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PubMed1998

Lactic acidosis rates in type 2 diabetes.

OBJECTIVE: To provide a context for the interpretation of lactic acidosis risk among patients using metformin, we measured rates of lactic acidosis in patients with type 2 diabetes before metformin was approved for use in the U.S. RESEARCH DESIGN AND METHODS: Using electronic databases of hospital discharge diagnoses and laboratory results maintained by a large, nonprofit health maintenance organization (HMO). we identified possible lactic acidosis events in three geographically and racially diverse populations with type 2 diabetes. We then reviewed hard-copy clinical records to confirm and describe each event and determine its likely cause(s). RESULTS: From >41.000 person-years of experience, we found four confirmed, three possible, and three borderline cases of lactic acidosis. In each case, we identified at least one severe medical condition that could have caused the acidosis. The annual confirmed event rate is similar to published rates of metformin-associated lactic acidosis. CONCLUSIONS: Lactic acidosis occurs regularly, although infrequently, among persons with type 2 diabetes, at rates similar to its occurrence among metformin users. The medical conditions with which both metformin-associated and naturally occurring lactic acidosis co-occur are also its potential causes. The observed association between metformin and lactic acidosis may be coincidental rather than causal. This possibility merits further study

Acidosis, Lactic↗

PubMed2006

Extracellular acidosis induces neutrophil activation by a mechanism dependent on activation of phosphatidylinositol 3-kinase/Akt and ERK pathways.

Inflammation in peripheral tissues is usually associated with the development of local acidosis; however, there are few studies aimed at analyzing the influence of acidosis on immune cells. We have shown previously that extracellular acidosis triggers human neutrophil activation, inducing a transient increase in intracellular Ca2+ concentration, a shape change response, the up-regulation of CD18 expression, and a delay of apoptosis. In this study, we analyzed the signaling pathways responsible for neutrophil activation. We found that acidosis triggers the phosphorylation of Akt (the main downstream target of PI3K) and ERK MAPK, but not that of p38 and JNK MAPK. No degradation of IkappaB was observed, supporting the hypothesis that NF-kappaB is not activated under acidosis. Inhibition of PI3K by wortmannin or LY294002 markedly decreased the shape change response and the induction of Ca2+ transients triggered by acidosis, whereas the inhibition of MEK by PD98059 or U0126 significantly inhibited the shape change response without affecting the induction of Ca2+ transients. We also found that acidosis not only induces a shape change response and the induction of Ca2+ transients in human neutrophils but also stimulates the endocytosis of FITC-OVA and FITC-dextran. Stimulation of endocytosis was partially prevented by inhibitors of PI3K and MEK. Together, our results support the notion that the stimulation of human neutrophils by extracellular acidosis is dependent on the activation of PI3K/Akt and ERK pathways. Of note, using mouse peritoneal neutrophils we observed that the enhancement of endocytosis induced by acidosis was associated with an improved ability to present extracellular Ags through a MHC class I-restricted pathway.

Acidosis↗

PubMed2005

Does ethanol explain the acidosis commonly seen in ethanol-intoxicated patients?

OBJECTIVE: Emergency physicians frequently treat ethanol-intoxicated trauma patients. In patients with apparently minor injuries, the presence of metabolic acidosis is often attributed to serum ethanol. We tested whether there is justification for the bias that ethanol reliably explains the acidosis commonly seen in alcohol-intoxicated patients. METHODS: Prospective, observational. INCLUSION CRITERIA: Ethanol-intoxicated patients admitted to the emergency department (ED) following significant trauma mechanisms, in whom diagnostic evaluation revealed only minor injury. EXCLUSION CRITERIA: Major trauma (blood transfusions, drop in Hct > 10 points over 24 h, or Injury Severity Score [ISS] >5) or positive urine toxicology screen. DEFINITIONS: Ethanol Intoxication: (Blood Alcohol Level (BAL) > or =80 mg/dl), Acidosis: BD < or = -3.0 mMol/L; Lactic Acidosis (LAC >2.2 mMol/L). Data were reported as mean+/-SD. Data were compared by t-tests or Fishers exact test as appropriate (alpha= 0.05, 2 tails) and correlations by Pearson correlation coefficient. RESULTS: 192 patients were studied (84% male) with a mean age of 31.7+/-15.6 years. Acidosis was observed in 19.3% (CI 95%, 14.5% to 25.0%) of all study patients. We observed significant (p<0.001) difference in prevalence of acidosis in ethanol intoxicated (42%) compared to nonintoxicated (1%) patients. Comparing the two study groups, patients with ethanol intoxication had lower BD (-2.24+/-2.74 vs. -0.05+/-2.35, p<0.001) and higher LAC (2.69+/-1.48 vs. 2.00+/-1.78, p=0.02). However, ethanol levels did not correlate significantly with BD (p=0.50) or LAC (p=0.14). CONCLUSION: Ethanol intoxication is associated with acidosis, which does not correlate with BD or LAC. The complexity of pathogenesis of acidosis in ethanol intoxication justifies further diagnostic evaluation of these patients in order to rule out other causes of acidosis.

Acidosis, Lactic↗

PubMed2006

Extracellular acidosis elevates carbonic anhydrase IX in human glioblastoma cells via transcriptional modulation that does not depend on hypoxia.

Most solid tumors display extracellular acidosis, which only partially overlaps with hypoxia and induces distinct adaptive changes leading to aggressive phenotype. Although acidosis is mainly attributable to excessive production of lactic acid, it also involves carbonic anhydrase (CA) IX-mediated conversion of CO(2) to an extracellular proton and a bicarbonate ion transported to cytoplasm. CA IX is pre-dominantly expressed in tumors with poor prognosis and its transcription and activity are induced by hypoxia. Here we investigated whether low extracellular pH in absence of hypoxia can influence CA IX expression in cell lines derived from glioblastoma, a tumor type particularly linked with acidosis. Our data show that extracellular acidosis increased the level of CA IX protein, mRNA and the activity of minimal CA9 promoter that contains binding sites for HIF-1 and SP-1 transcription factors. Mutation within each of these two biding sites reduced the promoter activity, but did not eliminate the increase by acidosis. Transfection of HIF-1alpha cDNA produced additive inducing effect with acidosis. Normoxic acidosis was accompanied by HIF-1alpha protein accumulation and transiently increased phosphorylation of ERK1/2. Expression of a dominant-negative mutant of ERK2 reduced the CA9 promoter activity in both standard and acidic conditions. Similar result was obtained by inhibitors of MAPK and PI3K pathways, whose combination completely suppressed CA IX expression and abolished induction by acidosis. Altogether, our results suggest that acidosis increases the CA IX expression via a hypoxia-independent mechanism that operates through modulation of the basic CA9 transcriptional machinery.

Acidosis↗

PubMed1993

[Effects of acidosis on the neuronal function following oxygen-glucose deprivation in the rat hippocampal slices].

This study was designed to examine 1) whether cerebral ischemic damage is aggravated by accompanying acidosis and 2) which has more potential to cause neural damage between respiratory and metabolic acidosis. To investigate these points, inhibition and recovery of hippocampal evoked potentials were studied in vitro with different pH solutions. Population spike (PS) activity was recorded from CA 1 region after stimulation of the Schaffer collaterals of the 400 microns hippocampal slices from young Wister rats. Ischemic insult was mimicked by combined oxygen and glucose deprivation (OGD) of the perfusate for 15 min. PS activity was almost abolished by OGD in the test solutions, the pH of which was adjusted at either 7.4, 6.5, 6.0, 5.5, 5.0 or 4.5. PS persisted (though markedly depressed to 31.5% of control) with pH 6.5 solution, indicating that mild acidosis had antagonistic effects on ischemic injury. The recovery of PS in the control solution was significantly inhibited for the slices tested with pH 4.5 and 5.0 solutions. The results suggest that acidosis had diverse effects of ischemic cerebral damage. When 15 mM lactate was added to the solution, the recovery of PS was significantly inhibited for the slices tested with pH 5.5 or lower. When 30 mM lactate was added, the critical pH point at which the recovery of population spike was inhibited changed to 6.0, suggesting that ischemic cerebral damage was enhanced by lactate in a dose dependent fashion. By addition of CO2, the recovery of PS following OGD was inhibited to a similar degree as with 30 mM lactic acidosis. It is concluded that concomitant acidosis has divergent effects on the cerebral ischemic damage depending on the pH; mild acidosis had a protective effect but profound acidosis had an aggravating effect, the cross over point being at around pH 6.0. Lactate and CO2 potentiated the aggravating effects of acidosis even though the extracellular pH remained the same.

Acidosis↗

PubMed2006

Use of base in the treatment of acute severe organic acidosis by nephrologists and critical care physicians: results of an online survey.

BACKGROUND: Acute severe metabolic acidosis associated with lactic acidosis or ketoacidosis can have severe detrimental effects on organ function, and might contribute to mortality. A general consensus exists that elimination of the cause of the acidosis is essential for treatment, but there is controversy concerning the use of base for the treatment of these disorders. Some physicians advocate administration of base when the acidosis is severe to prevent a decrease in cardiac output, whereas others oppose administration of base even when the acidosis is severe given the potential compromise of cardiac function. Nephrologists and critical care specialists are often the physicians developing recommendations for the treatment of severe acid-base disorders. METHODS: A short online survey of 20 questions was developed to assess the approach to the treatment of acute metabolic acidosis of program directors of fellowship programs and experts from the specialties of critical care and nephrology. RESULTS: Although there was variability among individual physicians from both specialties, a larger percentage of nephrologists than critical care physicians queried recommended administration of base for the treatment of lactic acidosis (86% vs 67%) and ketoacidosis (60% vs 28%). Also, critical care physicians in general used a lower level of blood pH when deciding when to initiate treatment. Of the physicians who gave base, most utilized sodium bicarbonate as the form of base given. CONCLUSIONS: The results of this survey indicate that the decisions whether to use base for the treatment of acute severe metabolic acidosis, and under which circumstances, vary among physicians, and indicate the need for further studies to develop evidence-based guidelines for therapy.

Acidosis↗

PubMed1994

[Swelling and damage to nerves and glial cells by acidosis].

OBJECTIVE: Development of acidosis is a prominent pathophysiological factor in acute cerebral disorders, such as ischaemia or severe brain trauma. The impairment of the acid-base state in brain parenchyma among others is involved in the development of brain oedema, eventually leading to irreversible damage of neurons and glial cells. In the present study the pathophysiological role of acidosis for cytotoxic cell swelling and damage of glial and neuronal cells was investigated in vitro under conditions found in the ischaemic penumbra in vivo--the still viable perifocal border zone surrounding an infarct with elevated interstitial K(+)- and H(+)-concentrations. Assessment of cell swelling by acidosis was combined with experiments on underlying mechanisms as a basis for therapeutical interventions to inhibit cytotoxic brain oedema in vivo. METHODS: C6 glioma cells, astrocytes from primary culture, as well as Neuro-2A cells were cultivated, harvested and suspended as single cells under continuous control of pH, pO2, and temperature according to a standard procedure. Cell volume and cell viability were quantified by flow cytometry. Acidosis was induced by isotonic sulfuric- or lactic acid, respectively. RESULTS: Acidification of the medium led to cell swelling once pH fell below 7.0. Cell viability, however, was not affected by the increasing acidosis down to pH 6.2, while pH 5.6 or below was associated with cell death dependent on the duration of exposure. Acidosis-induced cell swelling was attenuated or completely inhibited by blocking of ion exchange mechanisms, such as the Na+/H(+)-antiporter, or elimination of Na+ ions from the medium. CONCLUSION: The present results provide new information on the nature of cytotoxic cell swelling and damage in central nervous system by acidosis under consideration of underlying mechanisms. Accordingly, acidosis-induced cell swelling is attributable to activation of ion exchange mechanisms, such as the Na+/H(+)- and Cl-/HCO3(-)-antiporter, in order to maintain a normal cellular acid-base state. This compensation process, however, is associated with the loss of cell volume control by net uptake of osmotic active solutes. Consequently, cell swelling occurring under these conditions is a result of regulatory mechanisms to defend homoeostasis rather than a consequence of cytotoxic cell damage. If cell swelling is inhibited by appropriate treatment, care should be exercised not to enhance the vulnerability of the nerve and glial cells.

Acid-Base Equilibrium↗

PubMed1996

Normovolaemic haemodilution attenuates cardiac depression induced by sodium bicarbonate in canine metabolic acidosis.

This study was designed to determine if coexisting metabolic acidosis or normovolaemic haemodilution, or both, modifies the acute cardiodepressant effect of i.v. sodium bicarbonate. Thirty-one mongrel dogs were anaesthetized with halothane, and the lungs ventilated mechanically; dogs were allocated randomly to one of four groups: control group (pHa 7.39 (SD 0.03), base excess -1.0 (1.6) mmol litre-1, haemoglobin 13.9 (2.5) g dl-1 (n = 8)), metabolic acidosis group (pHa 7.21 (0.05), base excess -11.2 (2.1) mmol litre1, haemoglobin 13.4 (2.6) g dl-1 (n = 8)), anaemia group (pHa 7.40 (0.04), base excess 0.1 (2.0) mmol litre-1, haemoglobin 7.2 (1.1) g dl-1 (n = 8)) or anaemia acidosis group (pHa 7.22 (0.04), base excess -11.0 (2.2) mmol litre-1, haemoglobin 7.4 (0.3) g dl-1 (n = 7)). Metabolic acidosis was induced by continuous i.v. infusion of hydrochloric acid 2 mol litre-1. Normovolaemic haemodilution was undertaken by phlebotomy and simultaneous exchange with lactated Ringer's solution at 37 degrees C. Mean arterial pressure (MAP), pulmonary artery pressure, right atrial pressure (RAP), maximum rate of change of pressure in the right ventricle (RV dP/dtmax) and pulmonary blood flow (PBF) were measured at 30 s, 1 and 3 min after administration of 7% sodium bicarbonate solution 1 mmol kg-1 given into the right atrium over 5 s. Sodium bicarbonate produced significant decreases in MAP and RV dP/dtmax at 30 s in all groups except for the anaemia acidosis group (P < 0.05). There was a significant decrease in right ventricular stroke volume in the metabolic acidosis group from baseline values (P < 0.05), and compared with the three other groups (P < 0.05). These results indicate that the cardiodepressant effect of sodium bicarbonate 1 mmol kg-1 i.v. during metabolic acidosis was more pronounced than without acidosis, but was attenuated in the presence of normovolaemic haemodilution.

Acidosis↗

PubMed1994

Different effects of respiratory and metabolic acidosis on preganglionic sympathetic nerve activity.

We studied sympathetic nerve activity (SNA) responses, recorded in multifiber preparations of left third thoracic white ramus, to respiratory or isocapnic metabolic acidosis or to CO2 enhancement at constant pH in chloralose-anesthetized paralyzed artificially ventilated cats. Cardiopulmonary, baro-, and peripheral chemoreceptors were denervated by bilaterally cutting vagus and carotid sinus nerves. Acidosis was induced by either decreasing artificial ventilation or infusing HCl (0.5 M i.v.). Both respiratory and isocapnic metabolic acidosis induced a decrease in local extracellular pH, measured directly with pH-sensitive microelectrodes within medulla region containing sympathoexcitatory bulbospinal neurons. The magnitude of changes in medullary pH was independent of the way systemic acidosis was generated. Despite uniformity of changes in local medullary extracellular pH due to systemic respiratory or isocapnic metabolic acidosis, different responses were observed in preganglionic SNA. Isocapnic metabolic acidosis resulted in a slight increase in SNA, averaging 6.4% per 0.05 systemic pH unit decrease. In contrast, respiratory acidosis induced by decreasing artificial ventilation produced a more pronounced increase of SNA, reaching peak changes of approximately 70% compared with control level with normal blood gases, an average increase of 13% per 0.05 systemic pH unit decrease. We conclude that systemic CO2 and H+ concentrations represent different stimuli to sympathetic nervous system. Despite similar changes of local extracellular pH within rostral ventrolateral medulla during systemic acidosis, different responses of SNA suggest other sites or as yet unknown additional effects of CO2 as being responsible for excitation of sympathetic activity.

Acidosis↗

PubMed1991

Expression of rat renal Na/H antiporter mRNA levels in response to respiratory and metabolic acidosis.

The mammalian proximal tubule is an important mediator of the renal adaptive response to systemic acidosis. In chronic metabolic and respiratory acidosis the bicarbonate reabsorptive (or proton secretory) capacity is increased. This increase is mediated, at least in part, by an increase in Vmax of the luminal Na/H antiporter. To determine whether this adaptation involves increased mRNA expression, Na/H antiporter mRNA levels were measured by Northern analysis in renal cortex of rats with metabolic (6 mmol/kg body wt NH4Cl for 2 or 5 d) and respiratory (10% CO2/air balanced for 2 or 5 d) acidosis and of normal, pair-fed rats. Na/H antiporter mRNA levels were unchanged after 2 d of both metabolic and respiratory acidosis. After 5 d, however, Na/H antiporter mRNA expression was increased 1.76 +/- 0.12-fold in response to metabolic acidosis (P less than 0.005, n = 8), but was not different from normal in response to respiratory acidosis: 1.1 +/- 0.2 (NS, n = 8). Thus, the renal adaptive response to metabolic acidosis involves increased cortical Na/H antiporter mRNA levels. In contrast, the enhanced proximal tubule Na/H antiporter activity and bicarbonate reabsorption in respiratory acidosis seem to involve mechanisms other than increased Na/H antiporter gene expression.

Acidosis↗

PubMed1987

Renal excretion of divalent ions in response to chronic acidosis: evidence that systemic pH is not the controlling variable.

Although metabolic acidosis produces calciuric, phosphaturic, and magnesiuric effects, the consequences of chronic respiratory acidosis are unclear. To examine the role of systemic pH on renal divalent metabolism, 4-day balance studies were performed in rats with both metabolic acidosis induced by adding 1.5% NH4Cl to the drinking water, and respiratory acidosis produced by exposure to 10% atmospheric CO2 in an environmental chamber, and in controls pair-fed with each group. By the fourth day, blood pH had decreased to an identical degree with both chronic metabolic and respiratory acidosis and averaged 7.28. As anticipated, chronic metabolic acidosis resulted in significant calciuria, magnesiuria, and phosphaturia. However, despite the similar decrement in blood pH, calcium, phosphorus, and magnesium excretion was similar to that in the pair-fed controls with chronic respiratory acidosis. These findings indicate that a low systemic pH, per se, does not account for the modifications in urinary divalent ion handling that accompany chronic metabolic acidosis. However, additional observations suggest that differences in the intracellular pH of the proximal tubular epithelium may be an important regulatory variable.

Acidosis↗

PubMed1993

Effects of metabolic and respiratory acidosis on bone.

Acidosis had long been thought to influence the bone mineral; however, there was little direct evidence to support this impression. When neonatal mouse calvariae are cultured for 3 hours in medium with a reduced bicarbonate concentration, a model of acute metabolic acidosis, there is net calcium efflux from bone in addition to a net influx of protons into bone lessening the magnitude of the acidosis. The protons appear to exchange for sodium and potassium on the bone surface. In these acute experiments, the calcium efflux appears to be due to mobilization of carbonated apatite through an alteration in the physicochemical driving forces for bone accretion and dissolution. In more chronic cultures (greater than 48 hours) metabolic acidosis induces calcium efflux by stimulating osteoclastic bone resorption and inhibiting osteoblastic bone formation. When calvariae are cultured acutely in medium with an elevated partial pressure of carbon dioxide, a model of respiratory acidosis, there is also calcium efflux, but at the same decrement in pH the magnitude is far less than that observed during metabolic acidosis. There does not appear to be any measurable influx of protons into bone, and during chronic cultures there is no measurable calcium efflux. Thus, acidosis influences the bone mineral; however, for the same decrement in pH there is a marked difference in the response of bone to models of metabolic and respiratory acidosis.

Acidosis↗

PubMed1994

Acidosis and bone.

Acidosis has important effects on the bone mineral which can be investigated utilizing neonatal mouse calvariae in organ culture. When calvariae are cultured for 3 h in physiologically acidic medium produced by a reduction of the bicarbonate concentration, a model of acute metabolic acidosis, there is net calcium efflux from bone in addition to net proton influx into bone which lessens the severity of the acidosis. Utilizing a high resolution scanning ion microprobe to study the bone during acidosis we have found that the protons exchange for sodium and potassium on the bone surface. In acute experiments the calcium efflux is the result of mobilization of carbonated apatite through an alteration in the physicochemical driving forces for bone mineral accretion and dissolution. In the more chronic cultures (greater than 48 h) metabolic acidosis induces calcium efflux by stimulating osteoclastic bone resorption and inhibiting osteoblastic bone formation. When calvariae are cultured for 3 h in acidic medium produced by an increase in the partial pressure of carbon dioxide, a model of respiratory acidosis, there is also calcium efflux; however, at the same decrement in pH the net flux is far less than that observed during metabolic acidosis. During acute respiratory acidosis there is no measurable influx of protons into bone and during chronic studies there is no measurable calcium efflux.

Acidosis↗

PubMed2006

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.

BACKGROUND: Metformin is an oral anti-hyperglycemic agent used in the treatment of type 2 diabetes mellitus. The results of the UK Prospective Diabetes Study indicate that metformin treatment is associated with a reduction in total mortality compared to other anti-hyperglycemic treatments. Metformin, however, is thought to increase the risk of lactic acidosis, and is considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. OBJECTIVES: To assess the incidence of fatal and nonfatal lactic acidosis with metformin use compared to placebo and other glucose-lowering treatments in patients with type 2 diabetes mellitus. A secondary objective was to evaluate the blood lactate levels for those on metformin treatment compared to placebo or non-metformin therapies. SEARCH STRATEGY: A search was performed of The Cochrane Library (up to 8/2005), MEDLINE (up to 8/2005), EMBASE (up to 11/2000), OLD MEDLINE, and REACTIONS (up to 8/2005), in order to identify all studies of metformin treatment from 1966 to August 2005. The Cumulated Index Medicus was used to search relevant articles from 1959 to 1965. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Date of latest search: August 2005. SELECTION CRITERIA: Prospective trials in patients with type 2 diabetes that lasted longer than one month were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. Observational cohort studies of metformin treatment lasting greater than one month were also included. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials to be included, assessed study quality and extracted data. The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for placebo or other treatments. The upper limit for the true incidence of cases in the metformin and non-metformin groups were calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed effect model for continuous data. MAIN RESULTS: Pooled data from 206 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 47,846 patient-years of metformin use or in 38,221 patients-years in the non-metformin group. Using Poisson statistics with 95% confidence intervals the upper limit for the true incidence of metformin-associated lactic acidosis was 6.3 cases per 100,000 patient-years, and the upper limit for the true incidence of lactic acidosis in the non-metformin group was 7.8 cases per 100,000 patient-years. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to placebo or other non-biguanide therapies. The mean lactate levels were slightly lower for metformin treatment compared to phenformin (WMD -0.75 mmol/L, 95% CI -0.86 to -0.15). AUTHORS' CONCLUSIONS: There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments if prescribed under the study conditions.

Acidosis, Lactic↗

PubMed2000

Acidosis induces necrosis and apoptosis of cultured hippocampal neurons.

Acidosis, hypoxia, and hypoglycemia rapidly and transiently appear after reduction of cerebral blood flow. Acidosis also accompanies head trauma and subarachnoid hemorrhage. These insults result in necrotic and apoptotic loss of neurons. We previously demonstrated that transient acidification of intracellular pH from 7.3 to 6.5 induces delayed neuronal loss in cultured hippocampal slices (49). We now report that acidosis induced both necrotic and apoptotic loss of neurons. Necrosis and apoptosis were distinguished temporally and pharmacologically. Necrosis appeared rapidly and was dose dependent with the duration of the acidosis treatment. Apoptosis was delayed with maximal number of apoptotic cells seen with a 30-min acidosis treatment. Apoptotic neuronal loss was accompanied by DNA fragmentation and was blocked by inhibitors of protein and RNA synthesis, ectopic expression of the anti-apoptotic gene bcl-2, or an inhibitor of caspases, proteases known to be activated during apoptosis. Necrotic neuronal loss was unaffected by these treatments. Hypothermia, a treatment known to attenuate neuronal loss following a variety of insults, blocked both acidosis-induced necrosis and apoptosis. These results indicate that acidosis is neurotoxic in vitro and suggest that acidosis contributes to both necrotic and apoptotic neuronal loss in vivo.

Acidosis↗

PubMed2002

Effects of acid-base abnormalities on blood capacity of transporting CO(2): adverse effect of metabolic acidosis.

OBJECTIVE: To investigate the effects of some acid-base abnormalities on blood capacity of transporting CO(2). DESIGN: Prospective study. SETTING: General and Cardiosurgical ICUs of a University hospital. PATIENTS: Six groups of ten patients characterized by: metabolic alkalosis; respiratory alkalosis; absence of acid-base abnormalities; metabolic acidosis; uncompensated respiratory acidosis; and compensated respiratory acidosis. MEASUREMENTS AND RESULTS: The CO(2) dissociation curve, Haldane effect, and the ratio Ra-v between Ca-vCO(2) and Pa-vCO(2) were calculated from arterial and mixed-venous blood gas analyses. The CO(2) dissociation curve was shifted upwards by metabolic alkalosis and compensated respiratory acidosis and downwards by metabolic acidosis. The slope of the curve was unaffected, but CO(2) transport not due to Haldane effect was significantly lower in respiratory acidosis since the slope was less steep at higher PCO(2) values. In comparison with controls, patients affected by metabolic acidosis showed lower Haldane effect values (0.18+/-0.15 vs 0.59+/-0.26 ml of CO(2) per ml of arterial-mixed venous O(2) content difference; P <.05) and Ra-v values (0.43+/-0.10 vs 0.84+/-0.17 ml of CO(2) transported by 100 ml of blood per Torr of arterial-mixed venous PCO(2) gradient; P <.05). CONCLUSIONS: Our findings suggest that acid-base abnormalities, particularly metabolic acidosis, markedly affect blood capacity of transporting CO(2) and may worsen tissue hypercarbia associated with hypoperfusion. However, because of possible errors due to small measurements and the assumptions of the method, in the future definitive clarification will require the construction of original CO(2) dissociation curves for each acid-base abnormality.

Acidosis↗

PubMed1999

The aetiology and pathogenesis of cardiopulmonary bypass-associated metabolic acidosis using polygeline pump prime.

OBJECTIVE: The pathogenesis of the metabolic acidosis of cardiopulmonary bypass (CPB) is not fully understood. New quantitative methods of acid-base balance now make it possible to describe it more clearly. Accordingly, we studied acid-base changes during CPB with polygeline pump prime and defined and quantified the factors which contribute to metabolic acidosis. DESIGN: Prospective cohort study. SETTING: Tertiary institution. PARTICIPANTS: 10 cardiac bypass graft surgery patients. INTERVENTIONS: Sampling of arterial blood at four time intervals: post-induction, on CPB during cooling and rewarming, and at skin closure. Measurement of serum Na+, K+, Mg++, Ca++, Cl-, bicarbonate, and phosphate concentrations, arterial blood gases, and serum albumin, lactate, and pyruvate concentrations at each collection point. Analysis of findings according to quantitative physicochemical principles, including calculation of the strong ion difference apparent, the strong ion difference effective, and the strong ion gap (SIG). MEASUREMENTS AND MAIN RESULTS: All patients developed a mild metabolic acidosis. The median serum standard bicarbonate concentration decreased from 25.0 mEq/l post-induction to 22.3 mEq/l at cooling and 22.2 mEq/l at rewarming (p < 0.05). The standard base excess decreased from a median of 1.55 mEq/l prior to CPB, to -2.50 mEq/l at cooling, -1.65 mEq/l at rewarming and, -0.85 mEq/l at skin closure (p < 0.001). This mild metabolic acidosis occurred despite a decrease in the median serum lactate concentration from 3.20 mEq/l post-induction to 1.83, 1.80, and 1.58 mEq/l at the three other time points. The increase in the median serum chloride concentration from 104.9 mEq/l post induction to 111.0, 111.1, and 110.0 mEq/l at the subsequent time points (p < 0.0001) was the main cause of the acidosis. There was also a significant increase in the SIG of 3.8 mEq/l at cooling and rewarming (p < 0.0001), suggesting a role for other unmeasured anions (polygeline) in the genesis of this acidosis. CONCLUSIONS: Using quantitative biophysical methods, it can be demonstrated that, in patients receiving a pump prime rich in chloride and polygeline, the metabolic acidosis of CPB is mostly due to iatrogenic increases in serum chloride concentration and unmeasured strong anions (SIG). Its development is partially attenuated by iatrogenic hypoalbuminaemia. Changes in lactate concentrations did not play a role in the development of metabolic acidosis in our patients.

Acid-Base Equilibrium↗

PubMed1990

The association of fetal and newborn metabolic acidosis with severe periventricular leukomalacia in the preterm newborn.

One hundred twenty preterm newborns less than 34 weeks' gestational age have been studied prospectively to determine the frequency of fetal and newborn metabolic acidosis and to examine the relationship of metabolic acidosis to periventricular leukomalacia as demonstrated by serial newborn ultrasonographic examinations. Fetal metabolic acidosis, based on an umbilical artery buffer base less than 34 mmol/L at delivery, occurred in three cases (2%), one of which had evidence of periventricular leukomalacia. Newborn metabolic acidosis that is based on a buffer base less than 34 mmol/L during the 4 days after delivery occurred in 12 cases (10%), five of which had evidence of periventricular leukomalacia. There is a significant relationship between the degree and duration of newborn metabolic acidosis and the occurrence of periventricular leukomalacia. This study indicates that systemic metabolic acidosis is an important pathophysiologic marker of periventricular leukomalacia. Intrapartum fetal asphyxia with metabolic acidosis, although an infrequent occurrence in the preterm newborn, may account for a few cases of periventricular leukomalacia, while the more common newborn metabolic acidosis, when of sufficient degree and duration, carries a high risk of periventricular leukomalacia.

Acidosis↗