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PubMed1988

Comparison of sodium bicarbonate with dichloroacetate treatment of hyperlactatemia and lactic acidosis in the ischemic rat.

Serum lactic acidosis is characterized by a pH less than 7.25 and lactate greater than 5 mEq. Although sodium bicarbonate (NaHCO3) is standard treatment for this condition, clinical and experimental studies suggest that high doses of NaHCO3 may be ineffectual or even detrimental to brain, cardiovascular, and respiratory function, as well as survival. For this reason, low dose therapy with NaHCO3 has been recommended. Sodium dichloroacetate (NaDCA) has been used successfully to treat clinical and experimentally-induced lactic acidosis. The present study was designed to compare the effects of low dose NaHCO3 with NaDCA on blood pressure, blood chemistries and brain metabolites in rats with a low flow-induced (Type A, the most common type) lactic acidosis. Fasted male Wistar rats were subjected to cerebral ischemia and systemic hypotension for 30 min at which time, if the pH or HCO-3 fell to 7.2 or 10, respectively, the rat was treated with NaHCO3, NaDCA, or an equal volume of sterile water. Over the 30 min of recirculation that followed ischemia, treatment had no effect on blood pressure or glucose or on brain glucose or glycogen. NaHCO3 had no effect on lactate but appeared to stabilize pH and increase HCO3- more than in sham- or NaDCA-treated rats. Although NaDCA caused a greater increase in HCO3- than sham treatment, pH continued to decline. However, lactate decreased more in NaDCA- than in sham- or NaHCO3- treated rats. These results suggest that low dose NaHCO3 is not detrimental in this model; however, although NaHCO3 stabilized pH, it did not rapidly correct the acidosis. NaDCA at this dose had no effect on the acidosis but was effective in decreasing lactate. Since serum lactate has previously correlated with survival and since higher doses of NaDCA have corrected lactic acidosis in other studies, future evaluation of postischemic treatment with higher doses of NaDCA is warranted.

Acetates↗
PubMed2004

D-lactic acidosis in short-bowel syndrome managed with antibiotics and probiotics.

D-lactic acidosis sometimes occurs in malabsorbed patients with short-bowel syndrome and is characterized by recurrent episodes of encephalopathy and metabolic acidosis. The characteristic neurologic abnormalities and the presence of metabolic acidosis raises a diagnostic suspicion, and the diagnosis is made when the serum level of D-lactic acid is greater than 3 mmol/L. Standard treatment consists of restricting oral carbohydrates or fasting, correction of metabolic acidosis, and a long-term suppression of pathogenic floras with antibiotics. The authors present a case of D-lactic acidosis in a 22-year-old patient with short-bowel syndrome, to whom intestinal bacterial agents (probiotics) were given in addition to oral kanamycin. Recolonization of the intestine with nonpathogenic floras should be a long-term treatment for D-lactic acidosis.

Acidosis, Lactic↗
PubMed2005

Intraoperative regional myocardial acidosis and reduction in long-term survival after cardiac surgery.

BACKGROUND: Regional myocardial acidosis, as measured with tissue pH electrodes during cardiac surgery, has been shown to be reflective of regional myocardial ischemia. This study examined the relationship between intraoperative regional myocardial acidosis and long-term survival of patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: A total of 496 adult patients who underwent valve replacement, coronary artery revascularization, or both with intraoperative myocardial pH monitoring in the anterior and posterior left ventricular walls were followed up for 3 to 17 years (average 10.2 +/- 4.9 years) for all cause mortality. Regional myocardial acidosis in each patient was defined by the lower of the anterior and posterior wall pH values. RESULTS: A bivariate automatic interaction detection analysis identified three significant regional myocardial acidosis thresholds that affected long-term mortality: pH 37C less than 6.63 before aortic crossclamping, integrated mean pH 37C less than 6.34 during the period of aortic crossclamping, and pH 37C less than 6.73 at discontinuation of cardiopulmonary bypass. Cox proportional hazard regression analysis identified each of these thresholds to be independently determinant of survival, with pH 37C during aortic crossclamping having the highest risk ratio (risk ratio 2.15, 95% confidence interval 1.37-3.37). Raising pH 37C from lower than threshold before aortic crossclamping to higher than threshold during clamping increased the median survival by 40.2%. CONCLUSION: In adult patients undergoing cardiac surgery with cardiopulmonary bypass, regional myocardial ischemic acidosis before aortic crossclamping, during aortic crossclamping, and at discontinuation of cardiopulmonary bypass are independently associated with reduced long-term postoperative survival. Reversing or avoiding myocardial acidosis during cardiac surgery improves long-term patient survival.

Acidosis↗
PubMed1986

Acidosis as a presenting feature of chloramphenicol toxicity.

Metabolic acidosis has previously been described in the gray baby syndrome, but has not been documented as a presenting feature. Four seriously ill children (bronchiolitis, hypoaldosteronism, dysautonomia, Reye syndrome), ages 4 months to 11 years, received chloramphenicol (CAP) intravenously. After initial stabilization, unexplained metabolic acidosis occurred 40 to 81 hours after beginning CAP. Serum CAP concentrations were 84, 62, 80, and 30 micrograms/ml, respectively, when acidosis was recognized. Hypotension, hypothermia, and abdominal distension occurred a mean of 23 hours after the onset of acidosis. Acidosis resolved and signs of the gray baby syndrome cleared with the decrease in serum CAP concentrations. Metabolic acidosis should be considered an early sign of CAP toxicity, and CAP should be used in reduced doses in severely ill patients, especially those with liver dysfunction.

Acidosis↗
PubMed1987

The urine pH: a potentially misleading diagnostic test in patients with hyperchloremic metabolic acidosis.

The purpose of this case report is to illustrate that the urine pH may be a misleading index in the assessment of the normal renal response to metabolic acidosis. On presentation, the patient had a normal anion-gap type of metabolic acidosis; the cause of the acidosis was gastrointestinal bicarbonate loss. Since the urine pH was 6.0 when the patient was acidemic, distal renal tubular acidosis was also suspected. However, since the kidneys generated more than 190 mmol of bicarbonate per day (urine ammonium was 190 mmol/d), reduced renal acid excretion was not the cause of the acidosis. Therefore, the urine pH of 6.0 provided a false clue with respect to a renal cause for the acidosis in this setting; in contrast, the urine anion gap provides more reliable information concerning bicarbonate generation by the kidney.

Acidosis, Renal Tubular↗
PubMed1996

The correction of acidosis does not increase dietary protein intake in chronic renal failure patients.

In normal humans and in patients with chronic renal failure (CRF), acidosis increases whole-body protein degradation. Correction of acidosis reduces protein degradation. The mechanisms underlying these changes in protein metabolism are unclear. However, one possibility is that dietary protein intake is reduced in acidosis and that this causes increased protein degradation. This possibility has not been tested. In this study the effects of acidosis on protein intake in patients with CRF have been assessed using 7-day weighed dietary inventories in the acidotic state (venous bicarbonate 15.6 +/- 1.0 mmol/L) and following treatment with oral sodium bicarbonate (venous bicarbonate 21.0 +/- 1.4 mmol/L). Protein intake was also derived from urinary nitrogen excretion. There was no significant difference in protein intake calculated from dietary records (1.0 +/- 0.09 g/kg/d v 1.06 +/- 0.1 g/ kg/d) or calculated from urinary nitrogen (1.13 +/- 0.07 g/kg/d v 1.06 +/- 0.06 g/kg/d) between the untreated and bicarbonate-treated states in eight patients with CRF. We conclude that acidosis in CRF patients does not affect dietary protein intake and that dietary changes therefore do not contribute significantly to the changes in protein metabolism seen in acidosis.

Acidosis↗
PubMed1998

Stimulation of rat-liver branched-chain alpha-keto acid dehydrogenase activity by chronic metabolic acidosis.

During chronic metabolic acidosis, the degradation of protein and amino acids reportedly increases. Branched-chain alpha-keto acid dehydrogenase complex (BCKDH) relates amino-acid catabolism and mitochondrial-energy metabolism. This study was designed to evaluate the effect of acidosis on the activity of liver BCKDH, the key regulatory enzyme in the catabolism of branched-chain amino acids. Experimental acidosis was induced in rats by ingestion of 0.28 M ammonium chloride solution for 10 days. We made two different liver-mitochondrial extracts to assay independently the active form of BCKDH and the total BCKDH activity. Acidosis significantly increased both active and total BCKDH specific activities (P < 0.05). The mean value for the active form of the BCKDH complex was 9.27 +/- 1.10 (S.E.M., n = 7) mU/mg of mitochondrial protein in acidotic rats and 5.18 +/- 0.84 (n = 7) for the control rats. The value of the total complex was 16.10 +/- 1.22 (n = 7) for the acidosis and 11.51 +/- 0.58 (n = 7) for the control. No significant changes were found in the activity state of the complex. Citrate synthase activity did not show significant variations between treatments. The stimulation of liver BCKDH activities by the acidosis may contribute to maintaining the level of intermediates of the tricarboxylic-acid cycle in this metabolic situation in which the net release of glutamine are produced.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed2005

[Metformin-associated lactic acidosis in a patient with pre-existing risk factors].

Lactic acidosis is a serious clinical situation associated with a high case fatality rate. Lactic acidosis is particularly found in conditions with an insufficient supply of oxigen in the tissue. Other causes for lactic acidosis can be hepatic or renal insufficiency. For the therapy of overweight patients with type 2 diabetes metformin is the first choice if diet and physical training have been ineffective. Metformin, however, has the potential to increase serumlactate. Therefore its ability to cause lactic acidosis is controversely discussed. We present a 64-year-old female patient with metformin-associated lactic acidosis. She had several pre-existing risk factors to develop a lactic acidosis. On her referral to the hospital she suffered from acute renal failure which is considered to be a contraindication for the use of metformin.

Acidosis, Lactic↗
PubMed1989

Enhancement of iron-catalyzed free radical formation by acidosis in brain homogenates: differences in effect by lactic acid and CO2.

The influence of lactic acidosis and of extreme hypercapnia on free radical generation and lipid peroxidation in brain tissues was studied. Cortical homogenates were prepared from the rat brain in a bicarbonate buffer and incubated for 60 min. Lipid peroxidation was evaluated by measurements of thiobarbituric acid reactive (TBAR) material and alpha-tocopherol analysis. The pH during incubations were decreased to 6.10-6.20 by either lactic acid administration or equilibration with 60% CO2 gas in paired experiments. In homogenates treated with lactic acid there was a 20-fold increase in TBAR material and the alpha-tocopherol concentration decreased to approximately 60% of control. There was only a 10-fold increase in TBAR material and no change in alpha-tocopherol concentration if acidosis was induced by CO2. These differences between lactic acidosis and hypercapnic acidosis were statistically highly significant. The results indicate that lactic acidosis has a more pronounced effect in augmenting free radical generation in brain tissues than acidosis due to an increase in CO2 tension. It is suggested that this effect of lactic acid is mediated by increased dissociation of catalytic iron from proteins of the transferrin type.

Acidosis, Lactic↗
PubMed1979

Effects of metabolic acidosis and alkalosis on sodium and calcium transport in the dog kidney.

Clearance and micropuncture studies have been performed in dogs to examine the effects of acute and chronic metabolic acidosis and acute alkalosis on tubular sodium and calcium transport. Acute metabolic acidosis, induced by the infusion of hydrochloric acid, decreased proximal fluid reabsorption and increased the fractional delivery of sodium and calcium to the distal tubule, but not to the final urine. In comparison with normal dogs, dogs with chronic metabolic acidosis (induced by feeding ammonium chloride) showed an increase in proximal fluid reabsorption and a dissociation of calcium from sodium reabsorption more distally, leading to an increased delivery of calcium relative to sodium at the distal tubule and in the final urine. The infusion of sodium bicarbonate to correct chronic metabolic acidosis, both in intact and thyroparathyroidectomized (TPTX) dogs, reduced proximal fluid reabsorption and caused a selective enhancement of calcium reabsorption relative to sodium in the more distal nephron, resulting in a reversal of the dissociation observed in acidosis, both at the distal tubule and in the final urine. By contrastin fusion of sodium chloride in parathyroid-intact acidotic dogs did not reduce proximal fluid reabsorption or enhance tubular calcium reabsorption. In nonacidotic dogs, both intact and TPTX, infusion of sodium bicarconate to induce acute alkalosis resulted in selhese data demonstrate the presence of a component of tubular calcium reabsorption situated beyond the proximal tubule, which is inhibited by chronic (but not acute) metabolic acidosis and enhanced by metabolic alkalosis (or bicarbonate infusion) independently of parathyroid hormone.

Acidosis↗
PubMed1982

Effects of acute metabolic acidosis on renal, gut, liver, and muscle metabolism of glutamine and ammonia in the dog.

Previous studies have shown a rise in arterial glutamine in acute acidosis in the dog. In these experiments glutamine and ammonia metabolism was studied in anesthetized dogs during normal acid-base status and following acute hydrochloric acidosis to determine the mechanism for the rise in arterial glutamine in acidosis. Splanchnic, liver, renal, and hind-half extraction/production were measured by arteriovenous (A-V) sampling and simultaneous blood flow measurements using electromagnetic flow probes. In the normal dog, muscle produced glutamine, and the kidneys, gut, hepatosplanchnic bed, and liver extracted it. Whole blood arterial glutamine rose in acidosis. Renal and muscle glutamine and ammonia extraction/production were unchanged. Gut ammonia release and hepatic ammonia uptake increased by similar amounts in acidosis, but no change in gut glutamine uptake occurred. Hepatic and total hepatosplanchnic glutamine uptake was markedly reduced thereby contributing to the raised arterial glutamine. These results demonstrate that acute metabolic acidosis in the dog-influences marked changes in glutamine extraction and ammonia metabolism across the hepatosplanchnic bed without significant changes in kidney or muscle metabolism.

Acidosis↗
PubMed1984

Acute, but not chronic, metabolic acidosis disturbs 25-hydroxyvitamin D3 metabolism.

Previous studies in vitamin D deficient animals showing that acidosis may impair the production of 1,25(OH)2D3 are in conflict with studies in humans which have not shown convincing disturbances of 25OHD3 metabolism during acidosis. We have investigated the effect on renal 25OHD3 1- and 24-hydroxylase of acid loading for periods of 24 hr to 21 days. Acid loading resulted in immediate and sustained decrements in arterial pH and bicarbonate and increments in blood-ionized calcium. Acute (24-hr) acid loading decreased 1- and increased 24-hydroxylase activity. After 6 days of acid loading, no effect on 1- hydroxylase activity was observed and that on 24-hydroxylase activity was reduced. By 21 days the effect of acidosis on 24-hydroxylase activity was no longer observed. The results show that acidosis disturbs 25OHD3 metabolism in the physiological vitamin D and calcium replete state as well as in the vitamin D deficient state, but only acutely. Our data are consistent with studies in humans and suggest that, while short-term disturbances of 25OHD3 metabolism occur early in acidosis, they are transient and may not be causally related to the development of metabolic bone disease during chronic acidosis.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1988

Acidosis and hypoxic medullary injury in the isolated perfused kidney.

The effects of acidosis on renal function and morphology were examined in the isolated perfused rat kidney (IPK). Kidneys were perfused with oxygenated Krebs-Henseleit-albumin medium for 60 minutes at pH 7.4 or pH 7.0. At the lower pH, GFR was reduced by 25%, TRNa by 32% and oxygen consumption by 41% as compared to perfusion at pH 7.4 (all P less than 0.05). In addition, the usual hypoxic injury observed in the medullary thick ascending limb of the Loop of Henle (TAL) in the IPK at pH 7.4 (consisting of nuclear pyknosis and focal fragmentation necrosis) was reduced by acidosis from 62% to 14% of tubules involved (P less than 0.005). This cytoprotection was not the result of improved oxygenation since O2 delivery was actually slighty reduced at pH 7.0 compared to pH 7.4. Furthermore, acidosis was protective even after perfusion with non-oxygenated media (42% tubules damaged at pH 7.0 vs. 95% of tubules damaged at pH 7.4; P less than 0.01), making it very unlikely that the effect of acidosis is to improve TAL oxygenation. Since previous studies indicate that the TAL lesion is transport dependent and prevented in the non-filtering kidney, it was possible that the decrease in GFR associated with acidosis could account for decreased injury. The GFR was manipulated by alterations in perfusion pressure or albumin concentration, and no consistent relationship between the extent of injury and GFR could be shown at either pH over a wide range of GFR values. Therefore, acidosis protected the TAL from hypoxic injury by a mechanism apparently independent of oxygen or solute delivery.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1996

Glucocorticoids and acidosis stimulate protein and amino acid catabolism in vivo.

We have shown that chronic metabolic acidosis in awake rats accelerates whole body protein turnover using stochastic modeling and a continuous infusion of L-[1-13C] leucine. To delineate the role that glucocorticoids play in mediating these catabolic responses, we measured protein turnover in awake, chronically catheterized, adrenalectomized rats in the presence or absence of glucocorticoids and/or a NH4Cl feeding regimen which induced chronic metabolic acidosis. In adrenalectomized rats receiving no glucocorticoids there was no statistical difference in amino acid oxidation, protein degradation or synthesis whether or not the rats had acidosis. In contrast, chronically acidotic, adrenalectomized rats receiving glucocorticoids demonstrated accelerated whole body protein turnover with a 84% increase in amino acid oxidation and a 26% increase in protein degradation, compared to rats not receiving glucocorticoids or those given the same dose of glucocorticoids but without acidosis. We conclude that metabolic acidosis accelerates amino acid oxidation and protein degradation in vivo, and that glucocorticoids are necessary but not sufficient to mediate the catabolic effects of metabolic acidosis.

Acidosis↗
PubMed2006

Chronic metabolic acidosis alters osteoblast differentiation from human mesenchymal stem cells.

Bone histology of distal renal tubular acidosis patients showed decreased bone formation with impaired bone matrix mineralization that is not entirely explained by an alteration in the mineral balance. Data from in vitro studies suggests a direct inhibitory effect of metabolic acidosis on osteoblast function. We investigated the effects of chronic metabolic acidosis on osteoblast differentiation from mesenchymal stem cells (MSCs). Human MSCs were allowed to differentiate into osteoblasts in culture. Concentrated hydrochloric acid was added to the medium to lower the bicarbonate concentration and pH. The expression of various osteoblastic genes and proteins and bone matrix mineralization were examined. Chronic metabolic acidosis enhanced the messenger RNA (mRNA) and protein expression of early osteoblast transcription factor, runx-2, whereas inhibiting osterix and having no effect on ATF-4. The expression of type I collagen, the most abundant bone matrix protein, was increased following the same pattern of runx-2. Likewise, metabolic acidosis slightly enhanced the expression of mature osteoblastic gene, osteocalcin. Study on mineralization revealed suppressed alkaline phosphatase mRNA and enzyme activity. Despite the augmented collagen deposit in acidic culture, bone matrix mineralization was impaired. In conclusion, chronic metabolic acidosis alters osteoblast differentiation from MSCs through its diverse effect on osteoblastic genes and proteins resulting in an impairment of bone formation.

Acidosis, Renal Tubular↗
PubMed2006

Effects of hypoxia, glucose deprivation and acidosis on phosphatidylcholine synthesis in HL-1 cardiomyocytes. CTP:phosphocholine cytidylyltransferase activity correlates with sarcolemmal disruption.

A decrease in [3H]Cho (choline) incorporation in to PtdCho (phos-phatidylcholine) preceded the onset of LDH (lactate dehydrogenase) release in HL-1 cardiomyocytes submitted to simulated ischaemia. This observation led us to examine the role of PtdCho synthesis in sarcolemmal disruption in HL-1 cardiomyocytes. To address this objective we analysed the individual effects of hypoxia, glucose deprivation and acidosis, three prominent components of ischaemia, on the different steps of the Kennedy pathway for the synthesis of PtdCho. Pulse and pulse-chase experiments with [3H]Cho, performed in whole HL-1 cells submitted to hypoxia or normoxia, in the presence or absence of glucose at different pHs indicated first, that CK (choline kinase) was inhibited by hypoxia and acidosis, whereas glucose deprivation exacerbated the inhibition caused by hypoxia. Second, the rate-limiting reaction in PtdCho synthesis, catalysed by CCT (CTP:phosphocholine cytidylyltransferase), was inhibited by hypoxia and glucose deprivation, but unexpectedly activated by acidosis. In cellfree system assays, acidosis inhibited both CK and CCT. In experiments performed in whole cells, the effect of acidosis was likely to be direct on CK, but indirect or intact-cell-dependent on CCT. Since hypoxia and glucose deprivation favoured membrane disruption, but acidosis prevented it, we hypothesized that the modulation of CCT could be an important determinant of cell survival. Supporting this hypothesis, we show that CCT activity in whole-cell experiments clearly correlated with LDH release, but not with ATP concentration. Altogether our results suggest a significant role for CCT activity in sarcolemmal disruption during ischaemia.

Acidosis↗
PubMed1997

Bicarbonate therapy and intracellular acidosis.

1. The correction of metabolic acidosis with sodium bicarbonate remains controversial. Experiments in vitro have suggested possible deleterious effects after alkalinization of the extracellular fluid. Disequilibrium of carbon dioxide and bicarbonate across cell membranes after alkali administration, leading to the phenomenon of 'paradoxical' intracellular acidosis, has been held responsible for some of these adverse effects. 2. Changes in intracellular pH in suspensions of leucocytes from healthy volunteers were monitored using a fluorescent intracellular dye. The effect in vitro of increasing extracellular pH with sodium bicarbonate was studied at different sodium bicarbonate concentrations. Lactic acid and propionic acid were added to the extracellular buffer to mimic conditions of metabolic acidosis. 3. The addition of a large bolus of sodium bicarbonate caused intracellular acidification as has been observed previously. The extent of the intracellular acidosis was dependent on several factors, being most evident at higher starting intracellular pH. When sodium bicarbonate was added as a series of small boluses the reduction in intracellular pH was small. Under conditions of initial acidosis this was rapidly followed by intracellular alkalinization. 4. Although intracellular acidification occurs after addition of sodium bicarbonate to a suspension of human leucocytes in vitro, the effect is minimal when the conditions approximate those seen in clinical practice. We suggest that the observed small and transient lowering of intracellular pH is insufficient grounds in itself to abandon the use of sodium bicarbonate in human acidosis.

Acidosis, Lactic↗
PubMed2003

Acidosis has opposite effects on neuronal survival during hypoxia and reoxygenation.

To study the effect of extracellular acidosis on apoptosis and necrosis during ischemia and reoxygenation, we exposed human post-mitotic NT2-N neurones to oxygen and glucose deprivation (OGD) followed by reoxygenation. In some experiments, pH of the cell medium was lowered to 5.9 during either OGD or reoxygenation or both. Staurosporine, used as a positive control for apoptosis, caused Poly(ADP-ribose)-polymerase (PARP) cleavage and nuclear fragmentation, but no PARP cleavage and little fragmentation were seen after OGD. Low molecular weight DNA fragments were found after staurosporine treatment, but not after OGD. No protective effect of caspase inhibitors was seen after 3 h of OGD and 21 h of reoxygenation, but after 45 h of reoxygenation caspase inhibition induced a modest improvement in 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) cleavage. While acidosis during OGD accompanied by neutral medium during reoxygenation protected the neurones (MTT: 228 +/- 117% of neutral medium, p < 0.001), acidosis during reoxygenation only was detrimental (MTT: 38 +/- 25%, p < 0.01). We conclude that apoptotic mechanisms play a minor role after OGD in NT2-N neurones. The effect of acidosis on neuronal survival depends on the timing of acidosis, as acidosis was protective during OGD and detrimental during reoxygenation.

Acidosis↗