Chapter Eighteen, part 2

References

Part 2, March 1, 2023

  1. The alkaline tide phenomenon in studies that measured both the alkaline tide and acid secretion, the bicarbonate accumulation increased in linear fashion with the acid secretion. Melanie thought this was first recognized in the 60’s but later found this manuscript from 1939 in JCI! ALKALINE TIDES - PMC

  2. Melanie mentioned this old study that explores the respiratory response of metabolic acidosis and finds it “incomplete” compared to expected. EVALUATION OF RESPIRATORY COMPENSATION IN METABOLIC ALKALOSIS and there’s another image in a review by Michael Emmett Figure 1. Metabolic Alkalosis: A Brief Pathophysiologic Review - PMC

    (here’s the image from JCI) 

  3. The effect of changes in blood pH on the plasma total ammonia level - Surgery

  4. This is an interesting case that Melanie mentioned with the help of Stew Lecker Trust the Patient: An Unusual Case of Metabolic Alkalosis - PMC

  5. Got Calcium? Welcome to the Calcium-Alkali Syndrome : Journal of the American Society of Nephrology a favorite review of the “calcium alkali” syndrome- previously called milk alkali syndrome but now milk is not commonly part of the syndrome (as with Dr. Sippie). 

  6. Lety mentioned this issue with a new contaminant of street drugs: Tranq Dope: Animal Sedative Mixed With Fentanyl Brings Fresh Horror to U.S. Drug Zones

  7. Here are two references that illustrate how the urine pH changes over the course of the day. Circadian variation in urine pH and uric acid nephrolithiasis risk The diurnal variation in urine acidification differs between normal individuals and uric acid stone formers - PMC

  8. Notes for Melanie’s VOG on reference 47: Maladaptive renal response to secondary hypercapnia in chronic metabolic alkalosis

    From Biff Palmer Figure 4- Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023 - American Journal of Kidney Diseases

  9. Anna’s VOG- 

    GI composition of cats or something

Outline: Chapter 18 Metabolic Alkalosis

  • Elevation of arterial pH, increased plasma HCO3, and compensatory hypoventilation

    • High HCO3 may be compensatory for respiratory acidosis

    • HCO3 > 40 indicates metabolic alkalosis

  • Pathophysiology: Two Key Questions

    • How do patients become alkalotic?

    • Why do they remain alkalotic?

  • Generation of Metabolic Alkalosis

    • Loss of H+ ions

      • GI loss: vomiting, GI suction, antacids

      • Renal loss: diuretics, mineralocorticoid excess, hypercalcemia, post-hypercapnia

    • Administration of bicarbonate

    • Transcellular shift

      • K+ loss → H+ shifts intracellularly

      • Intracellular acidosis

      • Refeeding syndrome

    • Contraction alkalosis

      • Same HCO3, smaller extracellular volume → increased [HCO3]

      • Seen in CF (sweating), illustrated in Fig 18-1

    • Common theme: hypochloremia is essential for maintenance

  • Maintenance of Metabolic Alkalosis

    • Kidneys normally excrete excess HCO3

      • Example: Normal subjects excrete 1000 mEq NaHCO3/day with minor pH change

    • Impaired HCO3 excretion required for maintenance

      • Table 18-2

    • Mechanisms of Maintenance

      • Decreased GFR (less important)

      • Increased tubular reabsorption

        • Proximal tubule (PT): reabsorbs 90% of filtered HCO3

        • TALH and distal nephron manage the rest

        • Contributing factors:

          • Effective circulating volume depletion

            • Enhances HCO3 reabsorption

            • Ang II increases Na-H exchange

            • Increased tubular [HCO3] enables more H+ secretion

          • Distal nephron HCO3 reabsorption

            • Stimulated by aldosterone (↑ H-ATPase, ↑ Na reabsorption)

              • Negative luminal charge impedes H+ back-diffusion

          • Chloride depletion

            • Reduces NaK2Cl activity → ↑ renin → ↑ aldosterone

            • Luminal H-ATPase co-secretes Cl → low Cl increases H+ secretion

            • Cl-HCO3 exchanger needs Cl gradient → low Cl impairs HCO3 secretion

          • Key conclusion: Cl depletion > volume depletion in perpetuating alkalosis

            • Albumin corrects volume but not alkalosis

            • Non-N Cl salts correct alkalosis without fixing volume

    • Hypokalemia

      • Stimulates H+ secretion and HCO3 reabsorption

        • Transcellular shift (H/K exchange) → intracellular acidosis

        • H-K ATPase reabsorbs K and secretes H

        • Severe hypokalemia reduces Cl reabsorption → ↑ H+ secretion

      • Important with mineralocorticoid excess

  • Respiratory Compensation

    • Hypoventilation: 0.7 mmHg PCO2 ↑ per 1 mEq/L HCO3 ↑

    • PCO2 can exceed 60

    • Rise in PCO2 increases acid excretion (limited effect on pH)

  • Epidemiology

    • GI Hydrogen Loss

      • Gastric juice: high HCl, low KCl

      • Stomach H+ generation → blood HCO3

        • Normally recombine in duodenum

        • Vomiting/antacids prevent recombination → alkalosis

      • Antacids (e.g., MgOH)

        • Mg binds fats, leaves HCO3 unbound → alkalosis

        • Renal failure impairs excretion

      • Cation exchange resins (SPS, MgCO3) → same effect

      • Congenital chloridorrhea

        • High fecal Cl-, low pH → metabolic alkalosis

        • PPI may help by reducing gastric Cl load

    • Renal Hydrogen Loss

      • Mineralocorticoid excess & hypokalemia

        • Aldosterone → H+ ATPase stimulation, Na+ reabsorption → negative lumen → ↑ H+ secretion

      • Diuretics (loop/thiazide)

        • Volume contraction

        • Secondary hyperaldosteronism

        • Increased distal flow and H+ loss

      • Posthypercapnic alkalosis

        • Chronic respiratory acidosis → ↑ HCO3

        • Rapid correction (ventilation) → unopposed HCO3 → alkalosis

        • Gradual CO2 correction needed

        • Maintenance: hypoxemia, Cl loss

      • Low chloride intake (infants)

        • Na+ reabsorption must exchange with H+/K+

        • H+ co-secretion with Cl impaired if Cl is low

      • High dose carbenicillin

        • High Na+ load without Cl

        • Nonresorbable anion → hypokalemia, alkalosis

      • Hypercalcemia

        • ↑ Renal H+ secretion & HCO3 reabsorption

        • Can contribute to milk-alkali syndrome

        • Rarely causes acidosis via reduced proximal HCO3 reabsorption

    • Intracellular H+ Shift

      • Hypokalemia

        • Common cause and effect of metabolic alkalosis

        • H+/K+ exchange → intracellular acidosis → ↑ H+ excretion

      • Refeeding Syndrome

        • Rapid carb reintroduction → cellular shift

        • No volume contraction or acid excretion increase

    • Retention of Bicarbonate

      • Requires impaired excretion to become significant

      • Organic anions (lactate, acetate, citrate, ketoacids)

        • Metabolism → CO2 + H2O + HCO3

        • Citrate in blood transfusion (16.8 mEq/500 mL)

          • 8 units → alkalosis risk

      • CRRT + citrate anticoagulant

      • Sodium bicarbonate therapy

        • Rebound alkalosis possible with acid reversal (e.g., ketoacidosis)

        • Extreme cases: pH up to 7.9, HCO3 up to 70

    • Contraction Alkalosis

      • NaCl and water loss without HCO3

      • Seen in vomiting, diuretics, CF sweat

      • Mild losses neutralized by intracellular buffers

  • Symptoms

    • Often asymptomatic

    • From volume depletion: dizziness, weakness, cramps

    • From hypokalemia: polyuria, polydipsia, weakness

    • From alkalosis (rare): paresthesias, carpopedal spasm, lightheadedness

      • More common in respiratory alkalosis due to rapid pH shift across BBB

    • Physical exam not usually helpful

      • Clues: signs of vomiting

  • Diagnosis

    • History is key

      • If unclear, suspect:

        • Surreptitious vomiting

        • CF

        • Secret diuretic use

        • Mineralocorticoid excess

    • Use urine chloride

      • Table 18-3: urine Na is misleading in alkalosis

      • Table 18-4: urine chemistry changes with complete HCO3 reabsorption

        • Vomiting: low urine Na, K, Cl + acidic urine

        • Sufficient NaCl intake prevents this stage

        • Exceptions to low urine Cl:

          • Severe hypokalemia

          • Tubular defects

          • CKD

    • Distinguishing from respiratory acidosis

      • Use pH as guide

      • Caution with typo (duplicate pCO2)

      • A-a gradient might help

  • Treatment

    • Correct K+ and Cl− deficiency → kidneys self-correct

    • Upper GI losses: add H2 blockers

    • Saline-responsive alkalosis

      • Treat with NaCl

      • Mechanisms:

        • Reverse contraction component

        • Reduce Na+ retention → promote NaHCO3 excretion

        • ↑ distal Cl delivery → enable HCO3 secretion via pendrin

      • Monitor urine pH: from 5.5 → 7–8 with therapy

      • Give K+ with Cl, not phosphate, acetate, or bicarbonate

    • Saline-resistant alkalosis

      • Seen in edematous states or K+ depletion

        • Edema (CHF, cirrhosis): use acetazolamide, HCl, dialysis

          • Acetazolamide: may ↑ CO2 via RBC carbonic anhydrase inhibition

        • Mineralocorticoid excess: K+ + K-sparing diuretic (use caution)

        • Severe hypokalemia:

          • eNaC Na+ reabsorption must be countered by H+ if no K+

          • Corrects rapidly with K+ replacement

          • Restores saline responsiveness

        • Renal failure: requires dialysis