References Part 2, March 1, 2023 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 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) The effect of changes in blood pH on the plasma total ammonia level - Surgery This is an interesting case that Melanie mentioned with the help of Stew Lecker Trust the Patient: An Unusual Case of Metabolic Alkalosis - PMC 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). 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 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 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 Anna’s VOG- GI composition of cats or something Outline: Chapter 18Metabolic 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
