Quantitative T2 mapping-based longitudinal assessment of brain injury and therapeutic rescue in the rat following acute organophosphate intoxication.

Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T2 measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T2 values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T2 values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T2 characteristics. This study supports the utility of T2 mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication.

Assessment of sedation after intranasal administration of midazolam and midazolam-butorphanol in cockatiels (Nymphicus hollandicus).

OBJECTIVE To compare sedation in cockatiels (Nymphicus hollandicus) after intranasal administration of midazolam and midazolam-butorphanol. ANIMALS 9 healthy adult cockatiels. PROCEDURES A randomized, controlled, blinded, complete crossover study was conducted. Birds were assigned to 3 treatment groups. Midazolam (3 mg/kg), midazolam-butorphanol (3 mg/kg for each drug), or sterile saline (0.9% NaCl) solution (control treatment) was administered intranasally. Sedation quality was assessed at 3 time points by use of eye and body position; response to visual, auditory, and tactile stimulation; and response during manual restraint on the basis of eye position and struggling intensity. To evaluate attenuation of the manual restraint-induced stress response, heart rate, respiratory rate, and cloacal temperature were measured over a 15-minute period. Treatments were repeated after a minimum washout period of 7 days. RESULTS Median onset of first sedation effects was 85 seconds (range, 60 to 120 seconds) for midazolam and 90 seconds (range, 45 to 180 seconds) for midazolam-butorphanol. Midazolam-butorphanol resulted in significantly less vigorous struggling during restraint than did midazolam or the control treatment. Heart rate did not differ significantly among treatments. The stress-induced increase in respiratory rate was significantly attenuated by midazolam and midazolam-butorphanol, whereas the increase in cloacal temperature was not attenuated by midazolam or midazolam-butorphanol. CONCLUSIONS AND CLINICAL RELEVANCE Intranasal administration of midazolam and midazolam-butorphanol resulted in a rapid onset of sedation in cockatiels. Midazolam-butorphanol resulted in deeper sedation in both restrained and unrestrained birds than did midazolam alone. Midazolam and midazolam-butorphanol both provided safe and effective sedation in cockatiels.

Strategy for CYP3A Induction Risk Assessment from Preclinical Signal to Human: a Case Example of a Late-Stage Discovery Compound.

PURPOSE: The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of in vitro induction data to in vivo findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose. METHODS: Pharmacokinetic and induction potency (in vitro and in vivo) of G2917 in monkeys, and the in vitro human induction potency were studied. The hepatic CYP3A biomarkers 4ß-hydroxycholesterol (4ß-HC) and 6ß-hydroxycortisol/cortisol ratio (6ß-OHC/C) were monitored in in vivo studies. The static mechanistic model was used to quantitatively understand the in vitro-in vivo extrapolation (IVIVE) on the magnitude of induction retrospectively. Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and induction-based drug-drug interactions (DDI). RESULTS: All in vitro and in vivo data indicate that the significant reduction in exposure of G2917 in monkeys is caused by auto-induction of CYP3A. The mechanistic understanding of IVIVE of G2917 induction in monkey provides higher confidence in the induction risk prediction in human using the PBPK modeling. PBPK model analysis predicted minimum auto-induction and DDI liability in humans at the predicted efficacious dose. CONCLUSIONS: The learning of this example provided a strategy to address the human CYP3A induction risk prospectively when there is an auto-induction finding in preclinical toxicology study.

Reinforcing effectiveness of midazolam, ethanol, and sucrose: behavioral economic comparison of a mixture relative to its component solutions.

Benzodiazepines (BZs) are relatively safe when administered alone. However, these drugs can produce severe side effects when coadministered with ethanol. Despite these adverse consequences, rates of concurrent BZ and ethanol misuse are increasing, and it is unclear whether this behavior is maintained by an enhanced reinforcing effect of the mixture. To address this issue, the current study compared the reinforcing effectiveness of sucrose solutions mixed with midazolam, ethanol, or both. Eight male rats were trained to orally self-administer solutions of either sucrose (S), sucrose+midazolam (SM), sucrose+ethanol (SE), or sucrose+midazolam+ethanol (SME). The response requirement was increased between sessions until the number of reinforcers earned was zero and the relationship between response requirement and reinforcers earned was analyzed using the exponential model of demand. Although baseline intake was similar across drug conditions, consumption of SM was least affected by increases in cost, indicating that it possessed the highest reinforcing effectiveness (i.e. least elastic). The reinforcing effectiveness of S, SE, and SME did not differ significantly. The finding that the reinforcing effectiveness of the SME was less than that of SM does not support the supposition that BZ and ethanol coadministration is maintained by a higher reinforcing effectiveness of the mixture.

Preliminary assessment of midazolam, fentanyl and fluanisone combination for the sedation of rhesus macaques ( Macaca mulatta).

This study was undertaken to assess the suitability of fentanyl/fluanisone ('Hypnorm', VetaPharma; 0.315 mg/mL of fentanyl citrate and 10 mg/mL of fluanisone) alone or combined with midazolam in rhesus macaques. Fifteen rhesus macaques requiring sedation for veterinary procedures received an intramuscular (IM) dose range of Hypnorm from 0.01 mL/kg to 0.3 mL/kg either alone or combined with 0.5 mg/kg of midazolam. To reverse the sedation, flumazenil in combination with either naloxone, buprenorphine or butorphanol was administered intravenously (IV) or IM. Rhesus macaques were successfully sedated with 0.1 mL/kg of Hypnorm and 0.5 mg/kg of midazolam, and sedation was partially reversed by the administration of flumazenil and either naloxone or buprenorphine. However the primates remained slightly sedated and were only released into their home cage several hours post recovery. Butorphanol failed to induce recovery and caused marked respiratory depression. The neuroleptanalgesic combination, Hypnorm and midazolam, effectively immobilized rhesus macaques and was reversible with a combination of flumazenil and either naloxone or buprenorphine.

Evaluation of various static in vitro-in vivo extrapolation models for risk assessment of the CYP3A inhibition potential of an investigational drug.

Nine static models (seven basic and two mechanistic) and their respective cutoff values used for predicting cytochrome P450 3A (CYP3A) inhibition, as recommended by the US Food and Drug Administration and the European Medicines Agency, were evaluated using data from 119 clinical studies with orally administered midazolam as a substrate. Positive predictive error (PPE) and negative predictive error (NPE) rates were used to assess model performance, based on a cutoff of 1.25-fold change in midazolam area under the curve (AUC) by inhibitor. For reversible inhibition, basic models using total or unbound systemic inhibitor concentration [I] had high NPE rates (46-47%), whereas those using intestinal luminal ([I]gut) values had no NPE but a higher PPE. All basic models for time-dependent inhibition had no NPE and reasonable PPE rates (15-18%). Mechanistic static models that incorporate all interaction mechanisms and organ specific [I] values (enterocyte and hepatic inlet) provided a higher predictive precision, a slightly increased NPE, and a reasonable PPE. Various cutoffs for predicting the likelihood of CYP3A inhibition were evaluated for mechanistic models, and a cutoff of 1.25-fold change in midazolam AUC appears appropriate.

Using MRI for the assessment of paraoxon-induced brain damage and efficacy of antidotal treatment.

Organophosphate intoxication induces neural toxicity as demonstrated in histological analysis of poisoned animals. Diffusion-weighted magnetic resonance imaging (DWMRI) enables early noninvasive characterization of biological tissues based on their water diffusion characteristics. Our objectives were to study the application of MRI for assessment of paraoxon-induced brain damage and the efficacy of antidotal treatments. Seventy-six rats were poisoned with paraoxon followed by treatment with atropine and obidoxime. The rats were then divided into five treatment groups consisting of midazolam after 1 or 30 min, scopolamine after 1 or 30 min and a no anticonvulsant treatment group. Five untreated rats served as controls. Animals underwent MRI on days 1, 8, 15, 29 and 50 post poisoning. Histological evaluation was performed on representative rat brains. Acute DWMRI effects, such as enhancement of temporal brain regions, and chronic effects such as ventricular enlargement and brain atrophy, depicted on T2-weighted MRI, were significantly more prominent in late anticonvulsant treatment groups. There was no significant difference between the neuroprotective effects of midazolam and scopolamine as shown by DWMRI. Early MRI abnormalities were found to correlate significantly with histological analysis of samples obtained 15 days post treatment. In conclusion, our results demonstrate the feasibility of using DWMRI for depiction of early cytotoxic response to paraoxon and T2-weighted MRI for later changes, thus enabling assessment of early/late brain damage as well as treatment efficacy in rats. The ability to depict these changes early and noninvasively may be applied clinically in the acute phase of organophosphate poisoning.

Direct assessment of the antioxidant properties of midazolam by electron spin resonance spectroscopy.

Some antioxidant anesthetics directly inhibit lipid peroxidation mediated via the generation of reactive oxygen species (ROS). To date, the scavenging effects of midazolam on ROS have not been directly assessed. We investigated the inhibitory effect of midazolam on ROS [hydroxyl radical (HO(·)) and superoxide (O (2) (·-) )] by in vitro X-band electron spin resonance with the spin-trapping agent 5,5-dimethyl-1-pyrroline-N-oxide. Our results indicated that HO(·) and O (2) (·-) were not affected by midazolam at clinically relevant concentrations, but were directly scavenged by midazolam at high concentrations (i.e., >4.6 and >1.5 mM, respectively).

[Assessment of efficacy of hypertonic saline - hydroxyethylstarch in haemorrhagic shock]. / Intérêt du mélange sérum salé hypertonique-hydroxyéthylamidon lors du choc hémorragique.

OBJECTIVE: Assessment of haemodynamic, respiratory and renal effects of hypertonic saline-hydroxyethyl starch (HyperHES) in critically ill-patients with hemorrhagic shock. PATIENTS AND METHODS: Seventeen mechanically ventilated patients with hemorragic shock benefiting from a cardiovascular monitoring by PiCCO device and requiring rapid volume loading. Two hundred and fifty milliliters of HyperHES were given over 5 minutes. The efficacy of volume loading was assessed by the measure of the systolic arterial pressure (SAP), cardiac index (CI), stroke volume variation (SVV) and the indexed systemic vascular resistance (iSVR). Studied parameters were assessed at baseline, 5, 30, 60 and 180 minutes after the end of HyperHES infusion. RESULTS: SAP (105 + or - 23 vs 77 + or - 10; p<0.001) and CI (4.8 + or - 1.1 vs 3.5 + or - 0.9; p<0.001) were significantly increased whereas iSVR (1175 + or - 310 vs 1501 + or - 337; p<0.01) and SVV (13 + or - 7 vs 20 + or - 5; p<0.01) were significantly decreased 5 minutes after the HyperHES infusion. Sodium (145 + or - 6 vs 136 + or - 5; p<0.001) and chloride (118 + or - 7 vs 107 + or - 6; p<0.001) were increased 5 minutes after the infusion. The PaO(2)/FiO(2) ratio as the extravascular lung water was not influenced by the infusion. The follow-up of renal parameters during the three first days (creatinemia, uremia and diuresis) did not revelead significant variations. CONCLUSION: In patients with hemorrhagic shock, the infusion of hypertonic saline (7.5%) hydroxyethyl starch association was followed by an increase in SAP, CI serum sodium and chloride concentrations. STUDY DESIGN: Prospective observational study.

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.

Combining MCMC with 'sequential' PKPD modelling.

We introduce a method for preventing unwanted feedback in Bayesian PKPD link models. We illustrate the approach using a simple example on a single individual, and subsequently demonstrate the ease with which it can be applied to more general settings. In particular, we look at the three 'sequential' population PKPD models examined by Zhang et al. (J Pharmacokinet Pharmacodyn 30:387-404, 2003; J Pharmacokinet Pharmacodyn 30:405-416, 2003), and provide graphical representations of these models to elucidate their structure. An important feature of our approach is that it allows uncertainty regarding the PK parameters to propagate through to inferences on the PD parameters. This is in contrast to standard two-stage approaches whereby 'plug-in' point estimates for either the population or the individual-specific PK parameters are required.

Assessment of the CYP3A-mediated drug interaction potential of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy volunteers.

In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.

Assessment of brachial plexus blockade in chickens by an axillary approach.

OBJECTIVE: To assess the brachial plexus block in chickens by an axillary approach and using a peripheral nerve stimulator. STUDY DESIGN: Prospective, randomized, double-blinded study. ANIMALS: Six, 84-week old, female chickens. METHODS: Midazolam (1 mg kg(-1)) and butorphanol (1 mg kg(-1)) were administered into the pectoralis muscle. Fifteen minutes later, the birds were positioned in lateral recumbency and following palpation of the anatomic landmarks, a catheter was inserted using an axillary approach to the brachial plexus. Lidocaine or bupivacaine (1 mL kg(-1)) was injected after plexus localization by the nerve stimulator. Sensory function was tested before and after blockade (carpus, radius/ulna, humerus and pectoralis muscle) in the blocked and unblocked wings. The latency to onset of motor and sensory block and the duration of sensory block were recorded. A Friedman nonparametric one-way repeated-measures ANOVA was used to compare scores from baseline values over time and to compare the differences between wings at each time point. RESULTS: A total of 18 blocks were performed with a success rate of 66.6% (12/18). The latency for motor block was 2.8 +/- 1.1 and 3.2 +/- 0.4 minutes for lidocaine and bupivacaine, respectively. The latencies for and durations of the sensory block were 6.0 +/- 2.5 and 64.0 +/- 18.0 and 7.8 +/- 5.8 and 91.6 +/- 61.7 minutes for lidocaine and bupivacaine, respectively. There was no statistical difference between these times for lidocaine or bupivacaine. Sensory function was not abolished in nonblocked wings. CONCLUSIONS AND CLINICAL RELEVANCE: The brachial plexus block was an easy technique to perform but had a high failure rate. It might be useful for providing anesthesia or postoperative analgesia of the wing in chickens and exotic avian species that have similar wing anatomy.

Development of an in vitro drug-drug interaction assay to simultaneously monitor five cytochrome P450 isoforms and performance assessment using drug library compounds.

INTRODUCTION: Inhibition of cytochrome P450 (CYP) is a principal mechanism for metabolism-based drug-drug interactions (DDIs). This article describes a robust, high-throughput CYP-mediated DDI assay using a cocktail of 5 clinically relevant probe substrates with quantification by liquid chromatography/tandem mass spectrometry (LC/MS-MS). METHODS: The assay consisted of human liver microsomes and a cocktail of probe substrates metabolized by the five major CYP isoforms (tacrine for CYP1A2, diclofenac for CYP2C9, (S)-mephenytoin for CYP2C19, dextromethorphan for CYP2D6 and midazolam for CYP3A4). The assay was fully automated in both 96- and 384-well formats. RESULTS: A series of experiments were conducted to define the optimal kinetic parameters and solvent concentrations, as well as, to assess potential reactant and product interference. The assay was validated against known CYP inhibitors (miconazole, sulfaphenazole, ticlopidine, quinidine, ketoconazole, itraconazole, fluoxetine) and evaluated in a screening environment by testing 9494 compounds. DISCUSSION: Our findings show that this assay has application in early stage drug discovery to economically, reliably and accurately assess compounds for DDIs.

Assessment of GABAA benzodiazepine receptor (GBzR) sensitivity in patients with alcohol dependence.

AIM: The aim of this study was to measure GABAA benzodiazepine receptor (GBzR) sensitivity in alcohol-dependent patients and compare with matched non-dependent drinkers. METHODS: Nine abstinent alcohol-dependent male patients, age matched with nine male non-dependent social drinkers, received an intravenous infusion of midazolam. Objective (saccadic eye movement slowing) and subjective (visual analogue scales) measurements were recorded at 15-min intervals for 2 h. RESULTS: There were no differences in objective or subjective measures. CONCLUSIONS: Our hypothesis that patients with alcohol dependence would have less slowing of their eye movements in response to this challenge, reflecting reduced GBzR sensitivity, was not confirmed. The reasons for this could mean that GBzR function returns to normal with abstinence, or that this paradigm is unable to measure the subtle subtype-specific changes in GBzR sensitivity that occur following dependent alcohol use.

Comparison of the effect of protocol-directed sedation with propofol vs. midazolam by nurses in intensive care: efficacy, haemodynamic stability and patient satisfaction.

AIM: The aim of this study was to compare the effect of protocol-directed sedation propofol vs. midazolam by nurses in intensive care on efficacy, haemodynamic stability and patient satisfaction. BACKGROUND: Protocols represent one method potentially to reduce treatment delays and ensure that medical care is administered in a standardised manner. Propofol and midazolam are often used for sedation in intensive care units. METHOD: A randomised, prospective cohort study and data were collected in 2003. The subjects were randomised either into propofol (n = 32) or into midazolam (n = 28) group. Efficacy of sedation, haemodynamic stability, pulse oximetry saturation, Acute Physiology and Chronic Health Evaluation II (APACHE II score), weaning time from mechanical ventilation, duration of mechanical ventilation, length of stay at intensive care unit, sedative drugs cost and patient satisfaction were measured. RESULTS: The nursing staff were able to maintain patients at Ramsay sedation scale (RSS) 3-4 during the sedative period. The efficacy of sedation was 74.2% and 66.9% of time in propofol and midazolam group respectively. Both sedatives reduced the arterial blood pressure and heart rate, but did not alter haemodynamic stability. The mean score of satisfactory sedation was not significantly different between the two groups (propofol: 11.4 SEM 0.2 vs. midazolam: 11.5 SEM 0.7). CONCLUSION: Protocol-directed sedation with propofol vs. midazolam by nurses were similar in quality during the sedative period. Relevance to clinical practice. This sedation practice for titration of propofol and midazolam by nurses was of similar quality and able to achieve an appropriate depth of sedation during the sedative period. Furthermore, they should provide care for patients' needs during the sedative period.

[Pharmacoeconomical grounds for decision on a basic hypnotic for general anesthesia in surgical interventions].

A comparative pharmacoeconomical analysis of basic hypnotics has been made in 127 patients based on an assessment of quality of anesthesia using standard scales. The data obtained show the use of propofol and a combination propofol-midazolam to be expedient. These medicines give reliably better results than using propofol-H20, sodium thiopental, and a combination of thiopental with droperidol.

Sedation in the intensive care unit with remifentanil/propofol versus midazolam/fentanyl: a randomised, open-label, pharmacoeconomic trial.

INTRODUCTION: Remifentanil is an opioid with a unique pharmacokinetic profile. Its organ-independent elimination and short context-sensitive half time of 3 to 4 minutes lead to a highly predictable offset of action. We tested the hypothesis that with an analgesia-based sedation regimen with remifentanil and propofol, patients after cardiac surgery reach predefined criteria for discharge from the intensive care unit (ICU) sooner, resulting in shorter duration of time spent in the ICU, compared to a conventional regimen consisting of midazolam and fentanyl. In addition, the two regimens were compared regarding their costs. METHODS: In this prospective, open-label, randomised, single-centre study, a total of 80 patients (18 to 75 years old), who had undergone cardiac surgery, were postoperatively assigned to one of two treatment regimens for sedation in the ICU for 12 to 72 hours. Patients in the remifentanil/propofol group received remifentanil (6- max. 60 microg kg(-1) h(-1); dose exceeds recommended labelling). Propofol (0.5 to 4.0 mg kg(-1) h(-1)) was supplemented only in the case of insufficient sedation at maximal remifentanil dose. Patients in the midazolam/fentanyl group received midazolam (0.02 to 0.2 mg kg(-1) h(-1)) and fentanyl (1.0 to 7.0 microg kg(-1) h(-1)). For treatment of pain after extubation, both groups received morphine and/or non-opioid analgesics. RESULTS: The time intervals (mean values +/- standard deviation) from arrival at the ICU until extubation (20.7 +/- 5.2 hours versus 24.2 h +/- 7.0 hours) and from arrival until eligible discharge from the ICU (46.1 +/- 22.0 hours versus 62.4 +/- 27.2 hours) were significantly (p < 0.05) shorter in the remifentanil/propofol group. Overall costs of the ICU stay per patient were equal (approximately euro1,700 on average). CONCLUSION: Compared with midazolam/fentanyl, a remifentanil-based regimen for analgesia and sedation supplemented with propofol significantly reduced the time on mechanical ventilation and allowed earlier discharge from the ICU, at equal overall costs.

Pharmacological assessment of the freezing, antinociception, and exploratory behavior organized in the ventrolateral periaqueductal gray.

Opioid and serotonergic mechanisms of the ventrolateral periaqueductal gray (vlPAG) are recruited by conditioned freezing and antinociception. However, it is unclear whether freezing and antinociception induced by stimulation of the vlPAG are interrelated. To address this issue we looked at the effects of the opioid antagonist naltrexone, the 5-HT2 antagonist ketanserin, and the benzodiazepine agonist midazolam injected into the vlPAG on the freezing and antinociception induced by electrical stimulation of this region. This antinociception was evaluated by the tail-flick and formalin tests. To further characterize the involvement of the vlPAG in unconditioned fear, the effects of intra-vlPAG injections of midazolam on the exploratory behavior were also assessed in independent groups of rats submitted to the elevated plus-maze test (EPM). The data obtained showed that: (i) electrical stimulation of the vlPAG causes freezing blocked by midazolam but not by naltrexone and ketanserin; (ii) antinociception generated at the level of the vlPAG is inhibited by naltrexone, ketanserin, and midazolam; (iii) activation of benzodiazepine-mediated mechanisms in the vlPAG increased the exploratory behavior of rats in the closed arms but not the avoidance behavior of open arms of the EPM. Thus, freezing and antinociception generated in the vlPAG are dissociated pharmacologically. Whereas antinociception is a multimediated process sensitive to naltrexone, ketanserin, and midazolam, the freezing induced by vlPAG stimulation was reversed only by the benzodiazepine compound. As injections of midazolam into the vlPAG do not cause anxiolytic effects in the EPM, the aversive stimuli inherent of this test seem to bypass the vlPAG.

Pharmacoeconomic modeling of lorazepam, midazolam, and propofol for continuous sedation in critically ill patients.

STUDY OBJECTIVE: To compare the expected costs of short-, intermediate-, and long-term sedation (< 24, 24-72, and > 72 hrs, respectively) with propofol, lorazepam, and midazolam in an intensive care unit. METHODS: Decision-analysis models were constructed for each sedative and each duration by using institutional costs associated with drug administration and adverse events (including personnel time). Costs were expressed in 2002 U.S. dollars. Adverse events were agitation, hypertriglyceridemia and/or pancreatitis, hypotension, nutritional changes, ventilator-associated pneumonia, and prolonged awakening and/or extubation. MEDLINE and EMBASE databases were searched to obtain durations of sedation, the incidence of outcomes, and cost estimates of outcomes. The ability to maintain specific levels of sedation was assumed equivalent among the sedatives. Univariate sensitivity analyses were conducted to determine the cost-driving variables, and probabilistic sensitivity analyses were conducted by using second-order Monte Carlo simulations. RESULTS: Weighted mean durations of sedation from 50 studies were 13.46 (short term), 45.27 (intermediate term), and 119.78 (long term) hours. Expected costs for sedation with lorazepam, midazolam, and propofol, respectively, were 497 dollars, 294 dollars, and 272 dollars short term; 932 dollars, 587 dollars, and 674 dollars intermediate term; and 1604 dollars, 1737 dollars, and 2033 dollars long term. Propofol was least costly in 86% of the short-term simulations, midazolam was least costly in 97.5% of the intermediate-term simulations, and lorazepam was least costly in 84% of the long-term simulations. The most important cost-driver for all sedatives was drug cost. Prolonged extubation after sedation was an important cost-driver for lorazepam and midazolam, especially as sedation was lengthened. CONCLUSION: Propofol, midazolam, and lorazepam had the lowest expected costs for short-, intermediate-, and long-term sedation, respectively. Many factors aside from drug costs influenced the cost of sedation.