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AIMS: The field of cell-based therapies for human diseases is currently evolving from promising treatment options to established therapeutic concepts. The design of the nonclinical development program for cell-based products, intended to provide a rationale for treatment and to gain insight into the safety profile, is challenging because of limitations caused by species-specificity. The elements of the nonclinical package for cell-based products were evaluated using advice reports from the European Medicines Agency database from 2013 to 2018 to identify the approach followed for nonclinical development of these products. METHODS: The number and purpose of proposed and performed in vivo studies was recorded, as well as the type and design of in vitro and in vivo studies addressing biodistribution and tumorigenicity. Subsequently, the nonclinical development program was analysed for consistency across products. RESULTS: In vivo studies for cell-based therapies were primarily aimed at proof-of-concept (75/86), followed by addressing safety (64/86), biodistribution (49/86) and tumourigenicity (46/86). No animal studies were performed or proposed by sponsors or regulators for 6/86 products which contained cell types that have been studied in humans for a relatively long time. For one-third of the products in vivo biodistribution and/or tumourigenicity studies were not considered necessary. in vivo tumourigenicity studies were regarded as having limited value. CONCLUSIONS: Compared to more conventional medicinal products, the nonclinical development program for cell-based products was more tailored and focused on proof-of-concept. For tumourigenicity an in vitro approach may suffice. Total omission of in vivo studies appears to be possible for products with sufficient clinical experience.
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Proyectos de Investigación , Humanos , Distribución TisularRESUMEN
Regulatory T cells (Tregs) have a prominent role in the control of immune homeostasis. Pharmacological impact on their activity or balance with effector T cells could contribute to (impaired) clinical responses or adverse events. Monitoring treatment-related effects on T cell subsets may therefore be part of (pre-)clinical studies for medicinal products. However, the extent of immune monitoring performed in studies for marketing authorisation and the degree of correspondence with data available in the public domain is not known. We evaluated the presence of T cell immunomonitoring in 46 registration dossiers of monoclonal antibodies indicated for immune-related disorders and published scientific papers. We found that the depth of Treg analysis in registration dossiers was rather small. Nevertheless, data on treatment-related Treg effects are available in public academia-driven studies (post-registration) and suggest that Tregs may act as a biomarker for clinical responses. However, public data are fragmented and obtained with heterogeneity of experimental approaches from a diversity of species and tissues. To reveal the potential added value of T cell (and particular Treg) evaluation in (pre-)clinical studies, more cell-specific data should be acquired, at least for medicinal products with an immunomodulatory mechanism. Therefore, extensive analysis of T cell subset contribution to clinical responses and the relevance of treatment-induced changes in their levels is needed. Preferably, industry and academia should work together to obtain these data in a standardised manner and to enrich our knowledge about T cell activity in disease pathogenesis and therapies. This will ultimately elucidate the necessity of T cell subset monitoring in the therapeutic benefit-risk assessment.
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Disease suppressive T cell regulation may depend on cognate interactions of regulatory T cells with self-antigens that are abundantly expressed in the inflamed tissues. Heat shock proteins (HSPs) are by their nature upregulated in stressed cells and therefore abundantly present as potential targets for such regulation. HSP immunizations have led to inhibition of experimentally induced inflammatory conditions in various models. However, re-establishment of tolerance in the presence of an ongoing inflammatory process has remained challenging. Since tolerogenic DCs (tolDCs) have the combined capacity of mitigating antigen-specific inflammatory responses and of endowing T cells with regulatory potential, it seems attractive to combine the anti-inflammatory qualities of tolDCs with those of HSPs.
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Regulatory T cells (Treg) function in the prevention of excessive inflammation and maintenance of immunological homeostasis. However, these cells may also interfere with resolution of infections or with immune reactions following vaccination. Effects of Treg on vaccine responses are nowadays investigated, but the impact of vaccination on Treg homeostasis is still largely unknown. This may be a relevant safety aspect, since loss of tolerance through reduced Treg may trigger autoimmunity. In exploratory clinical trials, healthy adults were vaccinated with an influenza subunit vaccine plus or minus the adjuvant MF59®, an adjuvanted hepatitis B subunit vaccine or a live attenuated yellow fever vaccine. Frequencies and phenotypes of resting (rTreg) and activated (aTreg) subpopulations of circulating CD4+ Treg were determined and compared to placebo immunization. Vaccination with influenza vaccines did not result in significant changes in Treg frequencies and phenotypes. Vaccination with the hepatitis B vaccine led to slightly increased frequencies of both rTreg and aTreg subpopulations and a decrease in expression of functionality marker CD39 on aTreg. The live attenuated vaccine resulted in a decrease in rTreg frequency, and an increase in expression of activation marker CD25 on both subpopulations, possibly indicating a conversion from resting to migratory aTreg due to vaccine virus replication. To study the more local effects of vaccination on Treg in lymphoid organs, we immunized mice and analyzed the CD4+ Treg frequency and phenotype in draining lymph nodes and spleen. Vaccination resulted in a transient local decrease in Treg frequency in lymph nodes, followed by a systemic Treg increase in the spleen. Taken together, we showed that vaccination with vaccines with an already established safe profile have only minimal impact on frequencies and characteristics of Treg over time. These findings may serve as a bench-mark of inter-individual variation of Treg frequencies and phenotypes following vaccination.
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Linfocitos T Reguladores/efectos de los fármacos , Vacunas Virales/farmacología , Adulto , Animales , Femenino , Vacunas contra Hepatitis B/inmunología , Vacunas contra Hepatitis B/farmacología , Humanos , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/farmacología , Recuento de Linfocitos , Masculino , Ratones , Fragmentos de Péptidos , Protrombina , Linfocitos T Reguladores/inmunología , Vacunas/inmunología , Vacunas/farmacología , Vacunas Virales/inmunología , Vacuna contra la Fiebre Amarilla/inmunología , Vacuna contra la Fiebre Amarilla/farmacologíaRESUMEN
A new anesthesia machine incorporates a "coasting mode", but the extent to which a coasting technique can maintain anesthesia at the end of a procedure under optimal conditions (closed circuit anesthesia) remains unknown. Sixty-nine patients undergoing peripheral or abdominal surgery were assigned to 1 of 9 groups, depending on when desflurane coasting (in O2/air) was started (after 4, 9, 16, 25, 36, 49, 64, 81, or 100 min). The end-expired desflurane concentration was maintained at 4.5% in O2/air prior to coasting with a conventional anesthesia machine. After initiating coasting (using a closed-circuit technique), we examined when the end-expired desflurane concentration reached 70, 60, 50, and 40% of its value during maintenance (= 30, 40, 50 and 60% decrement times, respectively). Decrement times increased with increasing duration of anesthesia, and varied widely. After 64 min of maintenance anesthesia, the end-expired desflurane concentration remained at or above 70, 60, 50, and 40% of its maintenance value during 10.3 +/- 2.3, 16.0 +/- 3.5, 25.0 +/- 5.9, and 45.4 +/- 19.3 min, respectively (average +/- standard deviation). Coasting can briefly maintain anesthesia towards the end of a procedure. While savings with an automated coasting mode are likely to be modest per patient, they may become substantial when multiplied by the number of procedures per day per operating room with no increase in the clinical workload of the anesthesia provider.
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Anestesiología/instrumentación , Anestésicos por Inhalación/administración & dosificación , Isoflurano/análogos & derivados , Adulto , Anciano , Desflurano , Humanos , Isoflurano/administración & dosificación , Isoflurano/farmacocinética , Persona de Mediana EdadRESUMEN
A persistent left superior vena cava draining into the left atrium was diagnosed in an adult patient, scheduled for surgical correction of a large inferiorly located sinus venosus atrial septal defect. In the majority of cases a persistent left superior vena cava is found incidentally and causes little or no symptoms. Nevertheless, anaesthesiologist should be aware of its occurrence; because of different technical difficulties and clinical problems that can be encountered. Echocardiography plays an key role in the detection of a persistent left superior vena cava.
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Defectos del Tabique Interatrial/patología , Vena Cava Superior/anomalías , Adulto , Ecocardiografía Transesofágica , Femenino , Defectos del Tabique Interatrial/diagnóstico , Defectos del Tabique Interatrial/cirugía , Humanos , Imagen por Resonancia MagnéticaRESUMEN
The effects of blood solubility, cardiac output and ventilation on the rise of the alveolar towards the inspired concentration, the F(A)/F(I) curve, of an inhaled anaesthetic are often thought to reflect how these factors affect wash-in of the central nervous system compartment and, therefore, speed of induction because F(A) is the partial pressure ultimately attained in the central nervous system (F(VRG)). These classical F(A)/F(I) curves assumed a constant F(I). We used GasMan to examine whether changes in solubility, cardiac output and ventilation affect the relationship between the F(A)/F(I) curve and F(VRG) differently while either F(I) or F(A) are kept constant. Using GasMan, we studied the effects of solubility (desflurane vs isoflurane), cardiac output (5 vs. 10 l x min(-1)) and minute ventilation (4 vs. 8 l x min(-1)) on F(A), F(I), F(A)/F(I) and F(VRG) with either F(I) kept constant or F(A) kept constant (at 1 minimum alveolar concentration). High fresh gas flows were used to avoid rebreathing, so that the delivered concentration matched F(I). Despite similar effects on the F(A)/F(I) curve, the effects on F(VRG) differed. With constant F(I), lower solubility or higher ventilation results in a higher F(VRG) and a higher cardiac output results in a lower F(VRG). With constant F(A), solubility has only a minimal effect on F(VRG); an increase in cardiac output hastens the rise of F(VRG) to the same plateau value; and a change in ventilation has minimal effect on F(VRG). Despite similar effects on the F(A)/F(I) curve, the effects of solubility, cardiac output and ventilation on the F(VRG) are different when either F(I) or F(A) are kept constant. With the F(I) kept constant, induction of anaesthesia is slower with a higher cardiac output, but with F(A) kept constant, induction of anaesthesia is faster with a higher cardiac output. The introduction of an end-expired closed-loop feedback administration of inhaled anaesthetics makes this distinction clinically relevant.
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Anestesia por Inhalación/métodos , Anestésicos por Inhalación/administración & dosificación , Alveolos Pulmonares/fisiología , Presión del Aire , Anestésicos por Inhalación/química , Gasto Cardíaco/fisiología , Simulación por Computador , Desflurano , Humanos , Isoflurano/análogos & derivados , Isoflurano/química , Cinética , Presión Parcial , Mecánica Respiratoria/fisiología , Programas Informáticos , SolubilidadRESUMEN
Simple vaporiser setting (F(D)) and fresh gas flow (FGF) sequences make the practice of low-flow anaesthesia not only possible but also easy to achieve. We sought to derive a sevoflurane F(D) sequence that maintains the end-expired sevoflurane concentration (F(A)sevo) at 1.3% using the fewest possible number of F(D) adjustments with a previously described O2-N2O FGF sequence that allows early FGF reduction to 0.7 l min(-1). In 18 ASA physical status I to IH patients, F(D) was determined to maintain F(A)sevo at 1.3% with 2 l min(-1) O2 and 4 l min(-1) N2O FGF for three minutes, and with 0.3 and 0.4 l min(-1) thereafter. Using the same FGF sequence, the F(D) schedule that approached the 1.3% F(A)sevo pattern with the fewest possible adjustments was prospectively tested in another 18 patients. The following F(D) sequence approximated the F(D) course well: 2% from zero to three minutes, 2.6% from three to 15 minutes and 2.0% after 15 minutes. When prospectively tested, median (25th; 75th percentile) performance error was 0.8 (-2.9; 5.9)%, absolute performance error 6.7 (3.3; 10.6)%, divergence 18.2 (-5.6; 27.4)%.h(-1) and wobble 4.4 (1.7; 8.1) %. In one patient, FGF had to be temporarily increased for four minutes. One O2/N2O rotameter FGF setting change from 6 to 0.7 l min(-1) at three minutes and two sevoflurane F(D) changes at three and 15 minutes maintained predictable anaesthetic gas concentrations during the first 45 minutes in all but one patient in our study.
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Anestésicos por Inhalación/administración & dosificación , Éteres Metílicos/administración & dosificación , Óxido Nitroso/administración & dosificación , Adulto , Anestesia por Inhalación/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sevoflurano , Factores de TiempoRESUMEN
INTRODUCTION: During automated closed-circuit anesthesia (CCA), the Zeus (Dräger, Lübeck, Germany) uses a high initial fresh gas flow (FGF) to rapidly attain the desired agent and carrier gas concentrations, resulting in a desflurane consumption well above patient uptake. Because both FGF and carrier gas composition can affect consumption, we determined the Zeus' agent consumption with automated CCA and with automated low flow anesthesia (LFA) (= maintenance FGF of 0.7 L min(-1)) with 3 different carrier gases. METHODS: After IRB approval, 65 ASA PS I or II patients undergoing general surgery received desflurane in either O2, O2/air, or O2/N2O, with the Zeus to maintain the end-expired concentration (FA) at 6, 6, and 4% and the F1O2 at 1.0, 0.6, and 0.4, respectively. In addition, patients were assigned to either automated CCA (O2 n = 11; O2/air n = 11; O2/N2O n = 11) or automated LFA (selected FGF 0.7 L min(-1)) (O2 n = 12; O2/air n = 11; O2/N2O n = 9). Demographics and desflurane consumption at 2, 4, 6, 8, 10, 20, 30, 40 and 50 min were compared. RESULTS: With the same carrier gas, desflurane consumption was lower with the CCA mode than with LFA mode after 4 min in the O2 groups, 6 min in the O2/air groups, and 30 min in the O2/N2O groups. Within each mode, desflurane consumption in the O2 and O2/air groups was identical at all times. Despite the use of a lower FA in the N2O groups, initial desflurane consumption was higher than in the O2 and O2/air groups, but it was lower later (> or = 15 min) only with LFA. DISCUSSION: After 50 min, desflurane consumption with automated CCA is lower than with automated LFA. However, initial agent consumption is complex, and N2O in particular may increase initial desflurane consumption (though ultimately resulting in lower desflurane usage because of its MAC sparing effect) because initial FGF is increased to rapidly reach the target concentrations. Differences in desflurane consumption only become apparent after FGF has stabilized to the target FGF.
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Anestesia por Circuito Cerrado/instrumentación , Anestesia por Circuito Cerrado/métodos , Anestésicos por Inhalación/administración & dosificación , Isoflurano/análogos & derivados , Desflurano , Humanos , Isoflurano/administración & dosificación , Persona de Mediana Edad , Factores de TiempoRESUMEN
INTRODUCTION: During robot assisted hysterectomies and prostatectomies, surgical exposure demands the application of a CO2 pneumoperitoneum with a very steep Trendelenburg position (40 degrees). The extent to which oxygenation and ventilation might be compromised intra-operatively remains poorly documented. METHODS: Dead-space ventilation and venous admixture were determined in 18 patients undergoing robot assisted hysterectomy (n = 6) or prostatectomy (n = 12). Anesthesia was maintained with desflurane in O2 or O2/air, with the inspired O2 fraction left at the discretion of the attending anesthesiologist. Controlled mechanical ventilation was used, but 15 min after assuming the Trendelenburg position and up until resuming the supine position pressure controlled ventilation was used. Dead-space ventilation and venous admixture were determined using Bohr's formula and Nunn's iso-shunt diagram, respectively, at the following 7 stages of the procedure: 15 min after induction; 5 min after applying the CO2 pneumoperitoneum (intra-abdominal pressure 12 mm Hg) but while still supine; 5, 60, and 120 min after assuming the Trendelenburg positioning; and 5 and 15 min after reassuming the supine position. RESULTS: Venous admixture did not change. Dead-space ventilation increased after Trendelenburg positioning, and returned to baseline values after resuming the supine position. However, individual patterns varied widely. DISCUSSION: The lung has a remarkable yet incompletely understood capacity to withstand the effects of a CO2 pneumoperitoneum and steep Trendelenburg position during general anesthesia. While individual responses vary and should be monitored, effects on dead-space ventilation and venous admixture are small and should not be an obstacle to provide optimal surgical exposure during robot assisted prostatectomy or hysterectomy.
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Inclinación de Cabeza/fisiología , Histerectomía Vaginal , Prostatectomía , Intercambio Gaseoso Pulmonar , Robótica , Anestesia General , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neumoperitoneo Artificial , Respiración Artificial , Espacio Muerto Respiratorio , Pruebas de Función RespiratoriaRESUMEN
STUDY DESIGN: Systematic review. OBJECTIVES: To provide a quantitative analysis of all randomized controlled trials designed to determine the effectiveness of physical interventions for people with spinal cord injury (SCI). SETTING: Sydney, Australia. METHODS: A search was conducted for randomized controlled trials involving physical interventions for people with SCI. Two reviewers independently rated methodological quality using the PEDro scale and extracted key findings from the trials. RESULTS: Four thousand five hundred and forty three abstracts were identified of which 31 trials met the inclusion criteria. Trials examined the effectiveness of fitness and strength training (n=7), gait training (n=5), hand therapy (n=3), stretch (n=4), acupuncture (n=3), hand splinting (n=2) and other related therapies (n=7). Six trials reported a between-group mean difference with a clearly important treatment effect on at least one outcome measure. These trials supported the use of fitness, strength and gait training as well as acupuncture. CONCLUSION: There is initial evidence supporting the effectiveness of some physical interventions for people with SCI. However, there is a pressing need for high-quality trials to determine the effectiveness of all physical interventions commonly administered in clinical practice.
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Modalidades de Fisioterapia , Traumatismos de la Médula Espinal/rehabilitación , Bases de Datos Factuales/estadística & datos numéricos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Recent interest in the use of low-flow or closed circuit anesthesia has rekindled interest in the pharmacokinetics of inhaled anesthetics. The kinetic properties of inhaled anesthetics are most often modeled by physiologic models because of the abundant information that is available on tissue solubilities and organ perfusion. These models are intuitively attractive because they can be easily understood in terms of the underlying anatomy and physiology. The use of classical compartment modeling, on the other hand, allows modeling of data that are routinely available to the anesthesiologist, and eliminates the need to account for every possible confounding factor at each step of the partial pressure cascade of potent inhaled agents. Concepts used to describe IV kinetics can readily be applied to inhaled agents (e.g., context-sensitive half-time and effect site concentrations). The interpretation of the F(A)/F(I) vs time curve is expanded by reintroducing the concept of the general anesthetic equation-the focus is shifted from "how F(A) approaches F(I)" to "what combination of delivered concentration and fresh gas flow (FGF) can be used to attain the desired F(A)." When the desired F(A) is maintained with a FGF that is lower than minute ventilation, rebreathing causes a discrepancy between the concentration delivered by the anesthesia machine (=selected by the anesthesiologist on the vaporizer, F(D)) and that inspired by the patient. This F(D)-F(I) discrepancy may be perceived as "lack of control" and has been the rationale to use a high FGF to ensure the delivered matched the inspired concentration. Also, with low FGF there is larger variability in F(D) because of interpatient variability in uptake. The F(D)-F(I) discrepancy increases with lower FGF because of more rebreathing, and as a consequence the uptake pattern seems to be more reflected in the F(D) required to keep F(A) constant. The clinical implication for the anesthesiologist is that with high FGF few F(D) adjustments have to be made, while with a low FGF F(D) has to be adjusted according to a pattern that follows the decreasing uptake pattern in the body. The ability to model and predict the uptake pattern of the individual patient and the resulting kinetics in a circle system could therefore help guide the anesthesiologist in the use of low-flow anesthesia with conventional anesthesia machines. Several authors have developed model-based low FGF administration schedules, but biologic variability limits the performance of any model, and therefore end-expired gas analysis is obligatory. Because some fine-tuning based on end-expired gas analysis will always be needed, some clinicians may not be inclined to use very low FGF in a busy operating room, considering the perceived increase in complexity. This practice may be facilitated by the development of anesthesia machines that use closed circuit anesthesia (CCA) with end-expired feedback control--they "black box" these issues (see Chapter 21). In this chapter, we first explore how and why the kinetic properties of intravenous and inhaled anesthetics have been modeled differently. Next, we will review the method most commonly used to describe the kinetics of inhaled agents, the F(A)/F(I) vs time curve that describes how the alveolar (F(A)) approaches the inspired (F(I)) fraction (in the gas phase, either "fraction," "concentration," or "partial pressure" can be used). Finally, we will reintroduce the concept of the general anesthetic equation to explain why the use of low-flow or closed circuit anesthesia has rekindled interest in the modeling of pharmacokinetics of inhaled anesthetics. Clinical applications of some of these models are reviewed. A basic understanding of the circle system is required, and will be provided in the introduction.
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Anestesia por Inhalación , Anestésicos por Inhalación/farmacocinética , Anestésicos Intravenosos/farmacocinética , Anestesia por Circuito Cerrado/instrumentación , Anestésicos por Inhalación/administración & dosificación , Animales , Esquema de Medicación , Diseño de Equipo , Humanos , Éteres Metílicos/farmacocinética , Modelos Biológicos , Sevoflurano , Distribución TisularRESUMEN
BACKGROUND: Pulmonary embolism (PE) and intracardiac thrombosis (ICT) are rare but potentially lethal complications during orthotopic liver transplantation (OLT). METHODS: We aimed to review clinical and pathological correlates of PE and ICT in patients undergoing OLT. A systematic review of the literature was conducted using MEDLINE and ISI Web of Science. RESULTS: Seventy-four cases of intraoperative PE and/or ICT were identified; PE alone in 32 patients (43%) and a combination of PE and ICT in 42 patients (57%). Most frequent clinical symptoms included systemic hypotension and concomitant rising pulmonary artery pressure, often leading to complete circulatory collapse. PE and ICT occurred in every stage of the operation and were reported equally in patients with or without the use of venovenous bypass or antifibrinolytics. A large variety of putative risk factors have been suggested in the literature, including the use of pulmonary artery catheters or certain blood products. Nineteen patients underwent urgent thrombectomy or thrombolysis. Overall mortality was 68% (50/74) and 41 patients (82%) died intraoperatively. CONCLUSION: Mortality was significantly higher in patients with an isolated PE, compared to patients with a combination of PE and ICT (91% and 50%, respectively; P < 0.001). Intraoperative PE and ICT during OLT appear to have multiple etiologies and may occur unexpectedly at any time during the procedure.
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Cardiopatías/epidemiología , Complicaciones Intraoperatorias/epidemiología , Trasplante de Hígado , Embolia Pulmonar/epidemiología , Trombosis/epidemiología , Adolescente , Adulto , Niño , Preescolar , Terapia Combinada , Femenino , Cardiopatías/diagnóstico , Cardiopatías/etiología , Cardiopatías/terapia , Mortalidad Hospitalaria , Humanos , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/etiología , Hipotensión/epidemiología , Hipotensión/etiología , Lactante , Recién Nacido , Complicaciones Intraoperatorias/diagnóstico , Complicaciones Intraoperatorias/etiología , Complicaciones Intraoperatorias/terapia , Masculino , Persona de Mediana Edad , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/etiología , Embolia Pulmonar/terapia , Factores de Riesgo , Choque/epidemiología , Choque/etiología , Choque/terapia , Tromboelastografía/estadística & datos numéricos , Trombosis/diagnóstico , Trombosis/etiología , Trombosis/terapiaAsunto(s)
Anestésicos Combinados/administración & dosificación , Anestésicos por Inhalación/administración & dosificación , Éteres Metílicos/administración & dosificación , Óxido Nitroso/administración & dosificación , Anestesia General , Anestésicos por Inhalación/farmacocinética , Humanos , Éteres Metílicos/farmacocinética , SevofluranoRESUMEN
BACKGROUND: The second gas effect (SGE) is considered to be significant only during periods of large volume N(2)O uptake (VN(2)O); however, the SGE of small VN(2)O has not been studied. We hypothesized that the SGE of N(2)O on sevoflurane would become less pronounced when sevoflurane administration is started 60 min after the start of N(2)O administration when VN(2)O has decreased to approximately 125 ml min(-1), and that the kinetics of sevoflurane under these circumstances would become indistinguishable from those when sevoflurane is administered in O(2). METHODS: Seventy-two physical status ASA I-II patients were randomly assigned to one of six groups (n=12 each). In the first four groups, sevoflurane (1.8% vaporizer setting) administration was started 0, 2, 5 and 60 min after starting 2 litre min(-1) O(2) and 4 litre min(-1) N(2)O, respectively. In the last two groups, sevoflurane (1.8 or 3.6% vaporizer setting) was administered in 6 litre min(-1) O(2). The ratios of the alveolar fraction of sevoflurane (Fa) over the inspired fraction (Fi), or Fa/Fi, were compared between the groups. RESULTS: Sevoflurane Fa/Fi was larger in the N(2)O groups than in the O(2) groups, and it was identical in all four N(2)O groups. CONCLUSIONS: We confirmed the existence of a SGE of N(2)O. Surprisingly, when using an Fa of 65% N(2)O, the magnitude of the SGE was the same with large or small VN(2)O. The classical model and the graphical representation of the SGE alone should not be used to explain the magnitude of the SGE. We speculate that changes in ventilation/perfusion inhomogeneity in the lungs during general anaesthesia result in a SGE at levels of VN(2)O previously considered by most to be too small to exert a SGE.