was read the article
array:25 [ "pii" => "S2013251419300136" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2018.04.012" "estado" => "S300" "fechaPublicacion" => "2019-01-01" "aid" => "5003" "copyright" => "Sociedad Española de Nefrología" "copyrightAnyo" => "2018" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2019;39:35-43" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 1213 "formatos" => array:3 [ "EPUB" => 148 "HTML" => 674 "PDF" => 391 ] ] "Traduccion" => array:1 [ "es" => array:20 [ "pii" => "S0211699518300948" "issn" => "02116995" "doi" => "10.1016/j.nefro.2018.04.007" "estado" => "S300" "fechaPublicacion" => "2019-01-01" "aid" => "503" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Nefrologia. 2019;39:35-43" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 2885 "formatos" => array:3 [ "EPUB" => 216 "HTML" => 1775 "PDF" => 894 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original</span>" "titulo" => "Incidencia, factores relacionados con la presentación, evolución y mortalidad de la acidosis láctica asociada a metformina en el área sanitaria de un hospital de tercer nivel" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "35" "paginaFinal" => "43" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Incidence, factors related to presentation, course and mortality of metformin-associated lactic acidosis in the healthcare area of a tertiary hospital" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1296 "Ancho" => 1654 "Tamanyo" => 74600 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Correlación entre la dosis diaria de metformina y los niveles séricos del fármaco. r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,557, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,009.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "José María Peña Porta, Hilda Mercedes Villafuerte Ledesma, Carmen Vicente de Vera Floristán, Ana Ferrer Dufol, Tránsito Salvador Gómez, Rafael Álvarez Lipe" "autores" => array:6 [ 0 => array:2 [ "nombre" => "José María" "apellidos" => "Peña Porta" ] 1 => array:2 [ "nombre" => "Hilda Mercedes" "apellidos" => "Villafuerte Ledesma" ] 2 => array:2 [ "nombre" => "Carmen" "apellidos" => "Vicente de Vera Floristán" ] 3 => array:2 [ "nombre" => "Ana" "apellidos" => "Ferrer Dufol" ] 4 => array:2 [ "nombre" => "Tránsito" "apellidos" => "Salvador Gómez" ] 5 => array:2 [ "nombre" => "Rafael" "apellidos" => "Álvarez Lipe" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2013251419300136" "doi" => "10.1016/j.nefroe.2018.04.012" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251419300136?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0211699518300948?idApp=UINPBA000064" "url" => "/02116995/0000003900000001/v1_201901090606/S0211699518300948/v1_201901090606/es/main.assets" ] ] "itemSiguiente" => array:20 [ "pii" => "S2013251419300148" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2018.04.013" "estado" => "S300" "fechaPublicacion" => "2019-01-01" "aid" => "110" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2019;39:44-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 853 "formatos" => array:3 [ "EPUB" => 124 "HTML" => 400 "PDF" => 329 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Influence of calcium concentration in haemodialysis fluid on blood pressure control" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "44" "paginaFinal" => "49" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Influencia de la concentración de calcio en el líquido de hemodiálisis sobre el control de la tensión arterial" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jara Ampuero Mencía, Almudena Vega, Soraya Abad, Caridad Ruiz Caro, Úrsula Verdalles, Juan Manuel López Gómez" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Jara" "apellidos" => "Ampuero Mencía" ] 1 => array:2 [ "nombre" => "Almudena" "apellidos" => "Vega" ] 2 => array:2 [ "nombre" => "Soraya" "apellidos" => "Abad" ] 3 => array:2 [ "nombre" => "Caridad" "apellidos" => "Ruiz Caro" ] 4 => array:2 [ "nombre" => "Úrsula" "apellidos" => "Verdalles" ] 5 => array:2 [ "nombre" => "Juan Manuel" "apellidos" => "López Gómez" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S021169951830095X" "doi" => "10.1016/j.nefro.2018.04.008" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S021169951830095X?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251419300148?idApp=UINPBA000064" "url" => "/20132514/0000003900000001/v1_201903030617/S2013251419300148/v1_201903030617/en/main.assets" ] "itemAnterior" => array:20 [ "pii" => "S2013251419300239" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2019.01.007" "estado" => "S300" "fechaPublicacion" => "2019-01-01" "aid" => "546" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "ssu" "cita" => "Nefrologia (English Version). 2019;39:29-34" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 1376 "formatos" => array:3 [ "EPUB" => 140 "HTML" => 775 "PDF" => 461 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Brief review</span>" "titulo" => "The Spanish Society of Nephrology (SENEFRO) commentary to the Spain GBD 2016 report: Keeping chronic kidney disease out of sight of health authorities will only magnify the problem" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "29" "paginaFinal" => "34" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Comentario de la Sociedad Española de Nefrología (SENEFRO) al informe GBD 2016 España: mantener la enfermedad renal crónica fuera del radar de las autoridades sanitarias solo magnificará el problema" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1099 "Ancho" => 2165 "Tamanyo" => 165269 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Predicted growth of the top eight causes of death from 2016 to 2100 in Spain, based on growth from 2006 to 2016 according to the GBD 2016 study. Alzheimer is predicted to become the most frequent cause of death by 2026 and is not represented in the graph due to its magnitude, which would preclude appreciating details for the other causes of death. The 2006–2016 change in number of deaths was extrapolated to predict annual number of deaths up to 2100. COPD: Chronic Obstructive Pulmonary Disease; YLDs: Years Lived with Disability; DALYs: Disability Adjusted Life Years.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Alberto Ortiz, Maria Dolores Sanchez-Niño, Marta Crespo-Barrio, Patricia De-Sequera-Ortiz, Elvira Fernández-Giráldez, Rafael García-Maset, Manuel Macía-Heras, Miguel Pérez-Fontán, Mariano Rodríguez-Portillo, Mercedes Salgueira-Lazo, Emilio Sánchez-Álvarez, Rafael Santamaría-Olmo, Fernando Simal-Blanco, Maria Dolores Pino-Pino" "autores" => array:14 [ 0 => array:2 [ "nombre" => "Alberto" "apellidos" => "Ortiz" ] 1 => array:2 [ "nombre" => "Maria Dolores" "apellidos" => "Sanchez-Niño" ] 2 => array:2 [ "nombre" => "Marta" "apellidos" => "Crespo-Barrio" ] 3 => array:2 [ "nombre" => "Patricia" "apellidos" => "De-Sequera-Ortiz" ] 4 => array:2 [ "nombre" => "Elvira" "apellidos" => "Fernández-Giráldez" ] 5 => array:2 [ "nombre" => "Rafael" "apellidos" => "García-Maset" ] 6 => array:2 [ "nombre" => "Manuel" "apellidos" => "Macía-Heras" ] 7 => array:2 [ "nombre" => "Miguel" "apellidos" => "Pérez-Fontán" ] 8 => array:2 [ "nombre" => "Mariano" "apellidos" => "Rodríguez-Portillo" ] 9 => array:2 [ "nombre" => "Mercedes" "apellidos" => "Salgueira-Lazo" ] 10 => array:2 [ "nombre" => "Emilio" "apellidos" => "Sánchez-Álvarez" ] 11 => array:2 [ "nombre" => "Rafael" "apellidos" => "Santamaría-Olmo" ] 12 => array:2 [ "nombre" => "Fernando" "apellidos" => "Simal-Blanco" ] 13 => array:2 [ "nombre" => "Maria Dolores" "apellidos" => "Pino-Pino" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S0211699518301590" "doi" => "10.1016/j.nefro.2018.09.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0211699518301590?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251419300239?idApp=UINPBA000064" "url" => "/20132514/0000003900000001/v1_201903030617/S2013251419300239/v1_201903030617/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Incidence, factors related to presentation, course and mortality of metformin-associated lactic acidosis in the healthcare area of a tertiary hospital" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "35" "paginaFinal" => "43" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "José María Peña Porta, Hilda Mercedes Villafuerte Ledesma, Carmen Vicente de Vera Floristán, Ana Ferrer Dufol, Tránsito Salvador Gómez, Rafael Álvarez Lipe" "autores" => array:6 [ 0 => array:4 [ "nombre" => "José María" "apellidos" => "Peña Porta" "email" => array:1 [ 0 => "jpenaporta@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Hilda Mercedes" "apellidos" => "Villafuerte Ledesma" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Carmen" "apellidos" => "Vicente de Vera Floristán" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Ana" "apellidos" => "Ferrer Dufol" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "Tránsito" "apellidos" => "Salvador Gómez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 5 => array:3 [ "nombre" => "Rafael" "apellidos" => "Álvarez Lipe" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Toxicología, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Farmacia, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Incidencia, factores relacionados con la presentación, evolución y mortalidad de la acidosis láctica asociada a metformina en el área sanitaria de un hospital de tercer nivel" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1302 "Ancho" => 1668 "Tamanyo" => 79549 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Correlation between the daily dose of metformin and the serum levels of the drug. <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.557, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.009.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Metformin is currently one of the most prescribed drugs and everything suggests that in the future it will continue to be so.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">1</span></a> Thus it is particularly important to learn about the adverse effects of this drug. The possibility of inducing lactic acidosis stands out due to its severity, although with metformin this complication occurs to a lesser extent than with other biguanides such as butformin and phenformin, being removed from the market because this problem.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">2</span></a> According to some series, the mortality of this complication is very high (25–50%).<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">However, the true incidence and practical significance of metformin associated lactic acidosis (MALA) is being debated in the medical literature. The cause–effect relationship between metformin and lactic acidosis has been questioned.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">4,5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In the present study we intend to analyze what has been the incidence of MALA in recent years in our health area. We have also performed a descriptive analysis of our affected patients and the clinical and biochemical variables associated to an unfavorable outcome.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Material and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">The study was preformed in the Health Area III of the Aragón Region which attends a population of 306,200 inhabitants. The reference hospital is Lozano Blesa University Clinical Hospital of Zaragoza (HCULB). Study period: from January 2014 to March 2017.</p><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Source of data</span>: The Toxicology Service of the HCULB, which exclusively perform determinations of metformin levels in our health area, provided us with the list of the 23 patients who during the study period had metformin levels above 5<span class="elsevierStyleHsp" style=""></span>mcg/ml (therapeutic values: 1–2<span class="elsevierStyleHsp" style=""></span>mcg/ml), a limit above which it is considered toxic. In these patients it was also found that they met the analytical criteria of lactic acidosis: pH<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>7.35 with lactate level ≥5<span class="elsevierStyleHsp" style=""></span>mmol/l. The Clinical Documentation Service of the HCULB provided us with an additional list of twelve diabetic patients taking metformin with discharge diagnostic codes compatible with lactic acidosis; however in these cases the drug levels had not been determined. After reviewing the medical records of these patients, it was found that five of them did not strictly fullfill the analytical criteria of MALA (pH<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>7.35 and lactate level ≥5<span class="elsevierStyleHsp" style=""></span>mmol/l), so only seven out of the twelve patients were included in the study. The HCULB Pharmacy Service provided us with the number of diabetic patients receiving metformin treatment at two time points of the study period, June 2014 (10,636 patients) and January 2017 (12,510 patients). The arithmetic mean of the two values (11,573) was used to perform the calculations of incidence, expressed as cases/100,000 patients-year, with a total sample of 30 cases of MALA.</p><p id="par0030" class="elsevierStylePara elsevierViewall">It should be noted that shortly after completion of the observational period, an additional case was registered in the Nephrology Service, although it did not compute, it was included for the analysis of the clinical and analytical variables because the patient showed the highest levels of the active medication in the whole series (74.04<span class="elsevierStyleHsp" style=""></span>mcg/ml).</p><p id="par0035" class="elsevierStylePara elsevierViewall">The levels of metformin were determined by the liquid chromatography-tandem method (high-performance liquid chromatography coupled with triple-quad tandem mass spectrometry) Agilent Technologies<span class="elsevierStyleSup">®</span>.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The clinical records of all patients included in the study were reviewed and the following clinical and analytical variables were collected: gender, age, Charlson comorbidity index, metformin daily intake (mg), metformin formulation (alone or in combination), number of active ingredients taken daily, clinical features at admission, admission service, presence of Acute Kidney Failure (AKF), stage of AKF, etiology of AKF, baseline creatinine, baseline glomerular filtration rate (GFR) estimated by the CKD-EPI formula, peak of serum creatinine level during admission, serum creatinine at discharge, days of hospital stay, need for admission to Intensive Care Unit (ICU), need for renal replacement therapy (RRT), type of RRT (hemodialysis [HD]/continuous venovenous hemofiltration), number of sessions of RRT, pH, lactate, bicarbonate, anion gap, <span class="elsevierStyleItalic">p</span>CO<span class="elsevierStyleInf">2</span>, prothrombin activity, potassium, hemoglobin, plasma levels of metformin, final result of the admission (deceased/not deceased), cause of death, evidence of metformin overdose according to recommendations of the Spanish Agency of Medicines and Health Products<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">6</span></a>: GFR <30<span class="elsevierStyleHsp" style=""></span>ml/min, metformine is contraindicated; GFR between 30 and 44<span class="elsevierStyleHsp" style=""></span>ml/min, maximum dose of 1000<span class="elsevierStyleHsp" style=""></span>mg/day; GFR between 45 and 59, maximum dose 2000<span class="elsevierStyleHsp" style=""></span>mg/day, GFR between 60 and 89, maximum dose 3000<span class="elsevierStyleHsp" style=""></span>mg/day.</p><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Statistical analysis</span>: Nonparametric Mann Whitney test was used to compare the variables of deceased vs survivors. Categorical variables were analyzed by the Chi square test; if the conditions required for the use of this test were not met, it was replaced by Fisher's exact test. Spearman coefficient was used to analyze correlation between quantitative variables. Finally, a multivariate binary logistic regression analysis was performed to select the variables associated with mortality.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">The incidence of MALA in our health area during the study period was 79.76 cases per 100,000 patient-year (61.15 cases per 100,000 patients per year if we only consider cases in which metformin serum levels were available).</p><p id="par0055" class="elsevierStylePara elsevierViewall">Our patients were 19 males (61.3%) and 12 females (37.8%). Mean age was 75.39<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>934 years; males were 75.58<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.7 and females 75.08<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>10.71 showing no significant difference in age. Mean Charlson index was 6.77<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>11.71 (males 6.84<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>11.5, women 6.67<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>22.1, again without statistical difference). Number of active drugs taken per day 10.19<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.33 (males 9.58<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.1, women 11.17<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.7, no significant difference). Analysis of active ingredients prescribed show that 23 patients were taking an ACEI or ARA II, 22 were on diuretics, 20 on statins, 9 patients took NSAIDs, 5 patients were taking ACEI/ARA II together with diuretic and NSAIDs. A 58% of patients were on metformin alone and the remaining 42% were taking metformin in combination with another oral antidiabetic drug. The most frequent dose of metformin was 850<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h in 10 patients. Six patients also received insulin. The average daily dose of the drug was 1790<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>499<span class="elsevierStyleHsp" style=""></span>mg. The most frequent clinical condition that led to the consultation was nausea, vomiting or diarrhea in 15 cases, followed by far from chest pain, fever, heart failure or hypoglycemia. These symptoms motivated the consultation in two cases. The rest of the patients consulted for other reasons. Twelve cases were attended in the Nephrology Service, and 11 by the Internal Medicine Service. The rest of patients were admitted in other services: endocrinology, cardiology, psychiatry, general and the gastroenterology surgery received one case. Another patient was treated only in the Emergency Room where he died and finally two patients were admitted directly to the ICU, where they also died. The average duration of hospitalization was 11.23<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.7 days.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Regarding the baseline renal function, the majority, 20 cases (64.5%), had no history of chronic kidney disease (CKD), with abaseline GFR >60<span class="elsevierStyleHsp" style=""></span>ml/min. Three patients presented stage 3a (GFR between 60 and 45<span class="elsevierStyleHsp" style=""></span>ml/min), 6 patients had stage 3b (GFR between 44 and 30<span class="elsevierStyleHsp" style=""></span>ml/min) and finally 2 patients had stage 4 (FG <30). Metformin was overdosed in 9 patients (29% of the patients); two in stage 4 in which metformin was contraindicated, 6 cases in stage 3b and one case in stage 3a.</p><p id="par0065" class="elsevierStylePara elsevierViewall">There was only one case of voluntary overdose and it was the one without deterioration of renal function. All other patients presented an episode of AKF, in 3 cases of parenchymal origin and in 27 it was prerenal. In 25 cases (83.3%) the AKF reached stage III according to the KDIGO classification, in three cases it reached stage II and in the two remained in stages I.</p><p id="par0070" class="elsevierStylePara elsevierViewall">A total of twelve patients (38.7%) required admission to the ICU, and 19 cases (61.3%) did not require it. In 13 cases (41.9%) it was necessary to use RRT and 18 cases (58.1%) did not need it. Regarding the type of RRT, HD was used in 10 cases (76.9%), the number of sessions was 2.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.1 (range 1–5). Continuous venovenous hemofiltration was used in 3 cases (23.1%), and the number of sessions were 2.33<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.53 (range 1–4). The duration of the HD sessions performed by the Nephrology Department was 4<span class="elsevierStyleHsp" style=""></span>h. The duration of continuous venovenous hemofiltration sessions in the ICU was around 6<span class="elsevierStyleHsp" style=""></span>h.</p><p id="par0075" class="elsevierStylePara elsevierViewall">There was a significant correlation between the daily dose of metformin and the serum levels of the drug (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Correlation was also found between the levels of metformin and three other variables: peak creatinine, pH and serum lactate concentration (<a class="elsevierStyleCrossRefs" href="#fig0010">Figs. 2–4</a>). Likewise, a correlation was detected between the Charlson comorbidity index and the number of active drugs taken, as well as between the pH and the serum potassium level.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">A total of 8 patients (25.8%) died during admission, compared to 23 (74.19%) who survived. Three patients died in the ICU, one of them due to asistolia refractory to resuscitation maneuvers, the second as a consequence of refractory shock and multi-organ dysfunction and the third due to sepsis. Another patient died in the emergency department due to cardiorespiratory arrest without response to resuscitation maneuvers, an underlying mesenteric ischemia was suspected. The rest of deaths occurred in the hospital ward. One of them due to palliative sedation in the context of disseminated neoplasia, another case due to acute pulmonary edema with respiratory failure, the third presented heart and respiratory failure with poor outcome and the last patient presented a bilateral pneumonia with unfavorable evolution leading to sepsis and death.</p><p id="par0085" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the comparison between the clinical and analytical variables in patients deceased versus the survivors. The only significant differences were the final serum creatinine level and the length of hospital stay. None of the variables was independently associated with mortality in the multivariate logistic regression analysis.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">Since its description in 1957 by Jean Stern, metformin has become one of the most prescribed drugs in the world.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">2</span></a> Currently, it is estimated that 150 million patients are being treated with metformin worldwide for control of diabetes.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">1</span></a> The study United Kingdom Prospective Diabetes Study showed that in type 2 diabetic patients the use of this drug was associated with a decrease in mortality of all causes and of cardiovascular origin as compared to those treated with sulfonylureas or insulin.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a> In addition to its hypoglycemic effect, there are many other potential positive effects that have been described in recent years: cáncer,<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">8</span></a> polycystic ovary,<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">9</span></a> among others. It is also noteworthy the potential benefit against aging and neurodegenerative diseases even in non-diabetics, a fact that is currently being evaluated by a clinical trial.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">10</span></a> Therefore it would not be surprising that in the near future the use of this drug will increase even more. In this context it is important to remember that metformin can also produce side effects, among which traditionally the possible induction of lactic acidosis has been highlighted, which in some cases can be lethal. However, there is a debate in the literature about the true incidence and importance of this problem. In a 2010 a Cochrane review concluded that there is no clear evidence that metformin is associated with an increased risk of lactic acidosis compared to other hypoglycemic treatments.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">4</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">By contrast, in our study, the incidence of lactic acidosis is certainly high, well above what has been reported in other previous studies, as shown by the data presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>,<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">4,11–29</span></a> adapted and expanded from Lalau,<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">5</span></a> so that in our opinion we are facing a real an important clinical problem that should not be minimized. We did not obtain an average estimate of the patients treated with metformin during the entire study period because just collecting the data from the two specific dates of interval used was already extremely laborious. Therefore, calculations were made using the arithmetic mean of the two values available. With this strategy of data collection for estimation of the incidence, if there was any bias, it would have resulted in underestimation, because there could have been some case not detected in the search of the Clinical Documentation Service due to a fault in coding. However, all cases in which metformin levels were determined are adequately collected and without possibility of error since there is only one toxicology laboratory that centralizes these requests for quantification of drug levels. Therefore, we believe that the values obtained truly reflect the incidence of these events in the health area of our hospital during the study period.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Metformin acts by inhibiting hepatic neoglucogenesis as a consequence of a relative energy deficit caused by the decrease in adenosine triphosphate produced in the mitocondria.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">30</span></a> Other important actions of the drug are mediated by the activation of the enzyme AMPK, responsible for the pleiotropic effects of the drug.<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">1,31</span></a> A beneficial effect on the intestinal microbiota has also been described.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">32</span></a> In the mitochondria, the drug inhibits complex I of the respiratory chain by an unknown mechanism.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">30</span></a> It is better described the action on the inhibition of the mitochondrial glycerol-3-phosphate dehydrogenase enzyme that also causes a uncoupling of the mechanism of cell respiration.<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">33</span></a> In the presence of tissue hypoxia, pyruvic acid produced as a final product of cytoplasmic glycolysis is metabolized by the enzyme lactic acid dehydrogenase to lactic acid (type A lactic acidosis). In the absence of hypoxia pyruvic acid is incorporated into the mitochondria and is used as a substrate of the Krebs cycle that is coupled to the respiratory chain to produce adenosine triphosphate by oxidative phosphorylation. The final effect of biguanides is similar to that produced by hypoxia (type B lactic acidosis).<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">34</span></a> In the case of metformin when used at therapeutic doses this effect is negligible, but when taken in excess, intentionally, or at normal doses in a certain clinical context (heart failure, hypoxia situations, liver failure, dehydration, CKD) and if there is associated with certain factors (radiological contrasts, drugs such as NSAIDs, ACE inhibitors or ARA II) there is an increased risk of overdosage and induction of lactic acidosis,<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">35</span></a> especially if the clinical context is that of an AKF, since the drug is eliminated mainly by the kidney as unaltered molecule.<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">36</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The debate also extends to the definition of such a clinical situation. Some authors such as Lalau distinguish in clinical practice up to three different situations<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">5</span></a>: (1) the so-called <span class="elsevierStyleItalic">Metformin-unrelated hyperlactatemia</span> – MULA, in the absence of metformin accumulation. It is especially true if blood levels of metformin are normal, below normal or even undetectable. Lalau maintains that this group is the most numerous and the one that carries worse prognosis. (2) <span class="elsevierStyleItalic">Metformin-induced hyperlactatemia</span> – MILA. It refers to hyperlactacidemia caused only by metformin. A typical case is the voluntary intoxication by metformin in the absence of concomitant drugs. A similar case is the acute accumulation of metformin due only to acute renal failure. (3) <span class="elsevierStyleItalic">Metformin-associated hyperlactatemia</span> – MALA – is the most complex case. The word “associated” means that the induction of hyperlactataemia is a consequence (although to a different degree, perhaps) of the accumulation of metformin and one or more associated concomitant diseases. According to Lalau, this group would be less frequent than suspected and its prognosis would be better than that of MULA, granting metformin a “protective” factor. The difficulty of applying these definitions, somewhat cumbersome in itself, also lies in having available the determination of metformin levels in real time, a fact that usually does not occur in routine practice. In any case and for the sake of simplicity, patients could be divided into two groups, those in which metformin is not related to the induction of lactic acidosis (the so-called MULA) and those in which the drug is the main responsible (MILA) or share that responsibility with another series of concomitant pathologies (MALA).</p><p id="par0110" class="elsevierStylePara elsevierViewall">There is also disparity between the studies on the relationship between metformin levels and the degree of lactic acidosis, as the results between different studies are discordant.<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">37–41</span></a> However, the findings of the recent study by Boucaud-Maitre et al. of large sample of patients showed that the correlation between both parameters is clear,<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">42</span></a> as we have also reported in our study. The controversy also extends to recommendations for the dosage of the drug in patients affected by renal failure since they differ according to scientific societies and the opinion of some experts.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">43</span></a> In this line, it is pertinent to recall the results of a Taiwanese study that compared the mortality of a large cohort of CKD stage 5 patients treated with metformin vs untreated.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">44</span></a> The treated group showed significantly higher mortality that paradoxically was not related to a higher incidence of lactic acidosis in this group. The authors argue that the alteration of the mitochondrial respiratory chain could be more harmful in patients with advanced chronic kidney disease, even without causing lactic acidosis.</p><p id="par0115" class="elsevierStylePara elsevierViewall">In our study, we detected 29% of cases of overdosage according to GFR. This is a feature that must be emphasized, because it would be easily avoidable with an adequate prescription, for which the clinician who prescribes the drug should previously request a blood biochemistry to determine the baseline renal function of the patient and make appropriate adjustments in the dosage. In subsequent follow-up, renal function should be monitored periodically as recommended by the guidelines. We want to highlight that probably a high number of MALA episodes detected in our study has been due to inadequate monitoring of dose prescribed relative to the renal function (in all cases except one that was at the patient's will).</p><p id="par0120" class="elsevierStylePara elsevierViewall">Nevertheless, in defense of prescribing doctors, it can be argued that recently there has been disagreement between the latest European guidelines, which are more flexible for treatment with metformin in CKD<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">45</span></a> and American guidelines, which still contraindicate metformone administration if GFR is below 30<span class="elsevierStyleHsp" style=""></span>ml/min.<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">46</span></a> In fact, until recently the data sheet pointed out that metformin should not be used in patients with GFR <60<span class="elsevierStyleHsp" style=""></span>ml/min, but it was often prescribed below the GFR limits. Recently the metformin data sheet has been modified by the European Medicines Agency.<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">47</span></a> In the recent Spanish medical literature there are also guides and recent reviews on this subject.<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">48,49</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">From our data, a typical case presentation could be an elderly patient with important and polymedicated comorbidity, in many cases using drugs that can produce AKF, that undergoes dehydration due to gastrointestinal disorder but the patient continues to take metformin. The consequence is an episode of AKF stage III with metformin accumulation of elevation of the serum levels of the drug and an increase in lactate levels with reduction of the pH. Approximately 40% of the patients will require admission to the ICU and a similar percentage need RRT illustrating the clinical severity of the situation, which in our patients caused a 25% of mortality. The majority of patients were treated in the nephrology and internal medicine services. Between the deceased and the survivors the only significant differences were the final serum creatinine level, higher in deceased patients, and the duration of the hospital stay that was lower in the deceased ones. No variable maintained its significance in the multivariate analysis, perhaps reflecting the limited sample size. In the aforementioned study by Boucaud-Maitre, the lactate level was independently associated with mortality.<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">42</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Metformin is a small molecule (129<span class="elsevierStyleHsp" style=""></span>Da) with a low protein binding, so it diffuses freely through dialyzers and hemofilters. The limiting factor for its extracorporeal clearance is its relatively large volume of distribution (1–5<span class="elsevierStyleHsp" style=""></span>l/kg) although this may be reduced in the context of AKF. The justification of the RRT goes beyond the elimination of the drug from the organism since it also includes: (1) fast, predictable and effective correction of acidosis that is achieved with administration of bicarbonate, (2) improvement of hyperlactataemia, (3) correction of the electrolyte abnormalities, and (4) renal replacement therapy.<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">36</span></a> Regarding the modality of the RRT to be used, a recent systematic review of the working group of the extracorporeal treatment of intoxications highlights the superior efficacy of hemodialysis as compared to continuous techniques, so if the patient's hemodynamic stability allows, it is preferable to perform hemodialysis with bicarbonate in the dialysis fluid with exhaustive monitoring during the sesión.<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">36</span></a> An elegant work recently published has shown that the duration of the dialysis sessions should be prolonged to 5 or 6<span class="elsevierStyleHsp" style=""></span>h, and thereafter the levels of metformin and lactate should be monitored due to the possibility of rebound at the end of the dialysis session. There are no specific recommendations with respect to conductivity or other technical specifications.<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">50</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">This study presents a series of limitations. First, it is retrospective, which has led to biases in the selection of patients and errors in the collection and interpretation of data from clinical records, despite the attention paid when performing this task. Secondly, there is no control group, but it can argued that it would have been difficult to gather 31 cases from our hospital affected by lactic acidosis not attributable to MALA during the study period to be used as controls. Despite this, the sample size of our work is considerable and provides clinically relevant information.</p><p id="par0140" class="elsevierStylePara elsevierViewall">In conclusion, in this study we have detected a high incidence of MALA in our health area, although if we apply the definitions of Lalau, a good part of our cases could be included within the group called MILA. Our incidence is much higher than traditionally published, so we believe that we should be alert to detect and treat this clinical situation that may have serious consequences. We have had a 25% of deaths in our patients during admission. Base on the data extracted from our case series, and the substantial change issued by the European Medicines Agency in 2016,<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">47</span></a> it is important to warn patients at the time of prescription of the harmful effects that can be produced if the treatment is continued if there is a risk of extracellular volume depletion with AKF with accumulation of the drug. Therefore it is important to consult with the doctor in situations of gastrointestinal disorders with vomiting and diarrhea. Likewise, it is also necessary to perform an adequate initial dosage, according to the patient baseline renal function.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of interest</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1158880" "titulo" => "Abstract" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Results" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1085677" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1158879" "titulo" => "Resumen" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Resultados" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1085678" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-10-15" "fechaAceptado" => "2018-04-04" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1085677" "palabras" => array:3 [ 0 => "Metformin" 1 => "Lactic acidosis" 2 => "Acute kidney failure" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1085678" "palabras" => array:3 [ 0 => "Metformina" 1 => "Acidosis láctica" 2 => "Fracaso renal agudo" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To determine the incidence of metformin-induced lactic acidosis during the period January 2014 to March 2017 in Aragon Healthcare Area III. To analyze the associated clinical and analytical factors and mortality.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Results</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A total of 31 cases (61.3% males). Incidence: 79.76 cases/100,000 patients-year; mean age 75.39<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>9.34 years; 23 of them with levels of serum metformin (21.91<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>15.52<span class="elsevierStyleHsp" style=""></span>mcg/ml); milligrams/day of metformin ingested: 1790.32<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>499; 96.8% of cases in the context of acute kidney failure; 11 cases with a history of chronic kidney disease (35.5%); 12 required intensive care (38.7%); 13 required purification treatment (41.9%; 3 hemodiafiltration, 10 hemodialysis). There was a significant correlation between daily milligrams of metformin ingested and drug levels; levels of metformin; and peak creatinine, pH and lactate. Mortality was 25.8%. There were only significant differences between the deceased and survivors regarding the duration of stay and final creatinine. Multivariate logistic regression did not detect any study variables associated with mortality.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conclusions</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The incidence in our healthcare area is higher than in other series, with a 25.8% mortality rate. Virtually all cases were in the context of prerenal acute kidney failure. In 29% of cases, there was an overdose. Patients must be warned about the most common lactic acidosis-inducing situations, especially dehydration, if they continue taking the drug at such times.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Results" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Objetivos</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Conocer la incidencia de casos de acidosis láctica por metformina durante el periodo enero de 2014 y marzo de 2017 en el Área Sanitaria III de Aragón. Analizar los factores clínicos y analíticos asociados y la mortalidad.</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Resultados</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Treinta y un casos (61,3% varones). Incidencia: 79,76 casos/100000 pacientes-año; edad media 75,39<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>9,34 años; 23 de ellos con niveles séricos de metformina (21,91<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>15,52 mcg/mL); miligramos/día de metformina ingeridos: 1790,32<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>499; 96,8% de casos en el contexto de fracaso renal agudo; 11 casos con antecedentes de enfermedad renal crónica (35,5%); 12 requirieron UCI (38,7%); 13 requirieron tratamiento depurador (41,9%; 3 hemodiafiltración, 10 hemodiálisis) Existió correlación significativa entre: miligramos diarios ingeridos de metformina y niveles del fármaco; niveles de metformina y: creatinina pico, pH y lactato. La mortalidad fue del 25,8%. Solo hubo diferencias significativas entre los fallecidos y los supervivientes respecto a la duración de la estancia y la creatinina final. La regresión logística multivariante no detectó ninguna variable del estudio asociada con la mortalidad.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusiones</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La incidencia en nuestra área sanitaria es más elevada que en otras series, con 25,8% de mortalidad. Prácticamente todos los casos en el contexto de fracaso renal agudo de origen prerrenal. En un 29% de los casos hubo sobredosificación. Es necesario advertir a los pacientes de las situaciones más frecuentes potencialmente inductoras de acidosis láctica, especialmente la deshidratación, si siguen tomando el fármaco durante las mismas.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Resultados" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Peña Porta JM, Villafuerte Ledesma HM, Vicente de Vera Floristán C, Ferrer Dufol A, Salvador Gómez T, Álvarez Lipe R. Incidencia, factores relacionados con la presentación, evolución y mortalidad de la acidosis láctica asociada a metformina en el área sanitaria de un hospital de tercer nivel. Nefrologia. 2019;39:35–43.</p>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1302 "Ancho" => 1668 "Tamanyo" => 79549 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Correlation between the daily dose of metformin and the serum levels of the drug. <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.557, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.009.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1275 "Ancho" => 1626 "Tamanyo" => 78092 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Correlation between serum levels of metformin and peak creatinine. <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.491, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0015.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1376 "Ancho" => 1634 "Tamanyo" => 84652 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Correlation between serum levels of metformin and pH<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.635, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.001.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1294 "Ancho" => 1638 "Tamanyo" => 84359 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Correlation between serum levels of metformin and lactate. <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.650, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.001.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">ns: not significant difference; TRS: renal replacement therapy; ICU: Intensive Care Unit; eGFR: estimated glomerular filtration rate.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Deceased (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Not deceased (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>23) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Statistical significance \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">75.65<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">74.63<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>12.39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Charlson index \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.13<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.89 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.65<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No. of drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.26<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dose of metformin (mg/day) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1856<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>499 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1767.39<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>507.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Basal serum creatinine (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.06<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.16<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">baseline eGFR(ml/min) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">65.54<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>19.82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62.40<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>22.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Peak S. creatinine (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.37<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.81 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.07<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Final S. creatinine (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.54<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.41<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.76 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">pH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.055<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.151<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bicarbonate (mmol/l) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.64<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.51<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">p</span>CO<span class="elsevierStyleInf">2</span> (mmHg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">31.75<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>13.05 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">34.74<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>14.70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Anion GAP (mmol/l) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26.11<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26.9<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.62 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Serum lactate (mmol/l) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.33<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5.34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.70<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5.76 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prothrombin activity (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">52.24<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>29.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">71.35<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>30.96 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Potassium (meq/l) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.42<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.91<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hemoglobin (g/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.83<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.85 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11.95<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hospital stay (days) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.0<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.74<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.051 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Need for ICU (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 of 8 (37.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 of 23 (39.1%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.009 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Need for RRT (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 of 8 (25%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 of 23 (47.8%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">S. level of metformin (mcg/ml) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">23.61<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>16.61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24.24<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>19.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Overdose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 of 8 (25%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 of 23 (30.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1978520.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Comparison of various variables in the group of deceased patients and survivors.</p>" ] ] 5 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lucis (1987) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1972–1983 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Canada \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0/56,000 patients-year \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Health and Welfare Canada publication \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bailey (1988) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1976–1986 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">UK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.7/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Research data \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bailey (1988) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1972–1977 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Switzerland \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.7/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Research data \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bailey (1988) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1972–1981 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sweden \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8.4/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Research data \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Wiholm (1993) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1977–1991 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sweden \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1977–1981:<br>15/100,000<br>1981–1991:<br>2.4/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Publications of the Swedish Adverse Effects Advisor Committee \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">De Fronzo (1995) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1995–1996 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">US FDA Publications \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Misbin (1998) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1980–1995 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Canada \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cohort of Saskatchewan Health administrative databases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Stang (1999) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1984–1992 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">France \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.9/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not specified \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chan (1999) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">January 1993–June 1995 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Scotland \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Retrospective cohort of contraindications for the use of metformin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Emslie-Smith \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2000–2003 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Scotland \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Series of cases in the same hospital \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(2001) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1994–2005 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">UK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.3/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case-control analysis using the UK General Practice Research Database \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nyrienda (2006) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1993–2006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Australia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">57/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Patients from a population database \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bodmer (2008) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2001–2005 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Spain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2004: 138/100,000<br>2005: 76/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Retrospective cases of metabolic acidosis in hospitals \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kamber (2008) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1959–2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">All world \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.3/100,0000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Data from 347 trials and cohort studies (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>70,490 patients-year) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Almirall (2008) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2000–2008 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Holland \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">47/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hospital data of serum levels of metformin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Salpenter (2010) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2007–2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">UK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.37/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Publications of the Clinical Practice Research Datalink database \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Van Berlo-van de Laar (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2004–2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">UK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.4/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A cohort of the Clinical Practice Research Datalink (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>223,968) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Richy (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1971–2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Australia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">152 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.3/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Publications of the Terapheutic Goods Administration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Eppenga (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2013–2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Italy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Publications of Emergency Services (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>390,000) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Huang (2015) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2005–2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">New Zealand \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19.46/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Publication of the Hospital of the City of Auckland (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1,718,000 patient-year) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mosconi (2015) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">January 2010–August 2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Japan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.95/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Retrospective cohort study (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>504,169 patients-year) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Haloob (2016) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">January 2014–March 2017 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Spain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">79.76/100,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case serie from healthcare área III from the Aragon Region \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1978521.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Incidence of MALA published in various works.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:50 [ 0 => array:3 [ "identificador" => "bib0255" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Current understanding of metformin effect on the control of hyperglycemia in diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H. An" 1 => "L. He" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1530/JOE-15-0266" "Revista" => array:6 [ "tituloSerie" => "J Endocrinol" "fecha" => "2016" "volumen" => "228" "paginaInicial" => "97" "paginaFinal" => "106" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26577934" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0260" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin: from research to clinical practice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M.H. Tan" 1 => "H. Alquraini" 2 => "K. Mizokami-Stout" 3 => "M. MacEachern" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ecl.2016.06.008" "Revista" => array:6 [ "tituloSerie" => "Endocrinol Metab Clin North Am" "fecha" => "2016" "volumen" => "45" "paginaInicial" => "819" "paginaFinal" => "843" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27823607" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0265" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of metformin in Metformin-Associated Lactic Acidosis (MALA): case series and formulation of a model of pathogenesis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.K. Duong" 1 => "T.J. Furlong" 2 => "D.M. Roberts" 3 => "G.G. Graham" 4 => "J.R. Greenfield" 5 => "K.M. Williams" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s40264-013-0038-6" "Revista" => array:6 [ "tituloSerie" => "Drug Saf" "fecha" => "2013" "volumen" => "36" "paginaInicial" => "733" "paginaFinal" => "746" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23549904" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0270" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S.R. Salpeter" 1 => "E. Greyber" 2 => "G.A. Pasternak" 3 => "E.E. Salpeter" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Cochrane Database Syst Rev" "fecha" => "2010" "volumen" => "14" "paginaInicial" => "CD002967" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0275" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin-associated lactic acidosis (MALA): moving towards a new paradigm" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J.D. Lalau" 1 => "F. Kajbaf" 2 => "A. Protti" 3 => "M.M. Christensen" 4 => "M.E. de Broe" 5 => "N. Wiernsperger" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diab Obes Metab" "fecha" => "2017" "volumen" => "19" "paginaInicial" => "1502" "paginaFinal" => "1512" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0280" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Ficha técnica de la metformina. Disponible en: <a id="intr0010" class="elsevierStyleInterRef" href="https://www.aemps.gob.es/cima/pdfs/es/ft/55211/FichaTecnica_55211.html.pdf">https://www.aemps.gob.es/cima/pdfs/es/ft/55211/FichaTecnica_55211.html.pdf</a> [consultado 7 Ene 2018]." ] ] ] 6 => array:3 [ "identificador" => "bib0285" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of intensive blood-glucose control with metformina on complications in overweight patients with type 2 diabetes (UKDPS 34)" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "UK Prospective Diabetes Study Group" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1998" "volumen" => "352" "paginaInicial" => "854" "paginaFinal" => "865" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9742977" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0290" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin targets multiple signaling pathways in cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Lei" 1 => "Y. Yi" 2 => "Y. Liu" 3 => "X. Liu" 4 => "E.T. Keller" 5 => "Qian Ch-N" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s40880-017-0184-9" "Revista" => array:5 [ "tituloSerie" => "Chin J Cancer" "fecha" => "2017" "volumen" => "36" "paginaInicial" => "17" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28126011" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0295" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "N. Naderpoor" 1 => "S. Shorakae" 2 => "B. de Courten" 3 => "M.L. Misso" 4 => "L.J. Moran" 5 => "H.J. Teede" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/humupd/dmv025" "Revista" => array:6 [ "tituloSerie" => "Hum Reprod Update" "fecha" => "2015" "volumen" => "21" "paginaInicial" => "560" "paginaFinal" => "574" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26060208" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0300" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin as a tool to target aging" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "N. Barzilai" 1 => "J.P. Crandall" 2 => "S.B. Kritchevsky" 3 => "M.A. Espeland" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cmet.2016.05.011" "Revista" => array:6 [ "tituloSerie" => "Cell Metab" "fecha" => "2016" "volumen" => "23" "paginaInicial" => "1060" "paginaFinal" => "1065" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27304507" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0305" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The status of metformin in Canada" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "O.J. Lucis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Can Med Assoc J" "fecha" => "1983" "volumen" => "128" "paginaInicial" => "24" "paginaFinal" => "26" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6847752" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0310" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment–metformin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C.J. Bailey" 1 => "M. Nattrass" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Baillieres Clin Endocrinol Metab" "fecha" => "1988" "volumen" => "2" "paginaInicial" => "455" "paginaFinal" => "476" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3075902" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0315" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin-associated lactic acidosis in Sweden 1977–1991" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "B.E. Wiholm" 1 => "M. Myrhed" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur J Clin Pharmacol" "fecha" => "1993" "volumen" => "44" "paginaInicial" => "589" "paginaFinal" => "591" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8405019" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0320" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "Efficacy of metformin in patients with non-insulindependent diabetes mellitus. The Multicenter Metformin Study Group" "etal" => false "autores" => array:2 [ 0 => "R.A. DeFronzo" 1 => "A.M. Goodman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199508313330902" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "1995" "volumen" => "333" "paginaInicial" => "541" "paginaFinal" => "549" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7623902" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0325" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lactic acidosis in patients with diabetes treated with metformin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R.I. Misbin" 1 => "L. Green" 2 => "B.V. Stadel" 3 => "J.L. Gueriguian" 4 => "A. Gubbi" 5 => "G.A. Fleming" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199801223380415" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "1998" "volumen" => "338" "paginaInicial" => "265" "paginaFinal" => "266" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9441244" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0330" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Incidence of lactic acidosis in metformina users" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M. Stang" 1 => "D.K. Wysowski" 2 => "D. Butler-Jones" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diab Care" "fecha" => "1999" "volumen" => "22" "paginaInicial" => "925" "paginaFinal" => "927" ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0335" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin-associated lactic acidosis: a rare or very rare clinical entity?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "N.N. Chan" 1 => "H.P. Brain" 2 => "M.D. Feher" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diab Med" "fecha" => "1999" "volumen" => "16" "paginaInicial" => "273" "paginaFinal" => "281" ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0340" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Contraindications to metformin therapy in patients with Type 2 diabetes-a population-based study of adherence to prescribing guidelines" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A.M. Emslie-Smith" 1 => "D.I. Boyle" 2 => "J.M. Evans" 3 => "F. Sullivan" 4 => "A.D. Morris" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diab Med" "fecha" => "2001" "volumen" => "18" "paginaInicial" => "483" "paginaFinal" => "488" ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0345" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe acidosis in patients taking metformin – rapid reversal and survival despite high APACHE score" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Nyirenda MJ1" 1 => "T. Sandeep" 2 => "I. Grant" 3 => "G. Price" 4 => "J.A. McKnight" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diab Med" "fecha" => "2006" "volumen" => "4" "paginaInicial" => "432" "paginaFinal" => "435" ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0350" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Bodmer" 1 => "C. Meier" 2 => "S. Krähenbühl" 3 => "S.S. Jick" 4 => "C.R. Meier" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diab Care" "fecha" => "2008" "volumen" => "31" "paginaInicial" => "2086" "paginaFinal" => "2091" ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0355" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin and lactic acidosis in an Australian community setting: the Fremantle Diabetes Study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "N. Kamber" 1 => "W.A. Davis" 2 => "D.G. Bruce" 3 => "T.M. Davis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Med J Aust" "fecha" => "2008" "volumen" => "188" "paginaInicial" => "446" "paginaFinal" => "449" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18429709" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0360" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin-associated lactic acidosis in type 2 diabetes mellitus: incidence and presentation in common clinical practice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J. Almirall" 1 => "M. Bricullé" 2 => "J.M. Gonzalez-Clemente" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/ndt/gfn152" "Revista" => array:6 [ "tituloSerie" => "Nephrol Dial Transplant" "fecha" => "2008" "volumen" => "23" "paginaInicial" => "2436" "paginaFinal" => "2438" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18388117" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0365" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "I.R. Van Berlo-van de Laar" 1 => "C.G. Vermeij" 2 => "C.J. Doorenbos" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2710.2010.01192.x" "Revista" => array:6 [ "tituloSerie" => "J Clin Pharm Ther" "fecha" => "2011" "volumen" => "36" "paginaInicial" => "376" "paginaFinal" => "382" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21545617" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0370" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "F.F. Richy" 1 => "M. Sabidó-Espin" 2 => "S. Guedes" 3 => "F.A. Corvino" 4 => "U. Gottwald-Hostalek" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diab Care" "fecha" => "2014" "volumen" => "37" "paginaInicial" => "2291" "paginaFinal" => "2295" ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0375" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "W.L. Eppenga" 1 => "A. Lalmohamed" 2 => "A.F. Geerts" 3 => "H.J. Derijks" 4 => "M. Wensing" 5 => "A. Egberts" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diab Care" "fecha" => "2014" "volumen" => "37" "paginaInicial" => "2218" "paginaFinal" => "2224" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0380" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adverse event notifications implicating metformin with lactic acidosis in Australia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "W. Huang" 1 => "R.L. Castelino" 2 => "G.M. Peterson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Diab Complicat" "fecha" => "2015" "volumen" => "29" "paginaInicial" => "1261" "paginaFinal" => "1265" ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0385" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin-associated lactic acidosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Mosconi" 1 => "C. Gambaretto" 2 => "L. Zambianchi" 3 => "F. Lifrieri" 4 => "M. de Fabritiis" 5 => "S. Cristino" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "G Ital Nefrol" "fecha" => "2015" "volumen" => "32" "paginaInicial" => "8" ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0390" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin associated lactic acidosis in Auckland City Hospital 2005 to 2009" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "I. Haloob" 1 => "J.R. de Zoysa" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.5527/wjn.v5.i4.367" "Revista" => array:6 [ "tituloSerie" => "World J Nephrol" "fecha" => "2016" "volumen" => "5" "paginaInicial" => "367" "paginaFinal" => "371" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27458565" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0395" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidemiology of lactic acidosis in type 2 diabetes patients with metformin in Japan" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "C.H. Chang" 1 => "M. Sakaguchi" 2 => "P. Dolin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/pds.4030" "Revista" => array:6 [ "tituloSerie" => "Pharmacoepidemiol Drug Saf" "fecha" => "2016" "volumen" => "25" "paginaInicial" => "1196" "paginaFinal" => "1203" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27221971" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0400" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular mechanism of action of metformin: old or new insights?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "G. Rena" 1 => "E.R. Pearson" 2 => "K. Sakamoto" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00125-013-2991-0" "Revista" => array:6 [ "tituloSerie" => "Diabetologia" "fecha" => "2013" "volumen" => "56" "paginaInicial" => "1898" "paginaFinal" => "1906" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23835523" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0405" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of organelle function by metformin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J. Kim" 1 => "Y.J. You" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "IUBMB Life" "fecha" => "2017" "volumen" => "69" "paginaInicial" => "459" "paginaFinal" => "469" ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0410" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Wu" 1 => "E. Esteve" 2 => "V. Tremaroli" 3 => "M.T. Khan" 4 => "R. Caesar" 5 => "L. Mannerås-Holm" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nm.4345" "Revista" => array:6 [ "tituloSerie" => "Nat Med" "fecha" => "2017" "volumen" => "23" "paginaInicial" => "850" "paginaFinal" => "858" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28530702" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0415" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.K. Madiraju" 1 => "D.M. Erion" 2 => "Y. Rahimi" 3 => "X.M. Zhang" 4 => "D.T. Braddock" 5 => "R.A. Albright" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nature13270" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "2014" "volumen" => "510" "paginaInicial" => "542" "paginaFinal" => "546" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24847880" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0420" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lactic acidosis update for critical care clinicians" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "F.C. Luft" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "J Am Soc Nephrol" "fecha" => "2001" "volumen" => "12" "numero" => "Suppl. 17" "paginaInicial" => "S15" "paginaFinal" => "S19" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11251027" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0425" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin-related lactic acidosis: is it a myth or an underestimated reality?" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Visconti" 1 => "V. Cernaro" 2 => "D. Ferrara" 3 => "G. Costantino" 4 => "C. Aloisi" 5 => "L. Amico" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/0886022X.2016.1216723" "Revista" => array:6 [ "tituloSerie" => "Ren Fail" "fecha" => "2016" "volumen" => "38" "paginaInicial" => "1560" "paginaFinal" => "1565" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27686366" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0430" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Extracorporeal treatments in poisoning workgroup, extracorporeal treatment for metformin poisoning: systematic review and recommendations from the extracorporeal treatments in poisoning workgroup" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.P. Calello" 1 => "K.D. Liu" 2 => "T.J. Wiegand" 3 => "D.M. Roberts" 4 => "V. Lavergne" 5 => "S. Gosselin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/CCM.0000000000001002" "Revista" => array:6 [ "tituloSerie" => "Crit Care Med" "fecha" => "2015" "volumen" => "43" "paginaInicial" => "1716" "paginaFinal" => "1730" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25860205" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0435" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin in patients with type 2 diabetes and kidney disease: a systematic review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S.E. Inzucchi" 1 => "K.J. Lipska" 2 => "H. Mayo" 3 => "C.J. Bailey" 4 => "D.K. McGuire" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jama.2014.15298" "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "2014" "volumen" => "312" "paginaInicial" => "2668" "paginaFinal" => "2675" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25536258" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0440" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The prognostic value of blood pH and lactate and metformin concentrations in severe metformin-associated lactic acidosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "F. Kajbaf" 1 => "J.D. Lalau" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/2050-6511-14-22" "Revista" => array:5 [ "tituloSerie" => "BMC Pharmacol Toxicol" "fecha" => "2013" "volumen" => "14" "paginaInicial" => "22" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23587368" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0445" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute kidney injury, plasma lactate concentrations and lactic acidosis in metformin users: a GoDarts study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "P.J. Connelly" 1 => "M. Lonergan" 2 => "E. Soto-Pedre" 3 => "L. Donnelly" 4 => "K. Zhou" 5 => "E.R. Pearson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diab Obes Metab" "fecha" => "2017" "volumen" => "19" "paginaInicial" => "1579" "paginaFinal" => "1586" ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0450" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dose-related effects of metformin on acid-base balance and renal function in patients with diabetes who develop acute renal failure: a cross-sectional study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Cucchiari" 1 => "M.A. Podestà" 2 => "E. Merizzoli" 3 => "A. Calvetta" 4 => "E. Morenghi" 5 => "C. Angelini" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00592-016-0836-2" "Revista" => array:6 [ "tituloSerie" => "Acta Diabetol" "fecha" => "2016" "volumen" => "53" "paginaInicial" => "551" "paginaFinal" => "558" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26821225" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0455" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Vecchio" 1 => "A. Giampreti" 2 => "V.M. Petrolini" 3 => "D. Lonati" 4 => "A. Protti" 5 => "P. Papa" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Clin Toxicol (Phila)" "fecha" => "2014" "volumen" => "52" "paginaInicial" => "129" "paginaFinal" => "135" ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0460" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lactic acidosis: relationship between metformin levels, lactate concentration and mortality" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Boucaud-Maitre" 1 => "J. Ropers" 2 => "B. Porokhov" 3 => "J.J. Altman" 4 => "B. Bouhanick" 5 => "J. Doucet" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diab Med" "fecha" => "2016" "volumen" => "33" "paginaInicial" => "1536" "paginaFinal" => "1543" ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0465" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Should restrictions be relaxed for metformin use in chronic kidney disease?. No, we should never again compromise safety!" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K. Kalantar-Zadeh" 1 => "C.P. Kovesdy" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diab Care" "fecha" => "2016" "volumen" => "39" "paginaInicial" => "1281" "paginaFinal" => "1286" ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0470" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.C. Hung" 1 => "Y.K. Chang" 2 => "J.S. Liu" 3 => "K.L. Kuo" 4 => "Y.H. Chen" 5 => "C.C. Hsu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S2213-8587(15)00123-0" "Revista" => array:6 [ "tituloSerie" => "Lancet Diabetes Endocrinol" "fecha" => "2015" "volumen" => "3" "paginaInicial" => "605" "paginaFinal" => "614" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26094107" "web" => "Medline" ] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0475" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical practice guideline on management of patients with diabetes and chronic kidney disease stage 3b or higher (eGFR<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>45<span class="elsevierStyleHsp" style=""></span>mL/min)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Bilo" 1 => "L. Coentrão" 2 => "C. Couchoud" 3 => "A. Covic" 4 => "J. De Sutter" 5 => "C. Drechsler" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/ndt/gfu360" "Revista" => array:7 [ "tituloSerie" => "Nephrol Dial Transplant" "fecha" => "2015" "volumen" => "30" "numero" => "Suppl. 2" "paginaInicial" => "1" "paginaFinal" => "142" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25414374" "web" => "Medline" ] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0480" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "Standards of medical care in diabetes – 2016" ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diab Care" "fecha" => "2016" "volumen" => "39" "numero" => "Suppl. 1" "paginaInicial" => "S1" "paginaFinal" => "S109" ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0485" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Use of metformin to treat diabetes now expanded to patients with moderately reduced kidney function. Recommendations for patients with kidney impairment updated in product information. 12 December 2016. EMA/868987/2016. Availalbe from: <a id="intr0015" class="elsevierStyleInterRef" href="http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Metformin_31/WC500214235.pdf">http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Metformin_31/WC500214235.pdf</a> [accessed 07.01.18]." ] ] ] 47 => array:3 [ "identificador" => "bib0490" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Documento de Consenso sobre el tratamiento de la diabetes tipo 2 en el paciente con enfermedad renal crónica" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. Gómez-Huelgas" 1 => "A. Martínez-Castelao" 2 => "S. Artola" 3 => "J.L. Górriz" 4 => "E. Menéndez" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Nefrologia" "fecha" => "2014" "volumen" => "34" "paginaInicial" => "34" "paginaFinal" => "45" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24611186" "web" => "Medline" ] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0495" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "sobre la diabetes en la enfermedad renal crónica estadio 3B o mayor: ¿metformina para todos?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A. Martínez-Castelao" 1 => "J.L. Górriz" 2 => "A. Ortiz" 3 => "J.F. Navarro-González" 4 => "E.R.B.P. Guía" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.nefro.2017.06.001" "Revista" => array:6 [ "tituloSerie" => "Nefrologia" "fecha" => "2017" "volumen" => "37" "paginaInicial" => "567" "paginaFinal" => "571" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28669489" "web" => "Medline" ] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0500" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Toxicokinetics of metformin during hemodialysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Ayoub" 1 => "P.O. Hétu" 2 => "M. Cormier" 3 => "A. Benoit" 4 => "A. Palumbo" 5 => "M.C. Dubé" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ekir.2017.02.017" "Revista" => array:6 [ "tituloSerie" => "Kidney Int Rep" "fecha" => "2017" "volumen" => "2" "paginaInicial" => "759" "paginaFinal" => "765" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29318220" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003900000001/v1_201903030617/S2013251419300136/v1_201903030617/en/main.assets" "Apartado" => array:4 [ "identificador" => "42660" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003900000001/v1_201903030617/S2013251419300136/v1_201903030617/en/main.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251419300136?idApp=UINPBA000064" ]
Year/Month | Html | Total | |
---|---|---|---|
2024 November | 8 | 9 | 17 |
2024 October | 73 | 66 | 139 |
2024 September | 73 | 53 | 126 |
2024 August | 76 | 76 | 152 |
2024 July | 52 | 47 | 99 |
2024 June | 52 | 48 | 100 |
2024 May | 50 | 78 | 128 |
2024 April | 53 | 67 | 120 |
2024 March | 60 | 66 | 126 |
2024 February | 34 | 67 | 101 |
2024 January | 30 | 36 | 66 |
2023 December | 42 | 43 | 85 |
2023 November | 48 | 56 | 104 |
2023 October | 44 | 53 | 97 |
2023 September | 27 | 42 | 69 |
2023 August | 32 | 43 | 75 |
2023 July | 35 | 38 | 73 |
2023 June | 39 | 34 | 73 |
2023 May | 69 | 47 | 116 |
2023 April | 59 | 33 | 92 |
2023 March | 57 | 40 | 97 |
2023 February | 40 | 37 | 77 |
2023 January | 48 | 50 | 98 |
2022 December | 62 | 51 | 113 |
2022 November | 50 | 55 | 105 |
2022 October | 71 | 51 | 122 |
2022 September | 36 | 58 | 94 |
2022 August | 43 | 53 | 96 |
2022 July | 40 | 54 | 94 |
2022 June | 43 | 51 | 94 |
2022 May | 38 | 38 | 76 |
2022 April | 42 | 54 | 96 |
2022 March | 42 | 41 | 83 |
2022 February | 34 | 51 | 85 |
2022 January | 31 | 40 | 71 |
2021 December | 23 | 43 | 66 |
2021 November | 43 | 44 | 87 |
2021 October | 91 | 54 | 145 |
2021 September | 61 | 39 | 100 |
2021 August | 67 | 51 | 118 |
2021 July | 63 | 46 | 109 |
2021 June | 34 | 38 | 72 |
2021 May | 32 | 54 | 86 |
2021 April | 79 | 103 | 182 |
2021 March | 54 | 48 | 102 |
2021 February | 36 | 30 | 66 |
2021 January | 42 | 29 | 71 |
2020 December | 24 | 16 | 40 |
2020 November | 28 | 17 | 45 |
2020 October | 22 | 31 | 53 |
2020 September | 32 | 20 | 52 |
2020 August | 27 | 22 | 49 |
2020 July | 47 | 8 | 55 |
2020 June | 27 | 15 | 42 |
2020 May | 50 | 10 | 60 |
2020 April | 33 | 23 | 56 |
2020 March | 54 | 10 | 64 |
2020 February | 55 | 30 | 85 |
2020 January | 55 | 33 | 88 |
2019 December | 75 | 39 | 114 |
2019 November | 62 | 21 | 83 |
2019 October | 47 | 29 | 76 |
2019 September | 38 | 15 | 53 |
2019 August | 31 | 20 | 51 |
2019 July | 50 | 29 | 79 |
2019 June | 36 | 31 | 67 |
2019 May | 83 | 34 | 117 |
2019 April | 103 | 74 | 177 |
2019 March | 47 | 41 | 88 |
2019 February | 14 | 7 | 21 |