Global sensitivity analysis in physiologically-based pharmacokinetic/pharmacodynamic models of inhaled and opioids anesthetics and its application to generate virtual populations.

The integration between physiologically-based pharmacokinetics (PBPK) models and pharmacodynamics (PD) models makes it possible to describe the absorption, distribution, metabolism and excretion processes of drugs, together with the concentration-response relationship, being a fundamental framework with wide applications in pharmacology. Nevertheless, the enormous complexity of PBPK models and the large number of parameters that define them leads to the need to study and understand how the uncertainty of the parameters affects the variability of the models output. To study this issue, this paper proposes a global sensitivity analysis (GSA) to identify the parameters that have the greatest influence on the response of the model. It has been selected as study cases the PBPK models of an inhaled anesthetic and an analgesic, along with two PD interaction models that describe two relevant clinical effects, hypnosis and analgesia during general anesthesia. The subset of the most relevant parameters found adequately with the GSA method has been optimized for the generation of a virtual population that represents the theoretical output variability of various model responses. The generated virtual population has the potential to be used for the design, development and evaluation of physiological closed-loop control systems.

Modelado del sistema cardiovascular para evaluación de técnicas de estimación de reactividad vascular basadas en hiperemia reactiva / Modeling of cardiovascular system for evaluation of vascular reactivity estimation techniques based on reactive hyperemia

Resumen Introducción: La evaluación de la reactividad vascular (RV) se hace mediante la respuesta hiperémica después de una isquemia producida por oclusión arterial. Existen técnicas de medición de RV que permiten evaluar la función vascular con menor costo y sin dependencia del operador, pero se encuentran en desarrollo y requieren validación y aceptación clínica. Objetivo: Modelar computacionalmente la mecánica vascular con el fin de evaluar el desempeño de una técnica de RV. Materiales y métodos: Se modificó el modelo eléctrico de la vasculatura del brazo, obteniendo el volumen periférico con y sin oclusión de la arteria braquial. Se realizó una identificación computacional que relaciona el volumen periférico con los resultados de una técnica de evaluación de RV que presenta cambios de color en la mano ocluida durante hiperemia reactiva. El software utilizado fue Matlab(r). Resultados: El modelo modificado permitió obtener el volumen periférico con y sin oclusión representando la perfusión en la microvascultura. El modelo no lineal Hammerstein-Weiner fue el mejor descriptor de los cambios de color en función de la dinámica del sistema vascular y presentó porcentaje de ajuste promedio de 95,69%. Conclusiones: Es posible modelar computacionalmente la técnica de evaluación de la función vascular utilizando identificación no lineal.

Abstract Introduction: The evaluation of vascular reactivity (VR) is done by the hyperemic response after ischemia produced by arterial occlusion. There are VR measurement techniques that allow the evaluation of vascular function at lower cost and without dependence on the operator, but they are in development and require validation and clinical acceptance. Objective: To model vascular mechanics computationally in order to evaluate the performance of a VR technique. Materials and methods: The electrical model of the vasculature of the arm was modified, obtaining the peripheral volume with and without brachial artery occlusion. A computational identification, which relates the peripheral volume to the results of a VR evaluation technique and presents color changes in the occluded hand during reactive hyperemia, was performed. The software used was Matlab(r). Results: The modified model allowed to obtain the peripheral volume with and without occlusion, representing the perfusion in the microvasculature. The Hammerstein-Weiner non-linear model was the best descriptor of color changes depending on the dynamics of the vascular system and it presented an average adjustment percentage of 95.69%. Conclusions: It is possible to model computationally the technique of evaluation of vascular function using nonlinear identification.

Assessment of mechanically ventilated patients intoxicated with organophosphates by a novel surface electromyographic index.

PURPOSE: We present a new electromyographic index, named Engagement of Respiratory Muscle (ERM), for assessing the level of participation of respiratory muscles during spontaneous breathing test in patients poisoned with organophosphorus compound. METHODS: Diaphragm and sternocleidomastoid muscles activity was recorded by surface electromyography during spontaneous breathing test. A population of 23 patients poisoned with organophosphates and mechanically ventilated, and a control group of 28 healthy subjects were analyzed. RESULTS: All patients developed respiratory failure and 48% were diagnosed with intermediate syndrome by medical staff. The ERM index classified the patients in three clusters (p-value<0.005): Cluster I presented more engagement of the sternocleidomastoid compared to diaphragm, Cluster II had low muscle engagement of both muscles and also muscle weakness, Cluster III were characterized for the diaphragm recovery associated with higher engagement. The control group showed a similar muscle engagement to Cluster III. The capacity of ERM index for classifying patients with (sensitivity) and without (specificity) muscle weakness were 90.91% and 100% respectively. CONCLUSIONS: The ERM is a promising index to assess the level of participation of respiratory muscle on spontaneous breathing test in patients poisoned with organophosphorus compounds, which could improve the extubation prognosis for these patients.

Efecto del incremento de la PEEP en la actividad muscular respiratoria evaluado con electromiografía de superficie en individuos sanos bajo ventilación espontánea / Effect of PEEP increase on respiratory muscle activity assessed through surface electromyography in healthy subjects during spontaneous breathing / Efeito do incremento da PEEP na atividade mus-cular respiratória avaliado com eletromiografia de superfície em indivíduos saudáveis sob ventilação espontânea

Introducción: en un paciente bajo ventilación mecánica con resistencia aumentada de la vía aérea, la duración de la fase espiratoria es insuficiente para exhalar todo el volumen inspirado. Para mantener la oxigenación y reducir el trabajo de los músculos respiratorios, es común aplicar una presión positiva al final de la espiración (PEEP), que reduce la colapsabilidad del tejido, compensando el aumento de la resistencia. Diversos estudios han demostrado la utilidad de la electromiografía de superficie (EMGS) para cuantificar el trabajo respiratorio. Objetivo: evaluar el efecto de la PEEP en la actividad muscular respiratoria mediante EMGS en individuos sanos bajo ventilación mecánica no invasiva. Metodología: estudio de la actividad muscular en 10 hombres voluntarios sanos ventilados de manera no invasiva con variaciones de la PEEP desde 0 hasta 5 cm H2O en pasos de 1 cm H2O, cada 30 segundos. Resultados: los biopotenciales del diafragma y el esternocleidomastoideo permitieron detectar diferentes respuestas ante el estímulo incremental: 1) aumento del trabajo de los dos músculos durante la inspiración y la espiración; 2) aumento de la actividad en solo uno de los músculos; 3) aumento del trabajo muscular exclusivamente durante la espiración. Conclusión: en individuos ventilados de forma no invasiva, la EMGS relaciona cuantitativamente el nivel de PEEP con el cambio en la actividad del diafragma y el esternocleidomastoideo.

Introduction: In a mechanically ventilated patient with increased airway resistance, the expiratory time span is insufficient to exhale all the inspired volume. In order to maintain oxygenation and to reduce the workload of respiratory muscles, it is common to apply an extrinsic positive end-expiratory pressure (PEEP) that reduces tissue collapsibility, counterbalancing the increased resistance. Several studies have shown the usefulness of surface electromyography (sEMG) to quantify the work of breathing (WOB), particularly in patients with obstructive diseases. Objective: To assess the effect of incremental PEEP in the respiratory muscle activity through sEMG in healthy volunteers noninvasively ventilated. Methods: Study of muscle activity in 10 healthy male volunteers, noninvasively ventilated for 20 minutes. The extrinsic PEEP was applied from 0 to 5 cm H2O in steps of 1 cm H2O at 30 seconds intervals. Results: The bio-potentials of diaphragm and sternocleidomastoid muscles revealed different breathing patterns in response to incremental PEEP: 1) increase in the workload of both muscles during inspiration and expiration; 2) increase in the workload of only one muscle; 3) a remarkable increase in muscle activity only in expiration. Conclusion: In noninvasively ventilated volunteers, sEMG quantitatively relates the PEEP level with changes in sternocleidomastoid and diaphragm activity.

Introdução: Num paciente sob ventilação mecânica com resistência aumentada da via aérea, a duração da fase respiratória é insuficiente para exalar todo o volume inspirado. Para manter a oxigenação e reduzir o trabalho dos músculos respiratórios, é comum aplicar uma pressão positiva no final da respiração (PEEP), que reduz a colapsabilidade do tecido, compensando o aumento da resistência. Diversos estudos demostraram a utilidade da eletromiografia de superfície (EMGS) para quantificar o trabalho respiratório. Objetivo: avaliar o efeito da PEEP na atividade muscular respiratória mediante EMGS em indivíduos saudáveis sob ventilação mecânica não invasiva. Metodologia: estudo da atividade muscular em 10 homens voluntários saudáveis ventilados de maneira não invasiva com variações da PEEP desde 0 até 5 cm H2O em passos de 1 cm H2O, cada 30 segundos. Resultados: os biopotenciais do diafragma e o esternocleidomastoideo permitiram detectar diferentes respostas ante o estímulo incremental: 1) aumento do trabalho dos dois músculos durante a inspiração e a espiração; 2) aumento da atividade em só um dos músculos; 3) aumento do trabalho muscular exclusivamente durante a espiração. Conclusão: em indivíduos ventilados de forma não invasiva, a EMGS relaciona quantitativamente o nível de PEEP com o câmbio na atividade do diafragma e oesternocleidomastoideo.