Lactic acidosis treatment

A class of drug derived from guanidine, including metformin and phenformin. Metformin is currently widely used in humans for the treatment of type 2 diabetes. Phenformin was formerly also widely used but was withdrawn because of problems with lactic acidosis. 

Early goal-directed resuscitation decreases 28-day mortality in septic patients. The treatment goals of sepsis-induced hypoperfusion (hypotension or lactic acidosis) during the first 6 hours include 24,27-29... 

Benign Not evident while sole nutrition is breast milk Severe hypoglycemia and lactic acidosis after fructose ingestion Vomiting, apathy, diarrhea Liver damage and jaundice Proximal renal tubule disorder resembling Fanconi syndrome Treatment eliminate sources of fructose from diet... 

Lactic acidosis Lactic acidosis is a rare, but serious, metabolic complication that can occur because of metformin accumulation during treatment when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis also may occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever... 

If patients require treatment with amprenavir oral solution, monitor them closely for propylene glycol-associated adverse reactions, including seizures, stupor, tachycardia, hyperosmolality, lactic acidosis, renal toxicity, and hemolysis. Switch patients from amprenavir oral solution to capsules as soon as they are able to take the capsule formulation. 

Lactic acidosis/Severe hepatomegaly with steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination, including emtricitabine and other antiretrovirals. Treatment with emtricitabine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. 

The drug metformin is useful in the treatment of patients with type 2 diabetes mellitus who are obese and whose hyperglycemia cannot be controlled by other agents. There are reports that some patients are predisposed to the toxic side effects of this drug, which include potentially fatal lactic acidosis. 

Tenofovir should not be given to patients with renal insufficiency. Its coadministration with didanosine results in increased plasma levels of didanosine that can produce toxicity. Because lactic acidosis and severe hepatomegaly with steatosis have been reported with NRTIs, it is important to monitor patients with known risk factors during treatment with tenofovir. 

The principal toxicity of linezolid is hematologic—reversible and generally mild. Thrombocytopenia is the most common manifestation (seen in approximately 3% of treatment courses), particularly when the drug is administered for longer than 2 weeks. Anemia and neutropenia may also occur, most commonly in patients with a predisposition to or underlying bone marrow suppression. Cases of optic and peripheral neuropathy and lactic acidosis have been reported with prolonged courses of linezolid. These side effects are thought to be related to linezolid-induced inhibition of mitochondrial protein synthesis. 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

The mechanism of toxicity of ethylene glycol involves metabolism, but unlike previous examples, this does not involve metabolic activation to a reactive metabolite. Thus, ethylene glycol is metabolized by several oxidation steps eventually to yield oxalic acid (Fig. 7.84). The first step is catalyzed by the enzyme alcohol dehydrogenase, and herein lies the key to treatment of poisoning. The result of each of the metabolic steps is the production of NADH. The imbalance in the level of this in the body is adjusted by oxidation to NAD coupled to the production of lactate. There is thus an increase in the level of lactate, and lactic acidosis may result. Also, the intermediate metabolites of ethylene glycol have metabolic effects such as the inhibition of oxidative phosphorylation, glucose metabolism, Krebs cycle, protein synthesis, RNA synthesis, and DNA replication. 

Contraindications to the use of metformin have been debated (34), in relation to the reduced number of cardiovascular events seen in the obese patients treated with metformin in the UK prospective diabetes study (UKPDS) (35). The authors stated inter alia that lactic acidosis is rare (1-5 cases per 100 000) and that in the absence of renal insufficiency accumulation of metformin is rare. Moreover, the authors of a Cochrane systematic review concluded that treatment with metformin was not associated with an increased risk of lactic acidosis (36). Tissue hypoxia is often the trigger for metformin accumulation. Many physicians do not comply with the official British contraindications. The author suggested the following necessary precautionary measures ... 

The lower frequency of lactic acidosis during treatment with metformin compared with other biguanides may be caused by its short non-polar hydrophobic side chains substituted with two CH3 groups. This has a lower affinity for hydrophobic structures, such as phospholipids in mitochondrial and cellular membranes, than the longer monosubstituted side-chains of the other biguanides (64). 

In another review it was suggested that the risk of lactic acidosis when metformin is used as recommended is close to zero (84). The author discussed the COSMIC study, which compared metformin treatment for 1 year (n = 7227) with usual care with other antidiabetic agents (n = 1505). There were no cases of lactic acidosis. The findings in controlled trials contrast with case reports of lactic acidosis. About one million patients have received metformin in the USA and the FDA has received 47 reports of lactic acidosis (20 fatal). Of these, 43 patients had renal insufficiency or susceptibility factors for lactic acidosis, such as congestive cardiac failure. Only four cases appeared to have no other susceptibility factors, one of which may have been precipitated by urinary sepsis none of these four died. 

Guariglia A, Gonzi GL, Regolisti G, Vinci S. Treatment of biguanide-induced lactic acidosis reproposal of the physiological approach and review of the literature. Ann Ital Med Int 1994 9(l) 35-9. 

Panzer U, Kluge S, Kreymann G, Wolf G. Combination of intermittent haemodialysis and high-volume continous haemofiltration for the treatment of severe metformin-induced lactic acidosis. Nephrol Dial Transplant 2004 19 2157-8. 

Mariano F, Benzi L, Cecchetti P, Rosatello A, Merante D, Goia F, Capra L, Lanza G, Curto V, Cavalli PL. Efficacy of continuous venovenous haemofiltration (CWH) in the treatment of severe phenformin-induced lactic acidosis. Nephrol Dial Transplant 1998 13(4) 1012-5. 

Brivet FG, Nion I, Megarbane B, Slama A, Brivet M, Rustin P, Munnich A. Fatal lactic acidosis and liver steatosis associated with didanosine and stavudine treatment a respiratory chain dysfunction J Hepatol 2000 32(2) 364-5. 

Otsuka M, Akiba T, Okita Y, Tomita K, Yoshiyama N, Sasaoka T, Kanayama M, Marumo F. Lactic acidosis with hypoglycemia and hyperammonemia observed in two uremic patients during calcium hopantenate treatment. Jpn J Med 1990 29(3) 324-8. 

Adefovir is associated with a dose-dependent nephrotoxicity. The risk is low for treatment durations of up to 1 year at its recommended dosage for HBV but may rise in patients with preexisting renal dysfunction or in those treated for longer durations. Also, as with the antiretroviral nucleoside analogs (see Nucleoside Reverse Transcriptase Inhibitors), lactic acidosis and severe hepatomegaly with steatosis may occur. When coadministered with ibuprofen, the AUC of adefovir is increased by about 23%, apparently due to higher oral bioavailabilty. 

Several inherited disorders are associated with faulty operation of the electron transport pathway. ATP production is diminished in such cases. These disorders are known as mitochondrial myopathies, and they are associated with the absence of specific polypeptide chains found in complexes I, III, or IV. In many cases, the problem may be traced to specific lesions in mitochondrial DNA, which codes for at least 13 polypeptide chains found in these complexes. Myopathies are tissue specific some affect the heart, others the skeletal muscle. Many are accompanied by lactic acidosis, because the inability to reduce NADH normally results in its accumulation and the channeling of pyruvate toward lactic acid production. In complex I disorders, the oxidation of FADH2 is not impeded. In complex III lesions, neither NADH nor FADH2 can be oxidized. However, use has been made by B. Chance and colleagues of menadione (Chapter 6) and ascorbic acid in such cases. The former can oxidize UQH2, whereas ascorbate can oxidize menadione and reduce cytochrome c. Marked clinical improvement in affected patients follows such treatment. 

Kerr DS Treatment of congenital lactic acidosis review. Inlem Pediatr 10 75-81,1995. 

Stacpoole PW, Barnes CL, Hurbanis MD, et al. Treatment of congenital lactic acidosis with dichloroacetate a review. Arch Dis Child 77 535-541,1997. 

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