Kraut J.A.,Veterans Administration Greater Los Angeles VHAGLA |
Madias N.E.,St Elizabeths Medical Center
Nature Reviews Nephrology | Year: 2010
Metabolic acidosis is characterized by a primary reduction in serum bicarbonate (HCO3- ) concentration, a secondary decrease in the arterial partial pressure of carbon dioxide (PaCO2) of ∼ 1 mmHg for every 1 mmol/l fall in serum HCO 3 concentration, and a reduction in blood pH. Acute forms (lasting minutes to several days) and chronic forms (lasting weeks to years) of the disorder can occur, for which the underlying cause/s and resulting adverse effects may differ. Acute forms of metabolic acidosis most frequently result from the overproduction of organic acids such as ketoacids or lactic acid; by contrast, chronic metabolic acidosis often reflects bicarbonate wasting and/or impaired renal acidification. The calculation of the serum anion gap, calculated as [Na + ]- ([HCO 3- ] + [Cl - ]), aids diagnosis by classifying the disorders into categories of normal (hyperchloremic) anion gap or elevated anion gap. These categories can overlap, however. Adverse effects of acute metabolic acidosis primarily include decreased cardiac output, arterial dilatation with hypotension, altered oxygen delivery, decreased ATP production, predisposition to arrhythmias, and impairment of the immune response. The main adverse effects of chronic metabolic acidosis are increased muscle degradation and abnormal bone metabolism. Using base to treat acute metabolic acidosis is controversial because of a lack of definitive benefit and because of potential complications. By contrast, the administration of base for the treatment of chronic metabolic acidosis is associated with improved cellular function and few complications. © 20 Macmillan Publishers Limited. 10 All rights reserved.
Gorson K.C.,St Elizabeths Medical Center
Therapeutic Advances in Neurological Disorders | Year: 2012
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune mediated disorder of the peripheral nervous system with clinical features that include weakness, sensory loss, imbalance, pain and impaired ambulation which may lead to substantial disability. This review highlights current treatment strategies for CIDP, how best to utilize proven therapies such as intravenous immunoglobulin, oral prednisone, pulse dexamethasone, and plasma exchange, and when and how to use alternative immunosuppressive agents when first-line therapies are ineffective or poorly tolerated. © 2012 The Author(s).
Chapple C.R.,Royal Hallamshire Hospital |
Kaplan S.A.,Cornell University |
Mitcheson D.,St Elizabeths Medical Center |
Klecka J.,University Hospital Plzen |
And 4 more authors.
European Urology | Year: 2013
Background: Despite several antimuscarinic treatment options for overactive bladder (OAB), there is still a need for distinct treatment approaches to manage this condition. Mirabegron, a β3-adrenoceptor agonist, has demonstrated efficacy and tolerability for up to 12 wk in phase 3 trials. Objective: To assess the 12-mo safety and efficacy of mirabegron. Design, setting, and participants: Patients ≥18 yr of age with OAB symptoms for ≥3 mo. Interventions: After a 2-wk single-blind placebo run-in, patients with eight or more micturitions per 24 h and three or more urgency episodes in a 3-d micturition diary were randomized 1:1:1 to once-daily mirabegron 50 mg, mirabegron 100 mg, or tolterodine extended release (ER) 4 mg for 12 mo. Outcome measurements and statistical analysis: Primary variable: incidence and severity of treatment-emergent AEs (TEAEs). Secondary variables: change from baseline at months 1, 3, 6, 9, and 12 in key OAB symptoms. Results and limitations: A total of 812, 820, and 812 patients received mirabegron 50 mg, mirabegron 100 mg, and tolterodine ER 4 mg, respectively. Baseline demographic and OAB characteristics were similar across groups. TEAEs were reported in 59.7%, 61.3%, and 62.6% of patients, respectively; most were mild or moderate. Serious TEAEs were reported in 5.2%, 6.2%, and 5.4% of patients, respectively. The most common TEAEs were similar across groups. Dry mouth was reported by 2.8%, 2.3%, and 8.6% of patients, respectively. Adjusted mean changes from baseline to final visit in morning systolic blood pressure were 0.2, 0.4, and -0.5 mm Hg for mirabegron 50 mg, 100 mg, and tolterodine ER 4 mg, respectively. Mirabegron and the active control, tolterodine, improved key OAB symptoms from the first measured time point of 4 wk, and efficacy was maintained throughout the 12-mo treatment period. The study was not placebo controlled, which was a limitation. Conclusions: The safety and tolerability of mirabegron was established over 1 yr, with sustained efficacy observed over this treatment period. Trial registration: ClinicalTrials.gov identifier: NCT00688688. © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Kraut J.A.,Medical and Research Services |
Kraut J.A.,University of California at Los Angeles |
Madias N.E.,St Elizabeths Medical Center |
Madias N.E.,Tufts University
New England Journal of Medicine | Year: 2014
Lactic acidosis results from the accumulation of lactate and protons in the body fluids and is often associated with poor clinical outcomes. The effect of lactic acidosis is governed by its severity and the clinical context. Mortality is increased by a factor of nearly three when lactic acidosis accompanies low-flow states or sepsis,1 and the higher the lactate level, the worse the outcome.2 Although hyperlactatemia is often attributed to tissue hypoxia, it can result from other mechanisms. Control of the triggering conditions is the only effective means of treatment. However, advances in understanding its pathophysiological features and the factors causing cellular dysfunction in the condition could lead to new therapies. This overview of lactic acidosis emphasizes its pathophysiological aspects, as well as diagnosis and management. We confine our discussion to disorders associated with accumulation of the l optical isomer of lactate, which represent the vast majority of cases of lactic acidosis encountered clinically. Copyright © 2014 Massachusetts Medical Society.
Kraut J.A.,Veterans Health Administration Greater Los Angeles Heathcare System |
Madias N.E.,St Elizabeths Medical Center
Nature Reviews Nephrology | Year: 2012
Acute metabolic acidosis is associated with increased morbidity and mortality because of its depressive effects on cardiovascular function, facilitation of cardiac arrhythmias, stimulation of inflammation, suppression of the immune response, and other adverse effects. Appropriate evaluation of acute metabolic acidosis includes assessment of acid-base parameters, including pH, partial pressure of CO 2 and HCO 3 ĝ̂' concentration in arterial blood in stable patients, and also in central venous blood in patients with impaired tissue perfusion. Calculation of the serum anion gap and the change from baseline enables the physician to detect organic acidoses, a common cause of severe metabolic acidosis, and aids therapeutic decisions. A fall in extracellular and intracellular pH can affect cellular function via different mechanisms and treatment should be directed at improving both parameters. In addition to supportive measures, treatment has included administration of base, primarily in the form of sodium bicarbonate. However, in clinical studies of lactic acidosis and ketoacidosis, bicarbonate administration has not reduced morbidity or mortality, or improved cellular function. Potential explanations for this failure include exacerbation of intracellular acidosis, reduction in ionized Ca 2+, and production of hyperosmolality. Administration of tris(hydroxymethyl)aminomethane (THAM) improves acidosis without producing intracellular acidosis and its value as a form of base is worth further investigation. Selective sodium-hydrogen exchanger 1 (NHE1) inhibitors have been shown to improve haemodynamics and reduce mortality in animal studies of acute lactic acidosis and should also be examined further. Given the important effects of acute metabolic acidosis on clinical outcomes, more intensive study of the pathogenesis of the associated cellular dysfunction and novel methods of treatment is indicated. © 2012 Macmillan Publishers Limited. All rights reserved.