Changes in pulmonary mechanics from supine to prone position measured through esophageal manometry in critically ill patients with COVID-19 severe acute respiratory distress syndrome.

OBJECTIVE: To describe changes in pulmonary mechanics when changing from supine position (SP) to prone position (PP) in mechanically ventilated (MV) patients with Acute Respiratory Distress Syndrome (ARDS) due to severe COVID-19. DESIGN: Retrospective cohort. SETTING: Intensive Care Unit of the National Institute of Respiratory Diseases (Mexico City). PATIENTS: COVID-19 patients on MV due to ARDS, with criteria for PP. INTERVENTION: Measurement of pulmonary mechanics in patients on SP to PP, using esophageal manometry. MAIN VARIABLES OF INTEREST: Changes in lung and thoracic wall mechanics in SP and PP RESULTS: Nineteen patients were included. Changes during first prone positioning were reported. Reductions in lung stress (10.6 vs 7.7, p=0.02), lung strain (0.74 vs 0.57, p=0.02), lung elastance (p=0.01), chest wall elastance (p=0.003) and relation of respiratory system elastances (p=0.001) were observed between patients when changing from SP to PP. No differences were observed in driving pressure (p=0.19) and transpulmonary pressure during inspiration (p=0.70). CONCLUSIONS: Changes in pulmonary mechanics were observed when patients were comparing values of supine position with measurements obtained 24h after prone positioning. Esophageal pressure monitoring may facilitate ventilator management despite patient positioning.

Comparative Bioavailability and Pharmacokinetics Between the Solid Form of Metformin vs a Novel Liquid Extemporaneous Formulation in Children.

Metformin pharmacokinetics in a liquid extemporaneous formulation from commercial tablets was determined in paediatric patients. A randomized, transversal clinical trial was conducted in 34 children and adolescents between 7 and 17 years of age. 17 children were randomized to take metformin in the liquid formulation and, after a 1-week wash period, a 500 mg metformin tablet was administered to them. Blood samples were obtained in Whatman 903® cards at 0, 1, 2, 4, 8, 12 and 24 hours. Extraction was made by direct precipitation with acetonitrile (ACN) and methanol, detection by UPLC and tandem mass spectrometry. The method was accurate, precise, selective and linear from 50 to 1000 ng/mL (r = .9982). Comparative pharmacokinetics, tablet vs formulation, were as follows: Cmax 1503.2 ng/mL vs 1521.4, Tmax 1.5 h vs 2.3, and half-life 8.2 vs 7.5 h. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, and the ratios (90% CI) of geometric mean for metformin were 100.63% (89.13-113.6), 98.08% (88.04-109.2), and 97.52% (84.9-112.01), for Cmax, AUC0-t, and AUC 0-∞, respectively. Pharmacokinetics was determined using WinNonlin Pro 3.1 software. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, allowing a more precise dose adjustment and ease of administration.

Clinical Risk Factors for Mortality Among Critically Ill Mexican Patients With COVID-19.

Little literature exists about critically ill patients with coronavirus disease 2019 (COVID-19) from Latin America. Here, we aimed to describe the clinical characteristics and mortality risk factors in mechanically ventilated COVID-19 patients from Mexico. For this purpose, we recruited 67 consecutive mechanically ventilated COVID-19 patients which were grouped according to their clinical outcome (survival vs. death). Clinical risk factors for mortality were identified by machine-learning and logistic regression models. The median age of participants was 42 years and 65% were men. The most common comorbidity observed was obesity (49.2%). Fever was the most frequent symptom of illness (88%), followed by dyspnea (84%). Multilobe ground-glass opacities were observed in 76% of patients by thoracic computed tomography (CT) scan. Fifty-two percent of study participants were ventilated in prone position, and 59% required cardiovascular support with norepinephrine. Furthermore, 49% of participants were coinfected with a second pathogen. Two-thirds of COVID-19 patients developed acute kidney injury (AKIN). The mortality of our cohort was 44.7%. AKIN, uric acid, lactate dehydrogenase (LDH), and a longitudinal increase in the ventilatory ratio were associated with mortality. Baseline PaO2/FiO2 values and a longitudinal recovery of lymphocytes were protective factors against mortality. Our study provides reference data about the clinical phenotype and risk factors for mortality in mechanically ventilated Mexican patients with COVID-19.

A MULTIVARIATE PROGNOSTIC SCORE FOR PREDICTING MORTALITY OF ACQUIRED IMMUNODEFICIENCY SYNDROME PATIENTS WITH HYPOXEMIC RESPIRATORY FAILURE AND PNEUMOCYSTIS JIROVECI PNEUMONIA.

BACKGROUND: Severe hypoxemic respiratory failure (SHRF) due to Pneumocystis jiroveci pneumonia (PJP) in AIDS patients represents the main cause of admission and mortality in respiratory intensive care units (RICUs) in low- and middle-income countries. OBJECTIVE: The objective of this study was to develop a predictive scoring system to estimate the risk of mortality in HIV/AIDS patients with PJP and SHRF. METHODS: We analyzed data of patients admitted to the RICU between January 2013 and January 2018 with a diagnosis of HIV infection and PJP. Multivariate logistic regression and Kaplan-Meier method were used in data analysis. The RICU and inhospital mortality were 25% and 26%, respectively. Multivariate analysis identified four independent predictors: body mass index, albumin, time to ICU admission, and days of vasopressor support. A predictive scoring system was derived and validated internally. The discrimination was 0.869 (95% confidence interval: 0.821-0.917) and calibration intercept (α) and slope (ß) were 0.03 and 0.99, respectively. The sensitivity was 47.2%, specificity was 84.6%, positive predictive value was 89.2%, and negative predictive value was 82.6%. CONCLUSIONS: This scoring system is a potentially useful tool to assist clinicians, in low- and medium-income countries, in estimating the RICU and inhospital mortality risk in patients with HIV/AIDS and SHRF caused by PJP.

A multivariate prognostic score for predicting mortality of acquired immunodeficiency syndrome patients with Hypoxemic Respiratory Failure and Pneumocystis Jiroveci Pneumonia

Background Severe hypoxemic respiratory failure (SHRF) due to Pneumocystis jiroveci pneumonia (PJP) in AIDS patients represents the main cause of admission and mortality in respiratory intensive care units (RICUs) in low- and middle-income countries. Objective The objective of this study was to develop a predictive scoring system to estimate the risk of mortality in HIV/AIDS patients with PJP and SHRF. Methods We analyzed data of patients admitted to the RICU between January 2013 and January 2018 with a diagnosis of HIV infection and PJP. Multivariate logistic regression and Kaplan–Meier method were used in data analysis. The RICU and inhospital mortality were 25% and 26%, respectively. Multivariate analysis identified four independent predictors: body mass index, albumin, time to ICU admission, and days of vasopressor support. A predictive scoring system was derived and validated internally. The discrimination was 0.869 (95% confidence interval: 0.821-0.917) and calibration intercept (α) and slope (β) were 0.03 and 0.99, respectively. The sensitivity was 47.2%, specificity was 84.6%, positive predictive value was 89.2%, and negative predictive value was 82.6%. Conclusions This scoring system is a potentially useful tool to assist clinicians, in low- and medium-income countries, in estimating the RICU and inhospital mortality risk in patients with HIV/AIDS and SHRF caused by PJP.

Determination of blood dexmedetomidine in dried blood spots by LC-MS/MS to screen therapeutic levels in paediatric patients.

Dexmedetomidine is an imidazole derivative, with high affinity for α2 adrenergic receptors, used for sedation, analgesia and adjuvant anaesthesia. In this study, an analytical method for the quantification of dexmedetomidine in dried blood spots was developed, validated and applied. The drug was extracted from dried blood spot by liquid extraction; the separation was carried out by ultra high-resolution liquid chromatography in reverse phase coupled to tandem mass spectrometry method. An X Select cyano 5 µm HSS column (2.1 X 150 mm, Waters) and a mobile phase composed of 0.1% formic acid: acetonitrile [50:50 v/v], were used. The test was linear over the concentration range of 50 to 2000 pg/mL. The coefficients of variation for the intra and interday trials were less than 15%. The drug was stable under the conditions tested. The method was successfully applied for the quantification of 6 patients, aged 0 to 2 years, with classification ASA I, who underwent ambulatory surgeries, receiving a dose of 1 µg/Kg dexmedetomidine IV. The drug concentrations in the different sampling times were in the range of 76 to 868 pg/mL.

Population Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Children Undergoing Ambulatory Surgery.

BACKGROUND: Dexmedetomidine (DEX) is an α-2 adrenergic agonist with sedative and analgesic properties. Although not approved for pediatric use by the Food and Drug Administration, DEX is increasingly used in pediatric anesthesia and critical care. However, very limited information is available regarding the pharmacokinetics of DEX in children. The aim of this study was to investigate DEX pharmacokinetics and pharmacodynamics (PK-PD) in Mexican children 2-18 years of age who were undergoing outpatient surgical procedures. METHODS: Thirty children 2-18 years of age with American Society of Anesthesiologists physical status score of I/II were enrolled in this study. DEX (0.7 µg/kg) was administered as a single-dose intravenous infusion. Venous blood samples were collected, and plasma DEX concentrations were analyzed with a combination of high-performance liquid chromatography and electrospray ionization-tandem mass spectrometry. Population PK-PD models were constructed using the Monolix program. RESULTS: A 2-compartment model adequately described the concentration-time relationship. The parameters were standardized for a body weight of 70 kg by using an allometric model. Population parameters estimates were as follows: mean (between-subject variability): clearance (Cl) (L/h × 70 kg) = 20.8 (27%); central volume of distribution (V1) (L × 70 kg) = 21.9 (20%); peripheral volume of distribution (V2) (L × 70 kg) = 81.2 (21%); and intercompartmental clearance (Q) (L/h × 70 kg) = 75.8 (25%). The PK-PD model predicted a maximum mean arterial blood pressure reduction of 45% with an IC50 of 0.501 ng/ml, and a maximum heart rate reduction of 28.9% with an IC50 of 0.552 ng/ml. CONCLUSIONS: Our results suggest that in Mexican children 2-18 years of age with American Society of Anesthesiologists score of I/II, the DEX dose should be adjusted in accordance with lower DEX clearance.

Acute Respiratory Distress Syndrome Secondary to Influenza A(H1N1)pdm09: Clinical Characteristics and Mortality Predictors.

BACKGROUND: Acute respiratory distress syndrome secondary to influenza A(H1N1)pdm09 virus is the leading cause of death among this patient population. Expanding the knowledge of its course and predictors of mortality is relevant to decision making. We aimed to describe the clinical characteristics and identify factors associated with mortality in patients with acute respiratory distress syndrome secondary to influenza A(H1N1)pdm09 during the 2013-2014 influenza season. METHODS: This is an observational study of a prospective cohort of 70 patients with acute respiratory distress syndrome and influenza A(H1N1) pdm09 seen in an academic medical center. Multivariate logistic regression was used to identify the independent mortality predictors. Bootstrap was used for internal model validation. RESULTS: This cohort was represented by young adults (43 ± 11 years old). Obesity was present in 62.5% and was not associated with mortality. Mortality at 28 days and at discharge from the respiratory intensive care unit was 14 and 20%, respectively. All patients met the criteria for acute respiratory distress syndrome, 73% had vasodilatory shock, and 27.1% had acute kidney injury on respiratory intensive care unit admission. We observed a high incidence of intensive care unit-acquired weakness (81.4%). Ventilator-associated pneumonia developed in 47.1% and was not associated with mortality. In multivariate analysis, independent risk factors for intensive care unit mortality were age (odds ratio [OR] = 1.102), white blood cell count (OR = 1.22), and lactate dehydrogenase levels (OR = 1.004) on admission to the intensive care unit. CONCLUSIONS: We described the clinical characteristics and course of a cohort of patients with acute respiratory distress syndrome secondary to influenza A(H1N1)pdm09, and developed a predictive model of mortality based on the covariates age, levels of lactate dehydrogenase, and white cell count on admission to the respiratory intensive care unit.

Classifying Acute Respiratory Distress Syndrome Severity: Correcting the Arterial Oxygen Partial Pressure to Fractional Inspired Oxygen at Altitude.

In the well-known Berlin definition of acute respiratory distress syndrome (ARDS), there is a recommended adjustment for arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FIO2) at altitude, but without a reference as to how it was derived.

Population Pharmacokinetics of Gentamicin in Mexican Children With Severe Malnutrition.

BACKGROUND: To develop a population pharmacokinetic model of gentamicin in children with complicated severe malnutrition and to study the influence of covariates (weight and age) on pharmacokinetic indices. In addition, we use the model to perform Monte Carlo simulations to explore the efficacy of several dosage regimens. METHODS: Twenty-six children with severe complicated malnutrition were studied. Ninety-six samples of gentamicin plasma concentrations, obtained from 0.5 to 8 hours after intravenous dosing, were analyzed. Population pharmacokinetic models were built using the program Monolix 4.2 (Lixoft, Antony, France). Monte Carlo simulations were performed to evaluate optimal dosage regimens, using the final pharmacokinetic model, based on the probability of pharmacokinetic-pharmacodynamic target attainment. RESULTS: The concentration-time data were fitted best to 1-compartment model. The estimated population clearance was 1.1 L/h, and the volume of distribution was 2.23 L, with an interindividual variability of 47.2% and 35.6%, respectively. The final models for the clearance and volume of distribution were as follows: CL (L/h) = CL = 1.15 (age/median age) and V (L) = 2.33 (weight/median weight). In Monte Carlo simulations, gentamicin given in dosages of 7.5 to 15 mg/kg optical density was effective in achieving the pharmacodynamic target Cmax:minimal inhibitory concentration >10 for minimal inhibitory concentrations ≤2.5 mg/L, with a probability lower than 1% for Cmin >1 mg/L. CONCLUSIONS: Based on the available evidence, an intravenous dose of 7.5 to 15 mg/kg once daily in children with complicated severe malnutrition and normal renal function ensures high probability of efficacy and low risk of nephrotoxicity, which gives further support to the recommendations issued by the World Health Organization treatment for this patient population.

Effect of treatment and additional disease on pharmacokinetic of valproic acid in children with epilepsy.

BACKGROUND: Most of bayesian pharmacokinetic studies and the influence of clinical variables have been carried out in adults. PURPOSE: The aim was to estimate population-based pharmacokinetic of valproic acid (VPA) and to determine the effect of treatment and additional disease on its performance in children with epilepsy. MATERIAL AND METHODS: For the study steady-state serum concentrations of VPA were determined from 108 epileptic patients (44 females and 64 males) who were receiving the anticonvulsant as main drug of treatment with age range since 1 to 16 years (median 4y, 6m) and weight since 5.2 to 50 kg (median 17.5 kg). All patients had their renal, hepatic and nutritional functions normal. One compartment model using interactive two-stage Bayesian approach was employed in the analysis. RESULTS; Population estimates of CL/F and V/F for VPA were 0.022 +/- 0.013 L/h and 0.217 +/- 0.134 L/kg, respectively. These estimates were significantly affected by weight, age, carbamazepine (CBZ) and gastroesophageal reflux (GER). The final regression models were: CL/F (L/h) = 0.0696 + 0.0031 (Age) + 0.0075 (Weight); and V/F (L) = 0.674 + 0.0308 (Age) + 0.0756 (Weight). Prediction of VPA serum concentration in other validation group revealed an important improvement in the predictive performance of VPA concentrations in comparison with the basic model that did not include any co-variables. CONCLUSIONS: Based on a population model of children with epilepsy, the pharmacokinetic of VPA could be altered by weight, age and the administration of CBZ and additional GER to epilepsy.

Evaluación de las condiciones de intubación de Rocuronio y Vecuronio en cirugía ambulatoria / Evaluation of Intubating Conditions of Rocuronium and Vecuronium in Outpatient Surgery

Introducción: Las condiciones de intubación y los efectos neuromusculares de rocuronio y vecuronio se estudiaron en 30 pacientes ASA I/II sometidos a rinoseptumplastia o cirugía endoscópica de senos paranasales en forma ambulatoria. Material y Métodos: Los efectos neuromusculares de ambas drogas fueron evaluados registrando la respuesta del aductor del pulgar a la estimulación supramáxima del nervio cubital. Después de la inducción de la anestesia con Propofol y Fentanyl la intubación de la tráquea se realizó utilizando rocuronio (0.6 mg/kg) o vecuronio (0.1 mg/kg). Las condiciones de intubación fueron registradas en forma ciega, así como el curso temporal del bloqueo neuromuscular. Resultados: Las condiciones de intubación fueron superiores después de la administración de rocuronio que de vecuronio. El inicio y la duración del bloqueo fueron significativamente más rápidos con rocuronio que con vecuronio. La reversión del bloqueo neuromuscular fue necesaria en todos los pacientes que recibieron vecuronio, más no en aquellos que recibieron rocuronio. Conclusión: Rocuronio mostró un perfil más favorable con respecto a las condiciones para la intubación, curso temporal de acción y necesidad de reversión en comparación a vecuronio. Por lo tanto rocuronio es una mejor opción que vecuronio en el paciente ambulatorio que requiere relajación muscular

Predición bayesiana de las concentraciones séricas de clorafenicol en niños con sepsis y desnutrición / Evaluation on the performance of bayesian adaptive control system to forecast the chloramphenicol serum concentrations in pediatric patients with sepsis and malnutrition

Objetivo. Validar los parámetros farmacocinéticos de cloranfenicol en pacientes pediátricos con sepsis y desnutrición (PPSD) por medio de un programa de predicción bayesiano para cloranfenicol en PPSD. Lugar. Hospital Pediátrico de Enseñanza de Tercer Nivel. Pacientes. Quince PPSD y diez pacientes pediátricos con sepsis sin desnutrición (PPSN), que recibieron tratamiento con cloranfenicol. Método y resultados principales. En la primera parte del estudio, los expedientes clínicos de 10 PPSD y 10 PPSN quienes habían recibido tratamiento con cloranfenicol fueron revisados. Los parámetros farmcocinéticos poblacionales para cada grupo fueron estimados por medio de un algoritmo no paramétrico de maximización de expectativas (NPEM). En la segunda parte, cinco pacientes independientes con indicadores similares de desnutrición que recibieron cloranfenicol fueron utilizados para probar el desempeño predictivo de los modelos poblacionales, utilizados éstos como distribución a priori en un programa de control adaptado bayesiano. Las concentraciones séricas de cloranfenicol predichas por el método bayesiano fueron comparadas con las concentraciones observadas. El modelo específico para PPSD permitió pronosticar las concentraciones pico y valle de cloranfenicol con menor sesgo y con una mayor precisión, comparado con el modelo poblacional de PPSN. Conclusiones. Estos datos indican que la farmacocinética de cloranfenicol en PPSD puede predecirse con un sesgo mínimo y una buena precisión utilizando un programa bayesiano, permitiendo así, un mejor control sobre el grado de exposición a esta droga y con el beneficio económico adicional de requerir de un número limitado de muestras por paciente

Farmacocinética bayesiana de cefuroxima en niños infectados gravemente enfermos / Bayesian pharmacokinetics of cefuroxime in critically ill septic children

Objetivo. Estimar los párametros farmacocinéticos de cefuroxima en el paciente pediátrico críticamente enfermo utilizando un método farmacocinético bayesiano y un número limitado de muestras por paciente. Diseño. Estudio transversal de pacientes pediátricos gravemente enfermos que recibieron tratamiento y monitoreo de concentraciones séricas de cefuroxima. Lugar. Centro de atención de tercer nivel. Pacientes. Nueve pacientes pediátricos sépticos gravemente enfermos. Métodos. Se midió la cefuroxima a diferentes tiempos y se estimaron los parámetros Vd(volumen de distribución) y Kel(constante de eliminación) utilizando un algoritmo iterativo en dos etapas hayesiano y la información de tres muestras de cada paciente. El Vd y la Kel fueron también estimados por el método tradicional de regresión no lineal en 8 muestras. Resultados. La comparación de algunos métodos mostró que la Vd bayesiano fue muy similar al tradicional (r=0.99 y sesgo de -0.04 l/kg) mientras que para la Kel la correlación fue de 0.90 y el sesgo de -0.29 h. el Vd bayesiano promedio fue de 0.68 l/kg, un valor mayor que el reportado para pacientes no críticamente enfermos. Conclusiones. Ofrecemos un modelo farmacocinético de cefuroxima para niños sépticos gravemente enfermos que puede ser integrado a un predictor bayesiano para establecer dosis individualizadas. Asimismo, ilustran la utilidad de un abordaje farmacocinético bayesiano para establecer dosis individualizadas. Asimismo, ilustran la utilidad de un abordaje farmacocinético bayesiano como herramienta de investigación clínica

Efectos de la hipotermia sobre la extracción y el balance de oxígeno en pacientes de alto riesgo sometidos a cirugía mayor no cardiaca / The hypotermia effects on the extraction and balance of O2 in high risk patients during non-cardiac major surgery

Con el propósito de investigar el efecto de la hipotermia no intencional (HNI) durante anestesia sobre la capacidad de extracción de O2 (EO2) y el balance de O2 (BO2), se analizaron los datos clínicos, de transporte y utilización de O2 de 15 pacientes de alto riesgo que desarrollaron HNI y se compararon con los 12 pacientes que se mantuvieron normotérmicos (N). Todos los pacientes fueron monitorizados por medio de un catéter de flotación pulmonar con termistor y recibieron anestesia inhalada a base de enfluorano o isofluorano. Un nivel crítico de aporte de O2 (DO2c), consumo de O2 (VO2c) y extracción de O2 (EO2) fue determinado para cada paciente utilizando un método de regresión "dual line" por mínimos cuadrados. El DO2c no fue diferente entre los pacientes con HNI y N (385 ñ 58 vs 328 ñ 58, p. ns). Sin embargo, la EO2 fue significativamente menor en los pacientes con HNI (19 ñ 3 vs 29 ñ 4, p < 0.001). Los pacientes con HNI mostraron un mayor compromiso en el EO2 que los pacientes N, reflejado por un mayor gradiente AV de pH (0.04 ñ 0.1 vs 0.01 ñ.008, p < 0.01). Nuestros resultados sugieren que la HNI durante anestesia se asocia con una disminución en la EO2 y un compromiso en el BO2, reflejando probablemente, alteraciones en la función del endotelio vascular. El mantenimiento de condiciones de normotermia en esta población de pacientes de alto riesgo puede presentar una medida importante para la optimización de su BO2 durante anestesia