Pharmacokinetic and pharmacodynamic considerations of general anesthesia in pediatric subjects.

Introduction: The target concentration strategy uses PKPD information for dose determination. Models have also quantified exposure-response relationships, improved understanding of developmental pharmacokinetics, rationalized dose prescription, provided insight into the importance of covariate information, explained drug interactions and driven decision-making and learning during drug development.Areas covered: The prime PKPD consideration is parameter estimation and quantification of variability. The main sources of variability in children are age (maturation) and weight (size). Model use is mostly confined to pharmacokinetics, partly because anesthesia effect models in the young are imprecise. Exploration of PK and PD covariates and their variability hold potential to better individualize treatment.Expert opinion: The ability to model drugs using computer-based technology is hindered because covariate data required to individualize treatment using these programs remain lacking. Target concentration intervention strategies remain incomplete because covariate information that might better predict individualization of dose is absent. Pharmacogenomics appear a valuable area for investigation for pharmacodynamics and pharmacodynamics. Effect measures in the very young are imprecise. Assessment of the analgesic component of anesthesia is crude. While neuromuscular monitoring is satisfactory, depth of anaesthesia EEG interpretation is inadequate. Closed loop anesthesia is possible with better understanding of EEG changes.

Sex effects on behavioral markers of emergence from propofol and isoflurane anesthesia in rats.

Clinical studies have demonstrated sex-related differences in recovery from surgical anesthesia. This study aimed to characterize the emergence pattern following two anesthesia regimens in both sexes of rats. We considered six different markers of emergence from anesthesia: sigh, eye blinking, forelimb movement, mastication, neck extension, and recovery of the righting reflex (RORR). Spontaneous motor activity 24 h after the anesthesia induction was also examined. Our results showed that the rank order of the emergence latency after intraperitoneal propofol, PRO, exposure was forelimb movement < sigh < blink < mastication < neck extension < RORR, while after inhaled isoflurane, ISO, anesthesia the sequence was changed as sigh < blink < mastication < forelimb movement < neck extension < RORR in both male and female rats. Moreover, the latency to emergence after PRO in female rats was significantly higher than male rats, although following ISO there was no difference between the sexes (P < 0.001; P > 0.05, respectively). Open-field testing revealed no difference in PRO and ISO spontaneous locomotor activity due to drug administration (P > 0.05). These two anesthetics presented different emergence sequences. Although clinical data suggests that females arouse faster than males from anesthesia with propofol, our intraperitoneal technique in a rodent model had the opposite effect. Pharmacokinetic analysis demonstrated increased absorption of injected propofol for the female rats in our study, emphasizing the role of sexual dimorphism in drug distribution in rodents. Despite these pharmacokinetic differences, the pharmacodynamic effects of the drugs were remarkably consistent among both sexes through emergence.

The pharmacogenetics of medications used in general anesthesia.

General anesthesia is a state of unconsciousness, amnesia, analgesia and akinesia induced by drugs including opioids, hypnotic-sedative agents, muscle relaxants and antiemetics. Clinical and genetic factors are reported to influence the efficacy and side effects of these agents. Based on the evidence, clinical action is needed to improve clinical outcomes. This review summarizes the latest knowledge with regards to the pharmacogenetics of anesthetics and general anesthesia related complications.

Design, Synthesis, and Evaluation of Novel 2,6-Disubstituted Phenol Derivatives as General Anesthetics.

A novel series of optically active 2,6-disubstituted alkylphenols with improved anesthetic profiles compared to widely used propofol were synthesized. The incorporation of the cyclopropyl group not only increased the steric effect but also introduced stereoselective effects over their anesthetic properties. Compounds 1, 2, and 6 were selected as potential candidates for further preclinical development including studies of their water-soluble prodrugs. Clinical studies of candidate compound 6 (Haisco HSK3486) as a general anesthetic are being performed in Australia and China.

Impact of malnutrition on propofol consumption and recovery time among patients undergoing laparoscopic gastrointestinal surgery.

BACKGROUND: Malnutrition is a major health problem, especially in hospitalized patients as it can be closely related to many post-operative complications. However, research on malnutrition and its effect on the outcome of general anesthesia have been largely neglected. Here we investigated malnutrition status on propofol consumption and recovery time among patients undergoing laparoscopic gastrointestinal surgery under general anesthesia. METHODS: One hundred and one patients were recruited between January and June 2012 at Tongji Hospital and assigned into three groups according to Nutritional Risk Screening Tool 2002 score. A standard combined general anesthesia procedure was performed under regular monitoring. The dosage of propofol needed for induction, consumption during maintenance and recovery time were recorded. RESULTS: When compared with normal nutritional status individuals, the propofol dosage at induction was significantly decreased about 4.3% in moderate malnutritional status patients (P < 0.01) and about 16.8% in severely malnutritional status patients (P < 0.01). The average consumption of propofol was also significantly lower in malnourished individuals; for moderate malnutritional, the decrease was about 20% (P < 0.01) while for the severely malnutritional, it was 30% (P < 0.01) when compared with normal nutritional status individuals. For the recovery time of propofol anesthesia, the patients with severe malnutritional status awoke average 6.8 min later than those normally nourished (P < 0.01), but those patients with moderate malnutrition status did not (P = 0.885). CONCLUSION: The present results indicate that the dosage and recovery time of propofol does change in malnourished individuals. Therefore, malnutrition may somehow affect the outcome of general anesthesia.

Evaluation of risk factors, including fluconazole administration, for prolonged anesthetic recovery times in horses undergoing general anesthesia for ocular surgery: 81 cases (2006-2013).

OBJECTIVE--To determine risk factors for prolonged anesthetic recovery time in horses that underwent general anesthesia for ocular surgery. DESIGN--Retrospective cohort study. ANIMALS--81 horses that underwent general anesthesia for ocular surgery between 2006 and 2013. PROCEDURES--Descriptive information recorded included the ocular procedure performed, concurrent fluconazole treatments, analgesic and anesthetic agents administered, procedure duration, use of sedation for recovery, and recovery time. Data were analyzed for associations between recovery time and other variables. RESULTS--81 horses met inclusion criteria. In 72 horses, anesthesia was induced with ketamine and midazolam; 16 horses treated concurrently with fluconazole had significantly longer mean recovery time (109 minutes [95% confidence interval {CI}, 94 to 124 minutes]) than did 56 horses that were not treated with fluconazole (50 minutes [95% CI, 44 to 55 minutes]). In 9 horses anesthetized with a protocol that included ketamine but did not include midazolam, there was no difference between mean recovery time in horses that either received (59 minutes [95% CI, 36 to 81 minutes]; n = 5) or did not receive (42 minutes [95% CI, 16 to 68 minutes]; 4) fluconazole. Other variables identified as risk factors for prolonged recovery included duration of anesthesia and use of acepromazine for premedication. CONCLUSIONS AND CLINICAL RELEVANCE--Fluconazole administration was associated with prolonged anesthetic recovery time in horses when ketamine and midazolam were used to induce anesthesia for ocular surgery. Duration of anesthesia and premedication with acepromazine were also identified as risk factors for prolonged recovery time.

[Reversion of sedation and general anaesthesia--agonist-antagonist technique].

OBJECTIVE: To study an expediency and efficacy of application of different reverses drugs (naloxone, flumazenil, neostigmine, galantamine, sugammadex) either their separate or combined using. METHODS: We studied 119 patients underwent endoluminal endoscopic procedures and surgeries on trachea-bronchial tree and intestines under sedation or general anaesthesia. RESULTS: The article deals with conceptual approaches to the reversal of residual effects of opioids, benzodiazepine sedation and neuromuscular block (the so-called agonist-antagonist technique). CONCLUSIONS: A reversion of neuromuscular block without using of antagonists' combination does not provide complete recovery of psychomotor and cognitive functions for rapid socialization of patients after anaesthesia.

Comparison of relative distribution of ketamine and norketamine in decomposed skeletal tissues following single and repeated exposures.

Bone was analyzed for ketamine and norketamine to examine whether different patterns of drug exposure could be discriminated. Rats received (intraperitoneally) one 75 mg/kg dose (Acute-1 and Acute-2 groups), three 25-mg/kg doses 1 hour apart (Repeated group), or nine single daily ketamine doses of 75 mg/kg followed by a 24-h washout period (Chronic group). Following euthanasia, all animals decomposed to skeleton outdoors. Ground samples of recovered bone underwent methanolic extraction and analysis by gas chromatography-mass spectrometry after solid-phase extraction. Drug levels (mass normalized response ratios) were compared across bone types and exposure pattern. Bone type significantly influenced drug level for the Acute-1 and Repeated dose groups, and the drug/metabolite level ratio (DMLR) for the Acute-1 group. Mean ketamine and norketamine level and DMLR varied by up to 8-fold, 7-fold and 3-fold, respectively, in the Acute-1 group, and by up to 24-fold, 5-fold and 10-fold, respectively, in the Repeated group. Drug level and DMLR differed significantly between the Acute-1 and Repeated groups for most bone types. In the Chronic group, only 1/16 and 4/16 samples were positive for ketamine and norketamine, respectively. All Acute-2 samples were positive for ketamine and norketamine. The Acute-2 and Chronic groups differed significantly in ketamine and norketamine levels, and DMLR.

Special article: general anesthetic gases and the global environment.

General anesthetics are administered to approximately 50 million patients each year in the United States. Anesthetic vapors and gases are also widely used in dentists' offices, veterinary clinics, and laboratories for animal research. All the volatile anesthetics that are currently used are halogenated compounds destructive to the ozone layer. These halogenated anesthetics could have potential significant impact on global warming. The widely used anesthetic gas nitrous oxide is a known greenhouse gas as well as an important ozone-depleting gas. These anesthetic gases and vapors are primarily eliminated through exhalation without being metabolized in the body, and most anesthesia systems transfer these gases as waste directly and unchanged into the atmosphere. Little consideration has been given to the ecotoxicological properties of gaseous general anesthetics. Our estimation using the most recent consumption data indicates that the anesthetic use of nitrous oxide contributes 3.0% of the total emissions in the United States. Studies suggest that the influence of halogenated anesthetics on global warming will be of increasing relative importance given the decreasing level of chlorofluorocarbons globally. Despite these nonnegligible pollutant effects of the anesthetics, no data on the production or emission of these gases and vapors are publicly available. The primary goal of this article is to critically review the current data on the potential effects of general anesthetics on the global environment and to describe possible alternatives and new technologies that may prevent these gases from being discharged into the atmosphere.

Target Controlled Infusion algorithms for anesthesia: theory vs practical implementation.

Target Controlled Infusion (TCI) systems are based in drug pharmacokinetic and pharmacodynamic models implemented in an algorithm to drive an infusion pump. Infusion control algorithms have been designed, implemented and validated for several anesthetic drugs, devices and controllers. The maintenance phase in these algorithms is represented by an equation that compensates the loss of drug from the central compartment and maintains the set target concentration. The goal of the current study was to improve existing TCI software with a new method for the maintenance phase. We compared and analyzed two different methods to find the more efficient method for the maintenance phase in an open-loop control TCI system.

Low minimum alveolar concentration alarm: a standard for prevention of awareness during general anaesthesia maintained by inhalational anaesthetics.

Awareness during general anaesthesia is a rare but significant problem that can be frightening to the patients. We suggest that newer generation monitors should include this facility to provide a low alarm limit to MAC settings so as to improve the quality of patient care. Also we suggest that a "near empty" alarm be incorporated into vaporizers which can warn the anaesthesiologist prior to development of possible light plane of anaesthesia. We hope that adopting these two features can help enhance patient safety and can further aid in quality assurance.

A model-predictive hypnosis control system under total intravenous anesthesia.

In ambulatory surgery, anesthetic drugs must be administered at a suitable rate to prevent adverse reactions after discharge from the hospital. To realize more appropriate anesthesia, we have developed a hypnosis control system, which administers propofol as an anesthetic drug to regulate the bispectral index (BIS), an electroencephalography (EEG)-derived index reflecting the hypnosis of a patient. This system consists of three functions: 1) a feedback controller using a model-predictive control method, which can adequately accommodate the effects of time delays; 2) a parameter estimation function of individual differences; and 3) a risk control function for preventing undesirable states such as drug overinfusion or intraoperative arousal. With the approval of the ethics committee of our institute, 79 clinical trials took place since July 2002. The results show that our system can reduce the total amount of propofol infusion and maintain the BIS more accurately than anesthesiologist's manual adjustment.

Synchronization software for automation in anesthesia.

This work presents the development of a software for data acquisition and control (ASYS) on a clinical setup. Similar to the industrial Supervisory Control And Data Acquisition (SCADA) the software assembles a Target Controlled Infusion (TCI) monitoring and supervisory control data in real time from devices in a surgical room. The software is not a full controller since the TCI systems comprehend permanent interaction from the anesthesiologist. Based on pharmacokinetic models, the effect-site and plasma concentrations can be related with the drug dose infused and vice versa. The software determines the infusion rates of the drug which are given as commands to the infusion pumps. This software provides the anesthesiologist with a trustworthy tool for managing a safe and balanced anesthesia. Since it also incorporates the acquisition and display of patients brain signals.

Pharmacokinetic/pharmacodynamic modeling of anesthetics in children: therapeutic implications.

Modeling the pharmacokinetics and pharmacodynamics of anesthetics in children is performed as a response to the clinical need for safe and efficacious administration of drugs with a low therapeutic index. Rates and concentrations of these drugs, which are the primary parameters used by anesthesiologists, depend on physiologic parameters that are markedly affected by development. Volatile anesthetics have been used for >50 years in pediatric patients. The pharmacokinetics of inhalation agents are context sensitive, but little difference between age groups has been described. These agents are not only eliminated unchanged by the lung but they are also metabolized by the liver. Halothane has Michaelis-Menten kinetics, with up to 40% of the administered dose metabolized by the liver. For volatile anesthetics, the effect measured is the minimum alveolar concentration (MAC) that leads to movement of the limb in response to skin incision in 50% of the patients studied. The MAC is higher in infants than in children and adults. Infants aged 6 months have a MAC 1.5-1.8 times the MAC observed in adults aged 40 years. Children have a greater clearance and volume of distribution of propofol than adults. In order to achieve similar plasma concentrations, children require three times the initial dose used in adults. In adults, an increased sensitivity to propofol has been demonstrated with aging, but nothing is known about the effects in children. However, it is clear that equipotent doses of propofol induce marked deleterious hemodynamic effects in infants compared with children. Regional anesthesia is used in pediatrics, both in combination with general anesthesia during surgery or alone for postoperative analgesia. A marked decrease in protein binding has been described in infants. In the postoperative period, a rapid increase in binding because of inflammation decreases the free fraction, but the free drug concentration remains constant because of the resulting decrease in total clearance. A low clearance because of liver function immaturity has been observed during the first year(s) of life for bupivacaine and ropivacaine. Pharmacodynamic interactions between general anesthesia and regional anesthesia need to be modeled. This is one of the future tasks for pharmacokineticists. Methods such as the Dixon up-and-down allocation and the isobolographic technique are promising in this field.

Comparative binding character of two general anaesthetics for sites on human serum albumin.

Propofol and halothane are clinically used general anaesthetics, which are transported primarily by HSA (human serum albumin) in the blood. Binding characteristics are therefore of interest for both the pharmacokinetics and pharmacodynamics of these drugs. We characterized anaesthetic-HSA interactions in solution using elution chromatography, ITC (isothermal titration calorimetry), hydrogen-exchange experiments and geometric analyses of high-resolution structures. Binding affinity of propofol to HSA was determined to have a K(d) of 65 microM and a stoichiometry of approx. 2, whereas the binding of halothane to HSA showed a K(d) of 1.6 mM and a stoichiometry of approx. 7. Anaesthetic-HSA interactions are exothermic, with propofol having a larger negative enthalpy change relative to halothane. Hydrogen-exchange studies in isolated recombinant domains of HSA showed that propofol-binding sites are primarily found in domain III, whereas halothane sites are more widely distributed. Both location and stoichiometry from these solution studies agree with data derived from X-ray crystal-structure studies, and further analyses of the architecture of sites from these structures suggested that greater hydrophobic contacts, van der Waals interactions and hydrogen-bond formation account for the stronger binding of propofol as compared with the less potent anaesthetic, halothane.