Factors Influencing Blood Alkalosis and Other Physiological Responses, Gastrointestinal Symptoms, and Exercise Performance Following Sodium Citrate Supplementation: A Review.

This review aimed to identify factors associated with (a) physiological responses, (b) gastrointestinal (GI) symptoms, and (c) exercise performance following sodium citrate supplementation. A literature search identified 33 articles. Observations of physiological responses and GI symptoms were categorized by dose (< 500, 500, and > 500 mg/kg body mass [BM]) and by timing of postingestion measurements (in minutes). Exercise performance following sodium citrate supplementation was compared with placebo using statistical significance, percentage change, and effect size. Performance observations were categorized by exercise duration (very short < 60 s, short ≥ 60 and ≤ 420 s, and longer > 420 s) and intensity (very high > 100% VO2max and high 90-100% VO2max). Ingestion of 500 mg/kg BM sodium citrate induced blood alkalosis more frequently than < 500 mg/kg BM, and with similar frequency to >500 mg/kg BM. The GI symptoms were minimized when a 500 mg/kg BM dose was ingested in capsules rather than in solution. Significant improvements in performance following sodium citrate supplementation were reported in all observations of short-duration and very high-intensity exercise with a 500 mg/kg BM dose. However, the efficacy of supplementation for short-duration, high-intensity exercise is less clear, given that only 25% of observations reported significant improvements in performance following sodium citrate supplementation. Based on the current literature, the authors recommend ingestion of 500 mg/kg BM sodium citrate in capsules to induce alkalosis and minimize GI symptoms. Supplementation was of most benefit to performance of short-duration exercise of very high intensity; further investigation is required to determine the importance of ingestion duration and timing.

Intradialytic acid-base changes and organic anion production during high versus low bicarbonate hemodialysis.

The use of high dialysate bicarbonate for hemodialysis in end-stage renal disease is associated with increased mortality, but potential physiological mediators are poorly understood. Alkalinization due to high dialysate bicarbonate may stimulate organic acid generation, which could lead to poor outcomes. Using measurements of ß-hydroxybutyrate (BHB) and lactate, we quantified organic anion (OA) balance in two single-arm studies comparing high and low bicarbonate prescriptions. In study 1 (n = 10), patients became alkalemic using 37 meq/L dialysate bicarbonate; in contrast, with the use of 27 meq/L dialysate, net bicarbonate loss occurred and blood bicarbonate decreased. Total OA losses were not higher with 37 meq/L dialysate bicarbonate (50.9 vs. 49.1 meq using 27 meq/L, P = 0.66); serum BHB increased in both treatments similarly (P = 0.27); and blood lactate was only slightly higher with the use of 37 meq/L dialysate (P = 0.048), differing by 0.2 meq/L at the end of hemodialysis. In study 2 (n = 7), patients achieved steady state on two bicarbonate prescriptions: they were significantly more acidemic when dialyzed against a 30 meq/L bicarbonate dialysate compared with 35 meq/L and, as in study 1, became alkalemic when dialyzed against the higher bicarbonate dialysate. OA losses were similar to those in study 1 and again did not differ between treatments (38.9 vs. 43.5 meq, P = 0.42). Finally, free fatty acid levels increased throughout hemodialysis and correlated with the change in serum BHB (r = 0.81, P < 0.001), implicating upregulation of lipolysis as the mechanism for increased ketone production. In conclusion, lowering dialysate bicarbonate does not meaningfully reduce organic acid generation during hemodialysis or modify organic anion losses into dialysate.

Electrolyte and acid-base disorders in cancer patients and its impact on clinical outcomes: evidence from a real-world study in China.

Background: This study aims to delineate the incidence of electrolyte and acid-base disorders (EAD) in cancer patients, to figure out the risk factors of EAD, then to assess the impact of EAD on patients' in-hospital clinical outcomes.Methods: Patients with the diagnosis of malignancies hospitalized during 1 October 2014 and 30 September 2015 were recruited in Zhongshan Hospital, Fudan University in Shanghai of China. Demographic characteristics, comorbidities, and clinical data, including survival, length of stay and hospital cost, were extracted from the electronic medical record system. Electrolyte and acid-base data were acquired from the hospital laboratory database.Results: Of 25,881 cancer patients with electrolyte data, 15,000 (58.0%) cases had at least one electrolyte and acid-base abnormity. Hypocalcemia (27.8%) was the most common electrolyte disorder, followed by hypophosphatemia (26.7%), hypochloremia (24.5%) and hyponatremia (22.5%). The incidence of simple metabolic acidosis (MAC) and metabolic alkalosis (MAL) was 12.8% and 22.1% respectively. Patients with mixed metabolic acid-base disorders (MAC + MAL) accounted for 30.2%. Lower BMI score, preexisting hypertension and diabetes, renal dysfunction, receiving surgery/chemotherapy, anemia and hypoalbuminemia were screened out as the major risk factors of EAD. In-hospital mortality in patients with EAD was 2.1% as compared to those with normal electrolytes (0.3%). The risk of death significantly increased among patients with severe EAD. Similarly, the length of stay and hospital cost also tripled as the number and grade of EAD increased.Conclusion: EAD is commonly encountered in cancer patients and associated with an ominous prognosis. Patients with comorbidities, renal/liver dysfunction, and anti-tumor therapy have a higher risk of EAD. Regular monitoring of electrolytes, optimum regimen for intravenous infusion, timely correction of modifiable factors and appropriate management of EAD should not be neglected during anti-tumor treatment.

Effect of Bicarbonate-Buffered Dialysate on Ventricular Arrhythmias in Hemodialysis Patients.

BACKGROUND: The etiology of sudden cardiac death in patients with end-stage renal disease (ESRD) on hemodialysis (HD) is largely unknown, though there is evidence to suggest that metabolic alkalosis induced by HD with a high-bicarbonate dialysate/prescription may play a role. METHODS: We investigated the effects of metabolic alkalosis induced by HD with an acetate-containing bicarbonate-buffered dialysate on frequency of ventricular arrhythmia in 47 patients with ESRD on chronic HD using 48-h Holter monitoring in 3 phases: intra-HD, post-HD day 1, and post-HD day 2. Serum levels of bicarbonate, calcium, and potassium along with hemodynamics were measured pre-HD, post-HD, 20-h post-HD, and 44-h post-HD. Correlations were performed to verify the association between bicarbonate prescription and change in serum bicarbonate levels post-HD and to determine if the HD-induced change in serum bicarbonate level (metabolic alkalosis) had any direct association with ambient ventricular arrhythmia (premature ventricular contractions per hour) or indirect associations with ambient ventricular arrhythmia by affecting electrolytes or hemodynamics that are known to increase the risk of ventricular arrhythmia. RESULTS: Mean pre-HD serum bicarbonate level was 21.3 mEq/L. Dialysate bicarbonate prescription (mean of 36.4 mEq/L) correlated with changes in serum bicarbonate levels immediately post-HD 26.7 mEq/L (r = 0.46, p < 0.01), 20-h post-HD 25.2 mEq/L (r = 0.38), and 44-h post-HD 23.2 mEq/L (r = 0.35, p = 0.01). No statistically significant correlations were found between the post-HD change in serum bicarbonate levels (metabolic alkalosis) with ambient ventricular arrhythmia, changes in serum calcium, potassium, or hemodynamics in any phase. CONCLUSIONS: High-bicarbonate dialysate prescription is associated with metabolic alkalosis following the HD procedure. A mild metabolic alkalosis induced by HD with an acetate-containing bicarbonate-buffered dialysate solution had no direct association with ambient ventricular arrhythmia on Holter monitoring and was not associated with changes in hemodynamics or changes in serum total calcium or potassium levels. This study helps to provide guidance for the safe use of high bicarbonate dialysate/prescription in patients with ESRD on HD.

Potassium conservation is impaired in mice with reduced renal expression of Kir4.1.

To better understand the role of the inward-rectifying K channel Kir4.1 (KCNJ10) in the distal nephron, we initially studied a global Kir4.1 knockout mouse (gKO), which demonstrated the hypokalemia and hypomagnesemia seen in SeSAME/EAST syndrome and was associated with reduced Na/Cl cotransporter (NCC) expression. Lethality by ~3 wk, however, limits the usefulness of this model, so we developed a kidney-specific Kir4.1 "knockdown" mouse (ksKD) using a cadherin 16 promoter and Cre-loxP methodology. These mice appeared normal and survived to adulthood. Kir4.1 protein expression was decreased ~50% vs. wild-type (WT) mice by immunoblotting, and immunofluorescence showed moderately reduced Kir4.1 staining in distal convoluted tubule that was minimal or absent in connecting tubule and cortical collecting duct. Under control conditions, the ksKD mice showed metabolic alkalosis and relative hypercalcemia but were normokalemic and mildly hypermagnesemic despite decreased NCC expression. In addition, the mice had a severe urinary concentrating defect associated with hypernatremia, enlarged kidneys with tubulocystic dilations, and reduced aquaporin-3 expression. On a K/Mg-free diet for 1 wk, however, ksKD mice showed marked hypokalemia (serum K: 1.5 ± 0.1 vs. 3.0 ± 0.1 mEq/l for WT), which was associated with renal K wasting (transtubular K gradient: 11.4 ± 0.8 vs. 1.6 ± 0.4 in WT). Phosphorylated-NCC expression increased in WT but not ksKD mice on the K/Mg-free diet, suggesting that loss of NCC adaptation underlies the hypokalemia. In conclusion, even modest reduction in Kir4.1 expression results in impaired K conservation, which appears to be mediated by reduced expression of activated NCC.

Effects of pre-exercise alkalosis on the decrease in VO2 at the end of all-out exercise.

PURPOSE: This study determined the effects of pre-exercise sodium bicarbonate ingestion (ALK) on changes in oxygen uptake (VO2) at the end of a supramaximal exercise test (SXT). METHODS: Eleven well-trained cyclists completed a 70-s all-out cycling effort, in double-blind trials, after oral ingestion of either 0.3 g kg(-1) of sodium bicarbonate (NaHCO3) or 0.2 g kg(-1) body mass of calcium carbonate (PLA). Blood samples were taken to assess changes in acid-base balance before the start of the supramaximal exercise, and 0, 5 and 8 min after the exercise; ventilatory parameters were also measured at rest and during the SXT. RESULTS: At the end of the PLA trial, which induced mild acidosis (blood pH = 7.20), subjects presented a significant decrease in VO2 (P < 0.05), which was related to the amplitude of the decrease in minute ventilation (VE) during the SXT (r = 0.70, P < 0.01, n = 11). Pre-exercise metabolic alkalosis significantly prevented the exercise-induced decrease in VO2 in eleven well-trained participants (PLA:12.5 ± 2.1 % and ALK: 4.9 ± 0.9 %, P < 0.05) and the decrease in mean power output was significantly less pronounced in ALK (P < 0.05). Changes in the VO2 decrease between PLA and ALK trials were positively related to changes in the VE decrease (r = 0.74, P < 0.001), but not to changes in power output (P > 0.05). CONCLUSIONS: Pre-exercise alkalosis counteracted the VO2 decrease related to mild acidosis, potentially as a result of changes in VE and in muscle acid-base status during the all-out supramaximal exercise.

Induced Alkalosis and Gastrointestinal Symptoms After Sodium Citrate Ingestion: a Dose-Response Investigation.

Sodium citrate induces alkalosis and can provide a performance benefit in high-intensity exercise. Previous investigations have been inconsistent in the ingestion protocols used, in particular the dose and timing of ingestion before the onset of exercise. The primary aim of the current study was to quantify blood pH, blood bicarbonate concentration and gastrointestinal symptoms after ingestion of three doses of sodium citrate (500 mg⋅kg-1, 700 mg⋅kg-1 and 900 mg⋅kg-1). Thirteen participants completed four experimental sessions, each consisting of a different dose of sodium citrate or a taste-matched placebo solution. Blood pH and blood bicarbonate concentration were measured at 30-min intervals via analysis of capillary blood samples. Gastrointestinal symptoms were also monitored at 30-min intervals. Statistical significance was accepted at a level of p < .05. Both measures of alkalosis were significantly greater after ingestion of sodium citrate compared with placebo (p < .001). No significant differences in alkalosis were found between the three sodium citrate doses (p > .05). Peak alkalosis following sodium citrate ingestion ranged from 180 to 212 min after ingestion. Gastrointestinal symptoms were significantly higher after sodium citrate ingestion compared with placebo (p < .001), while the 900 mg.kg-1 dose elicited significantly greater gastrointestinal distress than 500 mg⋅kg-1 (p = .004). It is recommended that a dose of 500 mg⋅kg-1 of sodium citrate should be ingested at least 3 hr before exercise, to achieve peak alkalosis and to minimize gastrointestinal symptoms before and during exercise.

[HYPOKALEMIC METABOLIC ALKALOSIS ­ A REPORT OF SIX CASES].

In this article six patients with hypokalemic metabolic alkalosis, classified as Bartter or Gitelman syndrome are presented. Both syndromes result from different gene mutation inducing impaired function of the transporters involved in sodium, chloride and potassium reapsorption in thick ascending limb of the loop of Henle and distal convoluted tubules. These syndromes typically present with hypokalemia, metabolic alkalosis, hyperreninemic hyperaldosteronism without hypertension, polyuria and muscle weakness. Other clinical characteristics may vary considerably, depending on the gene expression. Correct diagnosis is only possible using expensive and not-routinely available genetic testing. Routine laboratory tests, especially those considering serum and urine electrolytes, can help in recognizing these syndromes and therefore in timely beginning of treatment. The most important distinctive laboratory findings are serum magnesium concentration and urine calcium excretion. In Bartter syndrome typically there is hypercalciuria with or without hypomagnesemia, while in Gitelman syndrome typical findings are hypocalciuria and hypomagnesemia. Recognizing and treating these patients is important due to possible increased morbidity and mortality induced by severe electrolyte imbalance.

Chloride Depletion Alkalosis as a Predictor of Inhospital Mortality in Patients with Decompensated Heart Failure.

OBJECTIVES: Chloride depletion alkalosis (CDA) is often seen as a consequence of diuresis in heart failure (HF) but its prognostic significance remains unknown. The purpose of this study was to evaluate the prognostic role of CDA in decompensated HF (DHF). METHODS: A retrospective cohort analysis was performed on 674 patients who were admitted with DHF. Patients were assigned to 2 groups based on the change in serum bicarbonate (median = 3 mmol/l) after diuresis, which was calculated by computing the difference in the admission and discharge serum bicarbonate: the CDA group (a change in serum bicarbonate ≥3 mmol/l) and the non-CDA group (change in serum bicarbonate <3 mmol/l). The primary end points were inhospital mortality and the composite end point of all-cause 30-day mortality and hospital readmission for HF. RESULTS: In a multivariable logistic regression model, the CDA group, i.e. 374 patients, had a lower inhospital mortality than the non-CDA group, i.e. 300 patients (OR 0.11, 95% CI 0.03-0.38; p = 0.0005) after adjusting for other covariates. There was no statistically significant difference in the combined end point of all-cause 30-day mortality and readmission between the 2 groups (OR 1.26, 95% CI 0.74-2.12; p = 0.39). CONCLUSION: The presence of CDA during hospitalization for DHF was independently associated with a better inhospital survival rate.

Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure.

The Na-Cl cotransporter (NCC), which is the target of inhibition by thiazides, is located in close proximity to the chloride-absorbing transporter pendrin in the kidney distal nephron. Single deletion of pendrin or NCC does not cause salt wasting or excessive diuresis under basal conditions, raising the possibility that these transporters are predominantly active during salt depletion or in response to excess aldosterone. We hypothesized that pendrin and NCC compensate for loss of function of the other under basal conditions, thereby masking the role that each plays in salt absorption. To test our hypothesis, we generated pendrin/NCC double knockout (KO) mice by crossing pendrin KO mice with NCC KO mice. Pendrin/NCC double KO mice displayed severe salt wasting and sharp increase in urine output under basal conditions. As a result, animals developed profound volume depletion, renal failure, and metabolic alkalosis without hypokalemia, which were all corrected with salt replacement. We propose that the combined inhibition of pendrin and NCC can provide a strong diuretic regimen without causing hypokalemia for patients with fluid overload, including patients with congestive heart failure, nephrotic syndrome, diuretic resistance, or generalized edema.

Comprehensive diagnosis of whole-body acid-base and fluid-electrolyte disorders using a mathematical model and whole-body base excess.

A mathematical model of whole-body acid-base and fluid-electrolyte balance was used to provide information leading to the diagnosis and fluid-therapy treatment in patients with complex acid-base disorders. Given a set of measured laboratory-chemistry values for a patient, a model of their unique, whole-body chemistry was created. This model predicted deficits or excesses in the masses of Na(+), K(+), Cl(-) and H2O as well as the plasma concentration of unknown or unmeasured species, such as ketoacids, in diabetes mellitus. The model further characterized the acid-base disorder by determining the patient's whole-body base excess and quantitatively partitioning it into ten components, each contributing to the overall disorder. The results of this study showed the importance of a complete set of laboratory measurements to obtain sufficient accuracy of the quantitative diagnosis; having only a minimal set, just pH and PCO2, led to a large scatter in the predicted results. A computer module was created that would allow a clinician to achieve this diagnosis at the bedside. This new diagnostic approach should prove to be valuable in the treatment of the critically ill.

Citrate metabolism and its complications in non-massive blood transfusions: association with decompensated metabolic alkalosis+respiratory acidosis and serum electrolyte levels.

BACKGROUND AND OBJECTIVES: Metabolic alkalosis, which is a non-massive blood transfusion complication, is not reported in the literature although metabolic alkalosis dependent on citrate metabolism is reported to be a massive blood transfusion complication. The aim of this study was to investigate the effect of elevated carbon dioxide production due to citrate metabolism and serum electrolyte imbalance in patients who received frequent non-massive blood transfusions. MATERIALS AND METHODS: Fifteen inpatients who were diagnosed with different conditions and who received frequent blood transfusions (10-30 ml/kg/day) were prospectively evaluated. Patients who had initial metabolic alkalosis (bicarbonate>26 mmol/l), who needed at least one intensive blood transfusion in one-to-three days for a period of at least 15 days, and whose total transfusion amount did not fit the massive blood transfusion definition (<80 ml/kg) were included in the study. RESULTS: The estimated mean total citrate administered via blood and blood products was calculated as 43.2 ± 34.19 mg/kg/day (a total of 647.70 mg/kg in 15 days). Decompensated metabolic alkalosis+respiratory acidosis developed as a result of citrate metabolism. There was a positive correlation between cumulative amount of citrate and the use of fresh frozen plasma, venous blood pH, ionized calcium, serum-blood gas sodium and mortality, whereas there was a negative correlation between cumulative amount of citrate and serum calcium levels, serum phosphorus levels and amount of urine chloride. CONCLUSION: In non-massive, but frequent blood transfusions, elevated carbon dioxide production due to citrate metabolism causes intracellular acidosis. As a result of intracellular acidosis compensation, decompensated metabolic alkalosis+respiratory acidosis and electrolyte imbalance may develop. This situation may contribute to the increase in mortality. In conclusion, it should be noted that non-massive, but frequent blood transfusions may result in certain complications.

Efficacy of oral potassium chloride administration in treating lactating dairy cows with experimentally induced hypokalemia, hypochloremia, and alkalemia.

Hypokalemia occurs commonly in lactating dairy cows. The objectives of this study were to determine (1) whether a 24-h oral KCl dose of 0.4 g/kg of body weight (BW) was effective and safe in hypokalemic cattle; (2) whether potassium was best administered as 2 large doses or multiple smaller doses over a 24-h period; and (3) the effect of oral KCl administration on plasma Mg concentration and urine Mg excretion in fasted lactating dairy cattle. Plasma K and Cl concentrations were decreased, and blood pH increased, in 15 lactating Holstein-Friesian cows by administering 2 intramuscular (i.m.) 10-mg injections of isoflupredone acetate 24h apart followed by 2 i.m. injections of furosemide (1mg/kg of BW) 8h apart and by decreasing feed intake. Cows were randomly assigned to 1 of 3 treatment groups with 5 cows/group: untreated control (group C); oral administration of KCl at 0.05 g/kg of BW 8 times at 3-h intervals (group K3); and oral administration of KCl at 0.2g/kg of BW twice at 12-h intervals (group K12). A 24-h KCl dose rate of 0.4 g/kg of BW increased plasma and milk K concentration and plasma Cl concentration, and corrected the metabolic alkalosis and alkalemia, with no clinically significant difference between 2 large doses (group K12) or multiple small doses (group K3) of KCl over 24 h. Oral KCl administration decreased peripheral fat mobilization in cattle with experimentally induced hypokalemia, as measured by changes in plasma nonesterified fatty acid concentration, and slightly augmented the fasting-induced decrease in plasma Mg concentration. Our findings support recommendations for a 24-h oral KCl dose of 0.4 g/kg of BW for treating moderately hypokalemic cattle. Additional Mg may need to be administered to inappetant lactating dairy cattle being treated with oral KCl to minimize K-induced decreases in magnesium absorption.

Diabetic ketoalkalosis in children and adults.

OBJECTIVES: Diabetic ketoacidosis (DKA) with metabolic alkalosis (diabetic ketoalkalosis [DKALK]) in adults has been described in the literature, but not in the pediatric population. The discordance in the change in the anion gap (AG) and the bicarbonate is depicted by an elevated delta ratio (DR; rise in AG/drop in bicarbonate), which is normally approximately 1. The primary aim of this study was to determine whether DKALK occurs in the pediatric population, as has been seen previously in the adult population. The secondary aim was to determine the factors that may be associated with DKALK. METHODS: A retrospective analysis of adult and pediatric cases with a primary or secondary discharge diagnosis of DKA between May 2008 and August 2010 at a large urban hospital was performed. DKALK was assumed to be present if the DR was >1.2 or in cases of elevated bicarbonate. RESULTS: Of 190 DKA cases, 91 were children, with 21% fulfilling the criterion for DKALK. There were 99 adult cases, 35% of which fulfilled the criterion for DKALK. Our final logistic model revealed that among patients with a discharge diagnosis of DKA, male patients, patients with a history of renal failure, and patients presenting with abdominal findings on physical examination were at greater odds of having a concomitant metabolic alkalosis. CONCLUSIONS: Although DKALK has been described in adults, it can occur in a significant number of children presenting with DKA. The recognition of DKA can be obscured in such situations unless the AG and DR are calculated because the pH and bicarbonate may be near normal or even elevated. In addition to having interesting biochemical features as a complex acid-base disorder, DKALK can pose diagnostic and/or therapeutic challenges.

Base excess (BE): reloaded.

The base excess value (BE, mmol/L), not standard base excess (SBE), correctly calculated including pH, pCO2 (mmHg), sO2 (%) and cHb (g/dl) is a diagnostic tool for several in vivo events, e.g., mortality after multiple trauma or shock, acidosis, bleeding, clotting, artificial ventilation. In everyday clinical practice a few microlitres of blood (arterial, mixed venous or venous) are sufficient for optimal diagnostics of any metabolic acidosis or alkalosis.The same applies to a therapeutic tool-then referred to as potential base excess (BEpot)-for several in vitro assessments, e.g., solutions for infusion, sodium bicarbonate, blood products, packed red blood cells, plasma. Thus, BE or BEpot has been a parameter with exceptional clinical significance since 2007.

Expanding the spectrum of genetic mutations in antenatal Bartter syndrome type II.

Bartter syndrome (BS) is a group of genetic disorders characterized by hypokalemic metabolic alkalosis, hyponatremia and elevated renin and aldosterone plasma concentrations. BS type II is caused by mutations in the KCNJ1 gene and usually presents with transient hyperkalemia. We report here a novel KCNJ1 mutation in a male neonate, prematurely born after a pregnancy complicated by polyhydramnios. The infant presented with typical clinical and laboratory findings of BS type II, such as hyponatremia, hypochloremic metabolic alkalosis, severe weight loss, elevated renin and aldosterone levels and transient hyperkalemia in the early postnatal period, which were later normalized. Molecular analysis revealed a compound heterozygous mutation in the KCNJ1 gene, consisting of a novel K76E and an already described V315G mutation, both affecting functional domains of the channel protein. Typical manifestations of antenatal BS in combination with hyperkalemia should prompt the clinician to search for mutations in the KCNJ1 gene first.