Ana Aldea-Perona

Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury

BACKGROUND & AIMS Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity. METHODS 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition. RESULTS Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis. CONCLUSIONS One year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery. LAY SUMMARY Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis.

Effect of intravenous and intracoronary melatonin as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: Results of the Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty trial

The MARIA randomized trial evaluated the efficacy and safety of melatonin for the reduction of reperfusion injury in patients undergoing revascularization for ST‐elevation myocardial infarction (STEMI). This was a prespecified interim analysis. A total of 146 patients presenting with STEMI within 6 hours of chest pain onset were randomized to receive intravenous and intracoronary melatonin (n=73) or placebo (n=73) during primary percutaneous coronary intervention (PPCI). Primary endpoint was myocardial infarct size as assessed by magnetic resonance imaging (MRI) at 6 ± 2 days. Secondary endpoints were changes in left ventricular volumes and ejection fraction (LVEF) at 130 ± 10 days post‐PPCI and adverse events during the first year. No significant differences in baseline characteristics were observed between groups. MRI was performed in 108 patients (86.4%). Myocardial infarct size by MRI evaluated 6 ± 2 days post‐PPCI, did not differ between melatonin and placebo groups (P=.63). Infarct size assessed by MRI at 130 ± 10 days post‐PPCI, performed in 91 patients (72.8%), did not show statistically significant differences between groups (P=.27). The recovery of LVEF from 6 ± 2 to 130 ± 10 days post‐PPCI was greater in the placebo group (60.0 ± 10.4% vs 53.1 ± 12.5%, P=.008). Both left ventricular end‐diastolic and end‐systolic volumes were lower in the placebo group (P=.01). The incidence of adverse events at 1 year was comparable in both groups (P=.150). Thus, in a nonrestricted STEMI population, intravenous and intracoronary melatonin was not associated with a reduction in infarct size and has an unfavourable effect on the ventricular volumes and LVEF evolution. Likewise, there is lack of toxicity of melatonin with the doses used.

Estimated Glomerular Filtration Rate in Renal Transplantation: The Nephrologist in the Mist.

Background Formulas do not estimate renal function with acceptable precision and accuracy. Methods We compared 51 creatinine-based and/or cystatin c–based formulas with a gold standard (iohexol plasma clearance) in 193 renal transplant recipients using concordance correlation coefficient, total deviation index, coverage probability and the error in chronic kidney disease (CKD) stage classification. Results No formula showed a concordance correlation coefficient greater than 0.90 (average for creatinine-based formulas: ∼0.70 and for cystatin c–based formulas: ∼0.85). A wide total deviation index was observed: approximately 70% (creatinine-based) and approximately 50% (cystatin c–based), indicating that 90% of the estimations showed bounds of error of ±70% or ±50%, respectively, compared with the gold standard. No formula included 90% of the estimations within a coverage probability of ±10%. Half the CKD stages classified by creatinine-based formulas were incorrect, mainly due to overestimation of renal function. One of 3 CKD stages diagnosed by cystatin c–based formulas was incorrect, with both overestimation and underestimation. Overall, the formulas showed very low precision and accuracy and a high degree of error in reflecting real renal function. Conclusions In conclusion, formulas do not properly reflect renal function in kidney transplantation, which makes their use in clinical practice unreliable. Moreover, their use in clinical trials should be avoided.

Drogas emergentes (II): el pharming

El uso por la poblacion joven de farmacos con y sin receta medica con fines recreativos, ha tenido escasa atencion por los medicos. En USA, uno de cada cinco adolescentes han usado farmacos con finalidad recreativa, y en el Servicio de Urgencias, las consultas por abuso de farmacos han superado a las de drogas ilegales. Aunque es Espana existen pocos datos, este consumo se situa entre el 3,1 y el 8,6% segun las encuestas. Los farmacos mas utilizados son el dextrometorfan y el metilfenidato. El primero, de venta sin receta, presenta una sintomatologia variable, dosis y accion metabolica dependiente, que va desde la euforia a las alucinaciones. El metilfenidato se utiliza como estimulante sustituto de la cocaina, tanto por via oral como nasal e intravenosa, siendo uno de los farmacos con mas desvio hacia el mercado ilicito a nivel mundial. Otras sustancias como el modafinilo y el propofol presentan un uso no medico en principio de escasa incidencia, pero con un probable potencial de abuso a tener en cuenta, sobre todo en el ambito sanitario. Finalmente, opiaceos como el fentanilo, la oxicodona y la buprenorfina, de reciente generalizacion en el arsenal terapeutico de muchas especialidades medicas y con nuevas presentaciones farmaceuticas, estan produciendo fenomenos de abuso, dependencia y desvio hacia el mercado ilicito. Las demandas de tratamiento de desintoxicacion, la mezcla con sustancias ilegales y los casos de muerte, alertan sobre el abuso de estos farmacos.

Cardioprotection with melatonin in the acute myocardial infarction: awaiting results of MARIA trial?

a Hospital Universitario de Canarias, Servicio de Cardiologia, Tenerife, Spain b Facultad de Ciencias de la Salud, Universidad Europea de Canarias, La Orotava, Santa Cruz de Tenerife, Spain c Universidad de La Laguna, Departamento de Fisiologia, Tenerife, Spain d Hospital Universitario de Canarias, Farmacologia Clinica, Tenerife, Spain e Hospital Marques de Valdecilla, Servicio de Cardiologia, Santander, Cantabria, Spain f Hospital General Universitario de Santa Lucia, Servicio de Cardiologia, Cartagena, Murcia, Spain

Study Design and Rationale of “A Multicenter, Open-Labeled, Randomized Controlled Trial Comparing MIdazolam Versus MOrphine in Acute Pulmonary Edema”: MIMO Trial

PurposeMorphine has been used for several decades in cases of acute pulmonary edema (APE) due to the anxiolytic and vasodilatory properties of the drug. The non-specific depression of the central nervous system is probably the most significant factor for the changes in hemodynamics in APE. Retrospective studies have shown both negative and neutral effects in patients with APE and therefore some authors have suggested benzodiazepines as an alternative treatment. The use of intravenous morphine in the treatment of APE remains controversial.MethodsThe MIdazolan versus MOrphine in APE trial (MIMO) is a multicenter, prospective, open-label, randomized study designed to evaluate the efficacy and safety of morphine in patients with APE. The MIMO trial will evaluate as a primary endpoint whether intravenous morphine administration improves clinical outcomes defined as in-hospital mortality. Secondary endpoint evaluation will be mechanical ventilation, cardiopulmonary resuscitation, intensive care unit admission rate, intensive care unit length of stay, and hospitalization length.ConclusionsIn the emergency department, morphine is still used for APE in spite of poor scientific background data. The data from the MIMO trial will establish the effect—and especially the risk—when using morphine for APE.

CKD staging with cystatin C or creatinine-based formulas: flipping the coin

Background Chronic kidney disease (CKD) affects 10-13% of the population worldwide. CKD classification stratifies patients in five stages of risk for progressive renal disease based on estimated glomerular filtration rate (eGFR) by formulas and albuminuria. However, the reliability of formulas to reflect real renal function is a matter of debate. The effect of the error of formulas in the CKD classification is unclear, particularly for cystatin C-based equations. Methods We evaluated the reliability of a large number of cystatin C and/or creatinine-based formulas in the definition of the stages of CKD in 882 subjects with different clinical situations over a wide range of glomerular filtration rates (GFRs) (4.2-173.7 mL/min). Results Misclassification was a constant for all 61 formulas evaluated and averaged 50% for creatinine-based and 35% for cystatin C-based equations. Most of the cases were misclassified as one stage higher or lower. However, in 10% of the subjects, one stage was skipped and patients were classified two stages above or below their real stage. No clinically relevant improvement was observed with cystatin C-based formulas compared with those based on creatinine. Conclusions The error in the classification of CKD stages by formulas was extremely common. Our study questions the reliability of both cystatin C and creatinine-based formulas to correctly classify CKD stages. Thus the correct classification of CKD stages based on estimated GFR is a matter of chance. This is a strong limitation in evaluating the severity of renal disease, the risk for progression and the evolution of renal dysfunction over time.