RESUMEN
BACKGROUND: Midazolam, at sedative levels, increases blood propofol concentrations by 25%. We evaluated the reverse interaction and determined the influence of propofol on the pharmacokinetics of midazolam. METHODS: Eight healthy male volunteers were studied on 2 occasions in a random crossover manner. During session A, volunteers received midazolam 0.035 to 0.05 mg x kg(-1) IV for 1 minute followed by an infusion of 0.035 to 0.05 mg x kg(-1) x h(-1) for 59 minutes. During session B, in addition to this midazolam infusion scheme, a target-controlled infusion of propofol (constant C(T): 0.6 or 1.0 microg x mL(-1)) was given from 15 minutes before the start until 6 hours after termination of the midazolam infusion. Arterial blood samples for propofol and midazolam concentration analysis were taken until 6 hours after termination of the midazolam infusion. Nonlinear mixed-effect models examining the influence of propofol and hemodynamic variables on midazolam pharmacokinetics were constructed using Akaike's information-theoretic criterion for model selection. RESULTS: In the presence of a mean blood propofol concentration of 1.2 microg x mL(-1), the plasma midazolam concentration was increased by 26.9% + or - 9.4% compared with midazolam given as a single drug. Propofol (C(blood): 1.2 microg x mL(-1)) reduced midazolam central volume of distribution from 5.37 to 2.98 L, elimination clearance from 0.39 to 0.31 L x min(-1), and rapid distribution clearance from 2.77 to 2.11 L x min(-1). Inclusion of heart rate further improved the pharmacokinetic model of midazolam. CONCLUSIONS: Propofol reduces the distribution and clearance of midazolam in a concentration-dependent manner. In addition, inclusion of heart rate as a covariate improved the pharmacokinetic model of midazolam predominantly through a reduction in the intraindividual variability.
Asunto(s)
Anestésicos Intravenosos/farmacología , Hipnóticos y Sedantes/farmacocinética , Midazolam/farmacocinética , Propofol/farmacología , Adulto , Algoritmos , Anestésicos Intravenosos/sangre , Simulación por Computador , Estudios Cruzados , Interacciones Farmacológicas , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Humanos , Hipnóticos y Sedantes/sangre , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Midazolam/sangre , Modelos Estadísticos , Dinámicas no Lineales , Propofol/sangre , Distribución TisularRESUMEN
BACKGROUND: Indocyanine green plasma disappearance rate (ICG-PDR) is used to evaluate hepatic function. Although hepatic failure is generally said to occur with an ICG-PDR <18%/min, ICG disappearance rate is poorly defined in the healthy population, and a clear cutoff value of ICG-PDR that discriminates between normal hepatic function and hepatic failure has not yet been described. We therefore defined the ICG disappearance rate in an otherwise healthy patient population. In addition, we evaluated the noninvasive measurement of ICG-PDR (transcutaneously by pulse dye densitometry [PDD] at the finger and the nose) and compared these with the simultaneously performed invasive measurements of ICG-PDR (in arterial blood). METHODS: In patients without signs of liver disease, scheduled for elective nonhepatic surgery, 10 mg ICG was administered IV and ICG-PDR measured by PDD (DDG-2001, Nihon Kohden, Tokyo, Japan). In a subset of patients, arterial blood samples were gathered to compare PDD with invasive ICG measurements. Methods were compared using Bland-Altman analysis. The results of our study and reported studies on discriminative use of ICG-PDR in assessing liver failure were used to construct receiver operating characteristic curves. RESULTS: Forty-one patients were studied: 33 using the finger probe and 8 using the nose probe. The mean +/- SD noninvasive ICG-PDR in this patient population is 23.1% +/- 7.9%/min (n = 41) with a range of 9.7% to 43.2%/min. Bias (+/-2 sd, limits of agreement) for ICG-PDR measured by PDD compared with those measured in arterial blood were 1.6%/min (-5.2% to 8.3%/min) for the finger probe and -6.0%/min (-15.5% to 3.4%/min) for the nose probe. CONCLUSION: ICG-PDR values in a population without liver failure ranged well below 18%/min, cited as the cutoff value for hepatic failure. This cutoff value needs reconsideration. In addition, we conclude that the ICG concentration is adequately determined noninvasively by PDD.
Asunto(s)
Colorantes , Densitometría , Estado de Salud , Verde de Indocianina , Pruebas de Función Hepática , Adulto , Colorantes/farmacocinética , Densitometría/métodos , Femenino , Humanos , Verde de Indocianina/farmacocinética , Masculino , Persona de Mediana Edad , EspectrofotometríaRESUMEN
BACKGROUND: Changes in patient length of stay (the duration of 1 clinic visit) as a result of the introduction of an electronic patient file system forced an anesthesia department to change its outpatient clinic organization. In this study, we sought to demonstrate how the involvement of essential employees combined with mathematical techniques to support the decision-making process resulted in a successful intervention. METHODS: The setting is the preanesthesia evaluation clinic (PAC) of a university hospital, where patients consult several medical professionals, either by walk-in or appointment. Queuing theory was used to model the initial set-up of the clinic, and later to model possible alternative designs. With the queuing model, possible improvements in efficiency could be investigated. Inputs to the model were patient arrival rates and expected service times with clinic employees, collected from the clinic's logging system and by observation. The performance measures calculated with the model were patient length of stay and employee utilization rate. Supported by the model outcomes, a working group consisting of representatives of all clinic employees decided whether the initial design should be maintained or an intervention was needed. RESULTS: The queuing model predicted that 3 of the proposed alternatives would result in better performance. Key points in the intervention were the rescheduling of appointments and the reallocation of tasks. The intervention resulted in a shortening of the time the anesthesiologist needed to decide upon approving the patient for surgery. Patient arrivals increased sharply over 1 yr by more than 16%; however, patient length of stay at the clinic remained essentially unchanged. If the initial set-up of the clinic would have been maintained, the patient length of stay would have increased dramatically. CONCLUSIONS: Queuing theory provides robust methods to evaluate alternative designs for the organization of PACs. In this article, we show that queuing modeling is an adequate approach for redesigning processes in PACs.
Asunto(s)
Servicio de Anestesia en Hospital/organización & administración , Hospitales Universitarios/organización & administración , Tiempo de Internación , Sistemas de Registros Médicos Computarizados/organización & administración , Modelos Organizacionales , Visita a Consultorio Médico , Objetivos Organizacionales , Servicio Ambulatorio en Hospital/organización & administración , Adolescente , Adulto , Citas y Horarios , Técnicas de Apoyo para la Decisión , Eficiencia Organizacional , Necesidades y Demandas de Servicios de Salud , Investigación sobre Servicios de Salud , Humanos , Cuerpo Médico de Hospitales/estadística & datos numéricos , Admisión y Programación de Personal , Desarrollo de Programa , Evaluación de Programas y Proyectos de Salud , Reproducibilidad de los Resultados , Factores de Tiempo , Estudios de Tiempo y Movimiento , Adulto JovenRESUMEN
BACKGROUND: Noninvasive cardiac output (CO) monitoring is possible by indocyanine green (ICG) dilution measured by pulse dye densitometry (PDD). To validate the precision of this method, we compared hemodynamic variables derived from PDD (DDG-2001, Nihon Kohden, Japan) with those derived from simultaneously taken arterial blood ICG concentrations. METHODS: In 20 patients (6 M/14 F), ASA I or II, 36 sessions were performed (n = 24 with the PDD-finger probe, n = 10 with the PDD-nose probe). After IV administration of 10 mg ICG, 34 arterial blood samples were taken during each session, with 20 samples taken during the first 2 min. CO, central blood volume (CBV), and total blood volume (TBV) were calculated independently from ICG and PDD and the results compared between methods using Bland-Altman analysis. The results are reported as mean difference (bias) and limits of agreement (LOA = +/- 2 sd). RESULTS: PDD using the finger probe underestimated CO (LOA) by 5% (-56% and 47%); overestimated CBV by 21% (-54% and 96%) and underestimated TBV by -15% (-38% and 8%). PDD using the nose probe overestimated CO (LOA) by 30% (-67% and 127%); CBV by 48% (-98% and 193%) and underestimated TBV by -10% (-47% and 27%). CONCLUSION: Despite the permissible bias, the wide LOA of the PDD-derived hemodynamic variables CO and CBV, compared with those simultaneously obtained by invasive arterial ICG measurements, suggest that PDD is unsuitable for evaluation of cardiovascular variables in the individual patient. Hence, the reliability and clinical use of this method seem limited.
Asunto(s)
Densitometría/métodos , Técnica de Dilución de Colorante , Hemodinámica/fisiología , Verde de Indocianina , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Volumen Sanguíneo/fisiología , Gasto Cardíaco/fisiología , Colorantes , Interpretación Estadística de Datos , Femenino , Dedos/irrigación sanguínea , Humanos , Masculino , Persona de Mediana Edad , Nariz/irrigación sanguínea , Flujo Sanguíneo Regional/fisiología , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
BACKGROUND: The combined administration of anesthetics has been associated with pharmacokinetic interactions that induce concentration changes of up to 30%. Midazolam is often used as a preoperative sedative in advance of a propofol-based anesthetic. In this study, we identified the influence of midazolam on the pharmacokinetics of propofol. METHODS: Eight healthy male volunteers were studied on two occasions in a random crossover manner. During Session A, volunteers received propofol 1 mg/kg in 1 min followed by an infusion of 2.5 mg x kg(-1) x h(-1) for 59 min. During Session B, in addition to this propofol infusion scheme, a target-controlled infusion of midazolam (constant C(t): 125 ng/mL) was given from 15 min before the start until 6 h after termination of the propofol infusion. Arterial blood samples for blood propofol and plasma midazolam concentration analysis were taken until 6 h after termination of the propofol infusion. Nonlinear mixed-effects models examining the influence of midazolam and hemodynamic variables on propofol pharmacokinetics were constructed using Akaike criterion for model selection. RESULTS: In the presence of midazolam (C(blood): 224.8 +/- 41.6 ng/mL), the blood propofol concentration increased by 25.1% +/- 13.3% compared with when propofol was given as single drug. Midazolam (C(blood): 225 ng/mL) reduced propofol Cl(1) from 1.94 to 1.61 L/min, Cl(2) from 2.86 to 1.52 L/min, and Cl(3) from 0.95 to 0.73 L/min. Inclusion of mean arterial blood pressure further improved the propofol pharmacokinetic model. CONCLUSIONS: Midazolam reduces the metabolic and rapid and slow distribution clearances of propofol. In addition, a reduction in mean arterial blood pressure is associated with propofol pharmacokinetic alterations that increase the blood propofol concentration.
Asunto(s)
Anestésicos Intravenosos/farmacocinética , Hipnóticos y Sedantes/farmacología , Midazolam/farmacología , Modelos Biológicos , Propofol/farmacocinética , Adulto , Anestésicos Intravenosos/administración & dosificación , Biotransformación/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Simulación por Computador , Estudios Cruzados , Esquema de Medicación , Interacciones Farmacológicas , Humanos , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/farmacocinética , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Midazolam/administración & dosificación , Midazolam/farmacocinética , Dinámicas no Lineales , Propofol/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: Lumbar epidural anaesthesia induces cardiovascular changes and decreases liver blood flow (Qh). We studied the effects of age on haemodynamics, blood volumes and Qh before and after epidural anaesthesia. METHODS: Thirty-six patients were enrolled as follows: group 1, 20-44 years; group 2, 45-70 years; group 3, >70 years. Using pulse dye densitometry, in addition to heart rate and arterial blood pressure (arterial BP), cardiac output, total blood volume, central blood volume and Qh were measured, before and after colloid infusion (500 ml hydroxyethyl starch, 6%) and after epidural administration of 15 ml of 0.75% ropivacaine. RESULTS: With age the level of analgesia [median (range)] increased from T7 (L2-T4) in group 1 to T4 (T10-C7) in group 3 (P = 0.04). After colloid infusion, heart rate (mean difference +/- SE; 2.1 +/- 0.7 beats min(-1)), systolic BP (4.1 +/- 2.2 mmHg) and Qh 162 ml min(-1) (ratio 0.90, 95% confidence interval 0.81-0.99) increased slightly but significantly, and were unaffected by age. Epidural anaesthesia induced a significant decrease in Qh (265 ml min(-1); ratio 1.20, 95% confidence interval 1.07-1.35) and arterial pressure (for systolic BP: P = 1 x 10(-7)). A significantly larger decrease in systolic BP occurred in the older, compared with the middle, age group (P = 0.04). Age did not affect epidural-induced changes in cardiac output, total and central blood volumes, and Qh. CONCLUSION: Age increases the level of analgesia after epidural ropivacaine and is associated with a more pronounced decrease in arterial pressure. A colloid preload mildly increases haemodynamics, but this insufficiently prevents younger and elderly patients from a decrease in Qh after lumbar epidural anaesthesia.
Asunto(s)
Envejecimiento/fisiología , Amidas/farmacología , Analgesia Epidural , Sistema Cardiovascular/efectos de los fármacos , Circulación Hepática/efectos de los fármacos , Hígado/irrigación sanguínea , Hígado/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Amidas/administración & dosificación , Coloides , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Infusiones Parenterales , Masculino , Persona de Mediana Edad , RopivacaínaRESUMEN
BACKGROUND: In previous studies, the authors reported on the absorption and disposition kinetics of levobupivacaine and ropivacaine. The current study was designed to develop a population pharmacokinetic-pharmacodynamic model capable of linking the kinetic data to the analgesic effects of these local anesthetics (i.e., sensory neural blockade). METHODS: A disposition compartmental model was fitted to concentration data of the intravenously administered deuterium-labeled anesthetics, and a model consisting of two parallel absorption compartments and the identified disposition compartments was fitted to concentration data of the concomitantly epidurally administered unlabeled anesthetics. The epidural segments were modeled by individual central and peripheral absorption compartments and effect sites, which were fitted to the simultaneously acquired pinprick data. A covariate model incorporated the effects of age. RESULTS: The threshold for epidural anesthesia increased from the lower to the higher segments. The central effect compartment equilibration half-lives were approximately 15 min for levobupivacaine and 25 min for ropivacaine. For levobupivacaine, age reduced the equilibration half-lives at all segments; for ropivacaine, age increased the anesthetic sensitivity at segments T12 and higher. CONCLUSIONS: A population pharmacokinetic-pharmacodynamic model was developed that quantitatively described sensory blockade during epidural anesthesia, including the effects of age. The model may be useful to individualize dose requirements, to predict the time course of sensory blockade, and to study new local anesthetics.
Asunto(s)
Amidas/farmacocinética , Anestesia Epidural , Anestésicos Locales/farmacología , Anestésicos Locales/farmacocinética , Adulto , Factores de Edad , Anciano , Amidas/farmacología , Bupivacaína/análogos & derivados , Bupivacaína/farmacocinética , Bupivacaína/farmacología , Femenino , Humanos , Levobupivacaína , Masculino , Persona de Mediana Edad , Modelos Biológicos , RopivacaínaRESUMEN
BACKGROUND: Morphine's metabolite, morphine-6-glucuronide (M6G), activates the mu-opioid receptor. Previous data suggest that M6G activates a unique M6G receptor that is selectively antagonized by 3-methoxynaltrexome (3mNTX). The authors compared the effects of M6G and morphine on breathing in the anesthetized cat and assessed whether 3mNTX reversal was selective for M6G. METHODS: Step changes in end-tidal carbon dioxide concentration were applied in cats anesthetized with alpha-chloralose-urethane. In study 1, the effect of the 0.15 mg/kg morphine followed by 0.2 mg/kg 3mNTX and next 0.8 mg/kg M6G was assessed in six cats. In study 2, the effect of 0.8 mg/kg M6G followed by 0.2 mg/kg 3mNTX and 0.15 mg/kg morphine was tested in another six cats. The ventilatory carbon dioxide responses were analyzed with a two-compartment model of the ventilatory controller, which consists of a fast peripheral and a slow central component. RESULTS: Both opioids shifted the ventilatory carbon dioxide responses to higher end-tidal carbon dioxide levels. Morphine had a preferential depressant effect within the central chemoreflex loop. In contrast, M6G had a preferential depressant effect within the peripheral chemoreflex loop. Irrespective of the opioid, 3mNTX caused full reversal of and prevented respiratory depression. CONCLUSIONS: In anesthetized cats, the mu-opioids morphine and M6G induce respiratory depression at different sites within the ventilatory control system. Because 3mNTX caused full reversal of the respiratory depressant effects of both opioids, it is unlikely that a 3mNTX-sensitive unique M6G receptor is the cause of the differential respiratory behavior of morphine and M6G.
Asunto(s)
Analgésicos Opioides/farmacología , Derivados de la Morfina/farmacología , Morfina/farmacología , Respiración/efectos de los fármacos , Anestesia , Animales , Barrera Hematoencefálica , Dióxido de Carbono/farmacología , Gatos , Femenino , Masculino , Morfina/farmacocinética , Derivados de la Morfina/farmacocinética , Naltrexona/análogos & derivados , Naltrexona/farmacologíaRESUMEN
BACKGROUND: Ropivacaine and one of its metabolites, pipecoloxylidide, inhibit CYP2D6 in. human liver microsomes in vitro with K(i) values of 5 microM (1.4 mg/L) and 13 microM (3.6 mg/L), respectively. We investigated the effect of a 50 h continuous epidural infusion of ropivacaine 2 mg/mL at a rate of 14 mL/h on CYP2D6 activity. METHODS: Nineteen patients (41-85 yr) undergoing hip or knee replacement, all extensive metabolizers with respect to CYP2D6 activity, were included. Medications known to inhibit or be metabolized by CYP2D6, or known to be strong inhibitors/inducers of CYP1A2 or CYP3A4 were not allowed. Patients received 10 mg debrisoquine (a marker for CYP2D6 activity) before surgery and after 40 h epidural infusion. The metabolic ratio (MR) for debrisoquine hydroxylation was calculated as the amount of debrisoquine/amount of 4-OH-debrisoquine excreted in 0-10 h urine. RESULTS: The median (range) of MR before and after ropivacaine were 0.54 (0.1-3.4) and 1.79 (0.3-6.7), respectively. The Hodges Lehman estimate of the ratio MR after/MR before ropivacaine was 2.2 with a 95% confidence interval 1.9-2.7 (P < 0.001). CONCLUSION: A continuous epidural infusion of ropivacaine inhibits CYP2D6 activity in patients who are extensive metabolizers resulting in a twofold increase in the MR for debrisoquine hydroxylation. However, since none of the patients was converted into a functional poor metabolizer (MR >12.6), the effect on the metabolism of other drugs metabolized by CYP2D6 is unlikely to be of major clinical importance.
Asunto(s)
Amidas/farmacología , Analgesia Epidural , Anestésicos Locales/farmacología , Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Inhibidores del Citocromo P-450 CYP2D6 , Inhibidores Enzimáticos/farmacología , Hígado/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Amidas/administración & dosificación , Amidas/farmacocinética , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Citocromo P-450 CYP2D6/metabolismo , Debrisoquina/análogos & derivados , Debrisoquina/farmacocinética , Debrisoquina/orina , Interacciones Farmacológicas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Humanos , Hidroxilación , Infusiones Parenterales , Hígado/enzimología , Persona de Mediana Edad , Países Bajos , Ropivacaína , Especificidad por Sustrato , Suecia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Knowledge about the systemic absorption and disposition of ropivacaine after epidural administration is important in regard to its clinical profile and the risk of systemic toxicity. We investigated the influence of age on the pharmacokinetics of ropivacaine 1.0% after epidural administration, using a stable-isotope method. Twenty-four patients were enrolled in 1 of 3 groups according to age (group 1: 18-40 yr; group 2: 41-60 yr; group 3: > or =61 yr). Patients received 150 mg ropivacaine hydrochloride epidurally. After 25 min, patients received 50 mL 0.44 mg/mL deuterium-labeled ropivacaine (D3-ropivacaine) IV. Arterial blood samples were collected up to 24 h after epidural administration. Total plasma concentrations of ropivacaine and D3-ropivacaine were determined using liquid chromatography mass spectrometry. In the oldest patients, elimination half-life was significantly longer (ratio of the geometric means 0.60; 95% confidence interval, 0.37-0.99) and clearance was significantly decreased (mean difference, 194 mL/min; 95% confidence interval, 18-370 mL/min) compared with the youngest patients. The systemic absorption was biphasic. Absorption kinetics for ropivacaine (fractions absorbed: (F1, F2) and half-lives: (t(1/2),a1), t(1/2),a2) during the fast and slow absorption process: 0.27 +/- 0.08 and 0.77 +/- 0.12, respectively; 10.7 +/- 5.2 min and 248 +/- 64 min, respectively) were in the same range as for other long-acting local anesthetics. F1 was on average 0.11 (95% confidence interval, 0.002-0.22) higher in the youngest compared with the middle age group. Observed age-dependent pharmacokinetic differences do not likely influence the risk of systemic toxicity in the elderly after a single epidural dose of ropivacaine.
Asunto(s)
Absorción/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Amidas/administración & dosificación , Amidas/farmacocinética , Anestesia Epidural/métodos , Absorción/fisiología , Adolescente , Adulto , Envejecimiento/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , RopivacaínaRESUMEN
BACKGROUND: Quantitative estimates of how anesthesia management impacts perioperative morbidity and mortality are limited. The authors performed a study to identify risk factors related to anesthesia management for 24-h postoperative severe morbidity and mortality. METHODS: A case-control study was performed of all patients undergoing anesthesia (1995-1997). Cases were patients who either remained comatose or died during or within 24 h of undergoing anesthesia. Controls were patients who neither remained comatose nor died during or within 24 hours of undergoing anesthesia. Data were collected by means of a questionnaire, the anesthesia and recovery form. Odds ratios were calculated for risk factors, adjusted for confounders. RESULTS: The cohort comprised 869,483 patients; 807 cases and 883 controls were analyzed. The incidence of 24-h postoperative death was 8.8 (95% confidence interval, 8.2-9.5) per 10,000 anesthetics. The incidence of coma was 0.5 (95% confidence interval, 0.3-0.6). Anesthesia management factors that were statistically significantly associated with a decreased risk were: equipment check with protocol and checklist (odds ratio, 0.64), documentation of the equipment check (odds ratio, 0.61), a directly available anesthesiologist (odds ratio, 0.46), no change of anesthesiologist during anesthesia (odds ratio, 0.44), presence of a full-time working anesthetic nurse (odds ratio, 0.41), two persons present at emergence (odds ratio, 0.69), reversal of anesthesia (for muscle relaxants and the combination of muscle relaxants and opiates; odds ratios, 0.10 and 0.29, respectively), and postoperative pain medication as opposed to no pain medication, particularly if administered epidurally or intramuscularly as opposed to intravenously. CONCLUSIONS: Mortality after surgery is substantial and an association was established between perioperative coma and death and anesthesia management factors like intraoperative presence of anesthesia personnel, administration of drugs intraoperatively and postoperatively, and characteristics of delivered intraoperative and postoperative anesthetic care.
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Anestesia/métodos , Complicaciones Intraoperatorias/mortalidad , Monitoreo Intraoperatorio/mortalidad , Anciano , Anestesia/efectos adversos , Anestesia/estadística & datos numéricos , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Estudios de Cohortes , Intervalos de Confianza , Femenino , Humanos , Complicaciones Intraoperatorias/epidemiología , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio/métodos , Oportunidad Relativa , Estudios Prospectivos , Factores de Riesgo , Estadísticas no ParamétricasRESUMEN
BACKGROUND: The effect of a single nucleotide polymorphism of the mu-opioid receptor at nucleotide position 118 (OPRM1:c.118A>G) was investigated on morphine-6-glucuronide (M6G)-induced analgesia and respiratory depression in a group of healthy volunteers. METHODS: Sixteen subjects of either sex received 0.4 mg/kg (n = 8) or 0.6 mg/kg M6G (n = 8). At regular time intervals, the isocapnic acute hypoxic ventilatory response, pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 14 h after drug infusion. Population pharmacokinetic-pharmacodynamic sigmoid Emax models were applied to the respiratory and pain data. All collected data were analyzed using the statistical program NONMEM (San Francisco, CA). RESULTS: Four of the subjects were OPRM1:c.118GA heterozygotes, and the remainder of the subjects were OPRM1:c.118AA homozygotes. M6G analgesia: In contrast to analgesic responses in OPRM1:c.118AA homozygotes, responses were small and inconsistent in OPRM1:c.118GA heterozygotes and best described by the function Effect(t) = baseline (P < 0.01 vs. OPRM1:c.118AA homozygotes). Emax and C50 values in heterozygotes equaled 0.55 +/- 0.18 (or a 55% increase in current above baseline) and 161 +/- 42 ng/ml, respectively. M6G-induced respiratory depression: For the acute hypoxic response, neither Emax nor C50 (value = 282 +/- 72 ng/ml) differed between genotypes. CONCLUSIONS: The data indicate that the OPRM1:c.118A>G polymorphism affects opioid analgesic and respiratory effects differentially. Despite reduced analgesic responses to M6G the OPRM1:c.118A>G single-nucleotide polymorphism does not protect against the toxic effects of the tested opioid. However, some caution in the interpretation of the data is needed because of the small sample size. Further studies are needed to explore the link between this polymorphism and respiratory/analgesic responses beyond the small human sample. In OPRM1:c.118AA homozygotes, the potency parameters differed by a factor of 2 for analgesic versus respiratory effect. In this respect, M6G differs favorably from morphine.
Asunto(s)
Analgésicos Opioides/efectos adversos , Derivados de la Morfina/efectos adversos , Polimorfismo Genético , Receptores Opioides mu/genética , Respiración/efectos de los fármacos , Adolescente , Adulto , Analgesia , Analgésicos Opioides/farmacología , Femenino , Humanos , Masculino , Derivados de la Morfina/farmacocinéticaRESUMEN
BACKGROUND: Extension of sensory blockade after an epidural top-up in combined spinal epidural (CSE) anesthesia is partly attributed to compression of the dural sac by the injected volume. This study investigated whether a volume effect plays a significant role when administering an epidural top-up after an initial epidural loading dose and assessed the predictive value of different factors with respect to the increase in sensory blockade. METHODS: After an epidural loading dose of 75 mg ropivacaine, 0.75%, 30 patients were randomly assigned to one of three groups. After the maximum level of sensory blockade (MLSB) had been established, patients received either an epidural top-up with 10 ml ropivacaine, 0.75% (group 1, n = 10) or saline (group 2, n = 10), or no epidural top-up (group 3, n = 10). Subsequently, sensory blockade was assessed at 5-min intervals for a further 30 min by a blinded observer. RESULTS: The MLSB increased significantly in the patients receiving an epidural top-up with ropivacaine but not in the patients receiving normal saline. Sensory block extension was inversely related to the number of segments blocked at the time of the epidural top-up, and female gender was associated with a smaller increase in MLSB. CONCLUSIONS: When using epidural ropivacaine, the extension of sensory blockade after administering an epidural top-up is caused by a local anesthetic effect and not by a volume effect. Under the conditions of this study, predictors of the increase in sensory blockade are the presence of ropivacaine in the top-up injectate, the number of segments blocked at the time of epidural top-up, and gender.
Asunto(s)
Anestesia Epidural/métodos , Anestesia Raquidea/métodos , Adulto , Anciano , Anciano de 80 o más Años , Amidas/líquido cefalorraquídeo , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Ropivacaína , SensaciónRESUMEN
BACKGROUND: Changing plasma protein concentrations may affect the protein binding and pharmacokinetics of drugs in the postoperative period. This study examined the effect of postoperative increases (in response to surgery) in plasma alpha1-acid-glycoprotein (AAG) concentrations on the plasma concentrations of the enantiomers of bupivacaine during continuous epidural infusion of racemic bupivacaine for postoperative pain relief. METHODS: Six patients scheduled for total hip surgery with combined epidural and general anesthesia received a bolus dose of bupivacaine (65 mg) followed by constant-rate (8 ml/h) epidural infusion of 2.5 mg/ml bupivacaine for 48 h. Total and unbound plasma concentrations of the enantiomers of bupivacaine and plasma AAG concentrations during the 48-h epidural infusion were determined. RESULTS: Total plasma concentrations of the enantiomers of bupivacaine increased steadily during the infusion (P < 0.0001), whereas unbound concentrations did not change after 12 h (P > 0.1). Total plasma concentrations of S(-)-bupivacaine were higher than those of R(+)-bupivacaine (P < 0.02), whereas unbound concentrations of S(-)-bupivacaine were lower than those of R(+)-bupivacaine (P < 0.002). AAG concentrations initially decreased, but thereafter increased steadily (P < 0.0001). Consequently, free fractions of the enantiomers initially increased and then decreased with time (P = 0.0002). Free fractions of S(-)-bupivacaine were smaller than those of R(+)-bupivacaine (P = 0.0003). CONCLUSIONS: The study confirmed that the pharmacokinetics of bupivacaine are enantioselective. During postoperative epidural infusion, changing plasma AAG concentrations affect the protein binding of both enantiomers of bupivacaine. Consequently, total plasma concentrations of the enantiomers increase with time, whereas unbound concentrations reach a plateau.
Asunto(s)
Analgesia Epidural , Anestésicos Locales/farmacocinética , Bupivacaína/farmacocinética , Dolor Postoperatorio/tratamiento farmacológico , Anciano , Algoritmos , Anestésicos Locales/química , Anestésicos Locales/uso terapéutico , Área Bajo la Curva , Bupivacaína/química , Bupivacaína/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Orosomucoide/metabolismo , Dimensión del Dolor , Unión Proteica , EstereoisomerismoRESUMEN
UNLABELLED: We studied the influence of age on the neural blockade and hemodynamic changes after the epidural administration of ropivacaine 1.0% in patients undergoing orthopedic, urological, gynecological, or lower abdominal surgery. Fifty-four patients were enrolled in one of three age groups (Group 1: 18-40 yr; Group 2: 41-60 yr; Group 3: > or=61 yr). After a test dose of 3 mL of prilocaine 1.0% with epinephrine 5 microg/mL, 15 mL of ropivacaine 1.0% was administered epidurally. The level of analgesia and degree of motor blockade were assessed, and hemodynamic variables were recorded at standardized intervals. The upper level of analgesia differed among all groups (medians: Group 1: T8; Group 2: T6; Group 3: T4). Motor blockade was more intense in the oldest compared with the youngest age group. The incidence of bradycardia and hypotension and the maximal decrease in mean arterial blood pressure during the first hour after the epidural injection (median of Group 1: 11 mm Hg; Group 2: 16 mm Hg; Group 3: 29 mm Hg) were more frequent in the oldest age group. We conclude that age influences the clinical profile of ropivacaine 1.0%. The hemodynamic effects in older patients may be caused by the high thoracic spread of analgesia, although a diminished hemodynamic homeostasis may contribute. IMPLICATIONS: Analgesia levels after the epidural administration of 15 mL of ropivacaine 1.0% increase with increasing age. This is associated with an increased incidence of hypotension in the elderly, although an effect of age on the hemodynamic homeostasis may have contributed. It appears that epidural doses should be adjusted for elderly patients.