Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom.

Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011-2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (Cmax ; geometric mean ratio (90% confidence interval) 0.99 (0.83-1.19) and 0.96 (0.78-1.19), respectively) but a modest increase in midazolam AUC and Cmax (1.39 (1.23-1.57) and 1.50 (1.32-1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98-1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (KI , ~4 µM; kinact , ~0.07 min-1 ). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.

Descriptive assessment of adverse events associated with midazolam-etomidate versus saline-etomidate in healthy hydromorphone premedicated dogs.

OBJECTIVES: To determine the frequency, severity and duration of adverse events including myoclonus, pain on injection, hypersalivation, regurgitation and apnoea after administration of midazolam or saline followed by etomidate in hydromorphone premedicated dogs. MATERIALS AND METHODS: Dogs undergoing elective dental prophylaxis or soft tissue surgeries were enrolled in this randomised trial. Dogs were premedicated with hydromorphone 0.1 mg/kg IV. Sixty seconds later, midazolam 0.3 mg/kg or saline at an equivalent volume was administered IV. Sixty seconds after that, etomidate 1.5 mg/kg IV was administered over 60 seconds. Additional doses of 0.5 mg/kg etomidate were administered until endotracheal intubation was successful. Observers were blinded to the treatment. Frequency, duration and a severity score of 0 to 3 were recorded for myoclonus, pain on injection, hypersalivation and regurgitation. Duration of apnoea and frequency of any additional complications was recorded. RESULTS: Forty variable breed healthy dogs were enrolled in the study. Myoclonus, pain on injection, regurgitation, hypersalivation, gagging, tachypnoea and pigmenturia occurred, respectively, in 10%, 40%, 0%, 15%, 35%, 25% and 5% of dogs in the saline group and 0%, 65%, 0%, 10%, 45%, 15% and 5% of dogs in the midazolam group. Apnoea occurred for 115 seconds (range 0 to 660 seconds) and 160 seconds (range 0 to 600 seconds) in the saline and midazolam groups, respectively. Two dogs developed pigmenturia. The trial was stopped early due to the occurrence of pigmenturia. CLINICAL SIGNIFICANCE: Due to early stopping of the trial, the predefined sample size was not reached. Further investigation is needed to determine if midazolam reduced the incidence of adverse events or improved the induction quality when combined with hydromorphone and etomidate.

Procedural sedation for direct current cardioversion: a feasibility study between two management strategies in the emergency department.

BACKGROUND: A cardiologist-only approach to procedural sedation with midazolam in the setting of elective cardioversion (DCC) for AF has already been proven as safe as sedation with propofol and anaesthesiologist assistance. No data exist regarding the safety of such a strategy during emergency procedures. The aim of this study is to compare the feasibility of sedation with midazolam, administered by a cardiologist, to an anaesthesiologist-assisted protocol with propofol in emergency DCC. METHODS: Single centre, prospective, open blinded, randomized study including all consecutive patients admitted to the Emergency Department requiring urgent or emergency DCC. Patients were randomized in a 1:1 fashion to either propofol or midazolam treatment arm. Patients in the midazolam group were managed by the cardiologist only, while patients treated with propofol group underwent DCC with anaesthesiologist assistance. RESULTS: Sixty-nine patients were enrolled and split into two groups. Eighteen patients (26.1%) experienced peri-procedural adverse events (bradycardia, severe hypotension and severe hypoxia), which were similar between the two groups and all successfully managed by the cardiologist. No deaths, stroke or need for invasive ventilation were registered. Patients treated with propofol experienced a greater decrease in systolic and diastolic blood pressure when compared with those treated with midazolam. As the procedure was shorter when midazolam was used, the median cost of urgent/emergency DCC with midazolam was estimated to be 129.0 € (1st-3rd quartiles 114.6-151.6) and 195.6 € (1st-3rd quartiles 147.3-726.7) with propofol (p < .001). CONCLUSIONS: Procedural sedation with midazolam given by the cardiologist alone was feasible, well-tolerated and cost-effective in emergency DCC.

Safety degree assessment of drugs used in conscious sedation for colonoscopy in patients that develop respiratory depression / Avaliação do grau de segurança dos fármacos utilizados na sedação superficial na colonoscopia em pacientes que desencadeiam depressão respiratória

ABSTRACT Objective: To analyze the safety degree of drugs used in colonoscopy during conscious sedation in patients developing respiratory depression. Methods: Cross-sectional observational study that evaluated 1120 patients who underwent colonoscopy between February 2015 and February 2016. Physical characteristics, surgical history and previous colonoscopies, indication and conditions of the current examination, fentanyl and midazolam doses and subsequent complications were analyzed. Level of significance: p < 0.05. Chi-square test was used for association of categorical variables, whereas Student's t test was used to compare means and Spearman's coefficient for correlation. Results: There were 661 female (59%) and 459 (41%) male patients, with a mean age of 54.90 (20-87) years and BMI of 27.00 (14.5-45.4). Of the 1120 patients, only 2 (0.2%) had respiratory depression, reversed with lanexat. Patients who had complications were of both genders, with a body mass index of 21.25 and 28.7. There was a correlation between the required dose of fentanyl and age (p < 0.001 to −0.121 Spearman's coefficient), as well as midazolam (p < 0.001 - Spearman's coefficient −0.452) and increasing age was associated with a lower dose of the drug. Conclusion: The number of patients with complications was 0.17%. The age of the patient showed an inverse association, i.e., the older the patient, the lower the required dose of medication. The drugs used in colonoscopy show a high degree of safety, corroborating their frequent use for superficial/conscious sedation in this procedure.

RESUMO Objetivo: Analisar o grau de segurança dos fármacos utilizados na colonoscopia sob sedação superficial em pacientes que desencadeiam depressão respiratória. Métodos: Estudo observacional transversal, que avaliou 1.120 pacientes que realizaram colonoscopia entre Fevereiro de 2015 e Fevereiro de 2016. Analisaram-se características físicas, histórico cirúrgico e colonoscopias prévias, indicação e condições do exame atual, dose de fentanil e midazolam e complicações apresentadas. Nível de significância adotado: p < 0,05. Utilizou-se teste Qui-quadrado para associação de variáveis categóricas, teste t de Student para comparação de médias e coeficiente de Spearman para correlação. Resultados: Foram 661 pacientes do sexo feminino (59%) e 459 (41%) do sexo masculino, com média de idade de 54,90 (20-87) anos e IMC de 27,00 (14,5-45,4). Dos 1120 pacientes, apenas 2 (0,2%) exibiram depressão respiratória revertida com lanexate. Os pacientes que apresentaram complicação eram de sexos diferentes, com índices de massa corpórea de 21,25 e 28,7. Houve correlação entre a dose necessária de fentanil e a idade (p < 0,001 - coef Spearmann - 0.121), assim como a de midazolam (p < 0,001 - coef Spearmann - 0.452), sendo que com o aumento da idade se correlacionou com uma menor dose utilizada de medicamento. Conclusão: O número de pacientes que apresentaram alguma complicação foi 0,17%. A idade do paciente tem associação inversa, quanto maior a idade do paciente, menor é a dose necessária de medicamentos. Verifica-se alto grau de segurança dos medicamentos utilizados na colonoscopia, corroborando sua utilização frequente para a sedação superficial/consciente neste procedimento.

A Novel Anesthetic Technique for PEVAR.

BACKGROUND: Percutaneous endovascular aneurysm repair (PEVAR) continues to evolve. Device profiles continue to decline, further reducing the physiological insult of the procedure. Anesthesia, however, has not evolved with a large proportion of patients continuing to receive general anesthesia for their increasingly less invasive procedures. We report on a novel anesthetic technique providing outstanding anesthesia in patients undergoing PEVAR in an outpatient setting. The total anesthesia used was remarkably cost effective. METHODS: Six patients underwent PEVAR in an outpatient setting. The patients received moderate intravenous (IV) access sedation using versed and fentanyl in combination with bilateral ilioinguinal nerve blocks. Patients received 25 mL bilaterally of 0.5% bupivicaine with epinephrine. All patients were American Society of Anesthesiologists class III. None received central venous access, arterial, or urinary catheters. Standard noninvasive monitoring was used. A board-certified anesthesiologist was present at all times during the procedures. RESULTS: All patients underwent successful repair. Average cost per case for anesthetic supplies averaged around $7.00. The fentanyl dose ranged from 100 to 200 µg with an average dose of 130 µg. Versed dose ranged from 2 to 3 mg with an average dose of 2.4 mg. No patient required conversion to general anesthesia. Postoperative pain relief was excellent. Two patients required pain medication before discharge. Two patients required oral narcotic analgesic the night of discharge. No patients required narcotics after that time. CONCLUSIONS: Bilateral ilioinguinal nerve block, when combined with moderate IV sedation allows outstanding anesthesia for patients undergoing PEVAR. This novel combination has not been reported previously. The technique provides safe, effective, care for of a subset of patients not requiring general anesthesia. It offers a greatly reduced cost when compared with general anesthesia. Additional benefits include prolonged pain relief perioperatively as well as potentially decreasing the physiologic and cognitive effects seen with general anesthesia.

Capnographic Monitoring of Moderate Sedation During Low-Risk Screening Colonoscopy Does Not Improve Safety or Patient Satisfaction: A Prospective Cohort Study.

OBJECTIVES: Appropriate monitoring during sedation has been recognized as vital to patient safety in procedures outside of the operating room. Capnography can identify hypoventilation prior to hypoxemia; however, it is not clear whether the addition of capnography improves safety or is cost effective during routine colonoscopy, a high volume, low-risk procedure. Our aim was to evaluate the value of EtCO2 monitoring during colonoscopy with moderate sedation. METHODS: We conducted a prospective study of sedation safety and patient satisfaction before and after the introduction of EtCO2 monitoring during outpatient colonoscopy with midazolam and fentanyl using the validated PROcedural Sedation Assessment Survey (PROSAS). Complications of sedation and PROSAS scores were compared among colonoscopies with and without capnography. RESULTS: A total of 966 patients participated in our study, 465 in the pre-EtCO2 group and 501 in the EtCO2 group. On multivariate analysis, patients and nurses reported higher levels of procedural discomfort after adoption of capnography (1.71 vs. 1.00, P<0.001). No serious adverse events were seen, and minor sedation-related adverse events occurred with similar frequency in both groups (8.2% pre-EtCO2 vs. 11.2% EtCO2, P=0.115). The cost of implementing EtCO2 in our unit was $40,169.95 and added $11.68 per case. CONCLUSIONS: Colonoscopy with moderate sedation is a low-risk procedure, and the addition of EtCO2 did not improve safety or patient satisfaction but did increase cost. These data suggest that routine capnography in this setting may not be cost effective and that EtCO2 might be reserved for patients at higher risk of adverse events.

Midazolam and propofol used alone or sequentially for long-term sedation in critically ill, mechanically ventilated patients: a prospective, randomized study.

INTRODUCTION: Midazolam and propofol used alone for long-term sedation are associated with adverse effects. Sequential use may reduce the adverse effects, and lead to faster recovery, earlier extubation and lower costs. This study evaluates the effects, safety, and cost of midazolam, propofol, and their sequential use for long-term sedation in critically ill mechanically ventilated patients. METHODS: A total of 135 patients who required mechanical ventilation for >3 days were randomly assigned to receive midazolam (group M), propofol (group P), or sequential use of both (group M-P). In group M-P, midazolam was switched to propofol until the patients passed the spontaneous breathing trial (SBT) safety screen. The primary endpoints included recovery time, extubation time and mechanical ventilation time. The secondary endpoints were pharmaceutical cost, total cost of ICU stay, and recollection to mechanical ventilation-related events. RESULTS: The incidence of agitation following cessation of sedation in group M-P was lower than group M (19.4% versus 48.7%, P = 0.01). The mean percentage of adequate sedation and duration of sedation were similar in the three groups. The recovery time, extubation time and mechanical ventilation time of group M were 58.0 (interquartile range (IQR), 39.0) hours, 45.0 (IQR, 24.5) hours, and 192.0 (IQR, 124.0) hours, respectively; these were significantly longer than the other groups, while they were similar between the other two groups. In the treatment-received analysis, ICU duration was longer in group M than group M-P (P = 0.016). Using an intention-to-treat analysis and a treatment-received analysis, respectively, the pharmaceutical cost of group M-P was lower than group P (P <0.01) and its ICU cost was lower than group M (P <0.01; P = 0.015). The proportion of group M-P with unbearable memory of the uncomfortable events was lower than in group M (11.7% versus 25.0%, P <0.01), while the proportion with no memory was similar (P >0.05). The incidence of hypotension in group M-P was lower than group (P = 0.01). CONCLUSION: Sequential use of midazolam and propofol was a safe and effective sedation protocol, with higher clinical effectiveness and better cost-benefit ratio than midazolam or propofol used alone, for long-term sedation of critically ill mechanically ventilated patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN01173443. Registered 25 February 2014.

Prospective multicentre randomised, double-blind, equivalence study comparing clonidine and midazolam as intravenous sedative agents in critically ill children: the SLEEPS (Safety profiLe, Efficacy and Equivalence in Paediatric intensive care Sedation) study.

BACKGROUND: Children in paediatric intensive care units (PICUs) require analgesia and sedation but both undersedation and oversedation can be harmful. OBJECTIVE: Evaluation of intravenous (i.v.) clonidine as an alternative to i.v. midazolam. DESIGN: Multicentre, double-blind, randomised equivalence trial. SETTING: Ten UK PICUs. PARTICIPANTS: Children (30 days to 15 years inclusive) weighing ≤ 50 kg, expected to require ventilation on PICU for > 12 hours. INTERVENTIONS: Clonidine (3 µg/kg loading then 0-3 µg/kg/hour) versus midazolam (200 µg/kg loading then 0-200 µg/kg/hour). Maintenance infusion rates adjusted according to behavioural assessment (COMFORT score). Both groups also received morphine. MAIN OUTCOME MEASURES: Primary end point Adequate sedation defined by COMFORT score of 17-26 for ≥ 80% of the time with a ± 0.15 margin of equivalence. Secondary end points Percentage of time spent adequately sedated, increase in sedation/analgesia, recovery after sedation, side effects and safety data. RESULTS: The study planned to recruit 1000 children. In total, 129 children were randomised, of whom 120 (93%) contributed data for the primary outcome. The proportion of children who were adequately sedated for ≥ 80% of the time was 21 of 61 (34.4%) - clonidine, and 18 of 59 (30.5%) - midazolam. The difference in proportions for clonidine-midazolam was 0.04 [95% confidence interval (CI) -0.13 to 0.21], and, with the 95% CI including values outside the range of equivalence (-0.15 to 0.15), equivalence was not demonstrated; however, the study was underpowered. Non-inferiority of clonidine to midazolam was established, with the only values outside the equivalence range favouring clonidine. Times to reach maximum sedation and analgesia were comparable hazard ratios: 0.99 (95% CI 0.53 to 1.82) and 1.18 (95% CI 0.49 to 2.86), respectively. Percentage time spent adequately sedated was similar [medians clonidine 73.8% vs. midazolam 72.8%: difference in medians 0.66 (95% CI -5.25 to 7.24)]. Treatment failure was 12 of 64 (18.8%) on clonidine and 7 of 61 (11.5%) on midazolam [risk ratio (RR) 1.63, 95% CI 0.69 to 3.88]. Proportions with withdrawal symptoms [28/60 (46.7%) vs. 30/58 (52.6%)] were similar (RR 0.89, 95% CI 0.62 to 1.28), but a greater proportion required clinical intervention in those receiving midazolam [11/60 (18.3%) vs. 16/58 (27.6%) (RR 0.66, 95% CI 0.34 to 1.31)]. Post treatment, one child on clonidine experienced mild rebound hypertension, not requiring intervention. A higher incidence of inotropic support during the first 12 hours was required for those on clonidine [clonidine 5/45 (11.1%) vs. midazolam 3/52 (5.8%)] (RR 1.93 95% CI 0.49 to 7.61). CONCLUSIONS: Clonidine is an alternative to midazolam. Our trial-based economic evaluation suggests that clonidine is likely to be a cost-effective sedative agent in the PICU in comparison with midazolam (probability of cost-effectiveness exceeds 50%). Rebound hypertension did not appear to be a significant problem with clonidine but, owing to its effects on heart rate, specific cardiovascular attention needs to be taken during the loading and early infusion phase. Neither drug in combination with morphine provided ideal sedation, suggesting that in unparalysed patients a third background agent is necessary. The disappointing recruitment rates reflect a reluctance of parents to provide consent when established on a sedation regimen, and reluctance of clinicians to allow sedation to be studied in unstable critically ill children. Future studies will require less exacting protocols allowing enhanced recruitment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02639863. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 71. See the NIHR Journals Library website for further project information.

A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and pharmacodynamic modeling and simulation.

BACKGROUND: A new benzodiazepine, remimazolam, which is rapidly metabolized by tissue esterases to an inactive metabolite, has been developed to permit a fast onset, a short, predictable duration of sedative action, and a more rapid recovery profile than currently available drugs. We report on modeling of the data and simulations of dosage regimens for future study. METHODS: A phase I, single-center, double-blind, placebo and active controlled, randomized, single-dose escalation study was conducted. Fifty-four healthy subjects in 9 groups received a single 1-minute IV infusion of remimazolam (0.01-0.3 mg/kg). There were 18 control subjects taking midazolam and 9 placebos. Population pharmacokinetic and pharmacodynamic modeling of the data was undertaken and the parameters obtained were used for Monte-Carlo simulations of alternative dosing regimens. RESULTS: A 4-compartment mammillary pharmacokinetic model of midazolam and a physiologically based recirculation model of remimazolam were fitted to the observed plasma levels. The recirculation model of remimazolam explained the observed high venous, compared with arterial, concentrations at later time points. The 2 models were used to simulate the arterial concentrations required for the pharmacodynamic models of sedation (Bispectral Index and Modified Observer's Assessment of Alertness/Sedation [MOAA/S]) and gave population mean pharmacodynamic parameters as follows: Bispectral Index-IC(50): 0.26, 0.07 µg/mL; γ: 1.6, 8.6; k(e0): 0.14, 0.053 min(-1); I(MAX): 39, 19, and MOAA/S-IC(50): 0.4, 0.08 µg/mL; γ: 1.4, 3.4; k(e0): 0.25, 0.050 min(-1) for remimazolam and midazolam, respectively. Simulations to obtain >70% of the population with MOAA/S scores of 2 to 4 were developed. This criterion was achieved (95% confidence intervals: 67%-74%) with a 6-mg initial loading dose of remimazolam followed by 3-mg maintenance doses at >2-minute intervals. Recovery to a MOAA/S score of 5 is predicted to be within 16 minutes for 89% (95% confidence intervals: 87%-91%) of the treated population after this loading/maintenance dose regimen. CONCLUSIONS: Population pharmacokinetic and pharmacodynamic models developed for remimazolam and midazolam fitted the observed data well. Simulations based on these models show that remimazolam delivers extremely rapid sedation, with maximal effect being reached within 3 minutes of the start of treatment. This property will enable maintenance doses to be given more accurately than with slower-acting drugs. No covariate effects considered to be clinically relevant were observed, suggesting that dosing by body weight may offer no advantage over fixed doses in terms of consistency of exposure to remimazolam within the weight range studied (65-90 kg).

Randomized controlled trial of interrupted versus continuous sedative infusions in ventilated children.

OBJECTIVE: To compare daily interruption vs. continuous sedative infusions in mechanically ventilated children with respect to lengths of mechanical ventilation and intensive care unit stay. DESIGN: Prospective randomized controlled trial. SETTING: Pediatric intensive care unit of a tertiary care teaching and referral hospital. PATIENTS: One hundred two patients mechanically ventilated for >48 hrs. INTERVENTIONS: Patients were randomized to receive either continuous (group 1) or interrupted (group 2) sedative infusion (midazolam bolus of 0.1 mg/kg, followed by infusion, to achieve a Ramsay score of 3-4). Each patient in group 2 had daily interruption of infusion at 8:00 AM till he/she became fully awake (response to verbal commands) or so agitated/uncomfortable that he/she needed restarting of infusion (whichever was earlier) at a dose 50% less than the previous dose. Primary outcome variables were the lengths of mechanical ventilation and intensive care unit stay, while the number and percentage of days awake on sedative infusions, frequency of adverse events, and total dose of sedatives required were the secondary outcome variables. MEASUREMENTS AND MAIN RESULTS: Of the 102 patients included in the study, 56 were randomized into the continuous sedation protocol and 46 into the interrupted sedation protocol. Both were statistically similar with respect to demography, primary diagnosis, severity of illness score (Pediatric Risk of Mortality I and III), indication for mechanical ventilation, and initial ventilatory variables except that the patients under the interrupted arm had lower peak inspiratory pressure and positive end-expiratory pressure requirements at the start of ventilation (p = .002 and p = .028, respectively). The mean (SD) length of mechanical ventilation in the interrupted sedation protocol was significantly less than that in the continuous sedation protocol (7.0 ± 4.8 days vs. 10.3 ± 8.4 days; p = .021). Similarly, the difference in the median duration of pediatric intensive care unit stay was significantly less in the interrupted sedation as compared to the continuous sedation protocol (10.7 days vs. 14.0 days; p = .048). The mean total dose of midazolam and the total calculated cost of midazolam in the former were significantly less compared to those of the latter (7.1 ± 4.7 mL vs. 10.9 ± 6.9 mL, p = .002; 4827 ± 5445 rupees vs. 13,865 ± 25,338 rupees, p = .020). The frequencies of adverse events in both the groups were however similar. CONCLUSION: The length of mechanical ventilation, duration of intensive care unit stay, total dose of midazolam, and average calculated cost of the therapy were significantly reduced in the interrupted as compared to the continuous group of sedation.

Efficacy of propofol sedation for endoscopic submucosal dissection (ESD): assessment with prospective data collection.

OBJECTIVE: The indications for endoscopic treatment in early stage cancer of the digestive tract are expanding with the emergence and technical development of endoscopic submucosal dissection (ESD). ESD requires longer term stable sedation than conventional endoscopic procedures due to the necessity of meticulous control of the devices during the procedure. Propofol has a very short half-life and can be administered continuously, which is advantageous for long-term sedation. Propofol, thus, is likely to be useful for sedation during ESD. METHODS: Fifty consecutive patients who underwent ESD for early gastric cancer with propofol sedation (Group P) and those with midazolam sedation (Group M) were included in this study. Cardiorespiratory suppression rate and the condition of arousal were compared between the groups. A questionnaire survey on the satisfaction of endoscopists, anesthesiologists, endoscopy nurses, and ward nurses with the use of propofol was also carried out. RESULTS: Respiratory suppression was observed in 50% in Group M and in 20% in Group P (p<0.05). Hypotension was seen in 14% and 36% in Groups M and P, respectively (p<0.05). No sedation-related complications were encountered in either of the groups. Arousal rates 1 hour and 3 hours after the procedure were 23% and 60% in group M and 86% and 100% in Group P (p<0.05). As for the questionnaire survey, most respondents, in particular the ward nurses, supported the use of propofol. CONCLUSION: Our data suggest that propofol is safe and useful during ESD as compared with midazolam.

Dreaming in sedation during spinal anesthesia: a comparison of propofol and midazolam infusion.

BACKGROUND: Although sedation is often performed during spinal anesthesia, the details of intraoperative dreaming have not been reported. We designed this prospective study to compare 2 different IV sedation protocols (propofol and midazolam infusion) with respect to dreaming during sedation. METHODS: Two hundred twenty adult patients were randomly assigned to 2 groups and received IV infusion of propofol or midazolam for deep sedation during spinal anesthesia. Patients were interviewed on emergence and 30 minutes later to determine the incidence, content, and nature of their dreams. Postoperatively, patient satisfaction with the sedation was also evaluated. RESULTS: Two hundred fifteen patients (108 and 107 in the propofol and midazolam groups, respectively) were included in the final analysis. The proportion of dreamers was 39.8% (43/108) in the propofol group and 12.1% (13/107) in the midazolam group (odds ratio=4.78; 95% confidence interval: 2.38 to 9.60). Dreams of the patients receiving propofol were more memorable and visually vivid than were those of the patients receiving midazolam infusion. The majority of dreams (36 of 56 dreamers, 64.3%) were simple, pleasant ruminations about everyday life. A similarly high level of satisfaction with the sedation was observed in both groups. CONCLUSIONS: In cases of spinal anesthesia with deep sedation, dreaming was almost 5 times more common in patients receiving propofol infusion than in those receiving midazolam, although this did not influence satisfaction with the sedation. Thus, one does not need to consider intraoperative dreaming when choosing propofol or midazolam as a sedative drug in patients undergoing spinal anesthesia.

Moderate sedation for echocardiography of preschoolers.

Preschoolers frequently require sedation for echocardiograms. This study compared various sedation drugs at the authors' institution, as well as the charges for moderate versus deep sedation. From 2001 to 2007, sedation was administered to 703 patients ages 2 to 4 years. Four drug regimens were used: chloral hydrate (CH), chloral hydrate with diphenhydramine (CH + D), chloral hydrate with hydroxyzine hydrochloride (CH + H), and midazolam. The mean onset of sedation was 37 min, and the mean duration of sedation was 47 min. The CH group fell asleep the most quickly (30 min; p < 0.001), and the CH + D patients experienced the most prolonged sedations (13%; p < 0.001). Studies were completed by 97% of the chloral hydrate group, 98% of the CH + D group, and 94% of the CH + H group compared with 66% of the midazolam group (p < 0.001). Complications (7.4%) were minor and not significant for any particular medication. The charges for moderate sedation averaged $709 compared with $3,628 for deep sedation. The findings demonstrated that chloral hydrate was the fastest-acting agent and had a high success rate with minimally prolonged sedations. The low complication rate for chloral hydrate, and the much lower cost for its use to induce moderate sedation have made chloral hydrate our preference for the echocardiographic sedation of preschoolers.

A cost-minimization analysis of dexmedetomidine compared with midazolam for long-term sedation in the intensive care unit.

OBJECTIVE: To compare the intensive care unit costs and determine factors influencing these costs in mechanically ventilated patients randomized to dexmedetomidine or midazolam by continuous infusion. DESIGN: Cost minimization analysis of a double-blind, multicenter clinical trial randomizing patients 2:1 to receive dexmedetomidine or midazolam from the institutional perspective. SETTING: Sixty-eight intensive care units in the United States, Australia, New Zealand, Brazil, and Argentina. PATIENTS: A total of 366 intubated intensive care unit patients anticipated to require sedation for >24 hrs. MEASUREMENTS AND MAIN RESULTS: Intensive care unit resource use was compared within the two treatment arms, using the U.S. representative costs for these resources. The analyses characterized patient costs from start of study drug until intensive care unit discharge including costs associated with the intensive care unit stay, costs during mechanical ventilation, study drug acquisition cost, and costs of treating adverse drug reactions probably or possibly related to study drugs. Blinded to treatment group, costs were calculated using Medicare reimbursement schedules, average IMS drug costs, expert opinion, and peer-reviewed literature. Censored lengths of intensive care unit stay and mechanical ventilation were imputed, using a nonparametric adjustment algorithm. Crude and multivariate median regressions were performed to relate intensive care unit cost and treatment. Including drug acquisition cost, sedation with dexmedetomidine was associated with a median total intensive care unit cost savings of $9679 (confidence interval, $2314-$17,045) compared with midazolam. The primary cost drivers were reduced costs of intensive care unit stay (median savings, $6584, 95% confidence interval, $727-$12,440) and reduced costs of mechanical ventilation (median savings, $2958, 95% confidence interval, $698-$5219). CONCLUSIONS: Continuous sedation with dexmedetomidine results in significantly lower total intensive care unit costs compared with midazolam infusion for intensive care unit sedation, primarily due to decreased intensive care unit stay costs and reduced mechanical ventilation costs.

Assessment of cardiac troponin I and C-reactive protein concentrations associated with anesthetic protocols using sevoflurane or a combination of fentanyl, midazolam, and sevoflurane in dogs.

OBJECTIVE: To report serum cardiac troponin I (cTnI) and C-reactive protein (CRP) concentrations in dogs anesthetized for elective surgery using two anesthetic protocols. STUDY DESIGN: Prospective, randomized clinical study. ANIMALS: Twenty client-owned dogs presenting for elective ovariohysterectomy or castration. METHODS: The dogs were randomized into two groups. All dogs were premedicated with glycopyrrolate (0.011 mg kg(-1)) and hydromorphone (0.1 mg kg(-1)) i.m. approximately 30 minutes prior to induction of anesthesia. Anesthesia in dogs in group 1 was induced with propofol (6 mg kg(-1)) i.v. to effect and in dogs in group 2 with diazepam (0.2 mg kg(-1)) i.v. followed by etomidate (2 mg kg(-1)) i.v. to effect. For maintenance of anesthesia, group 1 received sevoflurane (adjustable vaporizer setting 0.5-4%) and group 2 received a combination of fentanyl (0.8 microg kg(-1) minute(-1)) and midazolam (8.0 microg kg(-1) minute(-1)) i.v. plus sevoflurane (adjustable vaporizer setting 0.5-4%) to maintain anesthesia. Serum cTnI and CRP concentrations were measured at baseline and 6, 18, and 24 hours post-anesthetic induction. Biochemical analysis was performed at baseline. Lactate was obtained at baseline and 6 hours post-anesthetic induction. Heart rate and mean arterial blood pressure were measured intra-operatively. RESULTS: Baseline serum cTnI and CRP concentrations were comparable between groups. A significant difference in serum cTnI or CRP concentrations was not detected post-operatively between groups at any time point. Serum CRP concentrations were significantly increased post-anesthetic induction in both groups, which was attributed to surgical trauma. CONCLUSIONS AND CLINICAL RELEVANCE: There was no significant difference in serum cTnI and CRP concentrations between anesthetic protocols. Further investigation in a larger number of dogs is necessary to confirm the current findings.

Nurse-administered propofol sedation compared with midazolam and meperidine for EUS: a prospective, randomized trial.

BACKGROUND: The utility of nurse-administered propofol sedation (NAPS) compared with midazolam and meperidine (M/M) for EUS is not known. OBJECTIVE: To compare recovery times, costs, safety, health personnel, and patient satisfaction of NAPS and M/M for EUS. DESIGN: Prospective, randomized, single-blinded trial. SETTING: Tertiary-referral hospital in Indianapolis, Indiana. PATIENTS: Outpatients referred for EUS. INTERVENTIONS: Sedation with M/M or NAPS. The patient and recovery nurse were blinded; however, the sedating nurse, endoscopist, and recording research nurse were unblinded to the sedatives used. A capnography, in addition to standard monitoring, was used. A questionnaire and visual analog scale assessed patient, endoscopist, and sedating nurse satisfaction. MAIN OUTCOME MEASUREMENTS: Recovery times, costs, safety, health personnel, and patient satisfaction in both groups. RESULTS: Eighty consecutive patients were randomized to NAPS (n = 40) or M/M (n = 40). More patients in the propofol group were current tobacco users; patient demographics, procedures performed, mean procedure length, and the overall frequency of adverse events were otherwise similar. Compared with M/M, NAPS was associated with a faster induction of sedation (2.3 vs 5.7 minutes, respectively; P = .001) and full recovery time (29 vs 49 minutes, respectively; P = .001), higher postprocedure patient satisfaction, and quicker anticipated return to baseline function. At discharge, total costs (recovery plus medications) were similar between the propofol ($406) and M/M groups ($399; P = .79). LIMITATION: Low-risk patient population. CONCLUSIONS: Compared with M/M, NAPS for an EUS offered a faster sedation induction and full recovery time, higher postprocedure patient satisfaction, and a quicker anticipated return to baseline function. Total costs were similar between the groups.

Efficacy, safety, and cost effectiveness of intravenous midazolam and flunitrazepam for primary insomnia in terminally ill patients with cancer: a retrospective multicenter audit study.

BACKGROUND: Although intravenous midazolam and flunitrazepam are frequently administered for primary insomnia in Japan, there is no empirical study on their efficacy and safety. DESIGN AND SUBJECTS: To compare the efficacy, safety, and cost-effectiveness of midazolam and flunitrazepam, a multicenter retrospective audit study was performed on 104 and 59 patients receiving midazolam and flunitrazepam, respectively, from 18 certified palliative care units. RESULTS: Median administration periods were 6 days and 9 days for midazolam and flunitrazepam, respectively. The median initial and maximum doses were 10 mg per night and 18 mg per night for midazolam, and 2 mg per night and 2 mg per night for flunitrazepam, respectively. There were no significant differences in the efficacy (91% in the midazolam group versus 81% in the flunitrazepam group, p = 0.084), hangover effect (34% versus 19%, p = 0.094), delirium at night (12% versus 10%, p = 1.0) and delirium next morning (11% versus 15%, p = 0.33), treatment withdrawal (4.8% versus 1.7%, p = 0.41), and treatment-related death (0% versus 0%, p = 1.0). Flunitrazepam caused respiratory depression defined as physician or nurses records such as apnea, respiratory arrest, decreased respiratory rate, and respiratory depression significantly more frequently than midazolam (17% versus 3.8%, p = 0.0073). The maximum dose was more highly correlated with the administration period in the midazolam group than in the flunitrazepam group (rho = 0.52, versus rho = 0.39), and, for patients treated for 14 days or longer, the daily escalation dose ratio required for maintaining adequate sleep was significantly higher in the midazolam group than in the flunitrazepam group (11% versus 2.6%, p = 0.015). The costs of the initial and maximum administration were significantly higher in the midazolam group than in the flunitrazepam group (p < 0.001). CONCLUSION: Intravenous midazolam and flunitrazepam appeared to be almost equal about efficacy and safety for primary insomnia, but flunitrazepam is less expensive and shows lower risk of tolerance development. A future prospective comparison study is necessary.

Sedation in patients above 60 years of age undergoing urological surgery under spinal anesthesia: comparison of propofol and midazolam infusions.

CONTEXT: Propofol and midazolam are commonly used sedatives during regional anesthesia in adults. Smaller doses of these drugs are required in older age due to altered pharmacokinetics and pharmacodynamics. AIMS: To study the sedation, side-effects and the costs involved with smaller doses of propofol and midazolam in patients aged above 60 years during spinal anesthesia. SETTINGS AND DESIGN: A randomized single-blind study was conducted in 60 ASA I-II patients aged > or = 60 years undergoing urological surgery under spinal anesthesia. MATERIALS AND METHODS: Sedation was administered after spinal anesthesia using propofol (bolus 0.4 mg.kg -1; infusion 3 mg/kg/hr) or midazolam (bolus 0.02 mg/kg; infusion 0.06 mg.kg -1.h -1) and titrated to achieve a sedation score of 3 on the modified Observer's Assessment of Alertness/Sedation Scale. Perioperative sedation, hemodynamics and respiratory events were monitored. STATISTICAL ANALYSIS: The analysis for parametric data was done using Student's unpaired t test and the incidence data using Chi-square test. RESULTS: The onset (13.0+/-4.2 vs. 18.8+/-4.2 min, P < 0.001) and offset (8.9+/-2.8 vs. 12.5+/-3.5 min, P < 0.001) of sedation were faster and the duration of adequate sedation longer (44.7+/-12.5 vs. 29.8+/-12.9% of total infusion time, P < 0.001) with propofol than midazolam. More patients receiving propofol compared to midazolam had hypotension (16 [50%] vs.4 [14.3%], P= 0.003). Airway obstruction occurred frequently in both the groups. Sedation was significantly more expensive with propofol than midazolam (US$ 9.83 +/- 2.80 vs. US$ 0.33 +/- 0.06, P 0.001). CONCLUSIONS: Propofol provided better titration and adequacy of sedation than midazolam in patients above 60 years of age, but caused hypotension. Lighter sedation is recommended in this age group.