Abstract:
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).
journal_name
Anesth Analgjournal_title
Anesthesia and analgesiaauthors
Wiltshire HR,Kilpatrick GJ,Tilbrook GS,Borkett KMdoi
10.1213/ANE.0b013e318241f68asubject
Has Abstractpub_date
2012-08-01 00:00:00pages
284-96issue
2eissn
0003-2999issn
1526-7598pii
ANE.0b013e318241f68ajournal_volume
115pub_type
杂志文章,随机对照试验abstract::In addition to offering further data on the exposure of surgical and recovery-room personnel to low levels of halothane in room air, the authors demonstrate the presence of halothane levels in the blood of some surgical patients managed by other inhalation agents from machines previously used for halothane. The author...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/00000539-197507000-00010
更新日期:1975-07-01 00:00:00
abstract::Waste anesthetic gas scavenging technology has not changed appreciably in the past 30 years. Open reservoir systems entrain high volumes of room air and dilute waste gases before emission into the atmosphere. This process requires a large vacuum pump, which is both costly to install and, although efficient, operates c...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/ANE.0b013e31822c9a2c
更新日期:2011-11-01 00:00:00
abstract::In this study we investigated the effects of a racemic mixture of bupivacaine (RS(+/-)bupivacaine) and its isomers (S(-)bupivacaine and R(+)bupivacaine) on the Ca2+ handling by ventricular myocytes from Wistar rats. Single ventricular myocytes were enzymatically isolated and loaded with the fluorescent Ca2+ indicator ...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/01.ane.0000195341.65260.87
更新日期:2006-03-01 00:00:00
abstract:BACKGROUND:Given the controversy regarding the use of droperidol and the high cost of the 5-HT3 antagonists, a cost-effective alternative for routine use as a prophylactic antiemetic would be desirable. We designed two parallel, randomized, double-blind sham and placebo-controlled studies to compare the early and late ...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章,随机对照试验
doi:10.1213/01.ane.0000250364.91567.72
更新日期:2007-01-01 00:00:00
abstract::Rapid sequence induction and intubation (RSII) and awake tracheal intubation are commonly used anesthetic techniques in patients at risk of pulmonary aspiration of gastric or esophageal contents. Some of these patients may have a gastric tube (GT) placed preoperatively. Currently, there are no guidelines regarding whi...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章,评审
doi:10.1213/ANE.0b013e3182917f11
更新日期:2014-03-01 00:00:00
abstract:INTRODUCTION:The preoperative encounter may offer a cost-effective opportunity for diabetes screening. METHODS:Three hundred forty-seven fasting patients had a preoperative glucose measurement determined from blood residue left on the IV needle, measured with an Accu-Chek glucometer (Roche Diagnostics, Indianapolis, I...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/ANE.0b013e3181b7c626
更新日期:2009-11-01 00:00:00
abstract::Computer-based measuring of the level of sedation and hypnosis is difficult and has proven to be challenging. The electroencephalogram (EEG) has been proposed as a potential method. Response entropy (RE) and state entropy (SE) are multifactor, dimensionless parameters of a new technology of EEG monitoring, and we inve...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章,随机对照试验
doi:10.1213/01.ane.0000217188.71710.47
更新日期:2006-06-01 00:00:00
abstract:BACKGROUND:Operating rooms contribute significantly to the increasing volumes and costs of hospital waste. Little is known, however, about doctors' views of hospital waste recycling despite their potential influence in improving recycling programs. We surveyed the waste recycling views held by anesthesiologists in Aust...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/ANE.0b013e31824d273d
更新日期:2012-05-01 00:00:00
abstract::Alfentanil, a short-acting lipophilic opioid, is used for labor analgesia and cesarean section and may cause neonatal depression. However, direct placental alfentanil transfer has not been studied. We measured placental alfentanil transfer and uptake during in vitro perfusion. Placenta lobules from healthy parturients...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/00000539-199412000-00011
更新日期:1994-12-01 00:00:00
abstract:UNLABELLED:The sciatic nerve (SN) originates from the L4-S3 roots in the form of two nerve trunks: the tibial nerve (TN) and the common peroneal nerve (CPN). The TN and CPN are encompassed by a single epineural sheath and eventually separate (divide) in the popliteal fossa. This division of the SN occurs at a variable ...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1097/00000539-200101000-00041
更新日期:2001-01-01 00:00:00
abstract::The performance of five of the most commonly used halothane vaporizers and three enflurane vaporizers was tested under conditions encountered in low-flow and closed-circuit anesthesia. Anesthetic gas concentrations were measured continuously with a mass spectrometer connected to a circle system. The results indicated ...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:
更新日期:1980-05-01 00:00:00
abstract::The low solubility of sevoflurane in blood suggests that this agent should enter and leave the body more rapidly than isoflurane. However, the closeness of sevoflurane and isoflurane tissue/blood partition coefficients suggests that the rates of equilibration with and elimination from tissues should be similar. We tes...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/00000539-199103000-00007
更新日期:1991-03-01 00:00:00
abstract:BACKGROUND:Paravertebral analgesia is useful for breast surgery. Patient controlled analgesia by IV or epidural routes is well established for delivering postoperative analgesia. Our objective was to apply patient control to paravertebral analgesia and evaluate the efficacy and tolerability of two distinct dosing regim...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章,随机对照试验
doi:10.1213/ane.0b013e31817b7f01
更新日期:2008-08-01 00:00:00
abstract::Acute peripheral neuropathic pain after combat-related polytrauma is a common occurrence in the United States military that is often refractory to current drugs and regional anesthesia. Both spinal cord and peripheral nerve stimulation are successfully used for chronic neuropathic pain states, but are not reported for...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/ANE.0b013e318247f6b2
更新日期:2012-04-01 00:00:00
abstract:BACKGROUND:In this study, we hypothesized that leg positioning and distal tourniquet application, when compared with neutral positioning of the leg, alters the efficacy of sciatic nerve block performed by the double-stimulation technique. METHODS:Ninety randomized, consecutive, ASA physical status I to III patients un...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章,随机对照试验
doi:10.1213/ANE.0b013e31822f8b99
更新日期:2011-12-01 00:00:00
abstract::Transesophageal echocardiography (TEE) is increasingly used intraoperatively as a monitor of ventricular function and volume. Despite its increasing use, whether data from TEE monitoring can be interpreted accurately on-line in real-time is unknown. We studied the performance of five community-based, full-time cardiac...
journal_title:Anesthesia and analgesia
pub_type: 临床试验,杂志文章
doi:10.1097/00000539-199606000-00006
更新日期:1996-06-01 00:00:00
abstract:BACKGROUND:Many clinical pain states that are difficult to treat share a common feature of sensitization of nociceptive pathways. Drugs that could normalize hyperexcitable neural activity (e.g., antiepileptic drugs) may be useful in relieving these pain states. Eslicarbazepine acetate (ESL) is a novel antiepileptic dru...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/ANE.0000000000000953
更新日期:2015-12-01 00:00:00
abstract:UNLABELLED:In this study, we sought to determine the minimum analgesic doses and relative potencies of fentanyl and sufentanil when they are used as the sole epidural analgesic during the first stage of labor. Nulliparous parturients (n = 66) in spontaneous labor at term gestation and requesting epidural analgesia were...
journal_title:Anesthesia and analgesia
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1213/01.ane.0000054003.03645.cf
更新日期:2003-04-01 00:00:00
abstract:BACKGROUND:Ten to fifteen percent of awake patients develop neurological deficits secondary to cerebral hypoperfusion after carotid artery cross-clamping. The reversal of such deficits by increasing the inspired oxygen fraction (Fio(2)) has been demonstrated, and regional cerebral oxygenation (rSO(2)) has been shown to...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/ANE.0b013e3181c5f160
更新日期:2010-02-01 00:00:00
abstract:BACKGROUND:Calmodulin (CaM) activation by Ca(2+), its translocation to the nucleus, and stimulation of phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) (P-CREB) are necessary for new gene expression and have been linked to long-term potentiation, a process important in memory fo...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/ANE.0b013e3181b5a1b8
更新日期:2009-10-01 00:00:00
abstract:BACKGROUND:Xenon has many characteristics that make it very attractive as an anesthetic and therapeutic drug. Unfortunately, the supply of xenon is fixed, and therefore reclamation and recovery from even the most efficient breathing circuits is desirable. We built and evaluated a cryogenic device to recover xenon from ...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/01.ane.0000278148.56305.72
更新日期:2007-11-01 00:00:00
abstract::Using a standardized technique, spinal anesthesia was induced in 50 term parturients to study the correlation between patient height, weight, and body mass index (BMI) and the spread of sensory blockade. All patients received 12 mg hyperbaric bupivacaine while in the right lateral decubitus position on a horizontal op...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:
更新日期:1988-06-01 00:00:00
abstract::We evaluated empirically the extent to which the use of a cognitive aid during a high-fidelity simulation of a malignant hyperthermia (MH) event facilitated the correct and prompt treatment of MH. We reviewed the management of 48 simulated adult MH scenarios; 24 involving CA 1 and 24 involving CA 2 residents. In the C...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/01.ane.0000229718.02478.c4
更新日期:2006-09-01 00:00:00
abstract::This study evaluated the role of nitric oxide (NO) in spinal cord nociceptive transmission during peripheral inflammation evoked by formalin injection into the rat paw, using N omega-nitro-L-arginine (N-Arg), an NO synthase inhibitor. Male rats were prepared with intrathecal (IT) catheters. To quantify the formalin re...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/00000539-199311000-00003
更新日期:1993-11-01 00:00:00
abstract:UNLABELLED:Percutaneous needle liver biopsy is an important procedure for the diagnosis and evaluation of liver disease and is frequently associated with pain. In this prospective study, we investigated the prevalence and characteristics of this pain syndrome. Fifty-four subjects, who underwent liver biopsy under ultra...
journal_title:Anesthesia and analgesia
pub_type: 临床试验,杂志文章
doi:10.1213/01.ane.0000060453.74744.17
更新日期:2003-05-01 00:00:00
abstract::The effects of anesthetics on intracranial pressure (ICP) may be different in preterm neonates than in adults because the neonate's cranial sutures are not yet fused. The authors monitored changes in anterior fontanel pressure (AFP), a noninvasive indicator of ICP, during anesthesia in 44 preterm neonates without neur...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/00000539-198705000-00011
更新日期:1987-05-01 00:00:00
abstract:IMPLICATIONS:Chronic hiccups may be a serious therapeutic problem. Pharmacological treatment with increasing dosages of baclofen, carbamazepine, or gabapentin is not always successful. In this paper, the use of general anesthesia with positive-pressure ventilation and muscle relaxation for the termination of chronic hi...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1097/00000539-200208000-00050
更新日期:2002-08-01 00:00:00
abstract:BACKGROUND:Statins have been shown to possess antiinflammatory and immunomodulatory effects. In this study, we sought to determine if preoperative statin therapy is associated with a reduced frequency of postoperative acute respiratory distress syndrome (ARDS) in surgical populations at increased risk of developing ARD...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/ANE.0000000000000387
更新日期:2014-10-01 00:00:00
abstract::Lumbar cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, which are used as indicators of central nervous system serotonergic neuronal activity, were significantly higher in 67 patients with chronic pain and in 32 patients with acute pain (23.6 +/- 3.3 and 23.1 +/- 3.8, respectively) than in 30 patients (8.8 +/...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:
更新日期:1981-12-01 00:00:00
abstract:BACKGROUND:Synergistic neuromuscular blocking effects have been observed clinically with certain pairs of nicotinic acetylcholine receptor (nAChR) competitive antagonists. The mechanism for synergy has not been elucidated. We tested the hypothesis that synergy arises from a differential selectivity of antagonists for t...
journal_title:Anesthesia and analgesia
pub_type: 杂志文章
doi:10.1213/ane.0b013e31817b4469
更新日期:2008-08-01 00:00:00