Metabolic acidosis: pathophysiology, diagnosis and management.

Derangements in the intermediate metabolism of nutrients can lead to organic acid acidoses, which in turn can have severe clinical consequences that include even the patient's death. Lactic acidosis and ketoacidosis represent the most relevant clinical forms of this type of metabolic acidosis. Assessment and proper management of the organic acid acidoses require the intervention of a skillful clinician that balances the potential benefits and risks of the prescribed measures to the specific needs of the individual patient. To this aim, knowledge of the pathophysiology, diagnosis, and therapy of the various forms of acidoses including alkali administration, represent essential requirements.

Mixed acid-base disturbances.

Mixed acid-base disturbances, defined as the simultaneous presence of two or more acid-base disorders, are commonly observed in hospitalized patients, especially those in critical care units. Certain clinical settings are commonly associated with mixed acid-base disorders, including cardiorespiratory arrest, sepsis, drug intoxications, diabetes mellitus, and organ failure (especially renal, hepatic, and pulmonary failure). As a general rule, the symptoms and signs of the underlying disease that gives rise to the observed mixed acid-base disorder dominate the clinical picture. The basic principles underlying the diagnosis of mixed acid-base disorders are identical to those required for the identification of simple acid-base disturbances. The management of mixed acid-base disturbances is aimed at restoring the altered acid-base status by reversing all the elemental components present, thus it encompasses the therapy of each simple acid-base disorder.

Acid-base physiology.

Acid-base homeostasis involves chemical and physiologic processes responsible for the maintenance of the acidity of body fluids at levels that allow optimal function of the whole individual. The chemical processes represent the first line of defense to an acid or alkali load and include the extracellular and intracellular buffers, whereas the physiologic processes modulate acid-base composition by changes in cellular metabolism and by adaptive responses in the excretion of volatile acids by the lungs and fixed acids by the kidneys. The need for the existence of multiple mechanisms involved in acid-base regulation stems from the critical importance of the hydrogen ion (H+) concentration on the operation of many cellular enzymes and function of vital organs, most prominently the brain and the heart. The task imposed on the mechanisms that maintain acid-base homeostasis is large, since metabolic pathways are continuously consuming or producing H+, and the daily load of waste products for excretion in the form of volatile and fixed acids is substantial. We review the determinants of the acidity of body fluids, the mechanisms that maintain normal acid-base composition, and the overall defense to disruption in acid-base equilibrium. Specific topics include an examination of the scales of acidity, buffer systems, intracellular acid-base regulation, excretion of acids, alkali and acid loading, and normal acid-base composition. The limitations of arterial blood sampling in the assessment of acid-base status are also evaluated.

Low dialysate [K+] decreases efficiency of hemodialysis and increases urea rebound.

In a previous study, it was reported that hemodialysis with dialysate [K+] (KD) of 1.0 or 2.0 mmol/L caused an increase in BP shortly after completion of treatment due to arteriolar constriction. With this background, it was hypothesized that a low KD might decrease dialysis efficiency by a similar mechanism. To evaluate this hypothesis, paired observations of two consecutive 3-h treatments, with KD of 1.0 or 3.0 mmol/L, were performed in 14 stable end-stage renal disease patients. A KD of 1.0 mmol/L resulted in lower values for both urea reduction ratio and Kt/V evaluated at completion of dialysis and 1 h thereafter. Values at equilibrium were urea reduction ratio 42+/-1% versus 47+/-2% (P < 0.02), Kt/V 0.65+/-0.03 versus 0.73+/-0.03 (P < 0.02) for KD 1.0 or 3.0 mmol/L, respectively. The mechanisms responsible for the observed differences in dialysis efficiency were examined using a urea kinetics model that predicts urea sequestration caused by impaired blood flow to urea-rich tissues. For this purpose, urea rebound and its effect on Kt/V (by means of deltaKt/V, calculated as equilibrated minus single pool value) with KD 1.0 and 3.0 mmol/L were assessed. Greater urea rebound, 12.8+/-1.6% versus 8.6+/-1.4% (P < 0.001), and larger deltaKt/V, 0.12+/-0.01 versus 0.10+/-0.02 (P < 0.02), were observed with KD 1.0 mmol/L compared with 3.0 mmol/L. The theoretical model accurately predicted the deltaKt/V observed with KD 1.0 mmol/L. It is concluded that a low KD decreases dialysis efficiency. This effect is likely caused by reduced blood perfusion to nonvisceral organs, largely skeletal muscle. Conversely, hemodialysis with KD 3.0 mmol/L facilitates tissue perfusion, minimizes urea trapping in poorly perfused areas, and improves the efficiency of this treatment modality.

Aiding fluid prescription for the dysnatremias.

OBJECTIVE: The goal of the present study was to develop a novel approach that facilitates the prescription of fluid therapy in patients with abnormal serum sodium concentration. METHODOLOGY AND RESULTS: The novel approach is based on a simple equation, derived from established principles on the distribution of sodium in body fluids, that estimates the impact of a unit dose, i.e., 1 l of any infusate on the patient's serum sodium concentration. In accordance with the equation, the expected change in the patient's serum sodium concentration in response to 1 l of any infusate (delta[Na+]s) is obtained by subtracting the sodium concentration of the patient's serum from the sodium concentration of the infusate, each expressed in mEq/l, and dividing the result by the patient's estimated total body water expressed in liters (adding 1 l to account for the volume of the infusate). The amount of the particular infusate to be administered over the course of any given time period can be easily computed by dividing the desired delta[Na+]s at the end of the period by the calculated delta[Na+]s effected by 1 l of the infusate. The utility and limitations of the proposed approach are presented. CONCLUSIONS: The novel equation is not a means for formulating therapy. Rather, it provides, simply and expeditiously, quantitative projections that can assist the physician in implementing the selected treatment plan for patients with dysnatremias.

Evaluation of enalapril/diltiazem ER in hypertensive patients with coexisting renal dysfunction. Enalapril/Diltiazem ER in Hypertensive Renal Disease Group.

Both enalapril and long-acting diltiazem have been shown to effectively lower blood pressure (BP) in hypertensive patients. Furthermore, in clinical studies, these two agents provided beneficial renal effects in these patients when administered on a long-term basis. A combination of enalapril/diltiazem ER was evaluated in 62 patients with Stage 1-3 hypertension and coexisting renal disease. This trial used a multicenter, randomized, double-blind, parallel group design. The study consisted of a 12-week double-blind phase followed by a 6-month open-label extension phase. The combination of enalapril/diltiazem ER was shown to reduce BP following both short-term and long-term treatment phases. Patients in Renal Group I (creatinine clearance CrCl): 30-59 ml/min/1.73 m2) had decreases of -18/-16 and -25/-20 mm Hg after 12 weeks and 9 months of therapy, respectively. Those in Renal Group II (CrCl: 10-29 ml/min/1.73 m2) had similar decreases of -23/-18 and -23/-19 mm Hg at these time points. The adverse events, in both phases, were those associated with the respective monotherapies. A reduction in CrCl with a coincident decrease in proteinuria was noted for both renal groups. The combination of enalapril/diltiazem ER lowered BP and was generally well tolerated by the patients. The combination of these two agents should improve the management of hypertensive patients.

Glyburide increases the secretion, tissue uptake, and action of insulin in conscious normal dogs.

The action of glyburide on glucose homeostasis involves pancreatic and extrapancreatic mechanisms. The relative importance of each of these processes in the hypoglycemic response to sustained administration of glyburide is unknown. In addition, the effect of this drug on the hepatic extraction of insulin is controversial. This investigation uses direct techniques in conscious normal dogs to examine the impact of glyburide therapy (2.5 mg twice daily for 4 weeks) on glucose homeostasis. Preparatory surgery included placement of Doppler flow probes on hepatic vessels and insertion of catheters in carotid artery, portal vein, hepatic vein, and renal vein. After recovery from surgery, animals underwent an intravenous glucose tolerance test ([IGTT] 0.3 g - kg (-1) intravenous glucose bolus) and an insulin infusion clamp test ([IICT] 2 mU - kg (-1) - min (-1) intravenous insulin during 150 minutes) followed by glyburide therapy. After 4 weeks, the IGTT and IICT were repeated. Glyburide increased the insulin secretory response during the late phase of the IGTT and augmented glucose clearance during the IICT. Hepatic extraction of insulin was also stimulated by glyburide. We conclude that the hypoglycemic action of long-term glyburide administration involves stimulation of both insulin secretion by the pancreas and glucose disposal by peripheral tissues. In addition, glyburide augments the extraction of insulin by the liver, and such an effect might prevent the development of sustained high levels of insulin in blood perusing peripheral tissues.

Role of dietary factors in the hypertension of African Americans.

Epidemiological and experimental data suggest that dietary constituents are among the causative factors that contribute to the higher prevalence and severity of hypertension in African Americans as compared with European Americans. Given the difficulty of cleanly separating a change in one dietary nutrient from concomitant changes in others, it has been difficult to reliably attribute an observed effect on blood pressure level and hypertension prevalence to the specific dietary constituent under study. Nevertheless, because hypertension is virtually nonexistent in societies whose dietary sodium chloride intake is very low, it appears that a sodium chloride intake in excess of that required to maintain adequate extracellular fluid volume is necessary but not sufficient for hypertension to be manifest. Additional factors are clearly necessary in the development of hypertension because most individuals, including African Americans, can ingest a high sodium chloride diet without developing hypertension. Evidence for the potential importance of other dietary constituents is also discussed, as are dietary strategies that effectively reduce blood pressure in hypertensive individuals. The data presented support the need for continued research into dietary constituents as potential factors contributing to the etiology of hypertension, as well as effective adjuncts to the management of this very common health problem.

Increased production of PDGF by angiotensin and high glucose in human vascular endothelium.

The mechanisms responsible for the abnormalities in the vascular wall associated with long standing diabetes mellitus are incompletely understood. The aim of this investigation was to assess the effects of angiotensin II and high glucose on the production of platelet-derived growth factor (PDGF) in human endothelial cells. For this purpose, a primary culture was obtained from fresh human umbilical cords by collagenase digestion of the vein interior. A high glucose medium increased the production of PDGF and a similar effect was observed by the addition of mannitol. These data are consistent with a stimulatory effect of glucose on PDGF that is mediated by the osmotic effect of this substance. Angiotensin II significantly increased PDGF in human endothelial cells and the effect was accompanied by a transient increase in cytosolic calcium. The angiotensin II-induced intracellular Ca2+ increases, PDGF production were completely abolished by saralasin and neomycin, respectively. We postulate that the increased production of PDGF by the vascular endothelium in response to high glucose and angiotensin II may participate in the development of the diabetic angiopathy.

Inappropriately high plasma renin activity accompanies chronic loss of renal function.

Stimulation of both the systemic and local renin-angiotensin systems participates in the pathogenesis of tissue injury observed in experimental renal disease. However, substantial information demonstrating excessive activation of the renin-angiotensin system in patients with chronic renal disease is not available in spite of the well-established role of this system in the progression of renal damage. This investigation examined the plasma renin activity (PRA) and the ratio of this parameter to the simultaneously measured glomerular filtration rate (PRA/GFR) in normal volunteers (mean values 3.2 ng/ml/h and 3.0 ng/ml/h/100 ml GFR, respectively) and in patients with chronic renal disease (1.6 ng/ml/h and 28.5 ng/ml/h/100 ml GFR, respectively). A mean tenfold increase in the PRA/GFR ratio was observed in patients with chronic renal disease as compared to normal volunteers. The observed augmentation in PRA was not caused by physiologic mechanisms aimed at conserving urinary sodium since a positive correlation was found between PRA/GFR and the fractional excretion of sodium (y = 2.75 + 2.23x; r = 0.781, p < 0.01), as opposed to that of normal controls (y = 5.3 - 1.46x; r = -0.640, p < 0.01). Consequently, our results support the existence of inappropriate activation of the renin-angiotensin system in humans with chronic renal disease. Such stimulation might play a critical role in the pathophysiology of advanced renal injury.

Counterproductive effects of sodium bicarbonate in diabetic ketoacidosis.

Although a growing body of evidence supports that alkali therapy in diabetic ketoacidosis (DKA) might be counterproductive, our knowledge about the consequences of this treatment on ketone metabolism is limited. Consequently, we performed clinical and animal studies to further examine this topic. The clinical studies assessed seven patients with DKA treated with continuous insulin infusion at a low dosage. Three of them also received sodium bicarbonate (NaHCO3), whereas the remaining four acted as controls. The group receiving NaHCO3 showed a 6-h delay in the improvement of ketosis as compared with controls. In addition, there was an increase in acetoacetate (AcAc) levels during alkali administration, followed by an increase in 3-hydroxybutyrate (3-OHB) level after its completion. Significant differences were not found between groups in the response of plasma glucose to the overall therapy. The animal study examined the effects of a NaHCO3-rich perfusate on the hepatic production of ketones with the in situ rat-liver preparation. Alkali loading resulted in an immediate increase in the AcAc level followed by increases in both the 3-OHB level and the 3-OHB/AcAc ratio after its completion. Hepatic ketogenesis increased even further, to about twice the basal level, after termination of the NaHCO3 loading. This investigation confirms that alkali administration augments ketone production and unravels an effect of bicarbonate infusion that promotes a selective build up of AcAc in body fluids. The data support that alkali therapy in DKA has nonsaltuary effects in the metabolism and plasma levels of ketones.

Vascular relaxation probably mediates the antihypertensive effect of a high-potassium diet: a role for enhanced vascular Na,K-ATPase activity.

OBJECTIVE: to evaluate the effect of dietary potassium on blood pressure and vascular contractility in adult rats of two strains, spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. DESIGN: 'Potassium-induced relaxation' was evaluated in aortic rings as a functional measure of Na,K-ATPase activity in the vascular wall. The rats were fed one of three diets: regular (American Institute of Nutrition-76 rat chow); high-sodium (7% sodium chloride) or high-sodium plus potassium (7% sodium chloride and 13.4% potassium citrate) for 12 +/- 1 weeks. RESULTS: SHR fed the high-sodium diet had a mean blood pressure of 157 +/- 8 mmHg, as compared with 130 +/- 9 mmHg for those on a regular diet (P < 0.01). SHR fed the potassium-supplemented diet had a blood pressure of 122 +/- 9 mmHg (P < 0.01 versus the high-sodium diet group). The mean blood pressure of WKY rats was 78 +/- 3 mmHg and did not differ among the dietary groups. The 'potassium-induced relaxation' response of aortic rings from SHR and WKY rats fed a potassium-supplemented diet was significantly higher (P < 0.05) than that in animals in the corresponding high-sodium dietary group. This observation in potassium-supplemented rats is interpreted as indicative of increased Na,K-ATPase activity in the vascular wall. CONCLUSIONS: A potassium-rich diet in SHR receiving a high sodium intake was associated with lower blood pressure and higher vascular Na,K-ATPase activity. A similar effect of this diet on vascular Na,K-ATPase was observed in WKY. We propose that the antihypertensive effect of a potassium-rich diet is mediated, at least in part, by stimulation of vascular Na,K-ATPase activity.

Acute decreases in serum potassium augment blood pressure.

Potassium depletion is a risk factor for cardiovascular diseases, including hypertension, and frequently is encountered in patients with end-stage renal disease. Since the treatment of end-stage renal disease might result in K+ depletion and postdialysis hypokalemia, we investigated the relationship between acute K+ removal by hemodialysis and changes in blood pressure at the completion of treatment compared with predialysis and 1-hour postdialysis blood pressure. The effects of three different dialysate potassium concentrations ([K+]d; 1.0, 2.0, and 3.0 mmol/L) were investigated in 11 patients. Hemodialysis-induced K+ removal, serum [K+], total body K+, and blood pressure were measured. The use of 1.0, 2.0, or 3.0 mmol/L [K+]d resulted in the removal of 77.0 +/- 6.5, 54.5 +/- 7.9, and 42.5 +/- 9.9 mmol of K+ per treatment, respectively (P < 0.05, [K+]d 1.0 v [K+]d 3.0). Predialysis and postdialysis serum [K+] were 4.9 +/- 0.2 and 3.6 +/- 0.1 mEq/L for 1.0 mmol/L [K+]d, 5.1 +/- 0.3 and 3.9 +/- 0.1 mEq/L for 2.0 mmol/L [K+]d, and 5.3 +/- 0.3 and 4.2 +/- 0.2 mEq/L for 3.0 mmol/L [K+]d, respectively (P < 0.001 for each [K+]d). The baseline total body K+ corrected for gender, age, and race was 92% of predicted normal level and did not change significantly with the use of different [K+]d. Blood pressure decreased during hemodialysis as excess fluid was removed, regardless of [K+]d. Significant increases in blood pressure did occur 1 hour postdialysis compared with levels measured at the completion of treatment ("rebound hypertension") when hemodialysis was performed with 1.0 and 2.0 mmol/L, but not with 3.0 mmol/L [K+]d.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of GTP-binding proteins in turtle urinary bladder epithelial cells.

Water and electrolyte transport in turtle urinary bladder closely resembles that present in the mammalian collecting tubule. Although cAMP is known to participate in the control of mucosal transport processes, the GTP-binding inhibitory Gi and stimulatory Gs proteins which link receptors on the cell surface to the adenylate cyclase system remain to be identified in this urinary epithelium. To this end, individual cells harvested from the mucosal surface of the turtle bladder were isolated using a discontinuous density Ficoll gradient. Examination by electron microscopy of the material from the different layers of the Ficoll gradient confirmed that bands II and III contained carbonic anhydrase-rich cells and granular cells, respectively. Identification of Gi and Gs in carbonic anhydrase-rich and granular cells was accomplished using pertussis (PT) and cholera toxins to promote [32P] ADP ribosylation of the proteins. Separation of Gi and Gs from other cell proteins was accomplished using polyacrylamide gel electrophoresis and autoradiography. Pretreatment of cells with 0.2% triton X-100 substantially magnified the ADP-ribosylation of Gi by PT. A doublet form of Gi was present in the 40-kD region and indicated heterogeneity of the PT substrate in granular and carbonic anhydrase-rich cells. Gs was observed as a single polypeptide at the 42-kD region in both cell types. A distinct 45-kD peptide not present in mammalian collecting tubule was identified by both toxins in granular cells and by cholera toxin in carbonic anhydrase-rich cells. In summary, this investigation identified and characterized Gi and Gs proteins in carbonic anhydrase-rich and granular cells from the mucosa of turtle urinary bladder.(ABSTRACT TRUNCATED AT 250 WORDS)

Demonstration of an apical chloride conductive pathway in granular cells of toad urinary bladder.

Chloride electrodiffusion across the apical membrane of granular cells from toad urinary bladder, an analogue of mammalian principal cells, was examined using the patch clamp technique. A chloride conductance was demonstrated in cell-attached membrane patches exposed to barium chloride pipette solutions. A change in the pipette chloride concentration from 30 to 100 mM caused a shift in the current voltage curve which demonstrated chloride selectivity. The chloride conductance was also examined in excised, inside out membrane patches using choline chloride solutions (chloride:choline selectivity ratio was 18:1). A closed and two open chloride conductive states were found (states A and B, 10.1 +/- 1.0 and 17.2 +/- 5.5 pS, respectively, p < 0.01). Incubation of the preparation with arginine vasopressin, dibutyryl-cAMP, or 8-bromo-cAMP approximately doubled chloride conductance to 16.6 +/- 1.7 pS (p < 0.01). The enhanced electrodiffusion was accounted for by a shift in the channel kinetics from the closed state C to the high conductance state B (p < 0.05, n = 9). 4,4'-Diisothio-cyanatostilbene- 2,2'-disulfonic acid (DIDS) and 9-anthracene-carboxylic acid (9-AC) failed to block the chloride currents. In conclusion, the regulated apical chloride conductance described would balance the sodium and potassium electrodiffusive pathways and maintain a stable membrane potential, facilitating overall conductive transport by these cells.