[Metformin Therapy During Surgical Interventions and Iodinated Contrast Agent Use]. / Metformin-Therapie bei operativen Eingriffen und Gabe jodhaltiger Kontrastmittel.

Metformin as first-line treatment in type 2 diabetes mellitus (T2 D) shows benefits in terms of reducing cardiovascular events, but the risk of a lactic acidosis as a serious adverse event especially in patients with decreased renal function is still relevant. Since the perioperative management of Metformin or its use in diagnostic procedures with contrast agents is inconsistent in literature and different in practice, the results of various guidelines are reviewed below showing the current state of evidence. Despite many guidelines, the evidence on both issues is low, as they are mainly based on consensus recommendations. The guidelines are still based on weak data and many international recommendations have clearly different statements. A fundamental problem with drugs is that expert information does specify eGFR limits for dose reduction, but not the method to be used. Depending on the formula, this can then lead to different treatment decisions. At present, it is not possible to give reliable recommendations for practice with the aim of minimising the interruption of therapy. For this reason, only a strictly conservative approach with 48-hour breaks before and after both measures can be recommended at present. For the situations mentioned in this overview, the question of the right approach has not yet been conclusively and definitely answered, therefore further studies should be carried out.

Causes of death in feedlot beef cattle and their control: a brief review / Causas de morte em bovinos de corte confinados e seu controle: uma breve revisão

This review reports the leading causes of death in feedlot beef cattle. It describes economic losses resulting from these deaths and suggests control alternatives. Diseases associated with the respiratory and digestive systems were the most frequently observed. In different geographical areas, the importance of each one might vary. Outbreaks of diseases such as botulism occur occasionally and can cause important economic losses. Cattle tick fever can cause significant losses in zones of enzootic tick instability. Technical assistance and sanitary and food management are critical for the best productivity in feedlot cattle.(AU)

Esta revisão discute as principais causas de morte em bovinos de corte em confinamento. Descreve as perdas econômicas resultantes dessas mortes e sugere alternativas de controle. As doenças associadas aos sistemas respiratório e digestivo foram as mais frequentemente observadas. Em diferentes áreas geográficas, a importância de cada uma pode variar. Surtos de doenças como o botulismo ocorrem ocasionalmente e podem causar importantes perdas econômicas. A tristeza parasitária bovina pode causar perdas significativas em zonas de instabilidade enzoótica do carrapato. A assistência técnica e um bom gerenciamento sanitário e alimentar são essenciais para a melhor produtividade em bovinos de corte confinados.(AU)

Lactic acidosis due to metformin in type 2 diabetes mellitus and chronic kidney disease stage 3-5: is it significant?

PURPOSE: To study the incidence of lactic acidosis due to metformin in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) stage 3-5. METHODS: We estimated plasma lactate in patients of CKD stage 3 and worse who were continuing metformin on their own prior to stopping the drug. RESULT: Of 40 patients included, median duration of T2DM was 60 months (interquartile range IQR 24-120). The mean serum creatinine was 309.4 ± 159.1 µmol/L and mean eGFR was 27.82 ± 12.93 mL/min/1.73 m2 with 3 (7.5%), 16 (40%), 11 (27.5%) and 10 (25%) in CKD stages 3a, 3b, 4 and 5, respectively. They were receiving metformin for a median duration of 24 months (IQR 12.5-60), an average dose of 896 ± 350 mg per day. The median of plasma lactate was 1.36 mmol/L (IQR 1.11-1.75 mmol/L) with three (7.5%) having levels above normal, two (20%) in CKD stage 5 and one (9.1%) in stage 4. CONCLUSION: Metformin can be safely used in CKD stage 3 and with regular measurement of plasma lactate in later stages.

Using a semi-mechanistic model to identify the main sources of variability of metformin pharmacokinetics.

Metformin pharmacokinetics (PK) is highly variable, and researchers have for years tried to shed light on determinants of inter-individual (IIV) and inter-occasion variability (IOV) of metformin PK. We set out to identify the main sources of PK variability using a semi-mechanistic model. We assessed the influence of subject characteristics, including seven genetic variants. Data from three studies of healthy individuals with PK measurements of plasma and urine after single dose or at steady-state were used in this study. In total, 87 subjects were included (16 crossover subjects). Single nucleotide polymorphisms in ATM, OCT1, OCT2, MATE1 and MATE2-K were investigated as dominant, recessive or additive. A three-compartment model with transit absorption and renal elimination with a proportional error was fitted to the data using NONMEM 7.3. Oral parameters were separated from disposition parameters as dose-dependent absolute bioavailability was determined with support from urine data. Clearance was expressed as net renal secretion and filtration, assuming full fraction unbound and fraction excreted. Mean transit time and peripheral volume of distribution were identified as the main sources of variability according to estimates, with 94% IOV and 95% IIV, respectively. Clearance contributed only with 16% IIV. Glomerular filtration rate and body-weight were the only covariates found to affect metformin net secretion, reducing IIV to 14%. None of the genetic variants were found to affect metformin PK. Based on our analysis, finding covariates explaining absorption of metformin is much more valuable in understanding variability and avoiding toxicity than elimination.

Metformin in heart failure patients.

The use of metformin was considered a contraindication in heart failure patients because of the potential risk of lactic acidosis; however, more recent evidence has shown that this should no longer be the case. We reviewed the current literature and the recent guideline to correct the misconception.

Comparative assessment of probiotics and monensin in the prophylaxis of acute ruminal lactic acidosis in sheep.

BACKGROUND: Acute ruminal lactic acidosis (ARLA) is a major nutritional and metabolic disorder usually characterized by excessive or non-adapted intake of diets rich in nonstructural carbohydrates. Feed additives that regulate the ruminal environment have been used to prevent ARLA, such as ionophores and, more recently, yeast culture. Thus, we aimed to compare the efficacy of a yeast-based culture (Saccharomyces cerevisiae) with that of monensin sodium in the prevention of ARLA in sheep. Eighteen male, crossbred, rumen-cannulated sheep were randomly distributed into three groups of six animals: control, yeast culture and monensin. Thirty days after the start of supplementation with yeast culture (4 × 109 cfu/animal/day of S. cerevisiae) and monensin (33 mg/kg of total dry matter intake), 15 g/kg BW of sucrose was administered directly into the rumen of the animals to induce ARLA. Samples of blood and ruminal fluid were collected at the following time points: at baseline (T0 h) immediately before the induction of ARLA; 6 h (T6 h); 12 h (T12 h); 18 h (T18 h); 24 h (T24 h); 36 h (T36 h); and 48 h (T48 h) after ARLA induction. RESULTS: Ruminal pH was higher in monensin group at T12 h and in yeast culture group at T36 h when compared to control group. Lower values of L-Lactate were found at yeast culture group at T24 h and T36 h. Monensin showed prophylactic effect by decreasing the rate of ruminal pH decline and occasionally reducing ruminal acidosis, whereas probiotics resulted in less accumulation of lactic acid in the rumen and a lower degree of systemic acidosis. CONCLUSION: The use of yeast culture can be beneficial in the prevention and treatment of ARLA in sheep, because it can effectively reduce the accumulation of lactic acid, and thereby increase ruminal pH and reduce ruminal osmolarity. On the other hand, monensin showed prophylactic effect by decreasing the rate of ruminal pH decline and occasionally reducing ruminal acidosis, however, it did not directly prevent these conditions.

International practices in the dietary management of fructose 1-6 biphosphatase deficiency.

BACKGROUND: In fructose 1,6 bisphosphatase (FBPase) deficiency, management aims to prevent hypoglycaemia and lactic acidosis by avoiding prolonged fasting, particularly during febrile illness. Although the need for an emergency regimen to avoid metabolic decompensation is well established at times of illness, there is uncertainty about the need for other dietary management strategies such as sucrose or fructose restriction. We assessed international differences in the dietary management of FBPase deficiency. METHODS: A cross-sectional questionnaire (13 questions) was emailed to all members of the Society for the Study of Inborn Errors of Metabolism (SSIEM) and a wide database of inherited metabolic disorder dietitians. RESULTS: Thirty-six centres reported the dietary prescriptions of 126 patients with FBPase deficiency. Patients' age at questionnaire completion was: 1-10y, 46% (n = 58), 11-16y, 21% (n = 27), and >16y, 33% (n = 41). Diagnostic age was: <1y, 36% (n = 46); 1-10y, 59% (n = 74); 11-16y, 3% (n = 4); and >16y, 2% (n = 2). Seventy-five per cent of centres advocated dietary restrictions. This included restriction of: high sucrose foods only (n = 7 centres, 19%); fruit and sugary foods (n = 4, 11%); fruit, vegetables and sugary foods (n = 13, 36%). Twenty-five per cent of centres (n = 9), advised no dietary restrictions when patients were well. A higher percentage of patients aged >16y rather than ≤16y were prescribed dietary restrictions: patients aged 1-10y, 67% (n = 39/58), 11-16y, 63% (n = 17/27) and >16y, 85% (n = 35/41). Patients classified as having a normal fasting tolerance increased with age from 30% in 1-10y, to 36% in 11-16y, and 58% in >16y, but it was unclear if fasting tolerance was biochemically proven. Twenty centres (56%) routinely prescribed uncooked cornstarch (UCCS) to limit overnight fasting in 47 patients regardless of their actual fasting tolerance (37%). All centres advocated an emergency regimen mainly based on glucose polymer for illness management. CONCLUSIONS: Although all patients were prescribed an emergency regimen for illness, use of sucrose and fructose restricted diets with UCCS supplementation varied widely. Restrictions did not relax with age. International guidelines are necessary to help direct future dietary management of FBPase deficiency.

[Metformin and surgery before general anaesthesia].

Danish national guidelines recommend discontinuation of metformin 48 h prior to general anaesthesia due to the presumed increased risk of lactic acidosis. By reviewing recent studies concerning the risk of metformin-associated lactic acidosis it is found, that studies indicate, that metformin does not increase the risk of lactic acidosis. However, comorbidities such as cardiovascular insufficiency, sepsis, dehydration and impaired kidney function are risk factors. New guidelines propose discontinuation of metformin on the day of surgery. Patients with Type 2 diabetes and comorbidities should have the levels of arterial pH and lactate monitored.

Still sour about lactic acidosis years later: role of metformin in heart failure.

Metformin remains a widely-used, first-line pharmacotherapy agent for patients with type 2 diabetes mellitus because of its efficacy, mild side effects, and affordability.However, use of this medication has traditionally been shunned by clinicians in patient populations that are considered at risk of lactic acidosis, such as those with heart failure. The underutilization of metformin can largely be attributed to the historical stigma of its biguanide predecessor, phenformin, and its association with lactic acidosis. Despite various studies finding low rates of lactic acidosis and the United States Federal Drug Administration's subsequent removal of heart failure from metformin's contraindication labeling in 2006, this oral hypoglycemic remains underutilized in this patient population. In addition to reports of the safe use of metformin in the heart failure population, a multitude of studies have also additionally suggested a modest reduction in mortality and morbidity. Metformin's role should be strongly reconsidered in the armamentarium of diabetes management in heart failure patients.

The Phantom of Metformin-Induced Lactic Acidosis in End-Stage Renal Disease Patients: Time to Reconsider with Peritoneal Dialysis Treatment.

♦ OBJECTIVE: Metformin continues to be the safest and most widely used antidiabetic drug. In spite of its well-known benefits; metformin use in end-stage renal disease (ESRD) patients is still restricted. Little has been reported about the effect of peritoneal dialysis (PD) on metformin clearance and the phantom of lactic acidosis deprives ESRD patients from metformin therapeutic advantages. Peritoneal dialysis is probably a safeguard against lactic acidosis, and it is likely that using this drug would be feasible in this group of patients. ♦ MATERIAL AND METHODS: The study was conducted on 83 PD patients with type 2 diabetes mellitus. All patients were on automated PD (APD). Metformin was administered in a dose of 500 - 1,000 mg daily. Patients were monitored for glycemic control. Plasma lactic acid and plasma metformin levels were monitored on a scheduled basis. Peritoneal fluid metformin levels were measured. In addition, the relation between plasma metformin and plasma lactate was studied. ♦ RESULTS: Mean fasting blood sugar (FBS) was 10.9 ± 0.5 and 7.8 ± 0.7, and mean hemoglobin A1-C (HgA1C) was 8.2 ± 0.8 and 6.4 ± 1.1 at the beginning and end of the study, respectively (p < 0.001). The mean body mass index (BMI) was 29.1 ± 4.1 and 27.3 ± 4.5 at the beginning and at the end of the study, respectively (p < 0.001). The overall mean plasma lactate level across all blood samples was 1.44 ± 0.6. Plasma levels between 2 and 3 mmol/L were found in 11.8% and levels of 3 - 3.6 mmol/L in 2.4% plasma samples. Hyperlactemia (level > 2 and ≤ 5 mmol/L) was not associated with overt acidemia. None of our patients had lactic acidosis (levels > 5 mmol/L). Age ≥ 60 was a predictor for hyperlactemia. No relationship was found between plasma metformin and lactate levels. ♦ CONCLUSION: Metformin may be used with caution in a particular group of ESRD patients who are on APD. Metformin allows better diabetic control with significant reduction of BMI. Information on the relationship between metformin and plasma lactate levels is lacking. Peritoneal dialysis appears to be a safeguard against the development of lactic acidosis in this group of patients.

Development, implementation and outcome analysis of semi-automated alerts for metformin dose adjustment in hospitalized patients with renal impairment.

PURPOSE: Overdosing of the oral antidiabetic metformin in impaired renal function is an important contributory cause to life-threatening lactic acidosis. The presented project aimed to quantify and prevent this avoidable medication error in clinical practice. METHODS: We developed and implemented an algorithm into a hospital's clinical information system that prospectively identifies metformin prescriptions if the estimated glomerular filtration rate is below 60 mL/min. Resulting real-time electronic alerts are sent to clinical pharmacologists and pharmacists, who validate cases in electronic medical records and contact prescribing physicians with recommendations if necessary. RESULTS: The screening algorithm has been used in routine clinical practice for 3 years and generated 2145 automated alerts (about 2 per day). Validated expert recommendations regarding metformin therapy, i.e., dose reduction or stop, were issued for 381 patients (about 3 per week). Follow-up was available for 257 cases, and prescribers' compliance with recommendations was 79%. Furthermore, during 3 years, we identified eight local cases of lactic acidosis associated with metformin therapy in renal impairment that could not be prevented, e.g., because metformin overdosing had occurred before hospitalization. CONCLUSIONS: Automated sensitive screening followed by specific expert evaluation and personal recommendations can prevent metformin overdosing in renal impairment with high efficiency and efficacy. Repeated cases of metformin-associated lactic acidosis in renal impairment underline the clinical relevance of this medication error. Our locally developed and customized alert system is a successful proof of concept for a proactive clinical drug safety program that is now expanded to other clinically and economically relevant medication errors. Copyright © 2016 John Wiley & Sons, Ltd.

Should Restrictions Be Relaxed for Metformin Use in Chronic Kidney Disease? No, We Should Never Again Compromise Safety!

Metformin is and has been considered as first-line therapy for type 2 diabetes for over a quarter of a century. Like other biguanides, metformin can cause a lactic acidosis that is exceptionally rare but fatal. The likelihood of metformin-associated lactic acidosis is substantially higher in patients with kidney impairment and also among those with seemingly normal kidney function who are at risk of acute kidney injury (AKI). Hence, regulatory agencies in many industrialized nations have maintained strict renal restrictions surrounding metformin. However, there have been millions of people exposed to metformin for many years, many of them with serum creatinine values at or close to 1.5 mg/dL with estimated glomerular filtration rates (eGFRs) much below 60 mL/min/1.73 m(2) who have not developed lactic acidosis. Thus, there clearly remains controversy in this area, and there has been heightened pressure to remove the renal restrictions of metformin. To provide a discussion on the pros and cons of relaxing the renal restrictions for metformin use, we provide a Point-Counterpoint. In the point narrative below, Drs. Kalantar-Zadeh and Kovesdy provide their argument that although there is little evidence of the potential benefits of metformin in kidney disease, just considering the sheer numbers of metformin users and the high fatality rate of its associated lactic acidosis, the most appropriate practice is to avoid metformin use in people with eGFR <45 mL/min/1.73 m(2) or in those who are at high risk of AKI irrespective of underlying eGFR. In the following counterpoint narrative, Drs. Bakris and Molitch argue that the data from a very large analysis demonstrate clearly that serum creatinine should be supplanted with eGFR as the criteria for metformin use and that the incidence of lactic acidosis is only elevated in those with a reduced eGFR who become dehydrated for various reasons or in those exposed to some toxin resulting in AKI. Otherwise the data clearly support the use of metformin under normal circumstances down to eGFR >30 mL/min/1.73 m(2)-William T. CefaluEditor in Chief, Diabetes Care.

Should Restrictions Be Relaxed for Metformin Use in Chronic Kidney Disease? Yes, They Should Be Relaxed! What's the Fuss?

Metformin is and has been considered as first-line therapy for type 2 diabetes for over a quarter of a century. Like other biguanides, metformin can cause a lactic acidosis that is exceptionally rare but fatal. The likelihood of metformin-associated lactic acidosis is substantially higher in patients with kidney impairment and also among those with seemingly normal kidney function who are at risk of acute kidney injury (AKI). Hence, regulatory agencies in many industrialized nations have maintained strict renal restrictions surrounding metformin. However, there have been millions of people exposed to metformin for many years, many of them with serum creatinine values at or close to 1.5 mg/dL with estimated glomerular filtration rates (eGFRs) much below 60 mL/min/1.73 m(2) who have not developed lactic acidosis. Thus, there clearly remains controversy in this area, and there has been heightened pressure to remove the renal restrictions of metformin. To provide a discussion on the pros and cons of relaxing the renal restrictions for metformin use, we provide a Point-Counterpoint. In the preceding point narrative, Drs. Kalantar-Zadeh and Kovesdy provide their argument that although there is little evidence of the potential benefits of metformin in kidney disease, just considering the sheer numbers of metformin users and the high fatality rate of its associated lactic acidosis, the most appropriate practice is to avoid metformin use in people with eGFR <45 mL/min/1.73 m(2) or in those who are at high risk of AKI irrespective of underlying eGFR. In the counterpoint narrative below, Drs. Bakris and Molitch argue that the data from a very large analysis demonstrate clearly that serum creatinine should be supplanted with eGFR as the criteria for metformin use and that the incidence of lactic acidosis is only elevated in those with a reduced eGFR who become dehydrated for various reasons or in those exposed to some toxin resulting in AKI. Otherwise the data clearly support the use of metformin under normal circumstances down to eGFR >30 mL/min/1.73 m(2)-William T. CefaluEditor in Chief, Diabetes Care.

Inusual complicación en la edad pediátrica: encefalopatía de Wernicke asociada a nutrición parenteral deficiente en tiamina / Unusual complication in a paediatric patient: Wernicke encephalopathy associated with thiamine-deficient parenteral nutrition

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Use of Metformin for Cardiometabolic Risks in Psychiatric Practice: Need-to-Know Safety Issues.

Metformin, a biguanide drug, is emerging as an important treatment option for the prevention or treatment of weight gain, type 2 diabetes mellitus, and the metabolic syndrome in psychiatric patients, especially those who require or receive antipsychotic drugs. Metformin treatment is commonly associated with gastrointestinal adverse effects; the risk of these is reduced by gradual dose uptitration, administration of the drug with meals, and use of a time-release formulation. Lactic acidosis, a potentially fatal complication of biguanide therapy, is very rare with metformin; the risk can be reduced by avoidance of its prescription in patients with impaired renal function, impaired liver function, cardiac failure, and certain other conditions. Long-term metformin use is associated with decreased vitamin B12 levels, and even with biochemical B12 deficiency; this complication can detected early by annual assessments of serum B12 levels and prevented by annual intramuscular B12 administration.

Unexpectedly long half-life of metformin elimination in cases of metformin accumulation.

INTRODUCTION: In a study of the oral administration of a single dose of metformin to healthy participants, the estimated half-life (t½ ) for the elimination of the drug from erythrocytes was found to be 23.4 h (compared with 2.7 h for metformin in plasma). However, these pharmacokinetic indices have not been well defined in metformin accumulation. METHODS: We systematically reviewed all the data on plasma and erythrocyte metformin assays available in our centre. We then selected patients with a plasma metformin concentration ≥ 5 mg/l and in whom the metformin concentration had been remeasured once or more at least 5 days after admission. RESULTS: Twelve patients met the aforementioned criteria. All but one of these patients displayed generally severe lactic acidosis on admission (mean ± sd pH and lactate: 6.88 ± 0.35 and 14.8 ± 6.56 mmol/l, respectively) and 11 were treated with dialysis. The mean ± sd time interval between the first and last blood sample collections for metformin measurement was 8.3 ± 3.2 days (range 5-14 days). Five days after the first sample had been collected, metformin was still detectable in plasma and in erythrocytes in all patients. Metformin remained detectable for up to 13 days (both in plasma and in erythrocytes). The estimated mean terminal t½ for metformin in plasma and erythrocytes was 51.9 and 43.4 h, respectively. CONCLUSIONS: The prolonged elimination of accumulated metformin (even after dialysis therapy) challenges the traditional view that the drug clears rapidly because of a short half-life in plasma.

Hextend-perfluorocarbon cocktail inhibits mean arterial pressure response in a rabbit shock model.

BACKGROUND: Hextend (HEX) is standard of care resuscitation fluid for combat-related traumatic hemorrhage. Because HEX has limited oxygen-carrying capacity, combination therapy with oxygen therapeutics could improve oxygen delivery after hemodynamic shock. We hypothesized that addition of perfluorocarbon (PFC) to HEX would improve hemodynamics and oxygen delivery marker response in a rabbit model of hemorrhagic shock. METHODS: Anesthetized New Zealand rabbits (n = 23) were randomly allocated to resuscitation with fresh whole blood (FWB), HEX, or HEX plus PFC (HEX + PFC) after 60 min of hemorrhagic hypotension. Mean arterial pressure (MAP) was sampled every 2-3 min for 120 min postinfusion; MAP profiles were modeled by a one-compartment pharmacokinetic model to determine peak MAP (Pmax), time to peak MAP (tmax), and postinfusion MAP persistence. Arterial blood was sampled every 15 min to examine pH, blood gases PO2 and pCO2, metabolites lactate and glucose, methemoglobin (metHb), and electrolytes. RESULTS: Compared with FWB and HEX, HEX + PFC administration resulted in delayed peak MAP and less persistent (P < 0.0001) MAP elevation; metHb was significantly elevated (P < 0.0001) compared with FWB and HEX. There were no significant differences in PO2, pCO2, or pH. Glucose, hematocrit, and hemoglobin of both HEX and HEX + PFC were significantly lower relative to FWB. Lactate clearance was modest and transient for all treatments; base deficit was significantly more negative for HEX + PFC. CONCLUSIONS: Addition of PFC to HEX did not improve hemodynamics or acidosis. Further dose- and volume-range studies are required to test efficacy of PFC in combination with HEX for hemorrhagic shock.