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hypertension&#44; hyperuricemia&#44; obstructive sleep apnoea-hypopnoea syndrome&#44; normochromic normocytic anaemia and stage 3A chronic renal failure &#40;estimated glomerular filtration rate &#91;eGFR&#93;&#58; 35ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span> &#8211;MDRD-&#41;&#46; The patient sought treatment at his reference hospital due to anuria with 24 hours evolution along with hypogastralgia&#44; diarrhoea and dyspnoea&#44; but no fever or haemodynamic instability&#46; The initial laboratory analysis is described in the Table 1&#44; with the notable result of worsening renal function and hyperkalaemia&#44; with severe metabolic acidosis and elevated lactate and anion GAP levels&#46; The patient also suffered from psychomotor agitation&#44; tachypnoea&#44; a tendency toward arterial hypotension and hypoventilation&#44; for which he was intubated and administered dopamine perfusion&#46; Sodium bicarbonate was also administered to correct the pH imbalance and treatment was started for the hyperkalaemia&#46; The patient was then transferred to our centre&#44; where he was admitted to the intensive care unit &#40;ICU&#41;&#46; Upon arrival&#44; the patient&#8217;s metabolic acidosis and hyperkalaemia were being corrected&#44; but we observed a substantial increase in blood lactate levels and haemodynamic instability&#46; The patient continued to suffer anuria&#46; We started the patient on continuous veno-venous haemodiafiltration &#40;CVHDF&#41;&#44; bicarbonate&#44; a perfusion of noradrenaline and dopamine&#44; as well as empirical antibiotic treatment with piperacillin-tazobactam&#44; although no parameters of sepsis were observed and cell cultures were negative&#46; The patient was extubated 5 days after arrival in the ICU&#46; Amine perfusion was removed 72 hours after hospitalisation&#46; The CVHDF treatment was maintained for 5 days&#44; until spontaneous diuresis commenced&#46; The patient was then transferred to nephrology with no requirements for haemodialysis&#46; The patient was discharged after 16 days in the hospital&#44; with an eGFR of 32ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#44; which was sustained throughout the outpatient follow-up period&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Case 2</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A 75-year old male with type 2 diabetes on treatment with metformin at 850mg&#47;8h&#44; hypertension&#44; chronic obstructive pulmonary disease &#40;COPD&#41;&#44; and stage 3A chronic renal failure &#40;eGFR&#58; 35ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span> &#8211;MDRD-&#41;&#44; who sought treatment at another hospital for symptoms including diarrhoea&#44; dyspnoea&#44; and oligoanuria of 8 days evolution&#46; Upon arrival at the centre&#44; the patient was haemodynamically stable&#46; The initial laboratory analysis results are described in the Table 1&#59; notable findings included severe metabolic acidosis with an elevated anion GAP&#44; worsening renal function and severe hyperkalaemia&#46; Electrocardiogram tests revealed sinus tachycardia with peaked T-waves&#46; Neither the metabolic acidosis nor hyperkalaemia were treated and the patient was transferred to our hospital&#46; Upon arrival&#44; the patient had a blood pressure &#40;BP&#41; of 95&#47;50&#44; with worsening metabolic acidosis and increased lactate levels&#46; The patient was admitted to the ICU&#44; where CVHDF was commenced along with noradrenaline perfusion&#44; which was then removed after 24 hours&#46; The state of acidosis was treated with sodium bicarbonate&#44; along with empirical antibiotic treatment with ceftriaxone&#44; with no increase in parameters of sepsis and negative culture results&#46; The patient was also started on non-invasive mechanical ventilation with no need for intubation&#46; CVHDF was maintained for 2 days until spontaneous diuresis commenced along with improved renal function&#44; with no need for later haemodialysis sessions&#46; The patient was discharged with an eGFR&#62;60ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#44; under outpatient follow-up control&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Case 3</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A 70-year old male with type 2 diabetes on treatment with gliclazide and metformin at 850mg&#47;8h&#44; with hypertension and benign prostatic hyperplasia&#44; sought treatment at another hospital due to general discomfort and vomiting with 48 hours evolution&#46; Renal function prior to this point was normal&#46; Upon arrival&#44; the patient was haemodynamically stable&#46; Initial laboratory values are summarised in the Table 1&#46; Notable results included severe metabolic acidosis with an elevated anion GAP&#44; worsening renal function and severe hyperkalaemia&#46; Treatment was started for the hyperkalaemia and metabolic acidosis&#44; and the patient was transferred to our hospital&#46; Upon arrival&#44; we observed worsening renal function&#44; with increased blood lactate levels&#46; An electrocardiogram revealed sinus rhythm with peaked T-waves&#46; Given the patient&#8217;s stable condition&#44; we administered sodium bicarbonate and conventional intermittent haemodiafiltration&#44; which was tolerated without incident&#46; The patient progressed favourably&#44; with normalised laboratory values and no need for new sessions of haemodialysis&#46; The patient was discharged 5 days after hospitalisation&#44; with an eGFR&#62;60ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#44; under outpatient follow-up control&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Case 4</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A 78-year old female with type 2 diabetes on treatment with metformin at 850mg&#47;24h&#44; with hypertension&#44; dyslipidaemia and a history of ischaemic stroke and cardiological follow-up for monitoring angina and functional class II dyspnoea &#40;echocardiogram revealing apical wall motion abnormalities&#44; mild ventricular dysfunction and left ventricular ejection fraction at 63&#37;&#59; coronary angiography was normal&#41;&#46; Prior renal function was normal&#46; The patient sought treatment at another hospital due to general discomfort with asthenia and weakness in the legs with 2 days evolution and episodes of diarrhoea&#46; In the emergency department&#44; the patient developed epigastric pain radiating to the back&#44; haemodynamic instability&#44; BP of 65&#47;35&#44; bradycardia at 35bpm&#44; sweating and oligoanuria&#46; The initial laboratory analyses are summarised in the Table 1&#46; Notable results included severe metabolic acidosis with an elevated anion GAP&#46; Sodium bicarbonate and dopamine perfusion were initiated&#46; The patient was intubated due to respiratory failure and then transferred to our hospital&#46; Upon arrival&#44; the patient was haemodynamically unstable&#44; with a BP of 51&#47;42 and anuria&#59; we started perfusion with noradrenaline and maintained the dopamine treatment&#46; The laboratory analyses are summarised in the Table 1&#46; We performed an emergency echocardiogram that revealed no significant abnormalities and a thoraco-abdominal CAT scan with no detected acute pathology&#46; The patient was admitted to the ICU&#44; where the metabolic acidosis was corrected and CVHDF was started&#46; With poor evolution&#44; the patient developed refractory multi-organ failure and died 36 hours after hospitalisation&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Case 5</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A 76-year old male&#44; with type 2 diabetes and treatment with metformin at 850mg&#47;24h and vildagliptin&#59; the patient suffered from COPD and right nephrolithiasis diagnosed by haematuria and was on treatment with ibuprofen&#46; Prior renal function was normal&#46; The patient sought treatment at another hospital due to general discomfort and abdominal pain with three days evolution&#46; The initial laboratory analyses are summarised in the Table 1&#46; Notable results included severe metabolic acidosis&#44; worsening renal function and severe hyperkalaemia&#46; The patient rapidly progressed into respiratory failure&#44; requiring orotracheal intubation&#46; Treatment was started with sodium bicarbonate and the patient was transferred to our hospital&#46; Upon arrival&#44; the patient suffered from haemodynamic instability requiring high doses of noradrenaline&#59; the laboratory analysis revealed worsening of metabolic acidosis and increased lactate levels&#46; He was admitted to the ICU&#44; where CVHDF was administered for 24 hours&#46; The patient progressed quite favourably&#44; with normalised laboratory parameters and no need for renal replacement therapy and was discharged 15 days after hospitalisation with an eGFR of 48ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#44; under outpatient follow-up control&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Case 6</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A 52-year old male from Belgium was in Spain on vacation&#44; with type 2 diabetes on treatment with metformin at 850mg&#47;24h&#44; with COPD and a history of smoking&#46; Prior renal function was normal&#46; The patient sought treatment at another hospital due to general discomfort and decreased level of consciousness with several hours&#8217; evolution&#46; The patient apparently had also suffered diarrhoea during the last 24 hours&#46; The initial laboratory analyses are summarised in the Table 1&#46; Notable results included a Glasgow Coma Scale &#40;GCS&#41; of 10&#44; severe hypoglycaemia at 49mg&#47;dl&#44; severe metabolic acidosis&#44; acute renal failure with creatinine at 13&#46;7mg&#47;dl and severe hyperkalaemia&#46; The patient was transferred to our hospital&#44; where BP reached 110&#47;70&#44; with worsening metabolic acidosis and renal function&#44; increased lactate&#44; GCS of 13 and anisocoric photoreactive pupils&#46; We administered sodium bicarbonate and took a cranial computed tomography&#44; which ruled out intra-cranial pathology&#44; with a later spontaneous reversal of anisocoria&#46; The patient was unstable upon admission to the ICU&#44; where perfusion with high doses of noradrenaline was started along with orotracheal intubation&#46; CVHDF was also started along with antibiotic prophylaxis with piperacillin-tazobactam&#44; with no increases in parameters of sepsis and negative culture results&#46; Intoxication with methanol or ethylene glycol was ruled out at the same time as ethanol perfusion was started&#46; This treatment was removed 12 hours after hospitalisation after laboratory tests ruled out the possibility of intoxication&#46; The patient remained in a state of metabolic acidosis with lactate &#62;135mg&#47;dl and haemodynamic instability increased during the first 24 hours&#46; After 36 hours&#44; vaso-active amine treatment was reduced until fully suspended on the seventh day of hospitalisation&#46; Later progression was favourable&#44; with no need for renal replacement therapy&#59; the patient was transferred back to Belgium after 13 days in our hospital&#44; with a final creatinine value of 2&#46;59mg&#47;dl and an eGFR of 26ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Case 7</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A 75-year old male&#44; with allergy to aspirin&#44; penicillin&#44; and quinolones&#44; had hypertension&#44; asthma&#44; type 2 diabetes and was on treatment with metformin at 850mg&#47;24h&#46; The patient sought treatment at his reference hospital due to general discomfort&#44; fever and abundant vomiting&#46; Initial laboratory values are summarised in the Table 1&#46; Notable results included mild renal failure and metabolic acidosis&#46; An abdominal ultrasound resulted normal and the patient was transferred to our hospital&#46; Upon arrival in the emergency department&#44; the patient had haemodynamic instability with undetectable BP and respiratory failure&#46; We started the patient on low doses of perfused vasoactive amines&#46; Given the patient&#8217;s critical state&#44; we performed a CAT scan&#44; which yielded no pathological findings&#46; The patient was then admitted to the ICU&#44; where treatment with low doses of vasoactive amines was continued&#46; CVHDF was applied for 24 hours due to oligoanuria&#46; Antibiotic treatment was started with ceftriaxone and clarithromycin&#44; despite an absence of increase in sepsis parameters and negative culture results&#46; The patient progressed favourably&#44; with normalised laboratory values and no need for renal replacement therapy&#46; The patient was discharged after 11 days in the hospital&#44; with an eGFR&#62;60ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Lactic acidosis can appear during treatment with metformin&#44; although it has a low incidence rate&#59; different studies report an incidence of 1-8 cases per 100&#160;000 patients treated per year&#46;<span class="elsevierStyleSup">1-3</span> As in all of the cases described in our series&#44; this condition normally develops with non-specific symptoms such as general discomfort&#44; myalgia and abdominal symptoms &#40;diarrhoea&#44; nausea&#44; and vomiting&#41;&#46; Worsening renal function occurs as a result of dehydration and pharmacological nephrotoxicity caused by the accumulation of metformin due to reduced elimination by the kidneys &#40;type B lactic acidosis&#41;&#46; This condition is also defined by laboratory values included pH&#60;7&#46;35&#44; bicarbonate &#60;22mEq&#47;l&#44; lactate &#62;5mmol&#47;l and elevated anion GAP &#40;Na &#8211; &#91;HCO3 &#43; Cl&#93;&#62;10-12&#41;&#46; According to different studies&#44;<span class="elsevierStyleSup">4</span> MALA can produce lower blood pH levels than in cases of lactic acidosis of different origin&#46;</p><p class="elsevierStylePara">Metformin is a drug in the family of biguanides&#44; which has been used since 1950 in type 2 diabetes mellitus patients&#44; with reduced mortality rates of up to 36&#37; in obese patients&#44;<span class="elsevierStyleSup">5</span> and decreased morbidity and mortality due to cardiovascular pathologies&#46;<span class="elsevierStyleSup">4</span> Its hypoglycaemic effect is based on inhibition of hepatic gluconeogenesis&#44; increased cellular use of glucose&#44; decreased gastrointestinal absorption of glucose and reduced liver metabolism of lactate&#46;<span class="elsevierStyleSup">6</span> Metformin toxicity is based on its binding to the mitochondrial membrane and inhibiting oxidative phosphorylation&#44; thus converting pyruvate into lactate&#46; The half-life of metformin is 1&#46;5-2 hours&#44; it circulates freely &#40;without binding to proteins&#41; and is 90&#37; eliminated by the kidneys&#46; In situations of acute renal failure &#40;eGFR&#60;60ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#41;&#44; the half-life of metformin increases&#44; as does the risk of accumulation&#46;<span class="elsevierStyleSup">3</span></p><p class="elsevierStylePara">Lactate is produced through the metabolism of pyruvate&#46; Pyruvate is the ultimate result of glycolysis&#44; and is finally transformed through the Krebs cycle into CO<span class="elsevierStyleInf">2</span> and water or&#44; in anaerobic situations&#44; into lactate&#46; Increased serum concentrations of lactate &#40;&#62;45mg&#47;dl&#41; can be due to increased production&#44; decreased metabolisation&#44; or alterations in cellular reduction pathways&#46; Lactate concentrations can become elevated in situations of haemodynamic instability and tissue hypoxia &#40;type A lactic acidosis&#41;&#44; or when certain drugs become accumulated in the body &#40;type B lactic acidosis&#41;&#46;<span class="elsevierStyleSup">2</span></p><p class="elsevierStylePara">The relationship between lactic acidosis and metformin has been the subject of much debate&#44;<span class="elsevierStyleSup">4</span> but there does appear to be a causal relationship&#46; Certain risk factors have been identified for developing MALA&#44; such as acute renal failure&#44; situations of hypoxemia such as sepsis&#44; heart failure and respiratory failure&#44; a previous history of lactic acidosis&#44; liver disease&#44;<span class="elsevierStyleSup">4&#44;6&#44;8</span> and dehydration&#46;<span class="elsevierStyleSup">2</span> Precaution is recommended when using metformin in patients with an eGFR&#60;60ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#44; and it should not be used at all if GFR&#60;30ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#46;<span class="elsevierStyleSup">1&#44;9</span> In spite of these recommendations&#44; a recent Cochrane review concluded that no clear evidence exists suggesting that metformin is associated with an increased risk of lactic acidosis in comparison with other hypoglycaemic treatments&#46;<span class="elsevierStyleSup">10</span> Two of our patients already had a glomerular filtration rate &#60;45ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span> prior to the described episode&#44; which already constitutes a contraindication for the use of metformin&#46; In the other cases&#44; prior gastrointestinal symptoms and pre-renal acute renal failure predisposed the patient for an accumulation of metformin&#44; which favours the elevated production of lactate&#46;</p><p class="elsevierStylePara">MALA has a very poor prognosis if it is not diagnosed and treated early&#46;<span class="elsevierStyleSup">4</span> The treatment of choice consists of suspending the drug and&#44; since metformin is susceptible to dialysis&#44; renal replacement therapy<span class="elsevierStyleSup">2&#44;5&#44;11&#44;12</span> using prolonged haemodialysis or CVHDF in the case of haemodynamic instability&#46; This treatment corrects the acid-base imbalance&#44; eliminates lactate and decreases metformin levels&#46; Even so&#44; recent studies carried out in the ICU report a mortality rate of 30&#37;<span class="elsevierStyleSup">5</span> that has been associated with elevated lactate levels&#46;<span class="elsevierStyleSup">4</span> In our study&#44; patients with higher concentrations of lactate were those with a slower improvement&#44; and one of these patients died &#40;14&#46;2&#37;&#41;&#46; Paradoxically&#44; some studies&#44; conclude that MALA has a better prognosis<span class="elsevierStyleSup">4</span> despite lower pH levels than in other causes of lactic acidosis&#46;</p><p class="elsevierStylePara">We believe that MALA is a severe disease that requires early diagnosis and treatment&#46; Renal replacement therapy is not the solution for all patients&#44; but it can improve the prognosis of severe cases if started early&#46; We believe that the use of metformin should be limited in diabetic patients with altered renal function&#44; despite the current level of controversy surrounding this treatment&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The authors have no conflicts of interest to declare&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11395&#95;16025&#95;35700&#95;en&#95;t111395&#95;copy1&#46;jpg" class="elsevierStyleCrossRefs"><img src="11395_16025_35700_en_t111395_copy1.jpg" alt="Patient characteristics"></img></a></p><p class="elsevierStylePara">Table 1&#46; Patient characteristics</p>"
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        "resumen" => "<p class="elsevierStylePara">La metformina es un f&#225;rmaco muy utilizado en pacientes con diabetes tipo 2&#46; La acidosis l&#225;ctica asociada a metformina &#40;ALAM&#41; en pacientes diab&#233;ticos es poco frecuente&#44; pero puede llegar a ser grave&#46; De todas formas&#44; la relaci&#243;n entre metformina y acidosis l&#225;ctica ha sido muy controvertida&#46; Presentamos siete casos de pacientes con ALAM que llegaron a nuestro centro en un per&#237;odo de un a&#241;o y que fueron tratados de forma precoz con hemofiltraci&#243;n&#46; Existen algunos factores de riesgo que parecen predisponer a esa patolog&#237;a&#44; como fracaso renal agudo&#44; situaciones de hipoxemia y sepsis&#44; insuficiencia card&#237;aca o respiratoria&#44; historia previa de acidosis l&#225;ctica&#44; hepatopat&#237;a y en cuadros de deshidrataci&#243;n&#46; Es por ello por lo que se desaconseja su utilizaci&#243;n en pacientes con filtrado glomerular inferior a 30&#160;ml&#47;min&#47;1&#44;73 m<span class="elsevierStyleSup"><span class="elsevierStyleSup">2</span></span>&#46; Todos los pacientes que presentamos fueron tratados de forma precoz con hemofiltraci&#243;n&#46; La mortalidad de nuestra serie fue del 16&#44;6&#37;&#46; Consideramos que la ALAM es una enfermedad grave que requiere un diagn&#243;stico y un tratamiento precoces&#46; El tratamiento renal sustitutivo no es la soluci&#243;n para todos los pacientes&#44; pero puede mejorar el pron&#243;stico en aquellos que est&#225;n m&#225;s graves si se inicia de forma precoz&#46; Creemos importante limitar el uso de la metformina en los pacientes diab&#233;ticos con funci&#243;n renal alterada&#44; a pesar de que todav&#237;a existe controversia en los distintos estudios publicados&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara">Metformin is a drug widely used in type 2 diabetic patients&#46; Metformin-associated lactic acidosis &#40;MALA&#41; in diabetic patients is rare but can be serious&#46; However&#44; the relationship between metformin and lactic acidosis is under debate&#46; We present seven cases of patients with MALA who came to our centre over a period of one year and who were treated early with haemodiafiltration&#46; There are some risk factors that appear to predispose patients to this pathology&#44; such as&#58; acute renal failure&#44; situations of hypoxemia and sepsis&#44; cardiac or respiratory failure&#44; previous history of lactic acidosis&#44; liver disease and dehydration&#46; As such&#44; the use of metformin is discouraged in patients with GFR below 30ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#46; All patients in our study were treated early with haemodiafiltration&#46; The mortality in our study was 16&#46;6&#37;&#46; We believe that MALA is a serious condition that requires prompt diagnosis and early treatment&#46; Renal replacement therapy is not the solution for all patients&#44; but can improve prognosis in more severe cases if started early&#46; We should limit the use of metformin in diabetic patients with impaired renal function&#44; although there is still controversy in the medical literature&#46;</p>"
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                  "referenciaCompleta" => "Chico JL, Saborido E, Rivero C, Sanmartin E, Sayagues L, Casado R. Hemofiltración en acidosis láctica por biguanidas. NefroPlus 2008;1:37-9."
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                  "referenciaCompleta" => "Fitzgerald E, Mathieu S, Ball A. Metformin associated lactic acidosis. BMJ 2009;339:b3660. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19574308" target="_blank">[Pubmed]</a>"
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