Context-sensitive Half-time Research Articles

Comparison of different weight-based scalars of remimazolam tosylate for anesthesia induction in obese patients: study protocol for a prospective, controlled trial

BackgroundThe physiologic and anthropometric characteristics changes associated with obesity may result in the alternation of pharmacologic management. Remimazolam tosylate is a new type of ultra-short-acting benzodiazepine with stable context-sensitive half-time (CSHT) and no lipid accumulation after long-time infusion. Although remimazolam tosylate has potential advantages for the induction and maintenance of anesthesia in obese patients, the appropriate induction dosing scalars among obese patients are unknown. Therefore, we aim to compare the different weight-based scalars for dosing remimazolam tosylate of anesthesia induction among obese patients.Methods/designThe study will be performed as a prospective, single-center, double-blind, controlled clinical trial. The study design is a comparison of remimazolam tosylate requirements based on total body weight (TBW) or lean body weight (LBW) to reach a Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) score of 0 among obese subjects (BMI ≥ 35 kg/m2). Another twenty normal-weight subjects (18.5 kg/m2 ≤ BMI < 25 kg/m2) will be enrolled as a control group, whose induction dose is scaled based on TBW. The infusion rate of remimazolam tosylate during induction is 12 mg/kg/h in all groups.DiscussionResults of the present study will provide evidence of dose scalar of remimazolam tosylate to guide the clinical practice of anesthesia induction in obese patients.Trial registrationChinese Clinical Trial Registry ChiCTR220005664. Registered on 9 February 2022, https://www.chictr.org.cn/showproj.aspx?proj=151150.

Pharmacokinetics of remimazolam after intravenous infusion in anaesthetised children

BackgroundThe pharmacokinetic properties of the new benzodiazepine remimazolam have been studied only in adults. We investigated the pharmacokinetics of remimazolam after i.v. infusion in anaesthetised paediatric patients. MethodsTwenty-four children (2–6 yr, ASA physical status 1–2, BMI 15–18 kg m−2) undergoing general anaesthesia with sevoflurane were enrolled. During surgery, remimazolam was administered as an i.v. infusion over 1 h at 5 mg kg−1 h−1 for 5 min, followed by 1.5 mg kg−1 h−1 for 55 min. Plasma concentrations of remimazolam and its metabolite CNS7054 were determined from arterial blood samples using ultra-high performance liquid chromatography–mass spectrometry. Pharmacokinetic modelling was performed by population analysis. ResultsPharmacokinetics were best described by a three-compartment model for remimazolam and a two-compartment model for CNS7054 linked by a transit compartment. Remimazolam showed a high clearance of 15.9 (12.9, 18.2) ml kg−1 min−1 (median, Q25, Q75), a small central volume of distribution of 0.11 (0.08, 0.14) L kg−1 and a short terminal half-life of 67 (49, 85) min. The context-sensitive half-time after an infusion of 4 h was 17 (12, 21) min. The metabolite CNS7054 showed a low clearance of 0.89 (0.33, 1.40) ml kg−1 min−1, a small central volume of distribution of 0.011 (0.005, 0.016) L kg−1, and a long terminal half-life of 321 (230, 770) min. ConclusionsRemimazolam in children was characterised by a high clearance and short context-sensitive half-time. When normalised to weight, pharmacokinetic properties were similar to those reported for adults. Clinical trial registrationChiCTR2200057629.

Contemporary Anesthesia Perspectives for Ophthalmic Surgery: A Brief Review

In recent decades there have been few changes in the anesthesia management of eye surgery. By contrast, the 21st Century has witnessed major advancements in ophthalmic surgery with the adoption of minimally-invasive techniques, technologic innovations, and an expanding population seeking eye care. These factors have impacted intraoperative exposure such that many procedures are now performed on more complex patients, and completed in quicker time. Furthermore, in pursuit of economic savings and patient satisfaction there is a trend to divert eye surgeries away from the in-hospital setting to ambulatory centers or office locations. From an anesthesia perspective, these changes have imposed a demand on providers to shorten operating room turnover times and accelerate patient discharge while maintaining high standards of patient safety. This review will address five new avenues of anesthesia care, each of which offer possibilities in accommodating facets of this new order surgical experience. First, remimazolam is an ultra-short acting benzodiazepine that produces a predictable period of hypnosis and rapid, full recovery of consciousness because of its short context-sensitive half-time and inactive metabolites. A single 3-5 mg dose produces 11-15 minutes sleep that may be ideal for brief ocular interventions. Second, nasal CPAP/BiPAP and high flow nasal oxygen devices expand the profile of patients appropriately managed at an ambulatory center. Since their application improves arterial oxygenation and delays the onset of apneic hypoxemia, they are advantageous for patients afflicted by morbid obesity or severe obstructive sleep apnea. Third, open globe injuries have traditionally been managed under general anesthesia. However, recent studies attest to regional anesthesia as a viable alternative for many ocular insults, particularly for the elderly and patients with major organ dysfunction or risk for pulmonary aspiration. Fourth, the sub-Tenon block is a cannula-based regional ophthalmic skill performed predeominantly by ophthalmic surgeons because it necessitates conjunctival incision and dissection. Recently described variations of an incision-free, easily mastered sub-Tenon approach are likely to be included in residency and fellowship instruction, and so become an invaluable component of the anesthesiology armamentarium. This review concludes with a concise overview of the a2 agonist dexmedetomidine with the focus directed on its uses as an adjunct for adult sedation, and advantage in children for premedication and control of emergence delirium.

A population pharmacokinetic model of remimazolam for general anesthesia and consideration of remimazolam dose in clinical practice

Remimazolam besylate is a novel short-acting benzodiazepine. An appropriate pharmacokinetic model of remimazolam is desirable in anesthesia practice. The aim of the study was to develop a pharmacokinetic model using plasma samples from patients anesthetized with remimazolam. Influence of patient characteristics, context-sensitive decrement-times, and dose regimens were also examined. Data were obtained from four trials on patients, and seven trials on healthy volunteers. The characteristics of 416 male and 246 female subjects were as follows: age, 18-93years; body weight, 34-149kg; and American Society of Anesthesiologists physical status (ASA-PS), I-IV. 2231 arterial and 3200 venous samples were used for the final model. The equilibration rate constant between arterial plasma and effect-site was estimated using the concept of time to peak effect. The final model was used to generate context-sensitive decrement times and dose regimens for general anesthesia. A three-compartment model plus virtual venous compartment with allometric scaling of adjusted body weight (ABW), age, sex, and ASA-PS as covariates were selected as the final model. Elimination clearance was lower in males, and in subjects with higher ABW and ASA-PS scores. Approximately 10% or 20% higher dose rate was necessary in females than in males or ASA-PS I/II than III/IV patient. The context-sensitive half-time for effect-site concentration in a 55-year-old, 70-kg, 170-cm male or female ASA-PS I/II patient after > 6-h infusion was 16.7 or 15.9min. Remimazolam pharmacokinetic model for general anesthesia was successfully developed. ABW, ASA-PS, and sex has a considerable impact on the remimazolam concentration.

Remimazolam besylate; overview of a novel benzodiazepine for general anesthesia

Remimazolam, a novel, ultra-short-acting intravenous anesthetics, belongs to the benzodiazepine class of drugs and was approved for as a general anesthetic. Its pharmacological action is similar to that of midazolam. However, the differences in the metabolic pathway and pharmacokinetic profiles of its metabolites contribute to the faster offset of the action of remimazolam than midazolam. The context-sensitive half time (CSHT) is as short as 6.8 ± 2.4 min. An advantage of remimazolam over other intravenous anesthetics, such as propofol, is the presence of antagonists. Remimazolam-induced sedation is reversed by flumazenil, a benzodiazepine antagonist. Moreover, lower prevalence of injection site pain and less reduction in blood pressure in the are the advantages of remimazolam over propofol. Although our knowledge is limited at present, remimazolam may be useful for general anesthesia. We look forward to the future possibilities of this new anesthetic agent.&#x0D; Key words: Anesthesia, General; Anesthesia, Intravenous; Benzodiazepine; Remimazolam&#x0D; Citation: Morimoto Y. Remimazolam besylate; overview of a novel benzodiazepine for general anesthesia. Anaesth. pain intensive care 2022;26(3):277-279; DOI: 10.35975/apic.v26i3.1819&#x0D; Received: February 01, 2022; Reviewed: May 04, 2022; Accepted: May 07, 2022&#x0D;

Oxycodone target concentration dosing for acute pain in children.

Oxycodone pharmacokinetics have been described in premature neonates through to obese adults. Covariate influences have been accounted for using allometry (size) and maturation of oxycodone clearance with age. The target concentration is dependent on pain intensity that may differ over pain duration or between individuals. We assumed a target concentration of 35mcg.L-1 (acceptable range ±20%) to be associated with adequate analgesia without increased risk of adverse effects from respiratory depression. Pharmacokinetic simulation was used to estimate dose in neonates through to obese adults given intravenous or parenteral oxycodone. There were 84% of simulated oxycodone concentrations within the acceptable range during maintenance dosing. Variability around the simulated target concentration decreased with age. The maturation of oxycodone clearance is reflected in changes to context-sensitive halftime where clearance is immature in neonates compared with older children and adults. The intravenous loading and maintenance doses for a typical 5-year-old child are 100mcg.kg-1 and 33mcg.kg-1 .h-1 . In a typical adult, the loading dose is 100mcg.kg-1 and maintenance dose 23mcg.kg-1 .h-1 . Simulation was used to suggest loading and maintenance doses to attain an oxycodone concentration of 35mcg.L-1 predicted in adults. Although the covariates age and weight contribute 92% variability for clearance, there remains variability accounting for 16% of concentrations outside the target range. Duration of analgesic effect after ceasing infusion is anticipated to be longer in neonates where context-sensitive halftime is greater than older children and adults.

A comprehensive review of remimazolam for sedation.

Benzodiazepines are one of the most commonly used medications in the field of anesthesia. They offer excellent anxiolytic and amnestic properties ideal for the perioperative period when patient anxiety is understandably heightened. Remimazolam has presented a favorable alternative to some of the common intravenous anesthetic agents used given its fast onset of action, high safety profile, and reasonably short duration of action. The drugs within the four classes of benzodiazepines, 2-keto-benzodiazepines, 3-hydroxy-benzodiazepines, triazolo-benzodiazepines, and 7-nitro-benzodiazepines provide varying degrees of anxiolysis, sedation, and amnesia. This is provided by the benzodiazepine molecule binding and causing a conformational change to the chloride ion channel to cause hyperpolarization and thus inhibition of the central nervous system. Each type of benzodiazepine has a preferred role within the realm of medicine. For instance, diazepam is used for the treatment of seizures and anxiety. Midazolam's anxiolytic and anterograde amnestic properties are taking advantage of during the perioperative period. Lorazepam is beneficial for anxiety and status epilepticus. Remimazolam, currently in phase II and III clinical trials, has demonstrated a very short during of action and low context-sensitive half-time, allowing for its rapid removal even during a prolonged infusion. Much of its properties may be credited to being a soft drug, meaning it is a metabolically active drug that is rapidly inactivated in the body. This provides anesthesiologists and other practitioners administering it with a more predictable sedative. These properties have the potential to push it towards becoming the drug of choice for premedication during the perioperative period and sedation in the ICU. Furthermore, remimazolam does not seem to rely on any specific organ to be metabolized. The drug's ester moiety makes it a substrate for non-specific tissue esterase enzymes, meaning its metabolism and elimination are not impaired in patients with hepatic and/or renal disease. Its addictive potential closely resembles that of its parent compound, midazolam. Reports of its adverse reactions include headache and somnolence after an involuntary movement during infusion. Benzodiazepines are a great adjunct to anesthetic care. Remimazolam's safety profile, pharmacokinetics, pharmacodynamics, and potential practical use make it quite favorable in this regard. It has the potential to equip anesthesiologists and other medical practitioners with a more predictable medication that has a good safety profile. However, further large clinical trials will provide us with a better understanding of the advantages and disadvantages of remimazolam.

So Good It Hurts?

So Good It Hurts?

Ketamine Pharmacokinetics.

Several models describing the pharmacokinetics of ketamine are published with differences in model structure and complexity. A systematic review of the literature was performed, as well as a meta-analysis of pharmacokinetic data and construction of a pharmacokinetic model from raw data sets to qualitatively and quantitatively evaluate existing ketamine pharmacokinetic models and construct a general ketamine pharmacokinetic model. Extracted pharmacokinetic parameters from the literature (volume of distribution and clearance) were standardized to allow comparison among studies. A meta-analysis was performed on studies that performed a mixed-effect analysis to calculate weighted mean parameter values and a meta-regression analysis to determine the influence of covariates on parameter values. A pharmacokinetic population model derived from a subset of raw data sets was constructed and compared with the meta-analytical analysis. The meta-analysis was performed on 18 studies (11 conducted in healthy adults, 3 in adult patients, and 5 in pediatric patients). Weighted mean volume of distribution was 252 l/70 kg (95% CI, 200 to 304 l/70 kg). Weighted mean clearance was 79 l/h (at 70 kg; 95% CI, 69 to 90 l/h at 70 kg). No effect of covariates was observed; simulations showed that models based on venous sampling showed substantially higher context-sensitive half-times than those based on arterial sampling. The pharmacokinetic model created from 14 raw data sets consisted of one central arterial compartment with two peripheral compartments linked to two venous delay compartments. Simulations showed that the output of the raw data pharmacokinetic analysis and the meta-analysis were comparable. A meta-analytical analysis of ketamine pharmacokinetics was successfully completed despite large heterogeneity in study characteristics. Differences in output of the meta-analytical approach and a combined analysis of 14 raw data sets were small, indicative that the meta-analytical approach gives a clinically applicable approximation of ketamine population parameter estimates and may be used when no raw data sets are available.

Malfunctioning sufentanil intrathecal pain pump: a case report

BackgroundSufentanil is a potent opioid uncommonly used to manage pain and is rarely administered via an intrathecal pain pump system.Case presentationThis case illustrates the use of intrathecal sufentanil in a 50-year-old Caucasian man for the management of chronic pain; however, the intrathecal drug delivery system experienced a malfunction which led to 1/100th output of the correct dosage. Interesting aspects of this case report include the uncommon choice of sufentanil use for an intrathecal drug delivery system, as well as the unusual pharmacokinetics of this drug. Specifically, this patient did not experience the major withdrawal that would be expected given significant under dosing of opioid, and this may be explained by the lipophilicity and context-sensitive half-times of sufentanil.ConclusionsBecause of the absence of a clinically significant withdrawal in this case report, clinicians must be aware of relevant pharmacokinetic properties and unusual intrathecal drug delivery system technologies that influence a patient’s response when device malfunction occurs.

Basic Pharmacologic Concepts

Pharmacokinetic and pharmacodynamic principles specifically describe the different ways a drug and the body interact with each other. Pharmacokinetics focuses mainly on the absorption of medications into the body, the distribution into various tissues, how the body metabolizes and breaks down medications, and the elimination of any remaining medication or metabolites. Moreover, patient-specific characteristics, such as comorbidities and organ dysfunction, must be considered as they may also influence a drug’s absorption, distribution, metabolism, and elimination. Pharmacodynamics involves the different ways a medication affects the body, particularly when interacting with different receptors and the subsequent biochemical actions that elicit physiologic responses. Different drug-specific properties, such as affinity, efficacy, and agonism, also play a role in a patient’s response to the medication. When the concepts of pharmacokinetics and pharmacodynamics are joined together, computer models and simulations can be utilized to help predict the expected physiologic effects of a drug based on varying dosing parameters while taking tissue distribution and metabolism into consideration. This review contains 6 figures, 5 tables and 21 references. Keywords: biophase, compartment distribution, context-sensitive half-time, dose-response relationship, pharmacodynamics, pharmacokinetics, pharmacogenomics, receptor sensitization

Pharmacokinetics of alfaxalone infusions, context-sensitive half-time and recovery times in male neutered cats

ObjectivesTo determine the context-sensitive half-time of alfaxalone following intravenous infusions of various durations. To estimate the time necessary for plasma concentration to decrease by up to 95%. Study designProspective randomized and simulation studies. AnimalsA group of six 1-year-old male castrated research cats. MethodsCats were instrumented with catheters in a jugular and a medial saphenous vein. Alfaxalone was administered using a target-controlled infusion system, to target a plasma alfaxalone concentration of 7.6 mg L–1. The infusion lasted 30 (n = 2), 60 (n = 2) or 240 (n = 2) minutes. Blood samples were collected prior to drug administration, and at several times during and up to 8 hours after the infusion, for the determination of plasma alfaxalone concentration using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to each time–concentration profile, and a population model was fitted to data from all individuals. The context-sensitive half-time was determined from each individual model. In addition, times for plasma alfaxalone concentration to decrease by 50–95% following bolus administration and target-controlled infusions or continuous rate infusions of 0.5–8 hours were estimated by simulation using the population model. ResultsContext-sensitive half-times were 2 and 8, 6 and 9, and 18 and 20 minutes for the 30, 60 and 240 minutes, respectively. Time for plasma alfaxalone concentration to decrease by 90% was predicted to range from 7 to 120 or 113 minutes following a bolus to an 8 hour target-controlled or continuous rate infusion, respectively. Conclusion and clinical relevanceRecovery time from alfaxalone anesthesia in cats is predicted to be influenced by the duration of target-controlled infusion.

Anesthetic Pump Techniques Versus the Intermittent Bolus: What the Oral Surgeon Needs to Know.

The most popular agents in use for office-based anesthesia are propofol, ketamine, and remifentanil, which have the desirable properties of rapid onset and short duration of action. A useful parameter in assessing these agents is the context-sensitive half-time. These anesthetic agents demonstrate relatively low, flat plots compared with older agents. For delivery of intravenous anesthetics, oral and maxillofacial surgeons have relied small incremental boluses with great success. However, relatively simple syringe infusion pumps can provide an even "smoother" anesthetic. This article familiarizes oral and maxillofacial surgeons with the advantages of infusion pumps and provides examples of their use.

Influence of Cardiac Output on the Pharmacokinetics of Sufentanil in Anesthetized Pigs.

Sufentanil is used for general anesthesia and analgesia. The study aim was to determine the effect of pharmacologically induced changes in cardiac output on the pharmacokinetics of sufentanil in anesthetized pigs. Twenty-four pigs were randomly assigned to low, high, and control cardiac output groups. Cardiac output was decreased or increased from baseline by at least 40%, or maintained within ± 10% of baseline, respectively. Sufentanil was administered as a bolus followed by a continuous infusion for 120 min. Timed arterial samples were drawn for sufentanil concentration measurements. Data from 20 animals were analyzed. The cardiac outputs (means ± SD) were 2.9 ± 0.7, 5.4 ± 0.7, and 9.6 ± 1.6 l/min in the low, control, and high cardiac output groups, respectively. The parameters of the two-compartment pharmacokinetic model for these cardiac outputs were: CL1: 0.9, 1.2, and 1.7 l/min; CL2: 0.9, 3.1, and 6.9 l/min; V1: 1.6, 2.9, and 5.2 l; and V2: 27.5, 47.0, and 79.8 l, respectively. Simulated sufentanil doses to maintain a target plasma concentration of 0.5 ng/ml for 3 h were 99.5, 128.6, and 157.6 μg for cardiac outputs of 3, 5, and 7 l/min, respectively. The context-sensitive half-times for these cardiac outputs increased from 3.1 to 19.9 and 25.9 min, respectively. Cardiac output influences the pharmacokinetics of sufentanil. Simulations suggest that in the case of increased cardiac output, the dose should be increased to avoid inadequate drug effect at the expense of prolonged recovery, whereas for low cardiac output the dose should be reduced, and a faster recovery may be expected.

Sedation for Pediatric Patient with End-Stage Hepatic Disease Outside Operating Room

Sedation outside operating room for children has increasing importance. Pediatric patients with end stage liver disease are of great importance for various and frequent procedures including gastrointestinal endoscopy, magnetic resonance imaging, computerized tomography, brachytherapy, catheterisation, interventional radiology. Anesthesia plan plays critical role for the success of these procedures. Patient safety, ventilation, hemodynamic responses, side effects of anesthetics on liver and periprocedural analgesia are the main topics of attention. Airway management tools may be helpful because of edema and ascites pushing diaphragm upwards. Nasal capnography enables monitoring spontaneous ventilation. Enlargement of extravascular extracellular fluid and dysproteinemia, effects drug behaviors. Drug elimination half-time as well as context sensitive half-time have to be taken into account and designed individually. The pressure above vena cava inferior, results with decrease in preload, thus reduction in cardiac output. Pulse wave variation monitoring helps for estimating circulating fluid status. Tendency for bleeding can be anticipated with fresh frozen plasma. Patient-controlled analgesia may be a choice of favor but close monitoring required for repeated analgesics. Children's Hospital of Eastern Ontario Pain Scale would be a good monitoring tool for pain.

Sedation and Analgesia in Pediatric Cardiac Critical Care.

This review will focus on the pharmacokinetics (with an emphasis on the context-sensitive half-time), pharmacodynamics, and hemodynamic characteristics of the most commonly used sedative/hypnotic, analgesic, and IV anesthetics used in cardiac intensive care. In addition, the assessment of pain and agitation and withdrawal will be reviewed. MEDLINE, PubMed. Children in the cardiac ICU often require one or more components of general anesthesia: analgesia, amnesia (sedation and hypnosis), and muscle relaxation to facilitate mechanical ventilation, to manage postoperative pain, to perform necessary procedures, and to alleviate fear and anxiety. Furthermore, these same children are often vulnerable to hemodynamic instability due to unique underlying physiologic vulnerabilities. An assessment of hemodynamic goals, postoperative procedures to be performed, physiologic vulnerabilities, and the intended duration of mechanical ventilation should be made. Based on this assessment, the optimal selection of sedatives, analgesics, and if necessary, muscle relaxants can then be made.

Context-sensitive half-time of fentanyl in dogs.

Context-sensitive half-times (CSHTs) of fentanyl in dogs were determined using pharmacokinetic models reported by Murphy et al. and Sano et al., and compared with a human model. The CSHT was defined as the time required for a 50% decrease in drug concentration in the central compartment after the termination of infusion. Although CSHTs increased gradually as the infusion time increased, the CSHTs in dogs were shorter than those in humans. The CSHTs at steady-state were 31.3 and 69.2 min in dogs, and 306.5 min in humans. The CSHTs of fentanyl in dogs are apparently shorter than those in humans; therefore, a continuous infusion of fentanyl may be a rational regimen in dogs, even if duration of infusion is extended.

Population Pharmacokinetic Modeling of Hydromorphone in Cardiac Surgery Patients during Postoperative Pain Therapy

Hydromorphone is a µ-selective opioid agonist used in postoperative pain therapy. This study aimed to evaluate the pharmacokinetics of hydromorphone in cardiac surgery patients during postoperative analgesia with target-controlled infusion and patient-controlled analgesia. In this study, 50 adult patients were enrolled to receive intravenous hydromorphone during postoperative pain therapy. Arterial plasma samples were collected for measurements of drug concentration. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Results were validated and simulations were carried out to evaluate results. Data from 49 patients (age range, 40-81 yr) were analyzed. The pharmacokinetics of hydromorphone were best described by a three-compartment model. Age was incorporated as a significant covariate for elimination clearance and central volume of distribution. Scaling all parameters with body weight improved the model significantly. The final estimates of the model parameters for the typical adult patient (67 yr old, weighing 70 kg) undergoing cardiac surgery were as follows: CL1 = 1.01 l/min, V1 = 3.35 l, CL2 = 1.47 l/min, V2 = 13.9 l, CL3 = 1.41 l/min, and V3 = 145 l. The elimination clearance decreased by 43% between the age of 40 and 80 yr, and simulations demonstrated that context-sensitive half-time increased from 26 to 84 min in 40- and 80-yr-old subjects, respectively. The final pharmacokinetic model gave a robust representation of hydromorphone pharmacokinetics. Inclusion of age and body weight to the model demonstrated a significant influence of these covariates on hydromorphone pharmacokinetics. The application of this patient-derived population model in individualized pain therapy should improve the dosing of hydromorphone in patients undergoing cardiac surgery.

Assessing the Utility of the Utility Function

Over the last 40 years, anesthesiologists have incorporated a series of new pharmacologic concepts that give us a better understanding of how drugs behave when administered by intravenous bolus or infusion. Each of these concepts initially seemed arcane and theoretical, but most are now accepted as a fundamental part of anesthesia practice. For example, the rapid administration of neuromuscular blocking drugs produces effects that aren’t well-described by their plasma concentrations (after all, they don’t work in plasma). This discrepancy lead to the development of “pharmacokinetic-pharmacodynamic (PK-PD) modeling” and the concept of a hypothetical “biophase” or “effect compartment”.1,2 More than fifty years ago, clinicians noted that the recovery from opioid infusions had a poor correlation with the elimination half- life.3. This eventually lead to the development of the “context-sensitive half-time,” which describes the minutes required for a 50% decrement in plasma drug concentration after stopping infusions of varying durations.4–6 Traditional pharmacokinetics focused predominantly on drug elimination, but an understanding of anesthetic onset required models that described drug disposition from the moment of injection.7 Thus, the concept of recirculatory pharmacokinetic models, or “front-end kinetics” was introduced to anesthesiology.8 Subsequent to their introduction, these new concepts were validated through extensive additional investigation.

Context Sensitive Decrement Times of Remimazolam

To the Editor Two recently published papers describe the context sensitive half-time (CSHT) as a predictor of recovery for the novel benzodiazepine remimazolam (CNS 7056).1,2 The term CSHT was first proposed in 1992 by Hughes et al.3 and consists of curves constructed by computer simulations designed to determine how long it takes for the plasma concentration to decrease by 50% for different durations of infusion. Although Wiltshire et al.2 reported the “context sensitive half-time” of remimazolam, they used constant rate infusions for their simulations rather than a varying rate infusion designed to produce a constant concentration target-controlled infusion (TCI). Thus, we believe that the simulated remimazolam CSHT when calculated using TCI (rather than constant rate infusion) might be longer than those shown in Figure 10.2 We note that Wiltshire et al.2 present a recirculatory model as the optimal model in terms of the lowest objective function with meaningful model parameters. However, from a practical perspective (i.e., implementation in a TCI pump), a 3-compartment mammillary model would certainly be more appealing. Although the more complex model is supported from a statistical perspective, it could be that it represents only a marginal improvement from a clinical perspective. Therefore, it would be of interest to the pharmacokinetically inclined reader to see a plot showing the residuals over time, depicting the difference between the simple and the complex models. Importantly, we would not discount the potential use of the 3-compartment mammillary model with future remimazolam data sets, because it is possible that the “much poorer fits” obtained in this investigation could be avoided by the use of arterial sampling throughout the study. The family of recovery curves published by Shafer and Varvel4 provide the foundation to understanding the “relevant decrement time” published by Bailey.5 We believe that this is a clinically relevant concept because 2 drugs with different concentration response curves will require different decrements in their concentrations for the same decrement in drug effect. For example, based on the pharmacodynamic parameters given in Table 2,2 the required decrement in the effect site concentration to recover from a bispectral index (BIS) value of 80 to 92 for remimazolam is 72%, whereas for midazolam it is only 29% (this is due to the larger Hill coefficient estimated for midazolam than for remimazolam). Thus, relevant decrement time curves (based on effect site TCI simulations for different durations of infusion) for the same specified BIS end point would be a more clinically meaningful comparison than the simulations shown in Figure 11.2 However, we also note that the estimated lowest BIS value of 55.7 for remimazolam and 75.1 for midazolam are probably poor estimates of the “true” maximum effect because the electroencephalogram data are censored. Finally, we would encourage researchers to continue to use the existing phrase “relevant decrement time” introduced by Bailey5 rather than the new phrase “pharmacodynamic CSHT” introduced in the accompanying editorial by Johnson.6 Thomas Schnider, Prof. Dr. Med. Institut für Anästhesiologie, Kantonsspital St. Gallen, Switzerland University of Berne Berne, Switzerland [email protected] Charles Minto, FANZCA, PhD Anaesthetist Sydney, New South Wales, Australia