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1.
Anesthesiology ; 116(2): 311-23, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22222473

RESUMO

BACKGROUND: Various pharmacodynamic response surface models have been developed to quantitatively describe the relationship between two or more drug concentrations with their combined clinical effect. We examined the interaction of remifentanil and sevoflurane on the probability of tolerance to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy in patients to compare the performance of five different response surface models. METHODS: Forty patients preoperatively received different combined concentrations of remifentanil (0-12 ng/ml) and sevoflurane (0.5-3.5 vol.%) according to a criss-cross design (160 concentration pairs, four per patient). After having reached pseudosteady state, the response to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy was recorded. For the analysis of the probability of tolerance, five different interaction models were tested: Greco, Reduced Greco, Minto, Scaled C50(O) Hierarchical, and Fixed C50(O) Hierarchical model. All calculations were performed with NONMEM VI (Icon Development Solutions, Ellicott City, MD). RESULTS: The pharmacodynamic interaction between sevoflurane and remifentanil was strongly synergistic for both the hypnotic and the analgesic components of anesthesia. The Greco model did not result in plausible parameter estimates. The Fixed C50(O) Hierarchical model performed slightly better than the Scaled C50(O) Hierarchical and Reduced Greco models, whereas the Minto model fitted less well. CONCLUSION: We showed the importance of exploring various surface model approaches when studying drug interactions. The Fixed C50(O) Hierarchical model fits our data on sevoflurane remifentanil interaction best and appears to be an appropriate model for use in hypnotic-opioid drug interaction.


Assuntos
Anestésicos Inalatórios/metabolismo , Anestésicos Intravenosos/metabolismo , Éteres Metílicos/metabolismo , Modelos Biológicos , Piperidinas/metabolismo , Adulto , Anestésicos Inalatórios/administração & dosagem , Anestésicos Intravenosos/administração & dosagem , Interações Medicamentosas/fisiologia , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Éteres Metílicos/administração & dosagem , Piperidinas/administração & dosagem , Estudos Prospectivos , Remifentanil , Sevoflurano , Adulto Jovem
2.
Anesthesiology ; 112(4): 872-80, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20216387

RESUMO

BACKGROUND: The noxious stimulation response index (NSRI) is a novel anesthetic depth index ranging between 100 and 0, computed from hypnotic and opioid effect-site concentrations using a hierarchical interaction model. The authors validated the NSRI on previously published data. METHODS: The data encompassed 44 women, American Society of Anesthesiology class I, randomly allocated to three groups receiving remifentanil infusions targeting 0, 2, and 4 ng/ml. Propofol was given at stepwise increasing effect-site target concentrations. At each concentration, the observer assessment of alertness and sedation score, the response to eyelash and tetanic stimulation of the forearm, the bispectral index (BIS), and the acoustic evoked potential index (AAI) were recorded. The authors computed the NSRI for each stimulation and calculated the prediction probabilities (PKs) using a bootstrap technique. The PKs of the different predictors were compared with multiple pairwise comparisons with Bonferroni correction. RESULTS: The median (95% CI) PK of the NSRI, BIS, and AAI for loss of response to tetanic stimulation was 0.87 (0.75-0.96), 0.73 (0.58-0.85), and 0.70 (0.54-0.84), respectively. The PK of effect-site propofol concentration, BIS, and AAI for observer assessment of alertness and sedation score and loss of eyelash reflex were between 0.86 (0.80-0.92) and 0.92 (0.83-0.99), whereas the PKs of NSRI were 0.77 (0.68-0.85) and 0.82 (0.68-0.92). The PK of the NSRI for BIS and AAI was 0.66 (0.58-0.73) and 0.63 (0.55-0.70), respectively. CONCLUSION: The NSRI conveys information that better predicts the analgesic component of anesthesia than AAI, BIS, or predicted propofol or remifentanil concentrations. Prospective validation studies in the clinical setting are needed.


Assuntos
Analgésicos Opioides/farmacologia , Anestesia/normas , Hipnóticos e Sedativos/farmacologia , Monitorização Intraoperatória/métodos , Monitorização Intraoperatória/normas , Estimulação Física , Estimulação Acústica , Adulto , Algoritmos , Procedimentos Cirúrgicos Ambulatórios , Anestésicos Intravenosos , Interações Medicamentosas , Feminino , Procedimentos Cirúrgicos em Ginecologia , Humanos , Modelos Estatísticos , Dinâmica não Linear , Piperidinas , Propofol , Remifentanil
3.
Anesthesiology ; 111(4): 790-804, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19741484

RESUMO

BACKGROUND: Propofol and sevoflurane display additivity for gamma-aminobutyric acid receptor activation, loss of consciousness, and tolerance of skin incision. Information about their interaction regarding electroencephalographic suppression is unavailable. This study examined this interaction as well as the interaction on the probability of tolerance of shake and shout and three noxious stimulations by using a response surface methodology. METHODS: Sixty patients preoperatively received different combined concentrations of propofol (0-12 microg/ml) and sevoflurane (0-3.5 vol.%) according to a crisscross design (274 concentration pairs, 3 to 6 per patient). After having reached pseudo-steady state, the authors recorded bispectral index, state and response entropy and the response to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy. For the analysis of the probability of tolerance by logistic regression, a Greco interaction model was used. For the separate analysis of bispectral index, state and response entropy suppression, a fractional Emax Greco model was used. All calculations were performed with NONMEM V (GloboMax LLC, Hanover, MD). RESULTS: Additivity was found for all endpoints, the Ce(50, PROP)/Ce(50, SEVO) for bispectral index suppression was 3.68 microg. ml(-1)/ 1.53 vol.%, for tolerance of shake and shout 2.34 microg . ml(-1)/ 1.03 vol.%, tetanic stimulation 5.34 microg . ml(-1)/ 2.11 vol.%, laryngeal mask airway insertion 5.92 microg. ml(-1) / 2.55 vol.%, and laryngoscopy 6.55 microg. ml(-1)/2.83 vol.%. CONCLUSION: For both electroencephalographic suppression and tolerance to stimulation, the interaction of propofol and sevoflurane was identified as additive. The response surface data can be used for more rational dose finding in case of sequential and coadministration of propofol and sevoflurane.


Assuntos
Anestesia , Anestésicos Inalatórios/efeitos adversos , Anestésicos Intravenosos/efeitos adversos , Éteres Metílicos/efeitos adversos , Propofol/efeitos adversos , Adolescente , Adulto , Algoritmos , Interpretação Estatística de Dados , Interações Medicamentosas , Eletroencefalografia/efeitos dos fármacos , Entropia , Feminino , Humanos , Máscaras Laríngeas , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Estudos Prospectivos , Sevoflurano , Adulto Jovem
4.
Artigo em Inglês | MEDLINE | ID: mdl-19163978

RESUMO

The ability of anesthetic agents to provide adequate analgesia and sedation is limited by the ventilatory depression associated with overdosing in spontaneously breathing patients. Therefore, quantitation of drug induced ventilatory depression is a pharmacokinetic-pharmacodynamic problem relevant to the practice of anesthesia. Although several studies describe the effect of respiratory depressant drugs on isolated endpoints, an integrated description of drug induced respiratory depression with parameters identifiable from clinically available data is not available. This study proposes a physiological model of CO2 disposition, ventilatory regulation, and the effects of anesthetic agents on the control of breathing. The predictive performance of the model is evaluated through simulations aimed at reproducing experimental observations of drug induced hypercarbia and hypoventilation associated with intravenous administration of a fast-onset, highly potent anesthetic mu agonist (including previously unpublished experimental data determined after administration of 1 mg alfentanil bolus). The proposed model structure has substantial descriptive capability and can provide clinically relevant predictions of respiratory inhibition in the non-steady-state to enhance safety of drug delivery in the anesthetic practice.


Assuntos
Alfentanil/administração & dosagem , Alfentanil/farmacocinética , Dióxido de Carbono/metabolismo , Quimioterapia Assistida por Computador/métodos , Modelos Biológicos , Mecânica Respiratória/efeitos dos fármacos , Mecânica Respiratória/fisiologia , Anestésicos Intravenosos/administração & dosagem , Simulação por Computador , Humanos , Masculino
5.
Artigo em Inglês | MEDLINE | ID: mdl-18002943

RESUMO

Drug-induced respiratory depression is a common side effect of the agents used in anesthesia practice to provide analgesia and sedation. Depression of the ventilatory drive in the spontaneously breathing patient can lead to severe cardiorespiratory events and it is considered a primary cause of morbidity. Reliable predictions of respiratory inhibition in the clinical setting would therefore provide a valuable means to improve the safety of drug delivery. Although multiple studies investigated the regulation of breathing in man both in the presence and absence of ventilatory depressant drugs, a unified description of respiratory pharmacodynamics is not available. This study proposes a mathematical model of human metabolism and cardiorespiratory regulation integrating several isolated physiological and pharmacological aspects of acute drug-induced ventilatory depression into a single theoretical framework. The description of respiratory regulation has a parsimonious yet comprehensive structure with substantial predictive capability. Simulations relative to the synergistic interaction of the hypercarbic and hypoxic respiratory drive and the global effect of drugs on the control of breathing are in good agreement with published experimental data. Besides providing clinically relevant predictions of respiratory depression, the model can also serve as a test bed to investigate issues of drug tolerability and dose finding/control under non-steady-state conditions.


Assuntos
Anestesia/efeitos adversos , Hipnóticos e Sedativos/efeitos adversos , Modelos Biológicos , Respiração/efeitos dos fármacos , Insuficiência Respiratória/metabolismo , Doença Aguda , Sistemas de Liberação de Medicamentos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Cardiopatias/etiologia , Cardiopatias/metabolismo , Humanos , Hipercapnia/induzido quimicamente , Hipercapnia/metabolismo , Hipnóticos e Sedativos/administração & dosagem , Hipóxia/induzido quimicamente , Hipóxia/metabolismo , Insuficiência Respiratória/induzido quimicamente
6.
IEEE Trans Biomed Eng ; 53(3): 387-98, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16532765

RESUMO

During general anesthesia drugs are administered to provide hypnosis, ensure analgesia, and skeletal muscle relaxation. In this paper, the main components of a newly developed controller for skeletal muscle relaxation are described. Muscle relaxation is controlled by administration of neuromuscular blocking agents. The degree of relaxation is assessed by supramaximal train-of-four stimulation of the ulnar nerve and measuring the electromyogram response of the adductor pollicis muscle. For closed-loop control purposes, a physiologically based pharmacokinetic and pharmacodynamic model of the neuromuscular blocking agent mivacurium is derived. The model is used to design an observer-based state feedback controller. Contrary to similar automatic systems described in the literature this controller makes use of two different measures obtained in the train-of-four measurement to maintain the desired level of relaxation. The controller is validated in a clinical study comparing the performance of the controller to the performance of the anesthesiologist. As presented, the controller was able to maintain a preselected degree of muscle relaxation with excellent precision while minimizing drug administration. The controller performed at least equally well as the anesthesiologist.


Assuntos
Anestésicos Gerais/administração & dosagem , Quimioterapia Assistida por Computador/métodos , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Relaxamento Muscular/efeitos dos fármacos , Relaxamento Muscular/fisiologia , Fármacos Neuromusculares/administração & dosagem , Simulação por Computador , Combinação de Medicamentos , Humanos , Modelos Biológicos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia
7.
Anesthesiology ; 100(6): 1353-72, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15166553

RESUMO

BACKGROUND: The purpose of this investigation was to describe the pharmacodynamic interaction between propofol and remifentanil for probability of no response to shaking and shouting, probability of no response to laryngoscopy, Bispectral Index (BIS), and electroencephalographic approximate entropy (AE). METHODS: Twenty healthy volunteers received either propofol or remifentanil alone and then concurrently with a fixed concentration of remifentanil or propofol, respectively, via a target-controlled infusion. Responses to shaking and shouting and to laryngoscopy were assessed multiple times after allowing for plasma effect site equilibration. The raw electroencephalogram and BIS were recorded throughout the study, and AE was calculated off-line. Response surfaces were fit to the clinical response data using logistic regression or hierarchical response models. Response surfaces were also estimated for BIS and AE. Surfaces were visualized using three-dimensional rotations. Model parameters were estimated with NONMEM. RESULTS: Remifentanil alone had no appreciable effect on response to shaking and shouting or response to laryngoscopy. Propofol could ablate both responses. Modest remifentanil concentrations dramatically reduced the concentrations of propofol required to ablate both responses. The hierarchical response surface described the data better than empirical logistic regression. BIS and AE are more sensitive to propofol than to remifentanil. CONCLUSIONS: Remifentanil alone is ineffective at ablating response to stimuli but demonstrates potent synergy with propofol. BIS and AE values corresponding to 95% probability of ablating response are influenced by the combination of propofol and remifentanil to achieve this endpoint, with higher propofol concentrations producing lower values for BIS and AE.


Assuntos
Eletroencefalografia/efeitos dos fármacos , Hipnose/métodos , Laringoscopia/métodos , Piperidinas/farmacocinética , Propofol/farmacocinética , Adulto , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Sinergismo Farmacológico , Eletroencefalografia/métodos , Entropia , Feminino , Humanos , Modelos Logísticos , Masculino , Piperidinas/farmacologia , Propofol/farmacologia , Estudos Prospectivos , Remifentanil
8.
Anesthesiology ; 98(3): 621-7, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12606904

RESUMO

BACKGROUND: Several studies relating electroencephalogram parameter values to clinical endpoints using a single (mostly hypnotic) drug at relatively low levels of central nervous system depression (sedation) have been published. However, the usefulness of a parameter derived from the electroencephalogram for clinical anesthesia largely depends on its ability to predict the response to stimuli of different intensity or painfulness under a combination of a hypnotic and an (opioid) analgesic. This study was designed to evaluate the predictive performance of spectral edge frequency 95 (SEF95), BIS, and approximate entropy for the response to increasingly intense stimuli under different concentrations of both propofol and remifentanil in the therapeutic range. METHODS: Ten healthy male and ten healthy female volunteers were studied during coadministration of propofol and remifentanil. After having maintained a specific target concentration for 10 min, the depth of sedation-anesthesia was assessed using the responsiveness component of the Observer's Assessment of Alertness/Sedation (OAA/S) rating scale, which was modified by adding insertion of a laryngeal mask and laryngoscopy. The electroencephalogram derived parameters approximate entropy, bispectral index, and SEF95 were recorded just before sedation level was assessed. RESULTS: The prediction probability values for approximate entropy were slightly, but not significantly, better than those for bispectral index, SEF95, and the combination of drug concentrations. A much lower prediction ability was observed for tolerance of airway manipulation than for hypnotic endpoints. CONCLUSION: Approximate entropy revealed informations on hypnotic and analgesic endpoints using coadministration of propofol and remifentanil comparable to bispectral index, SEF95, and the combination of drug concentrations.


Assuntos
Anestesia , Anestésicos Intravenosos/administração & dosagem , Eletroencefalografia/efeitos dos fármacos , Entropia , Piperidinas/administração & dosagem , Propofol/administração & dosagem , Adulto , Feminino , Humanos , Masculino , Estudos Prospectivos , Remifentanil
9.
Anesth Analg ; 96(1): 142-7, table of contents, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12505940

RESUMO

UNLABELLED: We describe the development and evaluation of a simple slide rule that enables the bedside determination of the infusion rate for a particular target plasma concentration of propofol. The infusion rate to reach this target concentration at time (t) is the product of the target concentration, body weight, and a correction factor that depends on the time elapsed from the start of the initial infusion. Our target-controlled infusion (TCI) slide rule, constructed along this principle, performs the multiplications, analogous to the principle of the classical slide rule, as addition of logarithms. We calculated the percentage deviation of the predicted concentration obtained by STANPUMP versus predicted concentrations obtained using the infusion rates determined from the TCI slide rule. The evaluation using STANPUMP simulations showed, for a constant target concentration of 3 micro g/mL of propofol, a mean deviation of 4.05% (max, 6.97%) in the first 15 min and a mean deviation of 0.5% (max, 2.03%) between 16 and 300 min. The mean deviation after changing the target from 3 micro g/mL to 1, 2, 4, or 5 micro g/mL ranged from 1.15% to 17.76%. This pocket-sized TCI slide rule combines the advantages of minimal financial and technical cost with reasonable accuracy. IMPLICATIONS: We describe the development and evaluation of a simple slide rule that enables the bedside determination of the required infusion rate for a particular target plasma concentration. This pocket-sized target-controlled infusion slide rule combines the advantages of minimal financial and technical cost with reasonable accuracy.


Assuntos
Anestesia Intravenosa , Anestésicos Intravenosos/administração & dosagem , Propofol/administração & dosagem , Algoritmos , Anestésicos Intravenosos/sangue , Peso Corporal/fisiologia , Computadores Analógicos , Relação Dose-Resposta a Droga , Humanos , Infusões Intravenosas , Modelos Biológicos , Propofol/sangue
10.
Anesthesiology ; 96(1): 54-9, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11753002

RESUMO

BACKGROUND: Artifact robustness (i.e., size of deviation of an electroencephalographic parameter value from baseline caused by artifacts) and baseline stability (i.e., consistency of median baseline values) of electroencephalographic parameters profoundly influence electroencephalography-based pharmacodynamic parameter estimation and the usefulness of the processed electroencephalogram as measure of the arousal state of the central nervous system (depth of anesthesia). In this study, the authors compared the artifact robustness and the interindividual and intraindividual baseline stability of several univariate descriptors of the electroencephalogram (Shannon entropy, approximate entropy, spectral edge frequency 95, delta ratio, and canonical univariate parameter). METHODS: Electroencephalographic data of 16 healthy volunteers before and after administration of an intravenous bolus of propofol (2 mg/kg body weight) were analyzed. Each volunteer was studied twice. The baseline electroencephalogram was recorded for a median of 18 min before drug administration. For each electroencephalographic descriptor, the authors calculated the following: (1) baseline variability (= (median baseline - median effect) [i.e., signal]/SD baseline [i.e., noise]) without artifact rejection; (2) baseline variability with artifact rejection; and (3) baseline stability within and between individuals (= (median baseline - median effect) averaged over all volunteers/SD of all median baselines). RESULTS: Without artifact rejection, Shannon entropy and canonical univariate parameter displayed the highest signal-to-noise ratio. After artifact rejection, approximate entropy, Shannon entropy, and the canonical univariate parameter displayed the highest signal-to-noise ratio. Baseline stability within and between individuals was highest for approximate entropy. CONCLUSIONS: With regard to robustness against artifacts, the electroencephalographic entropy parameters and the canonical univariate parameter were superior to spectral edge frequency 95 and delta ratio. Electroencephalographic approximate entropy displayed the best interindividual and intraindividual baseline stability.


Assuntos
Eletroencefalografia , Adulto , Idoso , Artefatos , Humanos , Pessoa de Meia-Idade , Termodinâmica
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