Pharmacokinetics of remimazolam after intravenous infusion in anaesthetised children.

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, 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. 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.

Patient-Controlled Analgesia After Cardiac Surgery With Median Sternotomy: No Advantages of Hydromorphone When Compared to Morphine.

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.

Evaluation of antihyperalgesic and analgesic effects of 35% nitrous oxide when combined with remifentanil: A randomised phase 1 trial in volunteers.

BACKGROUND: Remifentanil is an effective drug in peri-operative pain therapy, but it can also induce and aggravate hyperalgesia. Supplemental administration of N2O may help to reduce remifentanil-induced hyperalgesia. OBJECTIVE: To evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion. DESIGN: Single site, phase 1, double-blind, placebo-controlled, randomised crossover study. SETTING: University Hospital, Germany from January 2012 to April 2012. PARTICIPANTS: Twenty-one healthy male volunteers. INTERVENTIONS: Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions in a randomised order: 50 to 50% N2-O2 and intravenous (i.v.) 0.9% saline infusion (placebo); 50 to 50% N2-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (remifentanil); 35 to 15 to 50% N2O-N2-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (tested drug) and 50 to 50% N2O-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (gas active control). Gas mixtures were inhaled for 60 min; i.v. drugs were administered for 30 min. MAIN OUTCOME MEASURES: Areas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min. RESULTS: Data from 20 volunteers were analysed. There were significant treatment and treatment-by-time effects regarding areas of hyperalgesia (P < 0.001). After the treatment period, the area of hyperalgesia was significantly reduced (P < 0.001) in the tested drug and in the gas active control (30.6 ±â€Š9.25 and 24.4 ±â€Š7.3 cm2, respectively) compared with remifentanil (51.0 ±â€Š17.0 cm2). There was also a significant difference between the gas active control and the tested drug sessions (P < 0.001). For the area of allodynia and pain rating, results were consistent with the results for hyperalgesia. CONCLUSIONS: Administration of 35% N2O significantly reduced hyperalgesia, allodynia and pain intensity induced after remifentanil. It might therefore be suitable in peri-operative pain relief characterised by hyperalgesia and allodynia, such as postoperative pain, and may help to reduce opioid demand. TRIAL REGISTRATION: EudraCT-No.: 2011-000966-37.

Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers: Part I. Pharmacokinetics and Clinical Pharmacodynamics.

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.

Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers: Part II. Pharmacodynamics of Electroencephalogram Effects.

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.

Postoperative pain therapy with hydromorphone; comparison of patient-controlled analgesia with target-controlled infusion and standard patient-controlled analgesia: A randomised controlled trial.

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 ±â€Š6 min during TCI-PCA, compared with 19 ±â€Š4 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.

Accuracy and Trending Ability of the Fourth-Generation FloTrac/EV1000 System in Patients With Severe Aortic Valve Stenosis Before and After Surgical Valve Replacement.

OBJECTIVE: Evaluate the accuracy and trending ability of the fourth-generation FloTrac/EV1000 (Edwards Lifesciences, Irvine, CA) system in patients with severe aortic valve stenosis by comparing FloTrac/EV1000-derived cardiac output (CCO-FT) with continuous thermodilution pulmonary artery catheter (CCO-PAC) measurements before and after surgical valve replacement. DESIGN: Prospective clinical study. SETTING: Anesthesia for cardiac surgery, operating room, single-center university hospital. PARTICIPANTS: Twenty-five patients were included. After exclusion, 20 patients undergoing elective aortic valve replacement were analyzed. INTERVENTIONS: After induction of general anesthesia, CCO-FT and CCO-PAC values were recorded every 30 seconds before and after aortic valve replacement with a bioprosthesis under cardiopulmonary bypass (CPB). MEASUREMENTS AND MAIN RESULTS: Data were analyzed separately from skin incision to last suture and before and after CPB. Regression analyses, Bland-Altman analyses, and trending analyses (4-quadrant plot, polar plot) were performed. The percentage errors of the FloTrac/EV1000 were 69.7% and 59.3% before and after CPB, respectively. The concordance rates (CRs) and angular CRs of the FloTrac/EV1000 were 50.9% and 57.1%, and 48.7% and 61.9% before and after CPB, respectively. CONCLUSION: This study revealed a low level of agreement and poor trending ability of the FloTrac/EV1000 system compared to continuous thermodilution pulmonary artery catheter in patients with severe aortic stenosis. Although there was a slight improvement after surgical valve replacement and CPB, the results were not within acceptable limits to replace CCO-PAC in this patient population.

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

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.

A high risk of sleep apnea is associated with less postoperative cognitive dysfunction after intravenous anesthesia: results of an observational pilot study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Intravenous theophylline is the most effective intervention to prolong EEG seizure duration in patients undergoing electroconvulsive therapy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Patient-controlled Analgesia with Target-controlled Infusion of Hydromorphone in Postoperative Pain Therapy.

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.

Anatomical location of the vocal cords in relation to cervical vertebrae: A new predictor of difficult laryngoscopy?

BACKGROUND: Several anatomical factors, such as prognathism, sex, short thyromental distance and others are known to make direct laryngoscopy difficult. OBJECTIVE: We investigated the hypothesis that the anatomical position of the vocal cords in relation to the cervical vertebrae correlates with difficult laryngoscopy. Existing MRI was used to identify the position of the vocal cords relative to the cervical spine in patients with and without difficult laryngoscopy. DESIGN: Observational study with adaptive enrichment. SETTING: University hospital. PATIENTS: A total of 142 adult patients, 91 with easy (Cormack-Lehane class 1 or 2) and 51 with difficult (Cormack-Lehane class 3 or 4) laryngoscopy. MAIN OUTCOME MEASURES: Position of the vocal cords relative to cervical vertebrae in patients with easy vs. difficult laryngoscopy. RESULTS: In patients with difficult laryngoscopy, we found a higher incidence of cranial position of the vocal cords in relation to the cervical spine compared with patients with easy laryngoscopy (P < 0.001). CONCLUSION: Anaesthesiologists should take advantage of existing imaging of the cervical spine when assessing the patient's airway.

Characterization of somatosensory profiles in patients with Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a painful chronic inflammatory bowel disease. It primarily affects terminal ileum, but the involvement of large and small intestines or extraintestinal manifestations is very common. CD may go along with neurogenic inflammation, mediated by substance P and CGRP, which are also key players in pain transmission. This may in turn contribute to hyperalgesia and altered somatosensory function in CD. METHODS: One hundred and three (103) patients with CD and 80 healthy volunteers were enrolled. Patient characteristics and disease history were documented. We used quantitative sensory testing (QST) to investigate the somatosensory profile in patients and volunteers. We also calculated z-scores for the QST results of the patients with CD based on the data of our control group. A 2-step cluster analysis, using all QST data, was performed to find subgroups within patients and volunteers. RESULTS: Thresholds of warm detection, mechanical pain, and vibration detection did significantly differ between patients with CD and volunteers. Z-scores indicated a general trend of sensory loss in CD patients with a significant relationship between patients with a sensory loss for cold and warm detection. In the hyposensitive cluster of the CD cohort, patients were more frequently male, had a higher incidence of extraintestinal manifestations, and suffered longer from CD. CONCLUSIONS: Our findings are consistent with the presence of a subclinical small fiber neuropathy. The group of CD patients with pronounced neuropathy findings were predominantly males, had a higher incidence of extraintestinal manifestations, and tended to have a longer history of disease duration.

Population pharmacokinetic modeling of hydromorphone in cardiac surgery patients during postoperative pain therapy.

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.

A randomized open-label phase I pilot study of the safety and efficacy of total intravenous anesthesia with fospropofol for coronary artery bypass graft 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.

Incidence and predictors of poor laryngoscopic view in children undergoing pediatric cardiac surgery.

OBJECTIVE: Previous investigations reported a higher incidence of poor laryngoscopic views in pediatric patients undergoing cardiac surgery. The objective of this study was to analyze why children undergoing cardiac surgery have such an increased incidence of poor laryngoscopic views during anesthesia induction. DESIGN: This study was designed as a retrospective analysis. SETTING: This analysis was based on a single-center cohort of a university hospital. PARTICIPANTS: One thousand one hundred seventy-seven general anesthesia procedures, including a direct laryngoscopic view over a period of 6 consecutive years, in pediatric patients undergoing cardiac surgery. INTERVENTIONS: Because of the retrospective character of this study, there were no study-related interventions. MEASUREMENTS AND MAIN RESULTS: Poor laryngoscopic views were defined as Cormack and Lehane (CML) grade III and IV. The overall incidence of poor laryngoscopic views was 3.5%. In patients younger than 1 year of age, the incidence of CML III or IV was significantly higher than in the older patients (5.6% v 1.7%). None of the patients with CML III/IV findings had Down syndrome; whereas in 9 of 41 patients with CML grade III/IV, a concomitant congenital syndrome like DiGeorge syndrome or CHARGE syndrome was found. CONCLUSIONS: The general incidence of CML III/IV findings during the induction of anesthesia for pediatric cardiac surgery is more than twice as high as reported in unselected pediatric cohorts. In patients below 1 year of age and in male patients, difficult laryngoscopy is more frequent. Concomitant Down syndrome was not associated with difficult laryngoscopy.

Postictal agitation after electroconvulsive therapy: incidence, severity, and propofol as a treatment option.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Incidence and predictors of difficult laryngoscopy in 11,219 pediatric anesthesia procedures.

OBJECTIVE: Difficult laryngoscopy in pediatric patients undergoing anesthesia. AIM: This retrospective analysis was conducted to investigate incidence and predictors of difficult laryngoscopy in a large cohort of pediatric patients receiving general anesthesia with endotracheal intubation. BACKGROUND: Young age and craniofacial dysmorphy are predictors for the difficult pediatric airway and difficult laryngoscopy. For difficult laryngoscopy, other general predictors are not yet described. METHODS: Retrospectively, from a 5-year period, data from 11.219 general anesthesia procedures in pediatric patients with endotracheal intubation using age-adapted Macintosh blades in a single center (university hospital) were analyzed statistically. RESULTS: The overall incidence of difficult laryngoscopy [Cormack and Lehane (CML) grade III and IV] was 1.35%. In patients younger than 1 year, the incidence of CML III or IV was significantly higher than in the older patients (4.7% vs 0.7%). ASA Physical Status III and IV, a higher Mallampati Score (III and IV) and a low BMI were all associated (P < 0.05) with difficult laryngoscopy. Patients undergoing oromaxillofacial surgery and cardiac surgery showed a significantly higher rate of CML III/IV findings. CONCLUSION: The general incidence of difficult laryngoscopy in pediatric anesthesia is lower than in adults. Our results show that the risk of difficult laryngoscopy is much higher in patients below 1 year of age, in underweight patients and in ASA III and IV patients. The underlying disease might also contribute to the risk. If the Mallampati score could be obtained, prediction of difficult laryngoscopy seems to be reliable. Our data support the existing recommendations for a specialized anesthesiological team to provide safe anesthesia for infants and neonates.

Long-Term Stability of Hydromorphone in Human Plasma Frozen at -20°C for Three Years Quantified by LC-MS/MS.

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.

Pharmacokinetics of Morphine and Morphine-6-Glucuronide During Postoperative Pain Therapy in Cardiac Surgery Patients.

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 (V1) = 8.1±2.2 L, steady-state volume of distribution (Vss) = 207±83 L, terminal elimination half-life (T1/2γ) = 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, V1 = 5.5±0.8 L, Vss = 15.8±0.8 L, T1/2ß = 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).