Treatment of severe metformin-associated lactic acidosis with renal replacement therapy and tris-hydroxymethyl aminomethane: a case report.

BACKGROUND: Type B lactic acidosis is a rare but serious side effect of metformin use. The risk of metformin-associated lactic acidosis is elevated in renal or liver impairment, heart failure and in metformin overdose. Metformin-associated lactic acidosis is treated with renal replacement therapy although this can be limited by metformin's large volume of distribution and a patient's hemodynamic instability. Tris-hydroxymethyl aminomethane is a buffer that rapidly equilibrates in liver cells and increases the intracellular pH of hepatocytes. Intracellular alkalosis increases lactate uptake by the liver and can promote gluconeogenesis which results in increased lactate metabolism and decreased lactate production. Unlike intravenous bicarbonate which can worsen acidosis due to carbon dioxide retention and hypocalcemia, tris-hydroxymethyl aminomethane does not generate large amounts of carbon dioxide and can improve cardiac contractility in experimental models. CASE PRESENTATION: We present a case of a 43-year-old African American male who intentionally ingested 480,000 g of metformin. He developed severe metformin-associated lactic acidosis that was refractory to 21 hours of high flux hemodialysis. This was followed by an additional 12 hours of high flux hemodialysis augmented by continuous intravenous infusion of tris-hydroxymethyl aminomethane. After initiating tris-hydroxymethyl aminomethane, the patient had rapid reversal of lactic acidosis and was weaned off vasopressors and mechanical ventilation. CONCLUSIONS: While metformin-associated lactic acidosis can be treated with renal replacement therapy, severe cases of lactic acidosis may not be amenable to renal replacement therapy alone. Through its unique buffer mechanisms, tris-hydroxymethyl aminomethane can be used in conjunction with dialysis to rapidly improve acidosis associated with metformin.

Assessing accuracy of estimated dry weight in dialysis patients post transplantation: the kidney knows best.

INTRODUCTION: Estimated dry weight is used to guide fluid removal during outpatient hemodialysis sessions. Errors in estimated dry weight can result in intradialytic hypotension and interdialytic fluid overload. The goal of this study was to assess the accuracy of estimated dry weight by comparing it to the 2-week post-transplant weight in two cohorts of hemodialysis patients. METHODS: This observational, multi-center, retrospective cohort study included maintenance hemodialysis patients who underwent kidney transplantation at two medical centers in Massachusetts. The relationship between estimated dry weight pre-transplant and weight at week 2 post-transplant in patients with good allograft function (serum creatinine ≤ 1.5 mg/dL) was analyzed. Estimated dry weight was considered accurate if it was within ± 2% of the week 2 post-transplant weight. RESULTS: Fifty seven patients with good allograft function were identified: mean age 54 ± 14 years, 32 (58%) from deceased donors, 22 (38.6%) females. 38 were Caucasian (66.7%), 11 Hispanic (19.3%), 3 black (5.3%), and 5 others (8.8%). 2-week mean post transplantation serum creatinine was 1.2 ± 0.2 mg/dL. Mean (SD) estimated dry weight was 71.4 ± 15.9. Before transplantation, only 14 (24.6%) patients were within ± 2% of the 2-week post-transplant weight; 23 (40.3%) were above and 20 (35.1%) were below. CONCLUSIONS: Our point of view, based on the assumption that the weight of patients with good allograft function at 2 weeks post-transplant approaches their accurate dry weight, is that a majority of maintenance hemodialysis patients (75.4%) are hypervolemic or hypovolemic prior to renal transplantation. This highlights the importance of finding novel tools to achieve euvolemia in patients undertaking dialysis. Timely feedback regarding achieved weight 2 weeks post-transplant to treating nephrologists and dialysis centers may be a starting point for assessing accuracy of dry weight.

Oxcarbazepine Therapy for Complete Central Diabetes Insipidus.

Oxcarbazepine and carbamazepine cause hyponatremia by unknown mechanisms. We describe a patient with complete central diabetes insipidus and seizures who developed worsening hyponatremia when her dose of oxcarbazepine was increased. The patient maintained a normal serum sodium level and has had appropriately concentrated urine for 5 years on just oxcarbazepine, despite undetectable antidiuretic hormone (ADH) levels. This suggests that oxcarbazepine (or one of its metabolites) may stimulate collecting tubule V2 receptor-G protein complex independent of ADH, resulting in increased renal tubular water reabsorption. Oxcarbazepine may be useful as an alternative therapy for patients with central diabetes insipidus.

Tissue Edema, Fluid Balance, and Patient Outcomes in Severe Sepsis: An Organ Systems Review.

Severe sepsis and septic shock remain among the deadliest diseases managed in the intensive care unit. Fluid resuscitation has been a mainstay of early treatment, but the deleterious effects of excessive fluid administration leading to tissue edema are becoming clearer. A positive fluid balance at 72 hours is associated with significantly increased mortality, yet ongoing fluid administration beyond a durable increase in cardiac output is common. We review the pathophysiologic and clinical data showing the negative effects of edema on pulmonary, renal, central nervous, hepatic, and cardiovascular systems. We discuss data showing increased morbidity and mortality following nonjudicious fluid administration and challenge the assumption that patients who are fluid responsive are also likely to benefit from that fluid. The distinctions between fluid requirement, responsiveness, and tolerance are central to newer concepts of resuscitation. We summarize data in each organ system showing a predictable increase in morbidity and mortality with nonbeneficial fluid administration, providing a better framework for precision in volume management of the patient with severe sepsis.

Real-time cell analysis of the inhibitory effect of vitamin K2 on adhesion and proliferation of breast cancer cells.

Breast cancer is the most prevalent cancer type worldwide. Continued efforts to improve treatment strategies for patients with breast cancer will be instrumental in reducing the death rates associated with this disease. In particular, the triple-negative breast cancer subtype of breast cancer has no targeted therapy available so it is essential to continue to work on any potential therapies. Vitamin K (VK) is known for its essential role in the clotting cascade. The antitumor properties of VK derivatives have been reported in both hepatocellular carcinoma and glioblastoma. Our hypothesis was that menaquinone-4, the most common form of vitamin K2 (VK2), is an effective anticancer agent against breast cancer cell types. In this study, we used a novel impedance-based live cell monitoring platform (xCELLigence) to determine the effects of VK derivatives on the triple-negative breast cancer cell line, MDA-MB-231, and the HER2+ breast cancer cell line, MDA-MB-453. Cells were treated with varying concentrations of menaquinone-4 (VK2) previously reported to have an antiproliferative effect on human glioblastoma cells. After initial testing, these concentrations were adjusted to 100, 125, and 150 µmol/L. A significant dose-dependent, growth inhibitory effect was found when cells were treated at these concentrations. These effects were seen in both adhesion and proliferation phases and show a dramatic reduction in cell growth. Additional analysis of MDA-MB-231 cells treated with VK2 (100 µmol/L) in combination with a low-glucose nutrient media showed a further decrease in adhesion and viability. This is the first study of its kind showing the real-time effects of VK derivatives on breast cancer cells and suggests that dietary factors may be an important consideration for patients.