Harald Ihmsen

Background: Remimazolam (CNS 7056) is a new ultra–short-acting benzodiazepine for intravenous sedation and anesthesia. Its pharmacokinetics and pharmacodynamics have been reported for bolus administration. This study aimed to investigate the pharmacokinetics and pharmacodynamics of remimazolam after continuous infusion. Methods: Twenty healthy male volunteers (20 to 38 yr, 64 to 99 kg) received remimazolam as continuous intravenous infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Pharmacokinetics of remimazolam and its metabolite were determined from arterial plasma concentrations. Sedation was assessed using the Modified Observer’s Assessment of Alertness and Sedation scale. Pharmacokinetic-pharmacodynamic modeling was performed by population analysis. Hemodynamics and the electrocardiogram were also investigated. Results: Pharmacokinetics was best described by a three-compartment model for remimazolam and a two-compartment model with transit compartment for the metabolite. Remimazolam showed a high clearance (1.15 ± 0.12 l/min, mean ± SD), a small steady-state volume of distribution (35.4 ± 4.2 l) and a short terminal half-life (70 ± 10 min). The simulated context-sensitive halftime after an infusion of 4 h was 6.8 ± 2.4 min. Loss of consciousness was observed 5 ± 1 min after start, and full alertness was regained 19 ± 7 min after stop of infusion. Pharmacodynamics of Modified Observer’s Assessment of Alertness and Sedation score was best described by a sigmoid probability model with effect site compartment. The half-maximum effect site concentration for a Modified Observer’s Assessment of Alertness and Sedation score less than or equal to 1 was 695 ± 239 ng/ml. The equilibration half-time between central and effect compartment was 2.7 ± 0.6 min. Mean arterial blood pressure decreased by 24 ± 6%, and heart rate increased by 28 ± 15%. Spontaneous breathing was maintained throughout the study. There was no significant prolongation of the QT interval of the electrocardiogram observed. Conclusions: Remimazolam was characterized by a pharmacokinetic–pharmacodynamic profile with fast onset, fast recovery, and moderate hemodynamic side effects. Editor’s Perspective: What We Already Know about This Topic: What This Article Tells Us That Is New:

The obstructive sleep apnea syndrome (OSAS) is characterized by temporary cerebral hypoxia which can cause cognitive dysfunction. On the other hand, hypoxia induced neurocognitive deficits are detectable after general anesthesia. The objective of this study was to evaluate the impact of a high risk of OSAS on the postoperative cognitive dysfunction after intravenous anesthesia. In this single center trial between June 2012 and June 2013 43 patients aged 55 to 80 years with an estimated hospital stay of at least 3 days undergoing surgery were enrolled. Patients were screened for a high risk of OSAS using the STOP-BANG test. The cognitive function was assessed using a neuropsychological test battery, including the DemTect test for cognitive impairment and the RMBT test for memory, the day before surgery and within 36 h after extubation. Twenty-two of the 43 analyzed patients were identified as patients with a high risk of OSAS. Preoperatively, OSAS patients showed a significant worse performance only for the DemTect (p = 0.0043). However, when comparing pre- and postoperative test results, the OSAS patients did not show a significant loss in any test but significantly improved in RMBT test, whereas the control group showed a significant worse performance in three of eight tests. In five tests, we found a significant difference between the two groups with respect to the change from pre- to postoperative cognitive function. Patients with a high risk of OSAS showed a less impairment of memory function and work memory performance after intravenous anesthesia. This might be explained by a beneficial effect of intrinsic hypoxic preconditioning in these patients.

Seizure duration in electroconvulsive therapy (ECT) is positively related with patients’ outcome. This study sought to investigate the impact of anesthetic management on seizure duration, and the impact of selected drugs (theophylline, remifentanil, S-ketamine) on seizure duration. Retrospective analysis of all patients undergoing ECT at our institution from January 2011 to April 2012 was performed based on electronic medical chart and review of existing quality improvement data. Patient data (N = 78), including gender, age, height, weight, and administered drugs, energy levels, and electroencephalic seizure duration were analyzed. Statistical analysis was performed using a generalized linear model. A total of 78 patients (male = 39, female = 39, age 51 ± 12 years) were included. Average number of session was 10 ± 6 (1–30). In our patient population, theophylline administration was the only parameter, which significantly prolonged seizure duration, whereas S-ketamine, remifentanil, thiopental, age, sex, session or energy level had no significant effect. Theophylline can be a useful adjunct for patients with inadequate seizure duration. If there is a concomitant beneficial effect on patients’ outcome needs to be investigated in further studies.

Dexmedetomidine is a highly selective alpha2-adrenoceptor agonist with sedative and analgesic properties which is also used in pediatric anesthesia. Although the pharmacokinetics of dexmedetomidine have been studied in pediatric patients, there are no data for Chinese children available. As alterations in pharmacokinetics due to ethnicity cannot be ruled out, it was the aim of this study to characterize the pharmacokinetics of dexmedetomidine in Chinese pediatric patients. Thirty-nine children aged 1–9 years undergoing surgery were enrolled in the study. Dexmedetomidine was administered as short intravenous infusion of 1–2 µg/kg in 10 min. Venous blood samples were drawn until 480 min after stopping of infusion. Dexmedetomidine plasma concentrations were measured with high-performance liquid chromatography and mass spectrometry. Pharmacokinetic modeling was performed by population analysis using linear compartment models. Data of 36 patients (age 1–9 years, weight 10–27 kg) were analyzed. The pharmacokinetics of dexmedetomidine were best described by a two-compartment model with an allometric power model and estimates standardized to 70 kg body weight. The population estimates (95 % CI) per 70 kg bodyweight were: clearance 36.2 (33.3–41.1) l/h, central volume of distribution 84.3 (70.3–91.4) l, intercompartmental clearance 82.8 (63.6–136.6) l/h, peripheral volume of distribution 114 (95–149) l, and terminal half-life 4.4 (3.6–5.3) h. Age did not show any influence on weight-adjusted parameters. Chinese children showed a similar clearance, but larger volumes of distribution and longer terminal half-life when compared to studies in Caucasians. ChiCTR-OPC-14005659.

Postictal agitation (PIA) after electroconvulsive therapy (ECT) is a major medical problem. This observational study investigated the incidence and severity of PIA and evaluated propofol as a treatment option in a patient population. The study included 14 patients that underwent a series of ECTs performed either with or without an approximately 0.5-mg/kg propofol bolus after the end of an electroencephalography (EEG) seizure. Among other values, we documented PIA incidence and severity as rated by a simple score; orientation to person, time, place, and situation; transfer times to the postanesthesia care (PACU) and inpatient unit; nurses' and patients' rating of recovery period, and others and tested for significant differences. Five minutes after the end of ECT, the patients showed moderate to severe PIA in 8 of 37 ECT sessions. Incidence was significantly lower when patients had received propofol (3/37). Transfer time to the PACU was longer, but transfer time to the inpatient unit was shorter after administration of propofol. The recovery period was rated significantly better after propofol administration by nurses and patients. A single bolus of propofol administered after the end of the seizure reduced the incidence of post-ECT PIA. The PACU staff and patients rated the emergence period significantly better when propofol was administered.

Mit Dexmedetomidin ist 2011 ein potenter selektiver α₂-Adrenozeptor-Agonist zur Sedierung erwachsener, intensivmedizinisch behandelter Patienten neu auf dem europäischen Markt zugelassen worden. Dexmedetomidin zeigt konzentrationsabhängig sowohl sedierende als auch analgetische und anxiolytische Wirkungen. Aktuelle Studien lassen Dexmedetomidin als eine Alternative zu Midazolam für die Langzeitsedierung erscheinen. In dieser Übersichtsarbeit werden die pharmakokinetischen und pharmakodynamischen Eigenschaften von Dexmedetomidin insbesondere bei intensivmedizinischen Patienten, unter besonderer Berücksichtigung des Einflusses von Kovariaten, zusammengefasst. Obwohl Dexmedetomidin nur für Erwachsene zugelassen ist und die Anwendung bei Kindern daher einem „off label use“ entspricht, wird auch auf die Pharmakokinetik und -dynamik bei Kindern eingegangen, da dazu ebenfalls zahlreiche Studien vorliegen. Dexmedetomidine is a highly selective, potent α₂-adrenoceptor agonist which was approved in 2011 by the European Medicines Agency for sedation of patients in intensive care units (ICU). Dexmedetomidine exhibits sedative as well as analgesic and anxiolytic effects. Recent studies suggest that dexmedetomidine may be an alternative to midazolam in long-term ICU sedation. This review summarizes the pharmacokinetics and pharmacodynamics of dexmedetomidine particularly in ICU patients and with special regard to covariate effects. Although dexmedetomidine is currently approved only for use in adults the pharmacokinetics and pharmacodynamics in children will also be addressed as there are numerous studies on this off-label use.

„Target-controlled infusion“ (TCI) ist seit der kommerziellen Einführung im Jahr 1996 zu einer etablierten Applikationsform intravenöser Anästhetika geworden. Zusätzliche Optionen der modernen TCI-Systeme wie die Wahl zwischen unterschiedlichen Modellen und Applikationsmodi verkomplizieren allerdings den Gebrauch für den wenig erfahrenen Benutzer. Die vorliegende Übersicht beschreibt die Unterschiede der pharmakokinetischen Modelle, der Applikationsmodi und den Einfluss von Kovariaten sowie die Konsequenzen für die Dosierung mit dem Ziel, dem Benutzer von modernen TCI-Systemen die zugrunde liegenden wissenschaftlichen Konzepte und deren Bedeutung für die klinische Praxis zu vermitteln. Since its commercial introduction in 1996, target-controlled infusion (TCI) has become an established technique for administration of intravenous anaesthetics. Modern TCI systems, however, are characterized by an increasing number of additional options and features, such as the choice between different pharmacokinetic models and modes of application, which may confuse the less experienced user. This review describes the differences between pharmacokinetic models, modes of application and the effect of covariates as well as the consequences for dosing. The aim is to explicate for the user of modern TCI systems the underlying scientific concepts and the relevance for clinical practice.

ANIMAL studies may help to investigate the pharmacodynamics of anesthetic drugs for example in the early phase of drug development or in interaction studies where drugs and dose combinations beyond the clinical use can be studied. However, such studies require reliable measures of drug effect. Besides the classic approach of measuring the response to various stimuli, the analysis of the spontaneous electroencephalogram has become an important tool for this purpose. Hereby, the complex information of the electroencephalogram is usually condensed in one variable, and numerous variables derived from the electroencephalogram have been proposed, from spectral parameters such as median frequency (MEF) or spectral edge frequency (SEF) to parameters of higher order such as Bispectral Index or parameters from nonlinear system analysis such as entropy measures.1 A suitable electroencephalographic parameter should meet the following conditions: (1) There must be a correlation between the anesthetic effect measured by the electroencephalographic parameter and the anesthetic effect measured by an appropriate clinical parameter, e.g. , response to stimuli. (2) There should be a clear relation between the concentration of the anesthetic drug and the effect measured by the electroencephalographic parameter. (3) Because the raw data of an electroencephalographic parameter must be smoothed to extract the “signal” out of the “noisy” data, and because every smoothing leads to an inevitable delay of the parameter with regard to sudden changes, the parameter should have a good signal-to-noise ratio (SNR) to keep the extent of necessary smoothing low.