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.

Treatment Guidelines for Hyponatremia: Stay the Course.

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in nine countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits.

Clinical Approach to Assessing Acid-Base Status: Physiological vs Stewart.

Evaluation of acid-base status depends on accurate measurement of acid-base variables and their appropriate assessment. Currently, 3 approaches are utilized for assessing acid-base variables. The physiological or traditional approach, pioneered by Henderson and Van Slyke in the early 1900s, considers acids as H+ donors and bases as H+ acceptors. The acid-base status is conceived as resulting from the interaction of net H+ balance with body buffers and relies on the H2CO3/HCO3- buffer pair for its assessment. A second approach, developed by Astrup and Siggaard-Andersen in the late 1950s, is known as the base excess approach. Base excess was introduced as a measure of the metabolic component replacing plasma [HCO3-]. In the late 1970s, Stewart proposed a third approach that bears his name and is also referred to as the physicochemical approach. It postulates that the [H+] of body fluids reflects changes in the dissociation of water induced by the interplay of 3 independent variables-strong ion difference, total concentration of weak acids, and PCO2. Here we focus on the physiological approach and Stewart's approach examining their conceptual framework, practical application, as well as attributes and drawbacks. We conclude with our view about the optimal approach to assessing acid-base status.

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.

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.

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.

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.

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.

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.

Secondary Response to Chronic Respiratory Acidosis in Humans: A Prospective Study.

INTRODUCTION: The magnitude of the secondary response to chronic respiratory acidosis, that is, change in plasma bicarbonate concentration ([HCO3-]) per mm Hg change in arterial carbon dioxide tension (PaCO2), remains uncertain. Retrospective observations yielded Δ[HCO3-]/ΔPaCO2 slopes of 0.35 to 0.51 mEq/l per mm Hg, but all studies have methodologic flaws. METHODS: We studied prospectively 28 stable outpatients with steady-state chronic hypercapnia. Patients did not have other disorders and were not taking medications that could affect acid-base status. We obtained 2 measurements of arterial blood gases and plasma chemistries within a 10-day period. RESULTS: Steady-state PaCO2 ranged from 44.2 to 68.8 mm Hg. For the entire cohort, mean (± SD) steady-state plasma acid-base values were as follows: PaCO2, 52.8 ± 6.0 mm Hg; [HCO3-], 29.9 ± 3.0 mEq/l, and pH, 7.37 ± 0.02. Least-squares regression for steady-state [HCO3-] versus PaCO2 had a slope of 0.476 mEq/l per mm Hg (95% CI = 0.414-0.538, P < 0.01; r = 0.95) and that for steady-state pH versus PaCO2 had a slope of -0.0012 units per mm Hg (95% CI = -0.0021 to -0.0003, P = 0.01; r = -0.47). These data allowed estimation of the 95% prediction intervals for plasma [HCO3-] and pH at different levels of PaCO2 applicable to patients with steady-state chronic hypercapnia. CONCLUSION: In steady-state chronic hypercapnia up to 70 mm Hg, the Δ[HCO3-]/ΔPaCO2 slope equaled 0.48 mEq/l per mm Hg, sufficient to maintain systemic acidity between the mid-normal range and mild acidemia. The estimated 95% prediction intervals enable differentiation between simple chronic respiratory acidosis and hypercapnia coexisting with additional acid-base disorders.

Osmotic Demyelination Unrelated to Hyponatremia.

Osmotic demyelination unrelated to hyponatremia is rarely reported. We present a case of osmotic demyelination in a patient with hypernatremia in the absence of preceding hyponatremia and review previously reported cases of osmotic demyelination in nonhyponatremic patients. We conclude that a rapid increase in serum sodium concentration and plasma tonicity even in the absence of preceding hyponatremia may surpass the brain's capacity for adaptation to hypertonicity and lead to osmotic demyelination in predisposed individuals. Risk factors for osmotic demyelination in patients with chronic hyponatremia and without hyponatremia are probably similar and are usually associated with states of limited brain osmolyte response, such as alcoholism, liver disease (including those undergoing orthotopic liver transplantation), malnutrition, malignancy, pregnancy/postpartum state, severe illness/sepsis, adrenal insufficiency, and metabolic derangements. Clinicians should be vigilant in identifying individuals who may, even in the absence of hyponatremia, have increased susceptibility to osmotic demyelination and avoid rapid fluctuations in serum sodium concentrations in such patients.

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.

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.

The impact of sodium and potassium on hypertension risk.

The pathogenic role of sodium surfeit in primary hypertension is widely recognized but that of potassium deficiency usually has been ignored or at best assigned subsidiary status. Weighing the available evidence, we recently proposed that the chief environmental factor in the pathogenesis of primary hypertension and the associated cardiovascular risk is the interaction of the sodium surfeit and potassium deficiency in the body. Here, we present the major evidence highlighting the relationship between high-sodium intake and hypertension. We then examine the blood pressure-lowering effects of potassium in conjunction with the pernicious impact of potassium deficiency on hypertension and cardiovascular risk. We conclude with summarizing recent human trials that have probed the joint effects of sodium and potassium intake on hypertension and its cardiovascular sequelae. The latter studies lend considerable fresh support to the thesis that the interaction of the sodium surfeit and potassium deficiency in the body, rather than either disturbance by itself, is the critical environmental factor in the pathogenesis of hypertension.