Acute sodium bicarbonate administration improves ventilatory efficiency in experimental respiratory acidosis: clinical implications.

Administering sodium bicarbonate (NaHCO3) to patients with respiratory acidosis breathing spontaneously is contraindicated because it increases carbon dioxide load and depresses pulmonary ventilation. Nonetheless, several studies have reported salutary effects of NaHCO3 in patients with respiratory acidosis but the underlying mechanism remains uncertain. Considering that such reports have been ignored, we examined the ventilatory response of unanesthetized dogs with respiratory acidosis to hypertonic NaHCO3 infusion (1 N, 5 mmol/kg) and compared it with that of animals with normal acid-base status or one of the remaining acid-base disorders. Ventilatory response to NaHCO3 infusion was evaluated by examining the ensuing change in PaCO2 and the linear regression of the PaCO2 vs. pH relationship. Strikingly, PaCO2 failed to increase and the ΔPaCO2 vs. ΔpH slope was negative in respiratory acidosis, whereas PaCO2 increased consistently and the ΔPaCO2 vs. ΔpH slope was positive in the remaining study groups. These results cannot be explained by differences in buffering-induced decomposition of infused bicarbonate or baseline levels of blood pH, PaCO2, and pulmonary ventilation. We propose that NaHCO3 infusion improved the ventilatory efficiency of animals with respiratory acidosis, i.e., it decreased their ratio of total pulmonary ventilation to carbon dioxide excretion (VE/VCO2). Such exclusive effect of NaHCO3 infusion in animals with respiratory acidosis might emanate from baseline increased VD/VT (dead space/tidal volume) caused by bronchoconstriction and likely reduced pulmonary blood flow, defects that are reversed by alkali infusion. Our observations might explain the beneficial effects of NaHCO3 reported in patients with acute respiratory acidosis.

Determinants of hypokalemia following hypertonic sodium bicarbonate infusion.

The hypokalemic response to alkali infusion has been attributed to the resulting extracellular fluid (ECF) expansion, urinary potassium excretion, and internal potassium shifts, but the dominant mechanism remains uncertain. Hypertonic NaHCO3 infusion (1 N, 5 mmol/kg) to unanesthetized dogs with normal acid-base status or one of the four chronic acid-base disorders decreased plasma potassium concentration ([K+]p) at 30 min in all study groups (Δ[K+]p, - 0.16 to - 0.73 mmol/L), which remained essentially unaltered up to 90-min postinfusion. ECF expansion accounted for only a small fraction of the decrease in ECF potassium content, (K+)e. Urinary potassium losses were large in normals and chronic respiratory acid-base disorders, limited in chronic metabolic alkalosis, and minimal in chronic metabolic acidosis, yet, ongoing kaliuresis did not impact the stability of [K+]p. All five groups experienced a reduction in (K+)e at 30-min postinfusion, Δ(K+)e remaining unchanged thereafter. Intracellular fluid (ICF) potassium content, (K+)i, decreased progressively postinfusion in all groups excluding chronic metabolic acidosis, in which a reduction in (K+)e was accompanied by an increase in (K+)i. We demonstrate that hypokalemia following hypertonic NaHCO3 infusion in intact animals with acidemia, alkalemia, or normal acid-base status and intact or depleted potassium stores is critically dependent on mechanisms of internal potassium balance and not ECF volume expansion or kaliuresis. We envision that the acute NaHCO3 infusion elicits immediate ionic shifts between ECF and ICF leading to hypokalemia. Thereafter, maintenance of a relatively stable, although depressed, [K+]e requires that cells release potassium to counterbalance ongoing urinary potassium losses.

Biomarkers of Covert Acid Stress in Patients with Chronic Kidney Disease: A Cross-Sectional Study.

INTRODUCTION: Like metabolic acidosis, earlier stages of acid (H+) stress, including an ongoing H+ challenge in the form of dietary H+, without or with steady-state H+ accumulation but with normal plasma total CO2 (PTCO2) (the latter state known as eubicarbonatemic acidosis), are associated with augmented progression of chronic kidney disease (CKD), but diagnosis of this covert H+ stress is clinically problematic. Prior published studies to identify clinically practical biomarkers of covert H+ stress did not include assessments of either dietary H+ or H+ retention. METHODS: We tested plasma pH (PpH), 8-h urine excretion of citrate (UcitV) or ammonium (UNH4+V) as biomarkers of dietary H+ assessed as potential renal acid load (PRAL), and of steady-state H+ retention by comparing observed to expected PTCO2 increase 2 h after an oral NaHCO3 bolus. We recruited 313 non-diabetic participants with PTCO2 ≥ 22 mM to exclude participants with metabolic acidosis and with eGFR (mean [SD], mL/min/1.73 m2) stages G1 (n = 62, 99.2 [7.3]), G2 (n = 167, 73.8 [6.3]), and G3 (n = 84, 39.9 [6.7]). We performed linear regressions (LR) between H+ retention or PRAL (dependent variables) and PpH, UcitV, or UNH4+V (independent variables) after adjusting for eGFR. RESULTS: Steady-state H+ retention (mean [SD], mmol) increased with stage (G1 = 3.8 [12.5], G2 = 18.2 [12.4], and G3 = 25.6 [9.0]). PpH was not significantly associated with PRAL in any group, and its association with H+ retention was significant only for G3 (p < 0.01). UcitV association with PRAL was significant only for G1 (p < 0.01) but not for G2 (p = 0.65) or G3 (p = 0.11). UcitV association with H+ retention was negative for both G2 (p < 0.01) and G3 (p < 0.01) but was not significant for G1 (p = 0.50). Adding UNH4+V to UcitV as a regressor for H+ retention increased r2 only marginally for G2 (0.61-0.63) and G3 (0.75-0.79). UNH4+V association with PRAL was positive (p < 0.01) for G1 and G2 but was not significant for G3 (p = 0.46). UNH4+V association with H+ retention was significant for both G2 (p < 0.04) and G3 (p < 0.01) but diverged directionally, being positive for G2 but negative for G3. DISCUSSION: Among patients with CKD at risk for covert H+ stress, lower UcitV better identified eubicarbonatemic acidosis than UNH4+V because the UNH4+V versus H+ retention relationship diverged between G2 and G3. Neither test identified eubicarbonatemic acidosis with certainty, indicating need for further work to establish a clinically useful test. On the other hand, UNH4+V had better utility identifying increased dietary H+ assessed as PRAL in G1 and G2.

Diagnosis and Management of Hyponatremia: A Review.

Importance: Hyponatremia is the most common electrolyte disorder and it affects approximately 5% of adults and 35% of hospitalized patients. Hyponatremia is defined by a serum sodium level of less than 135 mEq/L and most commonly results from water retention. Even mild hyponatremia is associated with increased hospital stay and mortality. Observations: Symptoms and signs of hyponatremia range from mild and nonspecific (such as weakness or nausea) to severe and life-threatening (such as seizures or coma). Symptom severity depends on the rapidity of development, duration, and severity of hyponatremia. Mild chronic hyponatremia is associated with cognitive impairment, gait disturbances, and increased rates of falls and fractures. In a prospective study, patients with hyponatremia more frequently reported a history of falling compared with people with normal serum sodium levels (23.8% vs 16.4%, respectively; P < .01) and had a higher rate of new fractures over a mean follow-up of 7.4 years (23.3% vs 17.3%; P < .004). Hyponatremia is a secondary cause of osteoporosis. When evaluating patients, clinicians should categorize them according to their fluid volume status (hypovolemic hyponatremia, euvolemic hyponatremia, or hypervolemic hyponatremia). For most patients, the approach to managing hyponatremia should consist of treating the underlying cause. Urea and vaptans can be effective treatments for the syndrome of inappropriate antidiuresis and hyponatremia in patients with heart failure, but have adverse effects (eg, poor palatability and gastric intolerance with urea; and overly rapid correction of hyponatremia and increased thirst with vaptans). Severely symptomatic hyponatremia (with signs of somnolence, obtundation, coma, seizures, or cardiorespiratory distress) is a medical emergency. US and European guidelines recommend treating severely symptomatic hyponatremia with bolus hypertonic saline to reverse hyponatremic encephalopathy by increasing the serum sodium level by 4 mEq/L to 6 mEq/L within 1 to 2 hours but by no more than 10 mEq/L (correction limit) within the first 24 hours. This treatment approach exceeds the correction limit in about 4.5% to 28% of people. Overly rapid correction of chronic hyponatremia may cause osmotic demyelination, a rare but severe neurological condition, which can result in parkinsonism, quadriparesis, or even death. Conclusions and Relevance: Hyponatremia affects approximately 5% of adults and 35% of patients who are hospitalized. Most patients should be managed by treating their underlying disease and according to whether they have hypovolemic, euvolemic, or hypervolemic hyponatremia. Urea and vaptans can be effective in managing the syndrome of inappropriate antidiuresis and hyponatremia in patients with heart failure; hypertonic saline is reserved for patients with severely symptomatic hyponatremia.

Malignancy-induced lactic acidosis in adult lymphoma.

Malignancy-induced lactic acidosis (MILA), a rare paraneoplastic phenomenon, is mostly described with hematologic malignancies (lymphomas and leukemias) but has also been reported with solid tumors. It is a subset of type B lactic acidosis being mediated without evidence of tissue hypoperfusion. Lymphoma-induced lactic acidosis is often considered an oncologic emergency and is associated with an increased risk of mortality and poor prognosis. It has a complex pathophysiology centered in the "Warburg effect," i.e., the programming of cancer cells to depend on aerobic glycolysis for promotion of their proliferation and anabolic growth. The treatment of lymphoma-induced lactic acidosis is focused on prompt administration of chemotherapy. The role of alkali therapy in this setting is controversial and has limited proven benefit with a potential for worsening the lactic acidosis. If alkali therapy is used in the presence of severe acidemia to optimize cardiovascular status, it should be administered judiciously.

Veverimer: An Emerging Potential Treatment Option for Managing the Metabolic Acidosis of CKD.

Sodium bicarbonate is the mainstay treatment of the metabolic acidosis of chronic kidney disease but associated concerns center on administering sodium to patients with hypertension and sodium-retentive states. Veverimer (formerly referred to as TRC101), a drug candidate for which Tricida, Inc is seeking approval from the US Food and Drug Administration, is a novel nonabsorbable polymer that binds hydrogen cations and chloride anions in the gastrointestinal tract and then is excreted fecally, thereby increasing serum bicarbonate concentration without administering sodium. We examine the published evidence on the investigational use of veverimer in patients with chronic kidney disease and metabolic acidosis. We highlight the achieved increase in serum bicarbonate concentration without coadministering sodium, effects on physical functioning, and the safety record of the drug. We also scrutinize certain unanticipated findings: a lack of dose dependency in the increase in serum bicarbonate concentration observed and that despite the presumed large hydrogen chloride losses in feces, veverimer induces an isochloremic increase in serum bicarbonate concentration that is accompanied by a decrease in serum anion gap. We propose likely explanations for these puzzling findings and raise questions about veverimer's mode of action and its potential interaction with colonic bacterial flora. Additional work is required to fill these knowledge gaps that could have important clinical implications.

Alkali Therapy for Respiratory Acidosis: A Medical Controversy.

Alkali therapy for certain organic acidoses remains a topic of ongoing controversy, but little attention has been given to a related medical controversy, namely the prescription of alkali for respiratory acidosis. We first describe the determinants of carbon dioxide retention in the 2 types of respiratory failure; hypercapnic respiratory failure and hypoxemic respiratory failure with coexisting hypercapnia. We then highlight the deleterious consequences of severe acidemia for several organ systems, particularly the cardiovascular and central nervous systems. We argue that alkali therapy is not indicated for respiratory acidosis as a simple acid-base disturbance. Notwithstanding, we recommend prescription of alkali for severe acidemia caused by mixed acidosis (ie, combined respiratory and metabolic acidosis) or permissive hypercapnia. We examine the utility of alkali therapy in various clinical scenarios incorporating respiratory acidosis. We conclude that controlled studies will be required to test the impact of alkali therapy on clinical outcomes of these clinical settings. Such studies should also examine the optimal mode of administering alkali (amount, rate, and tonicity) and the blood pH to be targeted. The development of new buffers should be explored, especially systems that do not generate carbon dioxide or even consume it.

Sodium Fate after Sodium Bicarbonate Infusion: Influence of Altered Acid-Base Status.

BACKGROUND: We have previously investigated the fate of administered bicarbonate infused as a hypertonic solution in animals with each of the 4 chronic acid-base disorders. Those studies did not address the fate of sodium, the coadministered cation. METHODS: We examined baseline total body water (TBW), Na+ space, HCO3- space, and urinary sodium and bicarbonate excretion after acute hypertonic NaHCO3 infusion (1-N solution, 5 mmol/kg body weight) in dogs with each of the 4 chronic acid-base disorders. Observations were made at 30, 60, and 90 min postinfusion. Retained sodium that remains osmotically active distributes in an apparent space that approximates TBW. Na+ space that exceeds TBW uncovers nonosmotic sodium storage. RESULTS: Na+ space approximated TBW at all times in normal and hyperbicarbonatemic animals (metabolic alkalosis and respiratory acidosis), but exceeded TBW by ~30% in hypobicarbonatemic animals (metabolic acidosis and respiratory alkalosis). Such osmotic inactivation was detected at 30 min and remained stable. The pooled data revealed that Na+ space corrected for TBW was independent of the initial blood pH but correlated with initial extracellular bicarbonate concentration (y = -0.01x + 1.4, p= 0.002). The fate of administered sodium and bicarbonate (internal distribution and urinary excretion) was closely linked. CONCLUSIONS: This study demonstrates that hypobicarbonatemic animals have a Na+ space that exceeds TBW after an acute infusion of hypertonic NaHCO3 indicating osmotic inactivation of a fraction of retained sodium. In addition to an expanded Na+ space, these animals have a larger HCO3- space compared with hyperbicarbonatemic animals. Both phenomena appear to reflect the wider range of titration of nonbicarbonate buffers (Δ pH) occurring during NaHCO3- loading whenever initial [HCO3-]e is low. The data indicate that the fate of administered bicarbonate drives the internal distribution and the external disposal of sodium, the co-administered cation, and is responsible for the early, but non-progressive, osmotic inactivation of a fraction of the retained sodium.

Urine citrate excretion identifies changes in acid retention as eGFR declines in patients with chronic kidney disease.

Previous studies have shown that acid (H+) retention in patients with chronic kidney disease (CKD) but without metabolic acidosis increases as the estimated glomerular filtration rate (eGFR) decreases over time. The present study examined whether changes in urine excretion of the pH-sensitive metabolite citrate predicted changes in H+ retention over time in similar patients with CKD that were followed for 10 yr. We randomized 120 CKD2 nondiabetic, hypertension-associated nephropathy patients with plasma total CO2 of >24 mM to receive 0.5 meq·kg body wt-1·day-1 NaHCO3 ([Formula: see text]; n = 40), 0.5 meq·kg body wt-1·day-1 NaCl (NaCl; n = 40), or usual care (UC; n = 40). We assessed eGFR (CKD-EPI) and H+ retention by comparing the observed with expected plasma total CO2 increase 2 h after an oral NaHCO3 bolus (0.5 meq/kg body wt). Although 10 yr versus baseline eGFR was lower for each group, 10-yr eGFR was higher (P < 0.01) in [Formula: see text] (59.6 ± 4.8 ml·min-1·1.73 m-2) than NaCl and UC (52.1 ± 5.9 and 52.3 ± 4.1 ml·min-1·1.73 m-2, respectively) groups. Less eGFR preservation was associated with higher 10-yr versus baseline H+ retention in the NaCl group (26.5 ± 13.1 vs. 18.2 ± 15.3 mmol, P < 0.01) and UC group (24.8 ± 11.3 vs. 17.7 ± 10.9 mmol, P < 0.01) and with lower 10-yr versus baseline 8-h urine citrate excretion (UcitrateV) for the NaCl group (162 ± 47 vs. 196 ± 52 mg, respectively, P < 0.01) and UC group (153 ± 41 vs. 186 ± 42 mg, respectively, P < 0.01). Conversely, better eGFR preservation in the [Formula: see text] group was associated with no differences in 10-yr versus baseline H+ retention (14.2 ±13.5 vs. 16.1 ± 15.1 mmol, P = 1.00) or UcitrateV (212 ± 45 vs. 203 ± 49 mg, respectively, P = 0.74). An overall generalized linear model for repeated measures showed that UcitrateV predicted H+ retention (P < 0.01). Less eGFR preservation in patients with CKD2 without metabolic acidosis was associated with increased H+ retention that was predicted by decreased UcitrateV.

Urine citrate excretion as a marker of acid retention in patients with chronic kidney disease without overt metabolic acidosis.

Acid (H+) retention appears to contribute to progressive decline in glomerular filtration rate (GFR) in patients with chronic kidney disease (CKD), including some patients without metabolic acidosis. Identification of patients with H+ retention but without metabolic acidosis could facilitate targeted alkali therapy; however, current methods to assess H+ retention are invasive and have little clinical utility. We tested the hypothesis that urine excretion of the pH-sensitive metabolite citrate can identify H+ retention in patients with reduced GFR but without overt metabolic acidosis. H+ retention was assessed based on the difference between observed and expected plasma total CO2 after an oral sodium bicarbonate load. The association between H+ retention and urine citrate excretion was evaluated in albuminuric CKD patients with eGFR 60-89 ml/min/1.73m2 (CKD 2, n=40) or >90 ml/min/1.73m2 (CKD 1, n = 26) before and after 30 days of base-producing fruits and vegetables. Baseline H+ retention was higher in CKD 2, while baseline urine citrate excretion was lower in CKD 2 compared to CKD 1. Base-producing fruits and vegetables decreased H+ retention in CKD 2 and increased urine citrate excretion in both groups. Thus, H+ retention is associated with lower urine citrate excretion, and reduction of H+ retention with a base-producing diet is associated with increased urine citrate excretion. These results support further exploration of the utility of urine citrate excretion to identify H+ retention in CKD patients with reduced eGFR but without metabolic acidosis, to determine their candidacy for kidney protection with dietary H+ reduction or alkali therapy.

Osmotic and Nonosmotic Sodium Storage during Acute Hypertonic Sodium Loading.

BACKGROUND: The Edelman equation has long guided the expected response of plasma [Na+] to changes in sodium, potassium, and water balance, but recent short-term studies challenged its validity. Plasma [Na+] following hypertonic NaCl infusion in individuals on low-sodium diet fell short of the Edelman predictions supposedly because sodium restriction caused progressive osmotic inactivation of 50% of retained sodium. Here, we examine the validity of this challenge. METHODS: We evaluated baseline total body water (TBW) and Na+ space following acute hypertonic NaHCO3 infusion in dogs with variable sodium and potassium stores, including normal stores, moderate depletion (chronic HCl feeding), or severe depletion (diuretics and dietary NaCl deprivation). RESULTS: TBW (percentage body weight) averaged 65.9 in normals, 62.6 in HCl-induced metabolic acidosis and moderate sodium and potassium depletion, and 57.6 in diuretic-induced metabolic alkalosis and severe sodium and potassium depletion (p < 0.02). Na+ space (percentage body weight) at 30, 60, and 90 min postinfusion averaged 61.1, 59.8, and 56.1, respectively, in normals (p = 0.49); 70.0, 74.4, and 72.1, respectively, in acidotic animals (p = 0.21); and 56.4, 55.1, and 54.2, respectively, in alkalotic animals (p = 0.41). Absence of progressive expansion of Na+ space in each group disproves progressive osmotic inactivation of retained sodium. Na+ space at each time point was not significantly different from baseline TBW in normal and alkalotic animals indicating that retained sodium remained osmotically active in its entirety. However, Na+ space in acidotic animals at all times exceeded by ∼16% baseline TBW (p < 0.01) signifying an early, but nonprogressive, osmotic inactivation of retained sodium, which we link to baseline bone-sodium depletion incurred during acid buffering. CONCLUSIONS: Our investigation affirms the validity of the Edelman construct in normal dogs and dogs with variable sodium and potassium depletion and, consequently, refutes the recent observations in human volunteers subjected to dietary NaCl restriction.

Retarding progression of chronic kidney disease: use of modalities that counter acid retention.

PURPOSE OF REVIEW: Acid retention because of chronic kidney disease (CKD) increases tissue acidity and accelerates progression of CKD, whereas reduction in acid retention slows progression of CKD. Herein, we describe the mechanisms through which increased tissue acidity worsens CKD, modalities for countering acid retention and their impact on progression of CKD, and current recommendations for therapy. RECENT FINDINGS: Studies in animals and humans show that increased tissue acidity raises the renal levels of endothelin, angiotensin II, aldosterone, and ammoniagenesis, thereby worsening renal fibrosis and causing progression of CKD. Measures that counter acid retention, such as providing alkali or modifying the quantity or type of dietary protein, reduce the levels of endothelin, angiotensin II, aldosterone, and ammoniagenesis, slowing progression of CKD. Alkali can be provided as NaHCO3, sodium citrate, or base in fruits and vegetables. A serum [HCO3] of 24-26 mEq/l is targeted, because higher values can be associated with adverse consequences. SUMMARY: Insights into the mechanisms through which increased tissue acidity mediates progression of CKD and the beneficial impact of ameliorating positive acid balance underlie our recommendation for modalities that counter acid retention in CKD.

Re-Evaluation of Total CO2 Concentration in Apparently Healthy Younger Adults.

The initial assessment of acid-base status is usually based on the measurement of total CO2 concentration ([TCO2]) in venous blood, a surrogate for [HCO3-]. Previously, we posited that the reference limits of serum [TCO2] in current use are too wide. Based on studies on the acid-base composition of normal subjects, we suggested that the reference limits of serum [TCO2] at sea level be set at 23-30 mEq/L. To validate this proposal, we queried the University of California at Los Angeles (UCLA's) Integrated Clinical and Research Data Repository, a database containing information on 4.5 million patients seen at UCLA from 2006 to the present. Criteria for inclusion included adults (18-40 years of age), who were free of disorders that could affect acid-base balance, were not taking medications that could affect acid-base balance, and were seen for a routine medical examination or immunization in the outpatient setting. The number of individuals who met the inclusion criteria (52% female and 48% male) was 28,480, with a mean age of 28.9 ± 5.1 years. The mean serum [TCO2] level was slightly higher in males than females, 26.6 ± 2.16 mEq/L vs. 25.0 ± 2.11 mEq/L (p < 0.05). Ninety-one percent of patient values were within the proposed 23-30 mEq/L range and 61.7% were within the 24-27 mEq/L range. These findings validate our proposal that the reference range of serum [TCO2] in venous blood at sea level be narrowed to 23-30 mEq/L. Subjects with serum [TCO2] outside this range might require assessment with a venous blood gas to exclude the presence of clinically important acid-base disorders.

Sodium and potassium in the pathogenesis of hypertension: focus on the brain.

PURPOSE OF REVIEW: Primary hypertension is characterized by Na excess and K deficit in the body, which together are key to its pathogenesis. These derangements work jointly in the brain and the peripheral vascular wall to establish hypertension. In this review, we highlight recent evidence describing the central mechanisms through which Na surfeit and K deficit enhance sympathetic nerve activity, thereby raising peripheral vascular resistance and generating hypertension. RECENT FINDINGS: Animal studies point to a small increase in plasma and cerebrospinal fluid (CSF) [Na], a small decrease in CSF [K], and increased levels of circulating angiotensin II, aldosterone, and endogenous ouabain as the central signals evoking hypertension. These signals are detected by circumventricular organ sensors in the forebrain, and are then relayed to hypothalamic nuclei, which project angiotensinergic effector pathways to brainstem nuclei and spinal preganglionic neurons, triggering increased sympathetic nerve activity and hypertension. These central processes depend on a noncirculating (brain) renin-angiotensin-aldosterone system, local production of endogenous ouabain, and increased oxidative stress. SUMMARY: Recent insights into the mechanisms mediating the central effects of Na excess and K deficit on raising sympathetic activity might pave the way for novel approaches to preventing and treating hypertensive disorders.

Lactic Acidosis: Current Treatments and Future Directions.

Mortality rates associated with severe lactic acidosis (blood pH<7.2) due to sepsis or low-flow states are high. Eliminating the triggering conditions remains the most effective therapy. Although recommended by some, administration of sodium bicarbonate does not improve cardiovascular function or reduce mortality. This failure has been attributed to both reduction in serum calcium concentration and generation of excess carbon dioxide with intracellular acidification. In animal studies, hyperventilation and infusion of calcium during sodium bicarbonate administration improves cardiovascular function, suggesting that this approach could allow expression of the positive aspects of sodium bicarbonate. Other buffers, such as THAM or Carbicarb, or dialysis might also provide base with fewer untoward effects. Examination of these therapies in humans is warranted. The cellular injury associated with lactic acidosis is partly due to activation of NHE1, a cell-membrane Na(+)/H(+) exchanger. In animal studies, selective NHE1 inhibitors improve cardiovascular function, ameliorate lactic acidosis, and reduce mortality, supporting future research into their possible use in humans. Two main mechanisms contribute to lactic acid accumulation in sepsis and low-flow states: tissue hypoxia and epinephrine-induced stimulation of aerobic glycolysis. Targeting these mechanisms could allow for more specific therapy. This Acid-Base and Electrolyte Teaching Case presents a patient with acute lactic acidosis and describes current and future approaches to treatment.

Metabolic Acidosis of CKD: An Update.

The kidney has the principal role in the maintenance of acid-base balance. Therefore, a decrease in renal ammonium excretion and a positive acid balance often leading to a reduction in serum bicarbonate concentration are observed in the course of chronic kidney disease (CKD). The decrease in serum bicarbonate concentration is usually absent until glomerular filtration rate decreases to <20 to 25mL/min/1.73 m(2), although it can develop with lesser degrees of decreased kidney function. Non-anion gap acidosis, high-anion gap acidosis, or both can be found at all stages of CKD. The acidosis can be associated with muscle wasting, bone disease, hypoalbuminemia, inflammation, progression of CKD, and increased mortality. Administration of base may decrease muscle wasting, improve bone disease, and slow the progression of CKD. Base is suggested when serum bicarbonate concentration is <22 mEq/L, but the target serum bicarbonate concentration is unclear. Evidence that increments in serum bicarbonate concentration > 24 mEq/L might be associated with worsening of cardiovascular disease adds complexity to treatment decisions. Further study of the mechanisms through which metabolic acidosis contributes to the progression of CKD, as well as the pathways involved in mediating the benefits and complications of base therapy, is warranted.

Assessing Acid-Base Status: Physiologic Versus Physicochemical Approach.

The physiologic approach has long been used in assessing acid-base status. This approach considers acids as hydrogen ion donors and bases as hydrogen ion acceptors and the acid-base status of the organism as reflecting the interaction of net hydrogen ion balance with body buffers. In the physiologic approach, the carbonic acid/bicarbonate buffer pair is used for assessing acid-base status and blood pH is determined by carbonic acid (ie, Paco2) and serum bicarbonate levels. More recently, the physicochemical approach was introduced, which has gained popularity, particularly among intensivists and anesthesiologists. This approach posits that the acid-base status of body fluids is determined by changes in the dissociation of water that are driven by the interplay of 3 independent variables: the sum of strong (fully dissociated) cation concentrations minus the sum of strong anion concentrations (strong ion difference); the total concentration of weak acids; and Paco2. These 3 independent variables mechanistically determine both hydrogen ion concentration and bicarbonate concentration of body fluids, which are considered as dependent variables. Our experience indicates that the average practitioner is familiar with only one of these approaches and knows very little, if any, about the other approach. In the present Acid-Base and Electrolyte Teaching Case, we attempt to bridge this knowledge gap by contrasting the physiologic and physicochemical approaches to assessing acid-base status. We first outline the essential features, advantages, and limitations of each of the 2 approaches and then apply each approach to the same patient presentation. We conclude with our view about the optimal approach.

Hospital-acquired acute kidney injury and hospital readmission: a cohort study.

BACKGROUND: Hospital-acquired acute kidney injury (AKI) is associated with increased mortality and resource consumption. Little is known about the association of AKI with short-term hospital readmissions. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We investigated whether adult survivors of hospital-acquired AKI were at increased odds for early hospital readmission. PREDICTOR: The peak-to-nadir serum creatinine difference during the index hospitalization was used to define AKI according to the KDIGO (Kidney Disease: Improving Global Outcomes) classification and staging system. MEASUREMENTS: Multivariable logistic regression analyses examined the association of AKI with 30-, 60-, and 90-day hospital readmission, adjusting for age, sex, race, Charlson-Deyo comorbidity index score, acute hospital-related factors, common causes of hospitalization, and baseline estimated glomerular filtration rate. RESULTS: 3,345 (15%) of 22,001 included patients experienced AKI during the index hospitalization. Compared to the non-AKI group, the AKI group had a significantly higher 30-day hospital readmission rate (11% vs 15%; P<0.001), which persisted at 60 and 90 days. The AKI group also was more likely to be readmitted to the hospital within 30 days for cardiovascular-related conditions, mainly heart failure (P<0.001) and acute myocardial infarction (P=0.01). AKI associated independently with higher odds of 30-day hospital readmission (OR, 1.21; 95% CI, 1.08-1.36), which persisted at 60 (OR, 1.15; 95% CI, 1.03-1.27) and 90 days (adjusted OR, 1.13; 95% CI, 1.02-1.25). Results were attenuated in a propensity score-matched cohort of 5,912 patients. LIMITATIONS: Single-center study of mild forms of AKI; ascertainment bias and outcome misclassification due to the use of administrative codes. CONCLUSIONS: Our results suggest that survivors of hospital-acquired AKI experience higher odds of early hospital readmission. Transitions of care services may be warranted for such patients to prevent readmissions and reduce health care costs.