Efficacy of extended infusion of ß-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients: protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE).

BACKGROUND: Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal ß-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN. METHODS: A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem-cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 min) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK model of the BLA studied. DISCUSSION: Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematological patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes. TRIAL REGISTRATION: European Clinical Trials Database: EudraCT 2018-001476-37. ClinicalTrials.gov, ID: NCT04233996.

Management of Tizanidine Withdrawal Syndrome: A Case Report.

Most drugs that act on the central nervous system (CNS) require dose titration to avoid withdrawal syndrome. Tizanidine withdrawal syndrome is caused by adrenergic discharge due to its α2-agonist mechanism and is characterized by hypertension, reflex tachycardia, hypertonicity, and anxiety. Although tizanidine withdrawal syndrome is mentioned as a potential side effect of cessation, it is not common and there have been few reports. We present the case of a 31-year-old woman with tizanidine withdrawal syndrome after discontinuing medication prescribed for a muscle contracture (tizanidine). She showed high adrenergic activity with nausea, vomiting, generalized tremor, dysthermia, hypertension, and tachycardia. Symptoms were reversed and successful reweaning was achieved by restarting tizanidine followed by slow downward titration. Withdrawal syndrome should be considered when drugs targeting the CNS are suddenly stopped. Weaning regimens should be closely monitored for acute withdrawal reactions.

Contribution of Population Pharmacokinetics to Dose Optimization of Ganciclovir-Valganciclovir in Solid-Organ Transplant Patients.

Treatment of solid-organ transplant (SOT) patients with ganciclovir (GCV)-valganciclovir (VGCV) according to the manufacturer's recommendations may result in over- or underexposure. Bayesian prediction based on a population pharmacokinetics model may optimize GCV-VGCV dosing, achieving the area under the curve (AUC) therapeutic target. We conducted a two-arm, randomized, open-label, 40% superiority trial in adult SOT patients receiving GCV-VGCV as prophylaxis or treatment of cytomegalovirus infection. Group A was treated according to the manufacturer's recommendations. For group B, the dosing was adjusted based on target exposures using a Bayesian prediction model (NONMEM). Fifty-three patients were recruited (27 in group A and 26 in group B). About 88.6% of patients in group B and 22.2% in group A reached target AUC, achieving the 40% superiority margin (P< 0.001; 95% confidence interval [CI] difference, 47 to 86%). The time to reach target AUC was significantly longer in group A than in group B (55.9 ± 8.2 versus 15.8 ± 2.3 days,P< 0.001). A shorter time to viral clearance was observed in group B than in group A (12.5 versus 17.6 days;P= 0.125). The incidences of relapse (group A, 66.67%, and group B, 9.01%) and late-onset infection (group A, 36.7%, and group B, 7.7%) were higher in group A. Neutropenia and anemia were related to GCV overexposure. GCV-VCGV dose adjustment based on a population pharmacokinetics Bayesian prediction model optimizes GCV-VGCV exposure. (This study has been registered at ClinicalTrials.gov under registration no. NCT01446445.).

[Nutritional support and risk factors of appearance of enterocutaneous fistulas]. / Soporte nutricional y factores de riesgo de aparición de fístulas enterocutáneas.

INTRODUCTION: Among the different factors described, nutritional support has been associated to prevention and management of enterocutaneous fistulae (ECF). OBJECTIVES: To assess the influence that the parameters related to nutritional, clinical status, and surgical variables have on the occurrence of ECF. METHODS: An observational case/control retrospective study was performed on patients admitted to the General and Digestive Surgery Department. The parameters analyzed were: diagnosis, body mass index (BMI), pathologic personal history, number of surgical interventions (SI) and complications (previous infection, bleeding, and ischemia). In patients with SI, we analyzed: number and type of SI, time until onset of nutritional support, and type of nutritional support. We performed a multiple logistic uni- and multivariate regression analysis by using the SPSSv.19.0 software. RESULTS: The primary diagnoses related to the occurrence of ECF were pancreatic pathology (OR = 5.346) and inflammatory bowel disease (IBD) (OR = 9.329). The surgical variables associated to higher prevalence of ECF emergency SI (OR = 5.79) and multiple SI (OR = 4.52). Regarding the nutritional variables, the late onset of nutrition (more than three days after SI) was associated to the occurrence of ECF (OR = 3.82). CONCLUSIONS: In surgical patients, early nutritional support , independently of the route of administration, decreases the occurrence of fistulae. Pancreatic pathology, IBD, emergency SI, and multiple SI were associated to higher prevalence of ECF. The variable hyponutrition appears as a risk factor that should be confirmed in further studies.

Soporte nutricional y factores de riesgo de aparición de fístulas enterocutáneas / Nutritional support and risk factors of appearance of enterocutaneous fistulas

Introducción: Entre los diferentes factores descritos, el soporte nutricional se ha asociado a la prevención y el tratamiento de las fístulas enterocutáneas (FEC). Objetivos: Evaluar la influencia que los parámetros relacionados con variables nutricionales, estado clínico y quirúrgicas tienen sobre la aparición de FEC. Métodos: Se realizó un estudio retrospectivo observacional de casos/controles en pacientes ingresados en Cirugía General y Digestiva. Se analizaron: diagnóstico, índice de masa corporal (IMC), antecedentes patológicos, número de intervenciones quirúrgicas (IQ) y complicaciones (infección previa, sangrado e isquemia). En los pacientes con IQ se analizaron: número y tipo de IQ, tiempo hasta el inicio del soporte nutricional y tipo de soporte nutricional. El análisis estadístico uni/multivariante de regresión logística múltiple se realizó mediante el software SPSSv.19.0. Resultados: Los diagnósticos primarios que se relacionaron con la aparición de FEC fueron la patología pancreática (OR = 5,346) y la enfermedad inflamatoria intestinal (EII) (OR = 9,329). Las variables quirúrgicas que se asociaron con mayor prevalencia de FEC fueron IQ de urgencia (OR = 5,79) e IQ múltiples (OR = 4,52). En cuanto a las variables nutricionales, el inicio tardío de la nutrición (más de tres días después de IQ) se relacionó con la aparición de FEC (OR = 3,82). Conclusiones: En los pacientes quirúrgicos, el soporte nutricional precoz, independientemente de la vía de administración, disminuye la aparición de fístulas. La patología pancreática, la EII, las IQ urgentes y las IQ múltiples se asociaron con mayor prevalencia de FEC. La variable desnutrición se apunta como un factor de riesgo que debería corroborarse en estudios posteriores (AU)

Introduction: Among the different factors described, nutritional support has been associated to prevention and management of enterocutaneous fistulae (ECF). Objectives: To assess the influence that the parameters related to nutritional, clinical status, and surgical variables have on the occurrence of ECF. Methods: An observational case/control retrospective study was performed on patients admitted to the General and Digestive Surgery Department. The parameters analyzed were: diagnosis, body mass index (BMI), pathologic personal history, number of surgical interventions (SI) and complications (previous infection, bleeding, and ischemia). In patients with SI, we analyzed: number and type of SI, time until onset of nutritional support, and type of nutritional support. We performed a multiplelogistic uni- and multivariate regression analysis by using the SPSSv.19.0 software. Results: The primary diagnoses related to the occurrence of ECF were pancreatic pathology (OR = 5.346) and inflammatory bowel disease (IBD) (OR = 9.329). The surgical variables associated to higher prevalence of ECF emergency SI (OR = 5.79) and multiple SI (OR = 4.52). Regarding the nutritional variables, the late onset of nutrition (more than three days after SI) was associated to the occurrence of ECF (OR = 3.82). Conclusions: In surgical patients, early nutritional support , independently of the route of administration, decreases the occurrence of fistulae. Pancreatic pathology, IBD, emergency SI, and multiple SI were associated to higher prevalence of ECF. The variable hyponutrition appears as a risk factor that should be confirmed in further studies (AU)

Determination of ganciclovir in human plasma by ultra performance liquid chromatography-UV detection.

OBJECTIVES: Implement a sensitive UHPLC method for the assay of ganciclovir in human plasma. DESIGN AND METHODS: We developed and validated a chromatographic method coupled to ultraviolet detection for quantification of ganciclovir, with a short run time using a small volume of human plasma. Comparison of system performance was made with respect to analysis time, efficiency and sensitivity. RESULTS: Correlation coefficients (r) of the calibration curves ranged from 0.999744 to 0.999784. Within-day and between-day imprecision and inaccuracy, specificity and recovery were also evaluated for validation. The method was precise and accurate and the retention time was 0.7 min. The calibration curves were linear between 0.5 and 30 µg/mL. There was a good correlation between HPLC and UHPLC techniques. CONCLUSIONS: We developed a method that is currently applied in a clinical study assessing GCV plasma concentration variability after ganciclovir and valganciclovir administration.

[Standard parenteral nutrition preparations and caloric adjustment]. / Preparados estándar de nutrición parenteral y ajuste calórico.

INTRODUCTION: In parenteral nutrition it is necessary to adjust the intake to the estimated caloric requirements. These needs may be achieved by the use of bi- or tricameral nutrition (EPN), although they present some rigidity regarding their composition. OBJECTIVE: To assess the adequacy of caloric intake using EPN, to determine the factors conditioning it and the associated complications. METHODS: Cohort, prospective, and observational study for 9 months in surgical patients. The calculated needs were compared with actual intake. The factors conditioning the excess and deficit (weight, age, stress factor, height, glycemia, and triglyceridemia) were studied by means of a multivariant method. The metabolic complications associated to the excess or deficit (hyperglycemias, hypertriglyceridemias) were studied by using the Student's t test. The theoretical calculations with the Harris-Benedict and the Mifflin equations were compared by lineal correlation regression. RESULTS: 94 patients were studied. In 87% of them, the caloric intake was within the +/- 15% range of the theoretical mean. Thirty patients had caloric excess, whereas 61 had deficit. Patients with high weight (> 68 kg), stress factor > 1.2, and hypertriglyceridemias (> 3 mmol/L) had higher risk for caloric deficit. Twenty two point eight percent had hyperglycemias that were correlated with caloric excess. Nineteen point eight percent had hypertriglyceridemias associated to caloric deficit. When comparing both formulas, the values correlated well except for those patients with low weight and advanced age. DISCUSSION: Although EPN fits the caloric requirements in most of the patients, in those with high weight, hypercatabolism, and hypertriglyceridemia there is a risk for caloric deficit.

Preparados estándar de nutrición parenteral y ajuste calórico / Standard parenteral nutrition preparations and caloric adjustment

Introducción: En nutrición parenteral es necesario adecuar el aporte a los requisitos calóricos estimados. Estas necesidades se podrían cubrir mediante preparados bi/tricamerales (NPE) aunque presenten rigidez en su composición. Objetivo: Evaluar la adecuación del aporte calórico al utilizar NPE, determinar los factores que la condicionan y las complicaciones asociadas. Métodos: Estudio de cohortes, observacional y prospectivo durante nueve meses en pacientes quirúrgicos. Se compararon las necesidades calculadas con el aporte real. Se estudiaron que factores condicionaban el exceso y el déficit (peso, edad, factor de estrés, altura, glucemia y trigliceridemia) mediante un modelo multivariante. Se estudiaron las complicaciones metabólicas (hiperglucemias, hipertrigliceridemias) asociadas al exceso o al déficit mediante la t de Student. Se compararon los cálculos teóricos de la ecuación de Harris-Benedict y de Mifflin mediante una regresión lineal-correlación. Resultados: Se estudiaron 94 pacientes. En el 87% el aporte calórico estaba dentro del rango ± 15% de la media teórica. 30 pacientes estuvieron en exceso calórico y 61 en déficit. Los pacientes de peso elevado (> 68 kg), factor de estrés superior a 1,2 e hipertrigliceridemias (> 3 mmol/L) tenían mayor riesgo de déficit calórico. El 22,8% presentaron hiperglucemias que se relacionaron con exceso calórico. El 19,8% presentaron hipertrigliceridemias que se asociaron con déficit calórico. En la comparación de las dos fórmulas los valores se correlacionaban excepto en pacientes con bajo peso y edad avanzada. Discusión: Aunque la NPE se adecua a los requisitos calóricos de la mayoría de los pacientes, en pacientes con elevado peso, hipercatabolismo e hipertrigliceridemia existe un riesgo de déficit (AU)

Introduction: In parenteral nutrition it is necessary to adjust the intake to the estimated caloric requirements. These needs may be achieved by the use of bi- or tricameral nutrition (EPN), although they present some rigidity regarding their composition. Objective: To assess the adequacy of caloric intake using EPN, to determine the factors conditioning it and the associated complications. Methods: Cohort, prospective, and observational study for 9 months in surgical patients. The calculated needs were compared with actual intake. The factors conditioning the excess and deficit (weight, age, stress factor, height, glycemia, and triglyceridemia) were studied by means of a multivariant method. The metabolic complications associated to the excess or deficit (hyperglycemias, hypertriglyceridemias) were studied by using the Student's t test. The theoretical calculations with the Harris-Benedict and the Mifflin equations were compared by lineal correlation regression. Results: 94 patients were studied. In 87% of them, the caloric intake was within the ± 15% range of the theoretical mean. Thirty patients had caloric excess, whereas 61 had deficit. Patients with high weight (> 68 kg), stress factor > 1.2, and hypertriglyceridemias (> 3 mmol/L) had higher risk for caloric deficit. Twenty two point eight percent had hyperglycemias that were correlated with caloric excess. Nineteen point eight percent had hypertriglyceridemias associated to caloric deficit. When comparing both formulas, the values correlated well except for those patients with low weight and advanced age. Discussion: Although EPN fits the caloric requirements in most of the patients, in those with high weight, hypercatabolism, and hypertriglyceridemia there is a risk for caloric deficit (AU)