Role of selective V2-receptor-antagonism in septic shock: a randomized, controlled, experimental study

ABSTRACT : INTRODUCTION : V2-receptor (V2R) stimulation potentially aggravates sepsis-induced vasodilation, fluid accumulation and microvascular thrombosis. Therefore, the present study was performed to determine the effects of a first-line therapy with the selective V2R-antagonist (Propionyl1-D-Tyr(Et)2-Val4-Abu6-Arg8,9)-Vasopressin on cardiopulmonary hemodynamics and organ function vs. the mixed V1aR/V2R-agonist arginine vasopressin (AVP) or placebo in an established ovine model of septic shock. METHODS : After the onset of septic shock, chronically instrumented sheep were randomly assigned to receive first-line treatment with the selective V2R-antagonist (1 g/kg per hour), AVP (0.05 g/kg per hour), or normal saline (placebo, each n = 7). In all groups, open-label norepinephrine was additionally titrated up to 1 g/kg per minute to maintain mean arterial pressure at 70 ± 5 mmHg, if necessary. RESULTS : Compared to AVP- and placebo-treated animals, the selective V2R-antagonist stabilized cardiopulmonary hemodynamics (mean arterial and pulmonary artery pressure, cardiac index) as effectively and increased intravascular volume as suggested by higher cardiac filling pressures. Furthermore, left ventricular stroke work index was higher in the V2R-antagonist group than in the AVP group. Notably, metabolic (pH, base excess, lactate concentrations), liver (transaminases, bilirubin) and renal (creatinine and blood urea nitrogen plasma levels, urinary output, creatinine clearance) dysfunctions were attenuated by the V2R-antagonist when compared with AVP and placebo. The onset of septic shock was associated with an increase in AVP plasma levels as compared to baseline in all groups. Whereas AVP plasma levels remained constant in the placebo group, infusion of AVP increased AVP plasma levels up to 149 ± 21 pg/mL. Notably, treatment with the selective V2R-antagonist led to a significant decrease of AVP plasma levels as compared to shock time (P < 0.001) and to both other groups (P < 0.05 vs. placebo; P < 0.001 vs. AVP). Immunohistochemical analyses of lung tissue revealed higher hemeoxygenase-1 (vs. placebo) and lower 3-nitrotyrosine concentrations (vs. AVP) in the V2R-antagonist group. In addition, the selective V2R-antagonist slightly prolonged survival (14 ± 1 hour) when compared to AVP (11 ± 1 hour, P = 0.007) and placebo (11 ± 1 hour, P = 0.025). CONCLUSIONS : Selective V2R-antagonism may represent an innovative therapeutic approach to attenuate multiple organ dysfunction in early septic shock.

Concomitant arginine-vasopressin and hydrocortisone therapy in severe septic shock: association with mortality

To evaluate the association between concomitant arginine-vasopressin (AVP)/hydrocortisone therapy and mortality in severe septic shock patients.

Novel approach to complex pulmonary arteriovenous malformation embolization using detachable coils and Amplatzer vascular plugs

We evaluated the feasibility of a modified embolization technique of pulmonary arteriovenous malformations (PAVM) using venous sac embolization with detachable coils combined with the feeding artery embolization with the Amplatzer vascular plug (AVP).

[Arginine-vasopressin in septic and vasodilatorial shock]

Current therapy of septic/vasodilatory cardiovascular failure includes volume resuscitation and infusion of inotropic and vasopressor agents. Norepinephrine is the first-line vasoconstrictor, and can stabilize hemodynamic variables in most patients. Nonetheless, irreversible cardiovascular failure which is resistant to conventional hemodynamic therapies still is the main cause of death in patients with severe sepsis and septic shock. In such advanced, catecholamine-resistant shock states, arginine-vasopressin (AVP) has repeatedly caused an increase in mean arterial blood pressure, a decrease in toxic norepinephrine-dosages, as well as further beneficial hemodynamic, endocrinologic and renal effects. Although AVP exerted negative inotropic effects in previous clinical trials and in selected animal experiments, a continuous low-dose AVP infusion during advanced septic/vasodilatory shock caused a decrease in cardiac index only in patients with a hyperdynamic circulation. Adverse effects on gastrointestinal circulation and the systemic microcirculation can not be excluded, but have not yet been confirmed in clinical prospective trials. Negative side effects of a supplementary AVP therapy are an increase in total bilirubin concentrations, and a decrease in platelet count. A transient increase in hepatic transaminases during AVP infusion is most likely related to preceding hypotensive episodes. Important points which must be considered when using AVP as a "rescue vasopressor" in septic/vasodilatory shock states are: 1) AVP infusion only in advanced shock states that can not be adequately reversed by conventional hemodynamic therapy (e.g. norepinephrine >0,5-0,6 mug/kg/min), 2) presence of normovolemia, 3) AVP infusion only in combination with norepinephrine, 4) strict avoidance of bolus injections and dosages >4 IU/h. Effects of a supplementary AVP infusion in advanced vasodilatory shock on survival are currently examined in a large, prospective multicenter trial in North America and Australia.

Copeptin and arginine vasopressin concentrations in critically ill patients

CONTEXT: Determination of arginine vasopressin (AVP) concentrations may be helpful to guide therapy in critically ill patients. A new assay analyzing copeptin, a stable peptide derived from the AVP precursor, has been introduced. OBJECTIVE: Our objective was to determine plasma copeptin concentrations. DESIGN: We conducted a post hoc analysis of plasma samples and data from a prospective study. SETTING: The setting was a 12-bed general and surgical intensive care unit (ICU) in a tertiary university teaching hospital. PATIENTS: Our subjects were 70 healthy volunteers and 157 ICU patients with sepsis, with systemic inflammatory response syndrome (SIRS), and after cardiac surgery. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Copeptin plasma concentrations, demographic data, AVP plasma concentrations, and a multiple organ dysfunction syndrome score were documented 24 h after ICU admission. RESULTS: AVP (P < 0.001) and copeptin (P < 0.001) concentrations were significantly higher in ICU patients than in controls. Patients after cardiac surgery had higher AVP (P = 0.003) and copeptin (P = 0.003) concentrations than patients with sepsis or SIRS. Independent of critical illness, copeptin and AVP correlated highly significantly with each other. Critically ill patients with sepsis and SIRS exhibited a significantly higher ratio of copeptin/AVP plasma concentrations than patients after cardiac surgery (P = 0.012). The American Society of Anesthesiologists' classification (P = 0.046) and C-reactive protein concentrations (P = 0.006) were significantly correlated with the copeptin/AVP ratio. CONCLUSIONS: Plasma concentrations of copeptin and AVP in healthy volunteers and critically ill patients correlate significantly with each other. The ratio of copeptin/AVP plasma concentrations is increased in patients with sepsis and SIRS, suggesting that copeptin may overestimate AVP plasma concentrations in these patients.

Arteriolar vasoconstrictive response: comparing the effects of arginine vasopressin and norepinephrine

INTRODUCTION: This study was designed to examine differences in the arteriolar vasoconstrictive response between arginine vasopressin (AVP) and norepinephrine (NE) on the microcirculatory level in the hamster window chamber model in unanesthetized, normotonic hamsters using intravital microscopy. It is known from patients with advanced vasodilatory shock that AVP exerts strong additional vasoconstriction when incremental dosage increases of NE have no further effect on mean arterial blood pressure (MAP). METHODS: In a prospective controlled experimental study, eleven awake, male golden Syrian hamsters were instrumented with a viewing window inserted into the dorsal skinfold. NE (2 microg/kg/minute) and AVP (0.0001 IU/kg/minute, equivalent to 4 IU/h in a 70 kg patient) were continuously infused to achieve a similar increase in MAP. According to their position within the arteriolar network, arterioles were grouped into five types: A0 (branch off small artery) to A4 (branch off A3 arteriole). RESULTS: Reduction of arteriolar diameter (NE, -31 +/- 12% versus AVP, -49 +/- 7%; p = 0.002), cross sectional area (NE, -49 +/- 17% versus AVP, -73 +/- 7%; p = 0.002), and arteriolar blood flow (NE, -62 +/- 13% versus AVP, -80 +/- 6%; p = 0.004) in A0 arterioles was significantly more pronounced in AVP animals. There was no difference in red blood cell velocities in A0 arterioles between groups. The reduction of diameter, cross sectional area, red blood cell velocity, and arteriolar blood flow in A1 to A4 arterioles was comparable in AVP and NE animals. CONCLUSION: Within the microvascular network, AVP exerted significantly stronger vasoconstriction on large A0 arterioles than NE under physiological conditions. This observation may partly explain why AVP is such a potent vasopressor hormone and can increase systemic vascular resistance even in advanced vasodilatory shock unresponsive to increases in standard catecholamine therapy.

Arginine vasopressin in advanced cardiovascular failure during the post-resuscitation phase after cardiac arrest

Arginine vasopressin (AVP) has been employed successfully during cardiopulmonary resuscitation, but there exist only few data about the effects of AVP infusion for cardiovascular failure during the post-cardiac arrest period. Cardiovascular failure is one of the main causes of death after successful resuscitation from cardiac arrest. Although the "post-resuscitation syndrome" has been described as a "sepsis-like" syndrome, there is little information about the haemodynamic response to AVP in advanced cardiovascular failure after cardiac arrest. In this retrospective study, haemodynamic and laboratory variables in 23 patients with cardiovascular failure unresponsive to standard haemodynamic therapy during the post-cardiac arrest period were obtained before, and 30 min, 1, 4, 12, 24, 48, and 72 h after initiation of a supplementary AVP infusion (4 IU/h). During the observation period, AVP significantly increased mean arterial blood pressure (58+/-14 to 75+/-19 mmHg, p < 0.001), and decreased noradrenaline (norepinephrine) (1.31+/-2.14 to 0.23+/-0.3 microg/kg/min, p = 0.03), adrenaline (epinephrine) (0.58+/-0.23 to 0.04+/-0.03 microg/kg/min, p = 0.001), and milrinone requirements (0.46+/-0.15 to 0.33+/-0.22 microg/kg/min, p < 0.001). Pulmonary capillary wedge pressure changed significantly (p < 0.001); an initial increase being followed by a decrease below baseline values. While arterial lactate concentrations (95+/-64 to 21+/-18 mg/dL, p < 0.001) and pH (7.27+/-0.14 to 7.4+/-0.14, p < 0.001) improved significantly, total bilirubin concentrations (1.12+/-0.95 to 3.04+/-3.79 mg/dL, p = 0.001) increased after AVP. There were no differences in the haemodynamic or laboratory response to AVP between survivors and non-survivors. In this study, advanced cardiovascular failure that was unresponsive to standard therapy could be reversed successfully with supplementary AVP infusion in >90% of patients surviving cardiac arrest.

Copeptin Is Associated with Kidney Length, Renal Function, and Prevalence of Simple Cysts in a Population-Based Study.

Arginine vasopressin (AVP) has a key role in osmoregulation by facilitating water transport in the collecting duct. Recent evidence suggests that AVP may have additional effects on renal function and favor cyst growth in polycystic kidney disease. Whether AVP also affects kidney structure in the general population is unknown. We analyzed the association of copeptin, an established surrogate for AVP, with parameters of renal function and morphology in a multicentric population-based cohort. Participants from families of European ancestry were randomly selected in three Swiss cities. We used linear multilevel regression analysis to explore the association of copeptin with renal function parameters as well as kidney length and the presence of simple renal cysts assessed by ultrasound examination. Copeptin levels were log-transformed. The 529 women and 481 men had median copeptin levels of 3.0 and 5.2 pmol/L, respectively (P<0.001). In multivariable analyses, the copeptin level was associated inversely with eGFR (β=-2.1; 95% confidence interval [95% CI], -3.3 to -0.8; P=0.002) and kidney length (β=-1.2; 95% CI, -1.9 to -0.4; P=0.003) but positively with 24-hour urinary albumin excretion (β=0.11; 95% CI, 0.01 to 0.20; P=0.03) and urine osmolality (β=0.08; 95% CI, 0.05 to 0.10; P<0.001). A positive association was found between the copeptin level and the presence of renal cysts (odds ratio, 1.6; 95% CI, 1.1 to 2.4; P=0.02). These results suggest that AVP has a pleiotropic role in renal function and may favor the development of simple renal cysts.

Diagnostic Accuracy of Copeptin in the Differential Diagnosis of the Polyuria-polydipsia Syndrome: A Prospective Multicenter Study

CONTEXT The polyuria-polydipsia syndrome comprises primary polydipsia (PP) and central and nephrogenic diabetes insipidus (DI). Correctly discriminating these entities is mandatory, given that inadequate treatment causes serious complications. The diagnostic "gold standard" is the water deprivation test with assessment of arginine vasopressin (AVP) activity. However, test interpretation and AVP measurement are challenging. OBJECTIVE The objective was to evaluate the accuracy of copeptin, a stable peptide stoichiometrically cosecreted with AVP, in the differential diagnosis of polyuria-polydipsia syndrome. DESIGN, SETTING, AND PATIENTS This was a prospective multicenter observational cohort study from four Swiss or German tertiary referral centers of adults >18 years old with the history of polyuria and polydipsia. MEASUREMENTS A standardized combined water deprivation/3% saline infusion test was performed and terminated when serum sodium exceeded 147 mmol/L. Circulating copeptin and AVP levels were measured regularly throughout the test. Final diagnosis was based on the water deprivation/saline infusion test results, clinical information, and the treatment response. RESULTS Fifty-five patients were enrolled (11 with complete central DI, 16 with partial central DI, 18 with PP, and 10 with nephrogenic DI). Without prior thirsting, a single baseline copeptin level >21.4 pmol/L differentiated nephrogenic DI from other etiologies with a 100% sensitivity and specificity, rendering a water deprivation testing unnecessary in such cases. A stimulated copeptin >4.9 pmol/L (at sodium levels >147 mmol/L) differentiated between patients with PP and patients with partial central DI with a 94.0% specificity and a 94.4% sensitivity. A stimulated AVP >1.8 pg/mL differentiated between the same categories with a 93.0% specificity and a 83.0% sensitivity. LIMITATION This study was limited by incorporation bias from including AVP levels as a diagnostic criterion. CONCLUSION Copeptin is a promising new tool in the differential diagnosis of the polyuria-polydipsia syndrome, and a valid surrogate marker for AVP. Primary Funding Sources: Swiss National Science Foundation, University of Basel.

A methodology to analyze, design and implement very fast and robust controls of Buck-type converters

La electrónica digital moderna presenta un desafío a los diseñadores de sistemas de potencia. El creciente alto rendimiento de microprocesadores, FPGAs y ASICs necesitan sistemas de alimentación que cumplan con requirimientos dinámicos y estáticos muy estrictos. Específicamente, estas alimentaciones son convertidores DC-DC de baja tensión y alta corriente que necesitan ser diseñados para tener un pequeño rizado de tensión y una pequeña desviación de tensión de salida bajo transitorios de carga de una alta pendiente. Además, dependiendo de la aplicación, se necesita cumplir con otros requerimientos tal y como proveer a la carga con ”Escalado dinámico de tensión”, donde el convertidor necesitar cambiar su tensión de salida tan rápidamente posible sin sobreoscilaciones, o ”Posicionado Adaptativo de la Tensión” donde la tensión de salida se reduce ligeramente cuanto más grande sea la potencia de salida. Por supuesto, desde el punto de vista de la industria, las figuras de mérito de estos convertidores son el coste, la eficiencia y el tamaño/peso. Idealmente, la industria necesita un convertidor que es más barato, más eficiente, más pequeño y que aún así cumpla con los requerimienos dinámicos de la aplicación. En este contexto, varios enfoques para mejorar la figuras de mérito de estos convertidores se han seguido por la industria y la academia tales como mejorar la topología del convertidor, mejorar la tecnología de semiconducores y mejorar el control. En efecto, el control es una parte fundamental en estas aplicaciones ya que un control muy rápido hace que sea más fácil que una determinada topología cumpla con los estrictos requerimientos dinámicos y, consecuentemente, le da al diseñador un margen de libertar más amplio para mejorar el coste, la eficiencia y/o el tamaño del sistema de potencia. En esta tesis, se investiga cómo diseñar e implementar controles muy rápidos para el convertidor tipo Buck. En esta tesis se demuestra que medir la tensión de salida es todo lo que se necesita para lograr una respuesta casi óptima y se propone una guía de diseño unificada para controles que sólo miden la tensión de salida Luego, para asegurar robustez en controles muy rápidos, se proponen un modelado y un análisis de estabilidad muy precisos de convertidores DC-DC que tienen en cuenta circuitería para sensado y elementos parásitos críticos. También, usando este modelado, se propone una algoritmo de optimización que tiene en cuenta las tolerancias de los componentes y sensados distorsionados. Us ando este algoritmo, se comparan controles muy rápidos del estado del arte y su capacidad para lograr una rápida respuesta dinámica se posiciona según el condensador de salida utilizado. Además, se propone una técnica para mejorar la respuesta dinámica de los controladores. Todas las propuestas se han corroborado por extensas simulaciones y prototipos experimentales. Con todo, esta tesis sirve como una metodología para ingenieros para diseñar e implementar controles rápidos y robustos de convertidores tipo Buck. ABSTRACT Modern digital electronics present a challenge to designers of power systems. The increasingly high-performance of microprocessors, FPGAs (Field Programmable Gate Array) and ASICs (Application-Specific Integrated Circuit) require power supplies to comply with very demanding static and dynamic requirements. Specifically, these power supplies are low-voltage/high-current DC-DC converters that need to be designed to exhibit low voltage ripple and low voltage deviation under high slew-rate load transients. Additionally, depending on the application, other requirements need to be met such as to provide to the load ”Dynamic Voltage Scaling” (DVS), where the converter needs to change the output voltage as fast as possible without underdamping, or ”Adaptive Voltage Positioning” (AVP) where the output voltage is slightly reduced the greater the output power. Of course, from the point of view of the industry, the figures of merit of these converters are the cost, efficiency and size/weight. Ideally, the industry needs a converter that is cheaper, more efficient, smaller and that can still meet the dynamic requirements of the application. In this context, several approaches to improve the figures of merit of these power supplies are followed in the industry and academia such as improving the topology of the converter, improving the semiconductor technology and improving the control. Indeed, the control is a fundamental part in these applications as a very fast control makes it easier for the topology to comply with the strict dynamic requirements and, consequently, gives the designer a larger margin of freedom to improve the cost, efficiency and/or size of the power supply. In this thesis, how to design and implement very fast controls for the Buck converter is investigated. This thesis proves that sensing the output voltage is all that is needed to achieve an almost time-optimal response and a unified design guideline for controls that only sense the output voltage is proposed. Then, in order to assure robustness in very fast controls, a very accurate modeling and stability analysis of DC-DC converters is proposed that takes into account sensing networks and critical parasitic elements. Also, using this modeling approach, an optimization algorithm that takes into account tolerances of components and distorted measurements is proposed. With the use of the algorithm, very fast analog controls of the state-of-the-art are compared and their capabilities to achieve a fast dynamic response are positioned de pending on the output capacitor. Additionally, a technique to improve the dynamic response of controllers is also proposed. All the proposals are corroborated by extensive simulations and experimental prototypes. Overall, this thesis serves as a methodology for engineers to design and implement fast and robust controls for Buck-type converters.

Output Impedance Correction Circuit (OICC): A New Concept to Improve the Dynamic Response of DC/DC Converters with Additional Energy Path

El desarrollo da las nuevas tecnologías permite a los ingenieros llevar al límite el funcionamiento de los circuitos integrados (Integrated Circuits, IC). Las nuevas generaciones de procesadores, DSPs o FPGAs son capaces de procesar la información a una alta velocidad, con un alto consumo de energía, o esperar en modo de baja potencia con el mínimo consumo posible. Esta gran variación en el consumo de potencia y el corto tiempo necesario para cambiar de un nivel al otro, afecta a las especificaciones del Módulo de Regulador de Tensión (Voltage Regulated Module, VRM) que alimenta al IC. Además, las características adicionales obligatorias, tales como adaptación del nivel de tensión (Adaptive Voltage Positioning, AVP) y escalado dinámico de la tensión (Dynamic Voltage Scaling, DVS), imponen requisitos opuestas en el diseño de la etapa de potencia del VRM. Para poder soportar las altas variaciones de los escalones de carga, el condensador de filtro de salida del VRM se ha de sobredimensionar, penalizando la densidad de energía y el rendimiento durante la operación de DVS. Por tanto, las actuales tendencias de investigación se centran en mejorar la respuesta dinámica del VRM, mientras se reduce el tamaño del condensador de salida. La reducción del condensador de salida lleva a menor coste y una prolongación de la vida del sistema ya que se podría evitar el uso de condensadores voluminosos, normalmente implementados con condensadores OSCON. Una ventaja adicional es que reduciendo el condensador de salida, el DVS se puede realizar más rápido y con menor estrés de la etapa de potencia, ya que la cantidad de carga necesaria para cambiar la tensión de salida es menor. El comportamiento dinámico del sistema con un control lineal (Control Modo Tensión, VMC, o Control Corriente de Pico, Peak Current Mode Control, PCMC,…) está limitado por la frecuencia de conmutación del convertidor y por el tamaño del filtro de salida. La reducción del condensador de salida se puede lograr incrementando la frecuencia de conmutación, así como incrementando el ancho de banda del sistema, y/o aplicando controles avanzados no-lineales. Usando esos controles, las variables del estado se saturan para conseguir el nuevo régimen permanente en un tiempo mínimo, así como el filtro de salida, más específicamente la pendiente de la corriente de la bobina, define la respuesta de la tensión de salida. Por tanto, reduciendo la inductancia de la bobina de salida, la corriente de bobina llega más rápido al nuevo régimen permanente, por lo que una menor cantidad de carga es tomada del condensador de salida durante el tránsito. El inconveniente de esa propuesta es que el rendimiento del sistema es penalizado debido al incremento de pérdidas de conmutación y las corrientes RMS. Para conseguir tanto la reducción del condensador de salida como el alto rendimiento del sistema, mientras se satisfacen las estrictas especificaciones dinámicas, un convertidor multifase es adoptado como estándar para aplicaciones VRM. Para asegurar el reparto de las corrientes entre fases, el convertidor multifase se suele implementar con control de modo de corriente. Para superar la limitación impuesta por el filtro de salida, la segunda posibilidad para reducir el condensador de salida es aplicar alguna modificación topológica (Topologic modifications) de la etapa básica de potencia para incrementar la pendiente de la corriente de bobina y así reducir la duración de tránsito. Como el transitorio se ha reducido, una menor cantidad de carga es tomada del condensador de salida bajo el mismo escalón de la corriente de salida, con lo cual, el condensador de salida se puede reducir para lograr la misma desviación de la tensión de salida. La tercera posibilidad para reducir el condensador de salida del convertidor es introducir un camino auxiliar de energía (additional energy path, AEP) para compensar el desequilibrio de la carga del condensador de salida reduciendo consecuentemente la duración del transitorio y la desviación de la tensión de salida. De esta manera, durante el régimen permanente, el sistema tiene un alto rendimiento debido a que el convertidor principal con bajo ancho de banda es diseñado para trabajar con una frecuencia de conmutación moderada para conseguir requisitos estáticos. Por otro lado, el comportamiento dinámico durante los transitorios es determinado por el AEP con un alto ancho de banda. El AEP puede ser implementado como un camino resistivo, como regulador lineal (Linear regulator, LR) o como un convertidor conmutado. Las dos primeras implementaciones proveen un mayor ancho de banda, acosta del incremento de pérdidas durante el transitorio. Por otro lado, la implementación del convertidor computado presenta menor ancho de banda, limitado por la frecuencia de conmutación, aunque produce menores pérdidas comparado con las dos anteriores implementaciones. Dependiendo de la aplicación, la implementación y la estrategia de control del sistema, hay una variedad de soluciones propuestas en el Estado del Arte (State-of-the-Art, SoA), teniendo diferentes propiedades donde una solución ofrece más ventajas que las otras, pero también unas desventajas. En general, un sistema con AEP ideal debería tener las siguientes propiedades: 1. El impacto del AEP a las pérdidas del sistema debería ser mínimo. A lo largo de la operación, el AEP genera pérdidas adicionales, con lo cual, en el caso ideal, el AEP debería trabajar por un pequeño intervalo de tiempo, solo durante los tránsitos; la otra opción es tener el AEP constantemente activo pero, por la compensación del rizado de la corriente de bobina, se generan pérdidas innecesarias. 2. El AEP debería ser activado inmediatamente para minimizar la desviación de la tensión de salida. Para conseguir una activación casi instantánea, el sistema puede ser informado por la carga antes del escalón o el sistema puede observar la corriente del condensador de salida, debido a que es la primera variable del estado que actúa a la perturbación de la corriente de salida. De esa manera, el AEP es activado con casi cero error de la tensión de salida, logrando una menor desviación de la tensión de salida. 3. El AEP debería ser desactivado una vez que el nuevo régimen permanente es detectado para evitar los transitorios adicionales de establecimiento. La mayoría de las soluciones de SoA estiman la duración del transitorio, que puede provocar un transitorio adicional si la estimación no se ha hecho correctamente (por ejemplo, si la corriente de bobina del convertidor principal tiene un nivel superior o inferior al necesitado, el regulador lento del convertidor principal tiene que compensar esa diferencia una vez que el AEP es desactivado). Otras soluciones de SoA observan las variables de estado, asegurando que el sistema llegue al nuevo régimen permanente, o pueden ser informadas por la carga. 4. Durante el transitorio, como mínimo un subsistema, o bien el convertidor principal o el AEP, debería operar en el lazo cerrado. Implementando un sistema en el lazo cerrado, preferiblemente el subsistema AEP por su ancho de banda elevado, se incrementa la robustez del sistema a los parásitos. Además, el AEP puede operar con cualquier tipo de corriente de carga. Las soluciones que funcionan en el lazo abierto suelen preformar el control de balance de carga con mínimo tiempo, así reducen la duración del transitorio y tienen un impacto menor a las pérdidas del sistema. Por otro lado, esas soluciones demuestran una alta sensibilidad a las tolerancias y parásitos de los componentes. 5. El AEP debería inyectar la corriente a la salida en una manera controlada, así se reduce el riesgo de unas corrientes elevadas y potencialmente peligrosas y se incrementa la robustez del sistema bajo las perturbaciones de la tensión de entrada. Ese problema suele ser relacionado con los sistemas donde el AEP es implementado como un convertidor auxiliar. El convertidor auxiliar es diseñado para una potencia baja, con lo cual, los dispositivos elegidos son de baja corriente/potencia. Si la corriente no es controlada, bajo un pico de tensión de entrada provocada por otro parte del sistema (por ejemplo, otro convertidor conectado al mismo bus), se puede llegar a un pico en la corriente auxiliar que puede causar la perturbación de tensión de salida e incluso el fallo de los dispositivos del convertidor auxiliar. Sin embargo, cuando la corriente es controlada, usando control del pico de corriente o control con histéresis, la corriente auxiliar tiene el control con prealimentación (feed-forward) de tensión de entrada y la corriente es definida y limitada. Por otro lado, si la solución utiliza el control de balance de carga, el sistema puede actuar de forma deficiente si la tensión de entrada tiene un valor diferente del nominal, provocando que el AEP inyecta/toma más/menos carga que necesitada. 6. Escalabilidad del sistema a convertidores multifase. Como ya ha sido comentado anteriormente, para las aplicaciones VRM por la corriente de carga elevada, el convertidor principal suele ser implementado como multifase para distribuir las perdidas entre las fases y bajar el estrés térmico de los dispositivos. Para asegurar el reparto de las corrientes, normalmente un control de modo corriente es usado. Las soluciones de SoA que usan VMC son limitadas a la implementación con solo una fase. Esta tesis propone un nuevo método de control del flujo de energía por el AEP y el convertidor principal. El concepto propuesto se basa en la inyección controlada de la corriente auxiliar al nodo de salida donde la amplitud de la corriente es n-1 veces mayor que la corriente del condensador de salida con las direcciones apropiadas. De esta manera, el AEP genera un condensador virtual cuya capacidad es n veces mayor que el condensador físico y reduce la impedancia de salida. Como el concepto propuesto reduce la impedancia de salida usando el AEP, el concepto es llamado Output Impedance Correction Circuit (OICC) concept. El concepto se desarrolla para un convertidor tipo reductor síncrono multifase con control modo de corriente CMC (incluyendo e implementación con una fase) y puede operar con la tensión de salida constante o con AVP. Además, el concepto es extendido a un convertidor de una fase con control modo de tensión VMC. Durante la operación, el control de tensión de salida de convertidor principal y control de corriente del subsistema OICC están siempre cerrados, incrementando la robustez a las tolerancias de componentes y a los parásitos del cirquito y permitiendo que el sistema se pueda enfrentar a cualquier tipo de la corriente de carga. Según el método de control propuesto, el sistema se puede encontrar en dos estados: durante el régimen permanente, el sistema se encuentra en el estado Idle y el subsistema OICC esta desactivado. Por otro lado, durante el transitorio, el sistema se encuentra en estado Activo y el subsistema OICC está activado para reducir la impedancia de salida. El cambio entre los estados se hace de forma autónoma: el sistema entra en el estado Activo observando la corriente de condensador de salida y vuelve al estado Idle cunado el nuevo régimen permanente es detectado, observando las variables del estado. La validación del concepto OICC es hecha aplicándolo a un convertidor tipo reductor síncrono con dos fases y de 30W cuyo condensador de salida tiene capacidad de 140μF, mientras el factor de multiplicación n es 15, generando en el estado Activo el condensador virtual de 2.1mF. El subsistema OICC es implementado como un convertidor tipo reductor síncrono con PCMC. Comparando el funcionamiento del convertidor con y sin el OICC, los resultados demuestran que se ha logrado una reducción de la desviación de tensión de salida con factor 12, tanto con funcionamiento básico como con funcionamiento AVP. Además, los resultados son comparados con un prototipo de referencia que tiene la misma etapa de potencia y un condensador de salida físico de 2.1mF. Los resultados demuestran que los dos sistemas tienen el mismo comportamiento dinámico. Más aun, se ha cuantificado el impacto en las pérdidas del sistema operando bajo una corriente de carga pulsante y bajo DVS. Se demuestra que el sistema con OICC mejora el rendimiento del sistema, considerando las pérdidas cuando el sistema trabaja con la carga pulsante y con DVS. Por lo último, el condensador de salida de sistema con OICC es mucho más pequeño que el condensador de salida del convertidor de referencia, con lo cual, por usar el concepto OICC, la densidad de energía se incrementa. En resumen, las contribuciones principales de la tesis son: • El concepto propuesto de Output Impedance Correction Circuit (OICC), • El control a nivel de sistema basado en el método usado para cambiar los estados de operación, • La implementación del subsistema OICC en lazo cerrado conjunto con la implementación del convertidor principal, • La cuantificación de las perdidas dinámicas bajo la carga pulsante y bajo la operación DVS, y • La robustez del sistema bajo la variación del condensador de salida y bajo los escalones de carga consecutiva. ABSTRACT Development of new technologies allows engineers to push the performance of the integrated circuits to its limits. New generations of processors, DSPs or FPGAs are able to process information with high speed and high consumption or to wait in low power mode with minimum possible consumption. This huge variation in power consumption and the short time needed to change from one level to another, affect the specifications of the Voltage Regulated Module (VRM) that supplies the IC. Furthermore, additional mandatory features, such as Adaptive Voltage Positioning (AVP) and Dynamic Voltage Scaling (DVS), impose opposite trends on the design of the VRM power stage. In order to cope with high load-step amplitudes, the output capacitor of the VRM power stage output filter is drastically oversized, penalizing power density and the efficiency during the DVS operation. Therefore, the ongoing research trend is directed to improve the dynamic response of the VRM while reducing the size of the output capacitor. The output capacitor reduction leads to a smaller cost and longer life-time of the system since the big bulk capacitors, usually implemented with OSCON capacitors, may not be needed to achieve the desired dynamic behavior. An additional advantage is that, by reducing the output capacitance, dynamic voltage scaling (DVS) can be performed faster and with smaller stress on the power stage, since the needed amount of charge to change the output voltage is smaller. The dynamic behavior of the system with a linear control (Voltage mode control, VMC, Peak Current Mode Control, PCMC,…) is limited by the converter switching frequency and filter size. The reduction of the output capacitor can be achieved by increasing the switching frequency of the converter, thus increasing the bandwidth of the system, and/or by applying advanced non-linear controls. Applying nonlinear control, the system variables get saturated in order to reach the new steady-state in a minimum time, thus the output filter, more specifically the output inductor current slew-rate, determines the output voltage response. Therefore, by reducing the output inductor value, the inductor current reaches faster the new steady state, so a smaller amount of charge is taken from the output capacitor during the transient. The drawback of this approach is that the system efficiency is penalized due to increased switching losses and RMS currents. In order to achieve both the output capacitor reduction and high system efficiency, while satisfying strict dynamic specifications, a Multiphase converter system is adopted as a standard for VRM applications. In order to ensure the current sharing among the phases, the multiphase converter is usually implemented with current mode control. In order to overcome the limitation imposed by the output filter, the second possibility to reduce the output capacitor is to apply Topologic modifications of the basic power stage topology in order to increase the slew-rate of the inductor current and, therefore, reduce the transient duration. Since the transient is reduced, smaller amount of charge is taken from the output capacitor under the same load current, thus, the output capacitor can be reduced to achieve the same output voltage deviation. The third possibility to reduce the output capacitor of the converter is to introduce an additional energy path (AEP) to compensate the charge unbalance of the output capacitor, consequently reducing the transient time and output voltage deviation. Doing so, during the steady-state operation the system has high efficiency because the main low-bandwidth converter is designed to operate at moderate switching frequency, to meet the static requirements, whereas the dynamic behavior during the transients is determined by the high-bandwidth auxiliary energy path. The auxiliary energy path can be implemented as a resistive path, as a Linear regulator, LR, or as a switching converter. The first two implementations provide higher bandwidth, at the expense of increasing losses during the transient. On the other hand, the switching converter implementation presents lower bandwidth, limited by the auxiliary converter switching frequency, though it produces smaller losses compared to the two previous implementations. Depending on the application, the implementation and the control strategy of the system, there is a variety of proposed solutions in the State-of-the-Art (SoA), having different features where one solution offers some advantages over the others, but also some disadvantages. In general, an ideal additional energy path system should have the following features: 1. The impact on the system losses should be minimal. During its operation, the AEP generates additional losses, thus ideally, the AEP should operate for a short period of time, only when the transient is occurring; the other option is to have the AEP constantly on, but due to the inductor current ripple compensation at the output, unnecessary losses are generated. 2. The AEP should be activated nearly instantaneously to prevent bigger output voltage deviation. To achieve near instantaneous activation, the converter system can be informed by the load prior to the load-step or the system can observe the output capacitor current, which is the first system state variable that reacts on the load current perturbation. In this manner, the AEP is turned on with near zero output voltage error, providing smaller output voltage deviation. 3. The AEP should be deactivated once the new steady state is reached to avoid additional settling transients. Most of the SoA solutions estimate duration of the transient which may cause additional transient if the estimation is not performed correctly (e.g. if the main converter inductor current has higher or lower value than needed, the slow regulator of the main converter needs to compensate the difference after the AEP is deactivated). Other SoA solutions are observing state variables, ensuring that the system reaches the new steady state or they are informed by the load. 4. During the transient, at least one subsystem, either the main converter or the AEP, should be in closed-loop. Implementing a closed loop system, preferably the AEP subsystem, due its higher bandwidth, increases the robustness under system tolerances and circuit parasitic. In addition, the AEP can operate with any type of load. The solutions that operate in open loop usually perform minimum time charge balance control, thus reducing the transient length and minimizing the impact on the losses, however they are very sensitive to tolerances and parasitics. 5. The AEP should inject current at the output in a controlled manner, thus reducing the risk of high and potentially damaging currents and increasing robustness on the input voltage deviation. This issue is mainly related to the systems where AEP is implemented as auxiliary converter. The auxiliary converter is designed for small power and, as such, the MOSFETs are rated for small power/currents. If the current is not controlled, due to the some unpredicted spike in input voltage caused by some other part of the system (e.g. different converter), it may lead to a current spike in auxiliary current which will cause the perturbation of the output voltage and even failure of the switching components of auxiliary converter. In the case when the current is controlled, using peak CMC or Hysteretic Window CMC, the auxiliary converter has inherent feed-forwarding of the input voltage in current control and the current is defined and limited. Furthermore, if the solution employs charge balance control, the system may perform poorly if the input voltage has different value than the nominal, causing that AEP injects/extracts more/less charge than needed. 6. Scalability of the system to multiphase converters. As commented previously, in VRM applications, due to the high load currents, the main converters are implemented as multiphase to redistribute losses among the modules, lowering temperature stress of the components. To ensure the current sharing, usually a Current Mode Control (CMC) is employed. The SoA solutions that are implemented with VMC are limited to a single stage implementation. This thesis proposes a novel control method of the energy flow through the AEP and the main converter system. The proposed concept relays on a controlled injection of the auxiliary current at the output node where the instantaneous current value is n-1 times bigger than the output capacitor current with appropriate directions. Doing so, the AEP creates an equivalent n times bigger virtual capacitor at the output, thus reducing the output impedance. Due to the fact that the proposed concept reduces the output impedance using the AEP, it has been named the Output Impedance Correction Circuit (OICC) concept. The concept is developed for a multiphase CMC synchronous buck converter (including a single phase implementation), operating with a constant output voltage and with AVP feature. Further, it is extended to a single phase VMC synchronous buck converter. During the operation, the main converter voltage loop and the OICC subsystem capacitor current loop is constantly closed, increasing the robustness under system tolerances and circuit parasitic and allowing the system to operate with any load-current shape or pattern. According to the proposed control method, the system operates in two states: during the steady-state the system is in the Idle state and the OICC subsystem is deactivated, while during the load-step transient the system is in the Active state and the OICC subsystem is activated in order to reduce the output impedance. The state changes are performed autonomously: the system enters in the Active state by observing the output capacitor current and it returns back to the Idle state when the steady-state operation is detected by observing the state variables. The validation of the OICC concept has been done by applying it to a 30W two phase synchronous buck converter with 140μF output capacitor and with the multiplication factor n equal to 15, generating during the Active state equivalent output capacitor of 2.1mF. The OICC subsystem is implemented as single phase PCMC synchronous buck converter. Comparing the converter operation with and without the OICC the results demonstrate that the 12 times reduction of the output voltage deviation is achieved, for both basic operation and for the AVP operation. Furthermore, the results have been compared to a reference prototype which has the same power stage and a fiscal output capacitor of 2.1mF. The results show that the two systems have the same dynamic behavior. Moreover, an impact on the system losses under the pulsating load and DVS operation has been quantified and it has been demonstrated that the OICC system has improved the system efficiency, considering the losses when the system operates with the pulsating load and the DVS operation. Lastly, the output capacitor of the OICC system is much smaller than the reference design output capacitor, therefore, by applying the OICC concept the power density can be increased. In summary, the main contributions of the thesis are: • The proposed Output Impedance Correction Circuit (OICC) concept, • The system level control based on the used approach to change the states of operation, • The OICC subsystem closed-loop implementation, together with the main converter implementation, • The dynamic losses under the pulsating load and the DVS operation quantification, and • The system robustness on the capacitor impedance variation and consecutive load-steps.

Developmental exposure to vasopressin increases aggression in adult prairie voles

Although the biological roots of aggression have been the source of intense debate, the precise physiological mechanisms responsible for aggression remain poorly understood. In most species, aggression is more common in males than females; thus, gonadal hormones have been a focal point for research in this field. Although gonadal hormones have been shown to influence the expression of aggression, in many cases aggression can continue after castration, indicating that testicular steroids are not completely essential for the expression of aggression. Recently, the mammalian neuropeptide arginine vasopressin (AVP) has been implicated in aggression. AVP plays a particularly important role in social behavior in monogamous mammals, such as prairie voles (Microtus ochrogaster). In turn, the effects of social experiences may be mediated by neuropeptides, including AVP. For example, sexually naïve prairie voles are rarely aggressive. However, 24 h after the onset of mating, males of this species become significantly aggressive toward strangers. Likewise, in adult male prairie voles, central (intracerebroventricular) injections of AVP can significantly increase intermale aggression, suggesting a role for AVP in the expression of postcopulatory aggression in adult male prairie voles. In this paper, we demonstrate that early postnatal exposure to AVP can have long-lasting effects on the tendency to show aggression, producing levels of aggression in sexually naïve, adult male prairie voles that are comparable to those levels observed after mating. Females showed less aggression and were less responsive to exogenous AVP, but the capacity of an AVP V1a receptor antagonist to block female aggression also implicates AVP in the development of female aggression.

Corticotropin-releasing hormone causes antidiuresis and antinatriuresis by stimulating vasopressin and inhibiting atrial natriuretic peptide release in male rats

In both normally hydrated and volume-expanded rats, there was a biphasic effect of corticotropin-releasing hormone (CRH) (1–10 μg, i.v.) on renal function. Within the first hour, CRH caused antidiuresis, antinatriuresis, and antikaliuresis together with reduction in urinary cGMP output that, in the fourth hour, were replaced by diuresis, natriuresis, and kaliuresis accompanied by increased cGMP output. Plasma arginine vasopressin (AVP) concentrations increased significantly within 5 min, reached a peak at 15 min, and declined by 30 min to still-elevated values maintained for 180 min. Changes in plasma atrial natriuretic peptide (ANP) were the mirror image of those of AVP. Plasma ANP levels were correlated with decreased ANP in the left ventricle at 30 min and increased ANP mRNA in the right atrium at 180 min. All urinary changes were reversed by a potent AVP type 2 receptor (V2R) antagonist. Control 0.9% NaCl injections evoked an immediate increase in blood pressure and heart rate measured by telemetry within 3–5 min. This elevation of blood pressure was markedly inhibited by CRH (5 μg). We hypothesize that the effects are mediated by rapid, direct vasodilation induced by CRH that decreases baroreceptor input to the brain stem, leading to a rapid release of AVP that induces the antidiuresis by direct action on the V2Rs in the kidney. Simultaneously, acting on V2Rs in the heart, AVP inhibits ANP release and synthesis, resulting in a decrease in renal cGMP output that is responsible for the antinatriuretic and antikaliuretic effects.

Localization of vasopressin mRNA and immunoreactivity in pituicytes of pituitary stalk-transected rats after osmotic stimulation.

The presence of [arginine] vasopressin (AVP) mRNA and AVP immunoreactivity in pituicytes of the neural lobe (NL) of intact and pituitary stalk-transected rats, with and without osmotic stimulation, was examined. AVP mRNA was analyzed by Northern blotting, as well as by in situ hybridization in combination with immunocytochemistry using anti-glial fibrillary acidic protein (GFAP) as a marker for pituicytes. In intact rats, a poly(A) tail-truncated 0.62-kb AVP mRNA was detected in the NL and was found to increase 10-fold with 7 days of continuous salt loading. Morphological analysis of the NL of 7-day salt-loaded rats revealed the presence of AVP mRNA in a significant number of GFAP-positive pituicytes in the NL and in areas most probably containing nerve fibers. Eight days after pituitary stalk transection the NL AVP mRNA diminished in animals given water to drink, whereas in those given 2% saline for 18 h followed by 6 h of water, a treatment repeated on 6 successive days beginning 2 days after surgery, the 0.62-kb AVP mRNA was present. The AVP mRNA in the pituitary stalk-transected, salt-loaded rats showed an exclusive cellular distribution in the NL, indicative of localization in pituicytes. Immunoelectron microscopy showed the presence of AVP immunoreactivity in a subpopulation of pituicytes 7 and 10 days after pituitary stalk transection in salt-loaded animals, when almost all AVP fibers had disappeared from the NL. These data show that a subset of pituicytes in the NL is activated to synthesize AVP mRNA and AVP in response to osmotic stimulation.

Extrapituitary expression of the rat V1b vasopressin receptor gene.

[Arg8]vasopressin (AVP) stimulates adrenocorticotropic hormone release from the anterior pituitary by acting on the V1b AVP receptor. This receptor can be distinguished from the vascular/hepatic V1a and renal V2 AVP receptors by its differential binding affinities for structural analogous of AVP. Recent studies have shown that the cloned V1a and V2 receptors are structurally related. We have isolated a clone encoding the V1b receptor from a rat pituitary cDNA library using polymerase chain reaction (PCR)-based methodology. The rat V1b receptor is a protein of 421 amino acids that has 37-50% identity with the V1a and V2 receptors. Homology is particularly high in the seven putative membrane-spanning domains of these guanine nucleotide-binding protein-coupled receptors. Expression of the recombinant receptor in mammalian cells shows the same binding specificity for AVP agonists and antagonists as the rat pituitary V1b receptor. AVP-stimulated phosphotidylinositol hydrolysis and intracellular Ca2+ mobilization in Chinese hamster ovary or COS-7 cells expressing the cloned receptor suggest second messenger signaling through phospholipase C. RNA blot analysis, reverse transcription PCR, and in situ hybridization studies reveal that V1b receptor mRNA is expressed in the majority of pituitary corticotropes as well as in multiple brain regions and a number of peripheral tissues, including kidney, thymus, heart, lung, spleen, uterus, and breast. Thus, the V1b receptor must mediate some of the diverse biological effects of AVP in the pituitary as well as other organs.