units for preadministered and coadministered lidocaine, respectively. The difference of 0.6 (95% CI -1.7, 2.8) units represented an inconclusive non-inferiority determination. CHEOPS and FLACC scores and cry duration were similar between groups. OSBD-R, CHEOPS, and FLACC scores and cry duration associated with intranasal lidocaine administration were 3.8, 9.9, and 6 units, and 56 seconds, respectively. Clinicians considered coadministered lidocaine easier to administer.<h4>Conclusion</h4>Pain and distress associated with intranasal midazolam administration were similar when using coadministered or preadministered lidocaine, but our non-inferiority determination was inconclusive. Administration of intranasal lidocaine by itself was associated with a measurable degree of pain and distress.Keywords: intranasal, midazolam, anxiolysis, sedation, emergency department, emergency medicine, pain, distress, pediatric, lidocaine, laceration.
Project description:Introduction The ?2 agonist dexmedetomidine is a new sedative and analgesic agent which is licensed in the USA for post-operative intensive care sedation. We compared dexmedetomidine with the mixture of midazolam and morphine for post-operative patient who required mechanical ventilation in intensive care unit (ICU). Objective : To compare the effect of dexmedetomidine and midazolam-morphine mixture among post-operative patients in ICU; in term of the amount of analgesic (PCA morphine) requirement, sedation score, haemodynamic profiles and time of extubation. Methodology : Prospective, double-blinded randomized controlled trial study design involved post-operative patients admitted to the Intensive Care Unit (ICU) of Hospital Universiti Sains Malaysia (HUSM) conducted from June 2003 to June 2004. Thirty-four mechanically ventilated post-operative patients were randomly assigned to receive short-term (minimum 4 hours) sedation with either continuous intravenous infusion of dexmedetomidine (group Dex. n=17) or midazolam-morphine mixture (group MM, n=17). Both groups received similar intraoperative anaesthetic regime. Patient controlled analgesia (PCA Morphine) was given to patient as rescue analgesic. Analgesic (PCA morphine) used (mg/hour), Ramsay sedation scoring, extubation time (minute), systolic blood pressure, diastolic blood pressure, mean arterial pressure and heart rate were Medical Sciences, Universiti Sains Malaysia had approved this study on 9th April 2003. Result : Mean extubation time of dexmedetomidine group was significantly lower than midazolam and morphine mixture group [mean (s.d.): 40.3 ± 16.5 minutes versus 57.9 ± 17.7 minutes. p=0.05]. Within the first 4 hours drug infusion, mean systolic blood pressure [mean (s.d.): 105 ±14 mmHg vs 127 ± 24 mmHg, (p=0.000)], mean diastolic blood pressure [mean (s.d.): 59 ± 8mmHg vs 66 ± 13 mmHg (p=0.000)], mean arterial pressure [mean (s.d.): 76 ± 9 mmHg vs 86 ± 15mmHg (p=0.000)] and mean heart rate [mean (s.d.): 88 ± 13 beats per minute vs 102 ± 24 beats per minute (p=0.000)] were significantly lower in dexmedetomidine group than those in midazolam and morphine mixture. There was significant difference of mean Ramsay sedation score between dexmedetomidine and midazolam morphine mixture (p=0.000). However, there was no significant difference of mean dose of morphine per hour between dexmedetomidine groups and midazolam morphine mixture [(mean (s.d.); 1.4 ± 0.7 mg/hour) versus mean (s.d.); 1.1 ± 0.8 mg/hour). p= 0.157 ]. Conclusion : Dexmedetomidine provides safe, effective sedation and analgesia for postoperative long surgical patient in intensive care unit. Haemodynamic variables of dexmedetomidine group was more stable than midazolam and morphine mixtures group. Thus dexmedetomidine provides better perioperative haemodynamic control or a long sugery. The use of dexmedetomidine also allowed for more rapid tracheal extubation. Dr. Saedah Ali : Supervisor Dr. Nik Abdullah Nik Mohamed : Co-Supervisor
Project description:The N-methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial.In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured.Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo (t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters.This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.
Project description:Preprocedural preparation of children scheduled for magnetic resonance imaging (MRI) is challenging. This prospective, randomized trial compared intranasal midazolam with intranasal dexmedetomidine as premedication for children scheduled for brain MRI.In total, 60 children, aged 1-8 years, scheduled for elective brain MRI, were randomly assigned to the intranasal dexmedetomidine (1 μg/kg; Group D) or intranasal midazolam (0.2 mg/kg; Group M) group. We compared hemodynamic and respiratory parameters, onset, level, sedation quality, and successful parental separation. All patients received intravenous propofol as an induction and maintenance agent for MRI.No significant differences were observed in demographic, hemodynamic, and respiratory parameters. Group D (14.3 ± 3.4 min [10-20 min]) had a longer time of sedation onset than Group M (8.7 ± 3.7 min [5-15 min]; P < 0.001). The median and mean sedation scores were lower in Group D (3 and 3.7 ± 0.8, respectively) than Group M (4 and 4.3 ± 1.2, respectively; P = 0.055). Group D (80%) had a higher percentage of children achieving satisfactory sedation at the time of induction than did Group M (53.3%; P = 0.0285). Parental separation was successful in 73.3% of patients in Group D compared with 46.7% of patients in Group M (P = 0.035).Intranasal dexmedetomidine results in more successful parental separation and yields a higher sedation level at the time of induction of anesthesia than intranasal midazolam as premedication, with negligible side effects. However, its onset of action is relatively prolonged.