Search

Background Standard methods fail to reveal late potentials in 20 to 30% of patients with ventricular arrhythmias after myocardial infarction. However, these patients may develop transient delayed ventricular activation during increases in heart rate. Methods and Results Atrial pacing was performed, at the rates of 100 min−1and 120 min−1, in 50 patients after myocardial infarction. Twenty-six patients had a history of documented, sustained ventricular tachycardia, 12 had a history of ventricular fibrillation and 12 no history of ventricular arrhythmias. The low-noise surface electrocardiogram was analysed before and during atrial pacing in the time and frequency domains. Fifteen of 26 patients with ventricular tachycardia, four of 12 with ventricular fibril-lation and three of 12 without ventricular arrhythmias experienced late potentials during sinus rhythm. Atrial pacing led to a shift of 26±15 ms of preexistent late potentials into the ST segment, this being greater in patients with anterior infarctions and to an increase in magnitude in patients with inferior infarctions. In patients without late potentials during sinus rhythm, atrial pacing provoked late potentials in eight of 11 patients with ventricular tachycardia, in four of eight patients with ventricular fibrillation and in one of nine patients without ventricular arrhythmias. Low amplitude signals (LAS) were increased in patients after inferior and filtered QRS in patients after anterior infarction. In 10 patients without cardiac disease no late potentials were detectable in the time and frequency domain either at rest or during increased heart rate. Conclusions Increase in heart rate may unmask late potentials in patients prone to malignant ventricular arrhythmias. Therefore, functional late potential analysis with non-invasive clinical stress tests, i.e. exercise tests, should be performed only with an adequate rate response. This might identify patients at risk of malignant ventricular arrhythmias otherwise not identified with conventional late potential analysis. [ABSTRACT FROM PUBLISHER]

The long-term stability of drug concentrations in human plasma samples when stored under normal laboratory conditions over several years is important for research purposes and clinical re-evaluation, but also for forensic toxicology. Fifty human plasma samples from a former clinical trial were re-analyzed after storage at -20°C for 11 years. Plasma samples were extracted using solid-phase extraction. Isotope labelled sufentanil-D5 was used as internal standard. Sufentanil plasma concentrations were determined by ultra-performance liquid chromatography (UPLC) with gradient elution, followed by tandem mass spectrometry with electrospray ionization. The linear dynamic range (LDR) was 25 - 2500 pg/mL, the limit of detection was 10 pg/mL, and the lower limit of quantification was 25 pg/mL. Intra- and inter-assay error did not exceed 6%. The deviation of the measured sufentanil plasma concentrations between the reanalysis and the first analysis was -63 ± 14% (mean ± SD). Therefore, sufentanil concentrations in human plasma were not stable in samples frozen at -20°C over 11 years., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Background: The 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., Methods: Twenty-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., Results: Pharmacokinetics 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, Q 25 , Q 75 ), 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., Conclusions: Remimazolam 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 Registration: ChiCTR2200057629., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objectives: To compare the efficacy, safety, and side effects of hydromorphone and morphine administered as patient-controlled analgesia (PCA) for postoperative pain therapy after cardiac surgery with median sternotomy., Design: A retrospective analysis of data from 2 prospective, single-blinded, randomized trials., Setting: A single-center intensive care unit at a university hospital., Participants: Forty-one adult patients undergoing cardiac surgery with median sternotomy., Interventions: Postoperative pain therapy at the intensive care unit was performed by PCA with intravenously administered bolus doses of 0.2 mg of hydromorphone (n = 21) or 2 mg of morphine (n = 20)., Measurements and Main Results: Pain at rest and under deep inspiration regularly was assessed using the 11-point numerical rating scale (NRS). Blood pressure, heart rate, cardiac output, oxygen saturation, and respiratory rate were monitored, and adverse events were registered. The median (range) NRS rating at rest was 1.5 (0-5) after hydromorphone and 0.5 (0-5) after morphine, respectively (p = 0.41). The median NRS rating under deep inspiration was 3 (0-6) after hydromorphone and 4 (0-7) after morphine, respectively (p = 0.074). The dose ratio of morphine to hydromorphone during PCA was 5.7 (95% confidence interval: 2.9-7.6). Hemodynamics and respiration were stable and did not differ significantly. Postoperative nausea and vomiting were the most frequent adverse events, which were observed in 29% of the patients after hydromorphone and in 35% after morphine, respectively (p = 0.74)., Conclusions: There were no significant differences in analgesic efficacy and safety between hydromorphone and morphine when used for postoperative pain therapy with PCA after cardiac surgery with median sternotomy., Competing Interests: Conflict of Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The long-term stability of drugs under normal laboratory storage conditions (-20°C) for years is important for research purposes, clinical re-evaluation, and also for forensic toxicology. To evaluate the stability of the analgesic opioid hydromorphone, 44 human frozen plasma samples of a former clinical trial were reanalyzed after at least three years. Blood samples were disposed using solid-phase extraction with an additional substitution of stable isotope labelled hydromorphone as an internal standard. Hydromorphone concentrations were determined by ultra-performance liquid chromatography (UPLC) with gradient elution, followed by tandem mass spectrometry with electrospray ionization. Calibration curves demonstrated linearity of the assay in the concentration range of 0.3-20 ng/mL hydromorphone. The limit of detection of the hydromorphone plasma concentration was 0.001 ng/mL, and the lower limit of quantification was 0.3 ng/mL. Intra- and interassay errors did not exceed 16%. The percentage deviation of the measured hydromorphone plasma concentrations between the reanalysis and the first analysis was -1.07% ± 14.8% (mean ± SD). These results demonstrate that hydromorphone concentration in human plasma was stable when the samples were frozen at -20°C over three years. This finding is of value for re-evaluations or delayed analyses for research purposes and in pharmacokinetic studies, such as in forensic medicine., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Andreas Wehrfritz et al.)

Background and Objective: Morphine is a standard analgesic drug for postoperative pain therapy. This study aimed to evaluate the pharmacokinetics of morphine and its active metabolite morphine-6-glucuronide (M6G) in cardiac surgery  patients during postoperative analgesia., Methods: Twenty-five adult patients undergoing cardiac surgery received postoperative pain therapy by patient-controlled analgesia with intravenous bolus doses of morphine. Plasma concentrations of morphine and M6G were determined from arterial samples. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling., Results: Data from twenty-one patients (aged 44-79 years) were analyzed. Pharmacokinetics were best described by a three-compartment model for morphine and a two-compartment model for M6G, linked by a transit compartment. Mean (±SD) population estimates for morphine were: clearance (CL) = 1.35±0.40 L/min, central volume of distribution (V 1 ) = 8.1±2.2 L, steady-state volume of distribution (V ss ) = 207±83 L, terminal elimination half-life (T 1/2 γ ) = 177±50 min. Clearance of morphine was proportional to cardiac output. Mean (±SD) population estimates for M6G were: CL = 0.098±0.037 L/min, V 1 = 5.5±0.8 L, V ss = 15.8±0.8 L, T 1/2 β = 227±74 min. The time to peak concentration of M6G after a bolus dose of morphine was 53±20 min. Clearance of M6G was proportional to estimated glomerular filtration rate., Conclusions: The pharmacokinetics of morphine and M6G in pain therapy of cardiac surgery  patients could be well described by standard compartmental models. Cardiac output was identified as a significant covariate for morphine clearance, whereas renal function was identified as the most significant covariate for clearance of M6G. These effects should be particularly considered if morphine is administered as a continuous infusion. The developed pharmacokinetic model also enables patient-controlled target-controlled infusion for pain therapy with morphine., Trial Registration: Clinical Trials NCT02483221 (June 26, 2015).

Background: The challenge of managing acute postoperative pain is the well tolerated and effective administration of analgesics with a minimum of side effects. The standard therapeutic approach is patient-controlled analgesia (PCA) with systemic opioids. To overcome problems of oscillating opioid concentrations, we studied patient-controlled analgesia by target-controlled infusion (TCI-PCA) as an alternative., Objective: To compare efficacy, safety and side effects of standard PCA with TCI-PCA for postoperative pain therapy with hydromorphone., Design: Single-blinded, randomised trial., Setting: University Hospital, Germany from December 2013 to April 2015., Participants: Fifty adults undergoing cardiac surgery., Interventions: Postoperative pain therapy on the ICU was managed with intravenous (i.v.) hydromorphone and patients randomised to TCI-PCA with target plasma concentrations between 0.8 and 10 ng ml, or PCA with bolus doses of 0.2 mg. Pain was regularly assessed using the 11-point numerical rating scale (NRS). Blood pressure, heart rate, oxygen saturation and cardiac output were continuously monitored, and adverse events were registered throughout the study., Main Outcome Measures: NRS pain ratings, hydromorphone doses, haemodynamic effects and side effects., Results: NRS pain ratings, total doses of hydromorphone and haemodynamic data did not differ significantly between TCI-PCA and PCA. The number of bolus doses during PCA was significantly higher than the number of target increases during TCI-PCA (P = 0.006). The number of negative requests was also significantly higher during PCA than during TCI-PCA (P = 0.02). The respiratory rate on the first postoperative morning was 25 ± 6 min during TCI-PCA, compared with 19 ± 4 min during PCA (P = 0.022). Nausea occurred in 30% after TCI-PCA and 24% after PCA (P = 0.46)., Conclusion: TCI-PCA was effective and well tolerated in acute postoperative pain management after cardiac surgery. Further studies are needed to evaluate this approach in clinical practice., Trial Registration: EudraCT Number: 2013-002875-16, and ClinicalTrials.gov Identifier: NCT02035709.

Background: Remimazolam (CNS 7056) is a new ultra-short acting benzodiazepine for IV sedation. This study aimed to investigate the electroencephalogram (EEG) pharmacodynamics of remimazolam infusion., Methods: Twenty healthy male volunteers received remimazolam as continuous IV infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Continuous EEG monitoring was performed by a neurophysiologic system with electrodes placed at F3, F4, C3, C4, O1, O2, Cz, and Fp1 (10/20 system) and using the Narcotrend Index. Sedation was assessed clinically by using the Modified Observer's Assessment of Alertness and Sedation scale. Pharmacodynamic models were developed for selected EEG variables and Narcotrend Index., Results: EEG changes during remimazolam infusion were characterized by an initial increase in beta frequency band and a late increase in delta frequency band. The EEG beta ratio showed a prediction probability of Modified Observer's Assessment of Alertness and Sedation score of 0.79, and could be modeled successfully using a standard sigmoid Emax model. Narcotrend Index showed a prediction probability of Modified Observer's Assessment of Alertness and Sedation score of 0.74. The time course of Narcotrend Index was described by an extended sigmoid Emax model with two sigmoid terms and different plasma-effect equilibration times., Conclusions: Beta ratio was identified as a suitable EEG variable for monitoring remimazolam sedation. Narcotrend Index appeared less suitable than the beta ratio for monitoring the sedative effect if remimazolam is administered alone.

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.

Preparations for anesthesiological management of patients build on preoperative patient self-reports concerning risk factors and comorbidities. In this setting, electronic documentation could facilitate innovative computerized functions, although patient-facing digital questionnaires require appropriate tools that patients can access effectively. To explore the feasibility of an electronic application for preoperative data acquisition directly from patients, a digital, tablet-based prototypical application has been developed within a user-centered design process in order to replace a previously used paper-based anamnesis sheet for perioperative risk evaluation. The implemented prototype has been extensively tested and iteratively improved to progressively provide an easy-to-use data entry function. To assess the suitability of this tool for everyday data acquisition by patients and physicians and to identify usability problems, the stepwise development process was accompanied by a heuristic evaluation as well as a think-aloud evaluation, while another 56 participating patients completed a feedback sheet according to ISO 9241/10. The latter method detected additional usability problems that occurred during the use of the application, which contributed to iterative improvements of the prototype. Throughout the development process, 81 issues were identified and largely resolved. After these revisions of the prototype, the number of problems found per tester decreased from 4.75 to 0.96, while the overall rating increased to 6.14 out of 7 points (SD = 1.2). These improvements demonstrate the value and efficiency of such a user-centered design process and illustrate that a user-friendly patient-facing digital data entry can replace preoperative paper questionnaires for anesthesiological management.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Background and Objective: We recently developed a new population pharmacokinetic model for hydromorphone in patients including age and bodyweight as covariates. The aim of the present study was to evaluate prospectively the predictive performance of this new model during postoperative pain therapy., Methods: This was a prospective, single-blinded, randomized, single-center study with two parallel arms. Fifty patients aged 40-85 years undergoing cardiac surgery involving thoracotomy were enrolled. Hydromorphone was administered postoperatively on the intensive care unit as target controlled infusion (TCI) for patient controlled analgesia (TCI-PCA) using the new pharmacokinetic model, or as conventional patient controlled analgesia (PCA). Arterial blood samples were taken for measurement of the hydromorphone plasma concentration. The predictive performance of the pharmacokinetic model was assessed by the median performance error (MDPE), the median absolute performance error (MDAPE), wobble and divergence. For comparison, the performance indices were also determined for three older models from the literature., Results: 903 plasma concentrations of 41 patients were analyzed. The mean values (95 % CI) of MDPE, MDAPE, wobble and divergence for the new pharmacokinetic model were 11.2 % (3.9 to 18.7 %), 28.5 % (23.9 to 33.0 %), 21.4 % (18.0 to 24.9 %) and -1.6 %/h (-2.3 to -0.8 %/h). When compared with older models from the literature, performance was better with less overshoot after bolus doses., Conclusion: The new pharmacokinetic model of hydromorphone showed a good precision and a better performance than older models. It is therefore suitable for TCI with hydromorphone during postoperative pain therapy., Trial Registration: EudraCT 2013-002875-16, Clinical Trials NCT02035709.

For the quantification of propofol total and unbound drug concentrations a sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated. To separate unbound propofol an ultrafiltration step before sample preparation was performed. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with deuterated propofol as an internal standard. Separation was performed by gradient elution using UPLC-like system and analyzed by MS/MS consisting of an electrospray ionization source. To detect low and high concentration levels of propofol two calibration curves were identified and showed linearity within the range of 1-50ng/ml and 50-20000ng/ml. The lower limit of quantification was 1ng/ml. Intra- and interassay precision and accuracy did not exceed ±15%. The method was applied to a clinical study during intensive care treatment of patients after coronary artery bypass grafting., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Patient-controlled analgesia (PCA) is a common method for postoperative pain therapy, but it is characterized by large variation of plasma concentrations. PCA with target-controlled infusion (TCI-PCA) may be an alternative. In a previous analysis, the authors developed a pharmacokinetic model for hydromorphone. In this secondary analysis, the authors investigated the feasibility and efficacy of TCI-PCA for postoperative pain therapy with hydromorphone., Methods: Fifty adult patients undergoing cardiac surgery were enrolled in this study. Postoperatively, hydromorphone was applied intravenously during three sequential periods: (1) as TCI with plasma target concentrations of 1 to 2 ng/ml until extubation; (2) as TCI-PCA with plasma target concentrations between 0.8 and 10 ng/ml during the following 6 to 8 h; and (3) thereafter as PCA with a bolus dose of 0.2 mg until the next morning. During TCI-PCA, pain was regularly assessed using the 11-point numerical rating scale (NRS). A pharmacokinetic/pharmacodynamic model was developed using ordinal logistic regression based on measured plasma concentrations., Results: Data of 43 patients aged 40 to 81 yr were analyzed. The hydromorphone dose during TCI-PCA was 0.26 mg/h (0.07 to 0.93 mg/h). The maximum plasma target concentration during TCI-PCA was 2.3 ng/ml (0.9 to 7.0 ng/ml). The NRS score under deep inspiration was less than 5 in 83% of the ratings. Nausea was present in 30%, vomiting in 9%, and respiratory insufficiency in 5% of the patients. The EC50 of hydromorphone for NRS of 4 or less was 4.1 ng/ml (0.6 to 12.8 ng/ml)., Conclusion: TCI-PCA with hydromorphone offered satisfactory postoperative pain therapy with moderate side effects.

Acute kidney injury (AKI) is a frequent complication after cardiopulmonary bypass, but early detection of postoperative AKI remains challenging. Protein biomarkers predict AKI excellently in homogeneous cohorts but are less reliable in patients suffering from various comorbidities. We employed nuclear magnetic resonance spectroscopy in a prospective study of 85 adult cardiac surgery patients to identify metabolites prognostic of AKI in plasma specimens collected 24 h after surgery. Postoperative AKI of stages 1-3, as defined by the Acute Kidney Injury Network (AKIN), developed in 33 cases. A random forests classifier trained on the NMR spectra prognosticated AKI across all stages, with an average accuracy of 80 ± 0.9% and an area under the receiver operating characteristic curve of 0.87 ± 0.01. Prognostications were based, on average, on 24 ± 2.8 spectral features. Among the set of discriminative ions and molecules identified were Mg(2+), lactate, and the glucuronide conjugate of propofol. Using creatinine, Mg(2+), and lactate levels to derive an AKIN index score, we found AKIN 1 disease to be largely indistinguishable from AKIN 0, in concordance with the rather mild nature of AKIN 1 disease.

Heart rate variability (HRV) analysis is increasingly used in anaesthesia and intensive care monitoring of spontaneous breathing and mechanical ventilated patients. In the frequency domain, different estimation methods of the power spectral density (PSD) of RR-intervals lead to different results. Therefore, we investigated the PSD estimates of fast Fourier transform (FFT), autoregressive modeling (AR) and Lomb-Scargle periodogram (LSP) for 25 young healthy subjects subjected to metronomic breathing. The optimum method for determination of HRV spectral parameters under paced respiration was identified by evaluating the relative error (RE) and the root mean square relative error (RMSRE) for each breathing frequency (BF) and spectral estimation method. Additionally, the sympathovagal balance was investigated by calculating the low frequency/high frequency (LF/HF) ratio. Above 7 breaths per minute, all methods showed a significant increase in LF/HF ratio with increasing BF. On average, the RMSRE of FFT was lower than for LSP and AR. Therefore, under paced respiration conditions, estimating RR-interval PSD using FFT is recommend.

Background: 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., Methods: 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., 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., Conclusions: 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.

Objective: To determine safety and efficacy of the water-soluble prodrug fospropofol for anesthesia in cardiac surgery and to compare the pharmacodynamic profiles of fospropofol and propofol., Design: Pilot study and a prospective, phase I, open-label, single-center, randomized clinical trial., Setting: University hospital; single institution., Participants: Sixteen patients undergoing elective first-time coronary artery bypass surgery., Interventions: Patients were randomized to receive total intravenous anesthesia with fospropofol (n = 8) or propofol (n = 8) combined with alfentanil as total intravenous anesthesia. Bispectral index, arterial blood pressure, and heart rate were recorded continuously, and pulmonary artery catheter measurements were obtained. Plasma concentrations of formate, phosphate, and Ca(2+) were monitored closely. Safety and tolerability were assessed by adverse events, neurologic examinations, clinical laboratory tests, and vital signs., Measurements and Main Results: The total doses of fospropofol and propofol during anesthesia were 11.3±2.5 and 4.4±1.0 mg/kg/h, respectively. According to the achieved bispectral index (BIS) values, fospropofol was as effective as propofol in providing general anesthesia and sedation. There were no clinical signs of formate toxicity in the fospropofol group. The only treatment-related adverse event after administration of fospropofol was a transient burning sensation in the perineal and perianal region during induction of sedation or anesthesia., Conclusions: Fospropofol could be used to provide general anesthesia in patients undergoing coronary artery bypass graft surgery. Further larger studies are needed to prove the safety of fospropofol when given to provide general anesthesia for major cardiac surgical procedures., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A method for a sensitive and specific analysis of hydromorphone total and unbound drug concentrations in human plasma was developed and validated. Sample preparation was preceded with an ultrafiltration step to separate the unbound drug from the protein bound fraction of hydromorphone. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with stable isotope-labeled hydromorphone that was used as internal standard. Chromatographic separation was performed by gradient elution with UPLC-like system and eluates were analyzed by tandem mass spectrometry equipped with an electrospray ionization source. Sample preparation was optimized for good recovery of hydromorphone and the results were consistent. Calibration curves demonstrated linearity in the concentration range of 78-5000pg/ml for analysis of both total and unbound concentrations of hydromorphone. The limit of detection was 1pg and the lower limit of quantification was 78pg/ml for both total and unbound hydromorphone plasma drug concentrations. Intra- and interassay reproducibility and inaccuracy did not exceed 10%. Hydromorphone was on the average 14% bound to plasma proteins, supporting the previously published unreferenced statements that the protein binding of hydromorphone is low. Method was applied to a clinical trial in patients undergoing open heart surgery to generate a target controlled infusion model for the postoperative patient controlled analgesia with hydromorphone., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of sufentanil total and unbound drug concentrations. Unbound drug was separated by an ultrafiltration step before sample preparation. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with deuterated sufentanil used as an internal standard. Separation was performed by gradient elution using UPLC-like system and analysed by MS/MS consisting of an electrospray ionization source. Calibration curves showed linearity in the concentration range of 5-2500 pg/ml for analysis of both total and unbound concentrations of sufentanil. The lower limit of quantification was 5 pg/ml for both total and unbound sufentanil plasma drug concentrations. Intra- and interassay precision and accuracy did not exceed 15%. Method was applied to pharmacokinetic study in patients undergoing coronary artery bypass grafting., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Today, propofol or 2,6-diisopropylphenol is the anesthetic mainly used for monitored anesthetic care sedation and during intravenous anesthesia. The formulation, a lipid macroemulsion, shows several disadvantages. Therefore, during the past years considerable scientific effort has been undertaken to find either a better formulation or a prodrug of propofol. Fospropofol is the first propofol prodrug that has been intensively studied in man. It has been licensed in 2008 by the FDA for monitored anesthetic care sedation., Objectives and Methods: This review describes first published study results of fospropofol with regard to its pharmacokinetics/pharmacodynamics, drug safety, tolerability and drug side effects. Using a Medline search all published articles and abstracts containing the words fospropofol or GPI 15715 were included., Results and Conclusion: As the impact of an errorness drug assay for propofol liberated from fospropofol is not exactly defined, no clear conclusions can be drawn from the first published pharmacokinetic/pharmacodynamic studies. Fospropofol was well tolerated in the first two clinical studies and no serious side effects were reported. After characterization of the true pharmacokinetic/pharmacodynamics profile, fospropofol, an aqueous solution, has the potential to favorably compare with benzodiazepines for procedural sedation and also may be used for long-term sedation and intravenous anesthesia.

Spontaneous or evoked electrical brain activity is increasingly used to monitor general anesthesia. Previous studies investigated the variables from spontaneous electroencephalogram (EEG), acoustic (AEP), or somatosensory evoked potentials (SSEP). But, by monitoring them separately, the available information from simultaneous gathering could be missed. We investigated whether the combination of simultaneous information from EEG, AEP, and SSEP shows a more discriminant power to differentiate between anesthesia states than from information derived from each measurement alone. Therefore, we assessed changes of 30 EEG, 21 SSEP, and 29 AEP variables recorded from 59 patients during four clinical states of general anesthesia: "awake," "light anesthesia," "surgical anesthesia," and "deep surgical anesthesia." The single and combined discriminant powers of EEG, AEP, and SSEP variables as predictors of these states were investigated by discriminant analysis. EEG variables showed a higher discriminant power than AEP or SSEP variables: 85%, 46%, and 32% correctly classified cases, respectively. The frequency of correctly classified cases increased to 90% and 91% with information from EEG + AEP and EEG + AEP + SSEP, respectively. Thus, future anesthesia monitoring should consider combined information simultaneously distributed on different electrophysiological measurements, rather than single variables or their combination from EEG or AEP or SSEP.

Bispectral analysis of the electroencephalogram (EEG) has been used for monitoring anesthesia. The estimation of bicoherence allows us to determine whether a given time series represents a linear random process in cases where the bicoherence is trivial, i.e., a mere constant independent of frequency. In this study, we investigated the proportion of EEG epochs with nontrivial bicoherence during surgical anesthesia with propofol and alfentanil as an indicator for the degree of nonlinearity in the EEG. We reanalyzed 90 h of EEG recorded from 20 patients undergoing abdominal surgery using the Hinich procedure, which provides a statistical test for the following hypothesis: the EEG is a linear random process. In approximately 90% of all artifact-free, stationary EEG epochs, the bicoherence was found to be zero or a mere constant. Under these conditions, the EEG can be considered as a linear random process. Our findings suggest that the spectral information in the frequency domain delivered by the EEG monitoring during anesthesia is largely contained in the power spectrum of the signal. This calls into question the benefit of EEG bispectral analysis for monitoring anesthesia effect.

GPI 15715 is the first water-soluble propofol prodrug that has been studied in humans. Present propofol lipid formulations have well known undesirable properties, for example, pain on injection and increased triglyceride concentrations. We investigated whether GPI 15715 is suitable to achieve and maintain moderate sedation for 2 h. Six male and six female volunteers received a target-controlled infusion of GPI 15715, with an initial propofol target concentration of 1.8 microg/mL and the possibility to adjust the propofol target once after 1 h. Propofol concentrations, the bispectral index, and modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) scores were monitored. The median MOAA/S score was 4 during the first hour and was 3 during the second hour of infusion. The propofol target had to be changed to 2.4 microg/mL in seven volunteers and to 3.0 microg/mL in two volunteers. A propofol concentration of 1.9 microg/mL had the highest probability to result in an MOAA/S score of 3, which corresponds with moderate sedation. We observed no serious side effects. We conclude that GPI 15715 produces excellent sedation.

Background: Target-controlled infusion (TCI) of propofol was initially realized as a device for prefilled syringes (Diprifusor). New TCI systems can be used with any propofol formulation. We compared two different propofol formulations with respect to accuracy of TCI and pharmacokinetics., Materials and Methods: A total of 10 volunteers received Diprivan 1% and Propofol 1% MCT Fresenius as TCI using the pharmacokinetic model of the Diprifusor. The prediction error was determined from measured arterial concentrations. A three-compartment model was fitted to the concentration data., Results: The median prediction error and the median absolute prediction error were -1.4% and 23.3% for Diprivan, and -5.9% and 17.8% for Propofol Fresenius. The drugs did not differ in pharmacokinetics but showed a smaller central volume of distribution than used for infusion control., Conclusions: The pharmacokinetic model of Diprifusor can also be used for TCI of Propofol Fresenius. The large volume of distribution in this model may cause an overshoot in concentration.

The computer-aided detection of artefacts became an essential task with increasing automation of quantitative electroencephalogram (EEG) analysis during anaesthesiological applications. The different algorithms published so far required individual manual adjustment or have been based on limited decision criteria. In this study, we developed an artificial neural networks-(ANN-)aided method for automated detection of artefacts and EEG suppression periods. 72 hr EEG recorded before, during and after anaesthesia with propofol have been evaluated. Selected parameterized patterns of 0.25 s length were used to train the ANN (22 input, 8 hidden and 4 output neurons) with error back propagation. The detection performance of the ANN-aided method was tested with processing epochs between 1 to10 s. Related to examiner EEG evaluation, the average detection performance of the method was 72% sensitivity and 80% specificity for artefacts and 90% sensitivity and 92% specificity for EEG suppression. The improvement in signal-to-noise ratio with automated artefact processing was 1.39 times for the spectral edge frequency 95 (SEF95) and 1.89 times for the approximate entropy (ApEn). We conclude that ANN-aided preprocessing provide an useful tool for automated EEG evaluation in anaesthesiological applications.

Objective: Bispectral analysis of the electroencephalogram (EEG) has been used to monitor depth of anesthesia. In the majority of publications this has been done using the so called Bispectral (BIS) Index. The exact relation of this index to bispectral quantities like the bispectrum and its normalized version the bicoherence has not yet been published. In case the EEG is a linear random process the bicoherence is trivial. It is a mere constant independent of the EEG frequency. If the signal is a linear Gaussian random process this constant is zero. In this case both the bispectrum and bicoherence are zero. The aim of this study was to determine the proportion of EEG epochs with non-trivial bicoherence during anesthesia with isoflurane/nitrous oxide., Methods: We reanalyzed 26.4 hr of EEG signal recorded in 8 patients during anesthesia for general abdominal surgery which were stored in digitized form on CD-Rom. The test developed by Hinich for Gaussianity and linearity was applied to these data. The test was validated with various kinds of surrogate data; especially the phase randomized (pr) EEG, synthetic Gaussian random data and the z-component of the Lorenz attractor and its pr version., Results: The proportion of epochs for which a non-trivial bicoherence was detected by the test was as follows: Lorenz data 95%, pr Lorenz data 5%, synthetic Gaussian data 13.8%, pr EEG 5.4%, original EEG 6.2%., Conclusion: As expected the test procedure correctly identified for the Lorenz data for 95% of all epochs a non-trivial bicoherence. For the original EEG data we could not find a significant greater percentage of epochs with non-trivial bicoherence than for the pr data and the synthetic Gaussian data. We conclude that the EEG during anesthesia with isoflurane/alfentanil appears to be largely a linear random process.