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ReferencesThis is the thiazide induced hyponatremia reference mentioned by Friedman: Thiazide-Induced Hyponatremia: Reproducibility by Single Dose Rechallenge and an Analysis of PathogenesisThis is the study that Josh mentioned regarding genetic predisposition Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia and it was considered by Neph JC too Thiazide induced hyponatremia, a detailed phenotypic and genotypic analysisAnd here’s a great review: Thiazide-Associated Hyponatremia: Clinical Manifestations and Pathophysiology - American Journal of Kidney Diseases in this excellent review, nice summary of the potential effect of female sex on NCC density (at least in rats!) Melanie wanted to clarify the term “desalination.” Here are a few references:• Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination  Mitch Halperin 10.7326/0003-4819-126-1-199701010-00003• Ewout Hoorn refers to “Desalination” here  Current and future treatment options in SIADH - PMCHere’s the abstract that Amy mentioned: Abstract P174: Incidence of Hyponatremia on Spironolactone in Patients With a Prior Episode of Chlorthalidone-Induce HyponatremiaWe mentioned the issue of solute intake again and this favorite reference: Impact of solute intake on urine flow and water excretionJoel alluded to the unsteady gait from this paper that did the “total traveled way” and showed unsteady gait: Mild Chronic Hyponatremia Is Associated With Falls, Unsteadiness, and Attention Deficits - ScienceDirect and the effect on bones: Hyponatremia-Induced Osteoporosis - PMC (this paper is a beauty, if you don’t like it, we can’t be friends!)For the mechanisms of hyponatremia in hypoadrenalism, Mel reviewed the mechanisms here and there is a good image too: Pattern Recognition versus Pathogenesis - PMC and you may also like this review from Schrier: Role of Glucocorticoid Hormones in Arginine Vasopressin Gene Regulation - ScienceDirect and mel mentioned Osmoregulation of plasma vasopressin in myxedemaAmy mentioned this reference: The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: results of a large prospective single-centre studySome musings we (especially Josh and JC) had about SIADH: Vasopressin and oxytocin release during prolonged environmental hypoxia in the rat, Urinary output and plasma levels of antidiuretic hormone during intermittent positive-pressure breathing in the dog, A Vasopressin-Induced Change in Prostaglandin Receptor Subtype Expression Explains the Differential Effect of PGE2 on AQP2 Expression,Pathogenesis of hyponatremia in an experimental model of the syndrome of inappropriate antidiuresis, Atrial natriuretic peptide in patients with the syndrome of inappropriate antidiuretic hormone secretion and with diabetes insipidusHere’s a reference on fetal vs maternal sodium gradient: Fetal diuretic responses to maternal hyponatremia: contribution of placental sodium gradient | Journal of Applied PhysiologyRoger mentions the nephrogenic syndrome of antidiuresis: Nephrogenic Syndrome of Inappropriate Antidiuresis - PMCThe NEJM manuscript looking at water dilution in schizophrenia: Mechanisms of Altered Water Metabolism in Psychotic Patients with Polydipsia and HyponatremiaTragic case of water loading Woman dies after being in water-drinking contest - Los Angeles TimesThe case report that Josh mentioned: Self-induced water intoxication without predisposing illnessRoger mentioned this case: Who killed Bruce Lee? The hyponatraemia hypothesis - PMC and this classic from NEJM: Mechanisms of Altered Water Metabolism in Psychotic Patients with Polydipsia and Hyponatremia | NEJM Pseudohyponatremia- check out this cute video from laboratorian Joseph El-Khoury: Episode 1 (Pilot): Ending Pseudohyponatremia and here’s a great picture that helps illustrate the issue of measuring the sodium when the solid phase is larger in the plasma: https://i0.wp.com/nephsim.com/wp-content/uploads/2019/02/PseudoHyponatremia1.png?resize=768%2C564&ssl=1And here’s an instructive case: Electrolyte Abnormalities in a Man With Plasma Cell Leukemia - American Journal of Kidney DiseasesAmy’s VoG on Legionella and Hyponatremia association with hyponatremiafirst description: https://pubmed.ncbi.nlm.nih.gov/434629/https://pubmed.ncbi.nlm.nih.gov/6997673/low UrNa as mechanism of hyponatremia?https://pubmed.ncbi.nlm.nih.gov/420455/https://pubmed.ncbi.nlm.nih.gov/6800542/https://pubmed.ncbi.nlm.nih.gov/6802400/Diagnosis with serology and Winthrop criteriasensitivity and specificity if the Winthrop criteria https://pubmed.ncbi.nlm.nih.gov/11591540/modified criteria https://pubmed.ncbi.nlm.nih.gov/18410967/atypical pneumonia diagnosis https://pubmed.ncbi.nlm.nih.gov/8493198/Association with hypophosphatemiahttps://pmc.ncbi.nlm.nih.gov/articles/PMC5399197/https://pubmed.ncbi.nlm.nih.gov/16828618/https://pubmed.ncbi.nlm.nih.gov/6997673/Chapter 23: Hypoosmolar States — HyponatremiaDiureticsMild hyponatremia is a common complication of diuretic therapy.Acute severe hyponatremia may occur as an idiosyncratic reaction, particularly in patients drinking large volumes of water.Thiazide-Associated HyponatremiaThe classic 1989 Friedman data:13 patients with a history of thiazide-associated hyponatremia.A single 50-mg dose of HCTZ produced an acute fall in serum Na.Increased water drinking appeared to contribute.Additional mechanisms include:Volume depletionPotassium depletionDirect inhibition of urinary dilution through decreased NaCl reabsorptionIf excessive water intake is important:Uric acid may be low.BUN may be low.Clinically significant diuretic-associated hyponatremia is almost always associated with thiazides rather than loop diuretics.Why Thiazides Are DifferentLoop diuretics:Reduce the hypertonicity of the medullary interstitium.Impair the kidney’s ability to concentrate urine.Can therefore actually be used as part of the treatment of SIADH.Thiazides:Do not disrupt the medullary concentration gradient in the same way.Impair urinary dilution.Can promote Na and K loss in excess of water.One cited example:Urine Na + K = 156 mEq/LPlasma Na <110 mEq/LThis is desalination: urinary fluid contains more effective cation than the plasma, so its loss can further lower serum sodium.In susceptible patients:Serum Na can begin falling within 6–24 hours.Most cases occur within 2 weeks of starting a thiazide.The largest physiologic effect occurs with the earliest doses.After several weeks, patients generally reach a new steady state.Renal FailureRenal failure impairs the ability to maximally dilute urine after a water load.Potential mechanism:Osmotic diuresis in the remaining nephronsSevere hyponatremia is relatively uncommon when patients remain non-oliguric.Risk increases as GFR approaches zero.SYNDROME OF INAPPROPRIATE ADH SECRETIONIntroductionSIADH is:CommonAssociated with a wide range of clinical conditionsCharacterized by nonphysiologic ADH activityAn unusual physiologic state in which water excretion is impaired while Na excretion remains relatively intactSee Table 23-3.PathogenesisSee Figure 23-3.Ingested water is retained because of ADH-mediated effects on the kidney.Yet patients generally do not develop edema because sodium remains in balance.The combination of:Water retentionSodium excretion…produces hyponatremia.In chronic SIADH, sodium loss may become as important as or more important than the initial water retention.Potassium LossHyponatremia causes cellular swelling.Cells adapt by ejecting intracellular solutes, including:PotassiumThe released potassium is subsequently excreted by the kidney.Chronic AdaptationA new steady state develops over approximately a couple of weeks.At steady state:Na intake = Na outputContributing mechanisms include:Relative ADH resistanceReduced urine osmolalityReduced aquaporin expressionImportantly, water ingestion remains essential. Without water intake, SIADH cannot produce hyponatremia.Patterns of ADH Secretion in SIADHFour patterns are described.Type A — Erratic ADH SecretionADH secretion is essentially independent of osmotic regulation.Type B — Reset OsmostatADH retains its normal relationship with plasma osmolality.The entire relationship is shifted to a lower set point.Serum Na is often relatively stable around 125–130 mEq/L.Patients may appropriately dilute their urine in response to a water load once they reach their lower osmotic set point.Type C — Failure to Completely Suppress ADHADH regulation appears normal around normal plasma osmolality.But ADH cannot be completely suppressed when plasma osmolality falls.Type D — Normal Measured ADHPossible explanations:Increased renal sensitivity to ADHAnother unidentified antidiuretic factorAcid-Base and Potassium Balance in SIADHInteresting question:Why does Na become diluted without equivalent dilution of K or bicarbonate?Potential mechanisms:H moves into cells.Renal H clearance increases.ADH directly stimulates H secretion.Dilutional hypokalemia is partly prevented by movement of intracellular K out of cells.Hypokalemia can occur, particularly when plasma osmolality falls below approximately 240 mOsm/kg.ETIOLOGY OF SIADHSIADH can result from:Increased hypothalamic ADH productionEctopic ADH productionPotentiation of ADH’s renal effectExogenous ADH or related hormonesCNS / Neuropsychiatric DiseaseNeuropsychiatric disorders can promote ADH release:DirectlyThrough cortical neuronal pathways stimulating the hypothalamusExamples:Approximately 20% of patients with subarachnoid hemorrhageApproximately 20–35% after transsphenoidal pituitary surgeryAdrenal insufficiency may contribute following pituitary surgery.Psychiatric patients may have abnormalities at several levels:Water intakeADH secretionRenal responsiveness to ADHAgain, much water intake is habitual rather than thirst-driven.HIVHyponatremia has been reported in approximately 40% of patients with HIV infection.Potential mechanisms include:Volume depletionAdrenal insufficiencySIADHPneumocystis pneumoniaMalignancyCNS diseaseDrugsMany drugs have been associated with SIADH, although most only rarely produce clinically significant hyponatremia.CyclophosphamideIncreases renal sensitivity to ADH.Particularly associated with IV rather than oral administration.Patients are often instructed to drink large quantities of water because of concern for hemorrhagic cystitis.Severe and occasionally fatal hyponatremia has occurred.ChlorpropamideOral hypoglycemic agent.Increases NaCl reabsorption in the TAL.Increases sensitivity to ADH.NSAIDsIncrease the renal action of ADH.Mechanism: inhibition of renal prostaglandin synthesis.PGE normally antagonizes ADH activity.NSAIDs alone rarely cause severe SIADH but can worsen pre-existing hyponatremia, particularly with concomitant volume depletion.Pulmonary DiseaseAssociated conditions include:PneumoniaAsthmaAtelectasisEmphysemaPneumothoraxTuberculosisAcute respiratory failurePossible mechanism:Reduced pulmonary venous return may activate volume receptors.Some patients therefore have a low urine sodium.Reset osmostat has been described with tuberculosis.Major SurgeryTransient SIADH may occur for 2–5 days after major surgery.Pain afferents can directly stimulate hypothalamic ADH secretion.Ectopic ADH ProductionClassic association:Small-cell carcinoma of the lungExogenous ADH and OxytocinOxytocin:Is synthesized by the hypothalamus.Normally regulates uterine function and lactation.Also possesses meaningful antidiuretic activity.Administration during pregnancy has caused hyponatremic seizures in both mother and fetus.Practical considerations:Avoid administering large amounts in D5W.Prefer isotonic saline when appropriate.Limit unnecessary water intake.Other ADH-related therapies mentioned:Vasopressin for GI bleedingDDAVP for:NocturiaPlatelet dysfunctionCentral diabetes insipidusIdiopathic SIADHOccasionally no cause is identified.Consider:Occult malignancyTemporal arteritisThese patients may have low serum uric acid because of increased urinary uric acid clearance.CEREBRAL SALT WASTINGRare syndrome associated with cerebral disease, particularly:Subarachnoid hemorrhagePhenotype:HyponatremiaHigh urine NaLow serum uric acidVolume depletionVolume depletion is the key proposed distinction from SIADH.A theoretical factor released from the injured brain may cause:Renal salt wastingUric acid wastingBNP has been proposed as one candidate.ADRENAL INSUFFICIENCYHyponatremia is common in adrenal insufficiency.Separating the contributions of:Cortisol deficiencyVolume depletion…can be difficult.Cortisol replacement can rapidly normalize serum sodium.The mechanism appears strongly ADH-mediated because ADH antagonism can reverse the defect.ADH is co-secreted with CRH. Cortisol normally provides negative feedback on both:Cortisol ↓ → CRH ↑ → ADH ↑HYPOTHYROIDISMHypothyroidism is often listed in the differential diagnosis of hyponatremia, but it is actually a rare cause of clinically significant hyponatremia.RESET OSMOSTATPatients fulfill many criteria for SIADH but regulate osmolality around a lower set point.Described in:Hypovolemic statesPsychosisChronic malnutritionPregnancyPossible mechanisms include:Baroreceptor-mediated ADH stimulationAltered cellular metabolism in malnutritionPregnancy-related hormonal effectsDuring pregnancy, hCG may promote release of ovarian relaxin.Potential mechanisms:Vasodilation → relative effective volume depletionDirect effects on osmoreceptor regulationPRIMARY POLYDIPSIAOccurs in approximately 7% of patients with schizophrenia.Clinical clues:Weight gain during the day from water accumulationExcessive water drinkingDry mouth from medicationsThere may also be a central abnormality of thirst regulation, with the osmotic threshold for thirst shifted below the threshold for ADH release.Examples:Reported Na 84 mEq/L with Uosm 74 mOsm/kgSymptomatic hyponatremia after drinking 3–4 L of water while anxiously awaiting a drug testSevere cases often involve stacked etiologies:Primary polydipsiaThiazidesAntipsychoticsNausea-induced ADHStress-induced ADHLow-solute intake / beer potomaniaPSEUDOHYPONATREMIA AND NON-HYPOOSMOLAR HYPONATREMIANormal Plasma OsmolalityClassic PseudohyponatremiaNormally, approximately 930 mL of each liter of plasma is water.With severe:HyperlipidemiaHyperproteinemia…plasma water may fall as low as approximately 720 mL/L.The sodium concentration in the plasma water remains normal, but sodium expressed per liter of total plasma appears low.Thus:Measured serum Na is low.Effective plasma osmolality remains normal.Direct ion-selective electrodes can identify the true sodium concentration, while methods involving sample dilution may reproduce the artifact.TURP / HysteroscopyAbsorption of non-electrolyte irrigation solutions can produce complex abnormalities.Probably historical enough to skip?Hyponatremia With Increased Plasma OsmolalityHyperglycemiaInteresting terminology issue: the chapter refers to hyperglycemia-associated hyponatremia as “pseudohyponatremia.”The key point is that treatment should target the hyperglycemia, not the sodium concentration itself.Traditional correction:Na increases approximately 1.6 mEq/L for every 100 mg/dL fall in glucose.At very high glucose concentrations, the correction may be closer to:2.4 mEq/L per 100 mg/dL, particularly above glucose ~400 mg/dL.MannitolMannitol can cause hyperosmolar hyponatremia.The amount of circulating mannitol can be estimated using the osmolar gap.IVIGSome IVIG preparations contain maltose, which can accumulate and contribute to hyperosmolar hyponatremia.

Roger’s Hydrogen to pH tableReferencesDecember 19, 2023Joel had a patient with severe hypothyroidism and hyponatremia- case reportMel reviewed the endocrine factors that can contribute to hyponatremia in this report (from the 2020 ASN quiz and questionnaire): Pattern Recognition versus Pathogenesis - PMC and amy shared this too: Impact of etiology, age and gender on onset and severity of hyponatremia in patients with hypopituitarism: retrospective analysis in a specialised endocrine unitJC mentioned reports of sodium loss from biliary sodium as a cause of hyponatremia: Severe Persistent Hyponatremia: A Rare Presentation of Biliary Fluid Loss - PMC , Hyponatremia after Choledochostomy and T Tube Drainage  but here’s a reference that did measure biliary sodium concentration in children and found the concentration in bile was similar to plasma (which can lead to significant sodium losses! But not hyponatremia unless replete with dilute fluids ;) 10.1001/archpedi.1986.02140200045024Here’s a set of articles by Tom Berl on hyponatremia- the first on solute intake and the second in setting of CKD (enjoy! These are really great!): Impact of solute intake on urine flow and water excretion (this figure is brilliant!) and  Dysnatremias in Patients With Kidney Disease - PMC  Especially enjoy Figure 6! (and check out notes from chapter 9 that review reduced ability to maximally dilute the urine in older individuals- plus here’s a few more great references on the aging kidney: THE AGING KIDNEY: PHYSIOLOGICAL CHANGES - PMC, Urine Concentrating and Diluting Ability During Aging - PMC , Aging and physiological changes of the kidneys including changes in glomerular filtration rateWe quickly referred to the Everest trial of tolvaptan in CHF and Anna shared the reference. Roger mentioned the weight gain that occurs in hyponatremia and marathon running: this study in the NEJM showed that the risk of hyponatremia was greatest in those with longer race times, more weight gain: https://www.nejm.org/doi/10.1056/NEJMoa043901Amy’s VOG on Gastric SecretionsDr. Boyer: https://medicine.yale.edu/profile/james-boyer/Dr. Boyer’s review on his original work on bile salts: https://pmc.ncbi.nlm.nih.gov/articles/PMC4091928/ Gastric secretionsFrom 1961! https://pubmed.ncbi.nlm.nih.gov/13714620/From 1959! https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/expphysiol.1960.sp001428Secretions (2 book in PDF form)Basic Concepts of Fluid and Electrolyte Therapy (see page 14) https://www.researchgate.net/publication/369203977_BASIC_CONCEPTS_OF_FLUID_AND_ELECTROLYTE_THERAPY_2nd_EditionBasic Facts of Body Water and Ions (see page 96) https://link.springer.com/book/10.1007/978-3-662-38375-9Chapter 23: Hypoosmolar States — HyponatremiaPATHOPHYSIOLOGYPlasma Sodium and Plasma OsmolalityPlasma sodium is the main determinant of plasma osmolality.Hyponatremia = Na <135 mEq/L, which usually reflects hypoosmolality.Why this matters:Low plasma osmolality causes water to move into cells.This cellular overhydration produces the symptoms of hyponatremia, particularly in the brain.The Basic Mechanism of HyponatremiaTwo questions provide a useful framework:How do patients develop hyponatremia?Why do they remain hyponatremic?Generation of HyponatremiaEither solute loss (Na or K) or water retention can produce hyponatremia.However, most fluid losses are approximately isoosmotic to plasma.Isoosmotic fluid loss by itself is neutral with respect to plasma sodium.It becomes a problem when the lost fluid is replaced with hypoosmotic fluid.Thus, hyponatremia is usually fundamentally a disorder of water gain relative to solute.Hypoosmolality generally cannot develop without water intake.Perpetuation of HyponatremiaThe normal response to falling plasma osmolality is suppression of ADH.Reduced ADH → dilute urine and increased water excretion.ADH secretion progressively falls as plasma osmolality falls.ADH secretion essentially ceases when:Plasma osmolality falls below approximately 275 mOsm/kg, orSerum Na approaches 135 mEq/L.Figure 23-1 appears closer to 280 mOsm/kg.With maximal ADH suppression:Urine osmolality falls to approximately 40–100 mOsm/kg H₂O.Specific gravity falls to approximately 1.001–1.003.The kidney can potentially excrete >10 L/day of dilute urine.Because the normal kidney can clear enormous quantities of free water, some defect in renal water excretion is generally required for hyponatremia to persist.Major exception: primary polydipsia, where water intake overwhelms otherwise intact renal water excretion.Requirements for Free-Water ExcretionFree-water excretion depends on two processes:Generation of dilute tubular fluidNaCl is reabsorbed without water in the diluting segments.Primarily the thick ascending limb of the loop of Henle.To a lesser degree, the distal tubule.See Table 23-1.Excretion of that dilute fluidRequires the collecting tubules to remain relatively impermeable to water.This requires suppression of ADH.Failure of either process can reduce free-water clearance.In almost every clinical case, the dominant problem is excess ADH activity, usually from:SIADHDecreased effective circulating volumeImportant exceptions include:Oliguric kidney failurePrimary polydipsiaLow-solute intake / “tea and toast” physiology? Not discussed here.Using Urine Osmolality as an ADH ReadoutUrine osmolality provides a functional assessment of ADH activity.Uosm <100 mOsm/kg: ADH is appropriately suppressed.Uosm >100 mOsm/kg: ADH effect is present.In clinically significant ADH-mediated hyponatremia, Uosm is often >300 mOsm/kg.Thought Experiment: It Doesn’t Take MuchAssume:Daily solute load = 400 mOsmDaily water intake = 2 LIf the kidney can dilute urine to 200 mOsm/kg:400 mOsm ÷ 200 mOsm/kg = 2 L urineAll 2 L of ingested water can be excreted.But if minimum urine osmolality rises only slightly to 220 mOsm/kg:400 ÷ 220 = 1.8 L urineThat leaves approximately 200 mL/day of retained water.Over days or weeks, even this modest impairment can produce progressive hyponatremia.Why doesn’t suppression of thirst protect the patient?Because much of human water consumption is habitual, social, or cultural rather than driven strictly by osmotic thirst.ETIOLOGYSee Table 23-2.The disorders in which water excretion is impaired are much more important causes of hyponatremia than disorders in which water excretion remains normal.Effective Circulating Volume DepletionEffective circulating volume refers to the fluid that is effectively perfusing tissues.It may be reduced in patients with either decreased or increased total extracellular volume.True Volume DepletionLoss of both:Intravascular fluidInterstitial fluidPotential sources:GI tractKidneysSkinOther Causes of Reduced Effective Circulating VolumeDecreased vascular resistanceExample: advanced liver diseaseReduced cardiac outputExample: heart failureWhy Effective Volume Depletion Causes HyponatremiaEffective volume depletion affects:ThirstPotassium balanceWater excretionADHHypovolemia sensed through arterial baroreceptors is a potent non-osmotic stimulus for ADH secretion.Reduced Delivery to the Diluting SegmentsVolume depletion can also cause:Reduced GFRIncreased proximal Na reabsorptionReduced fluid delivery to the diluting segmentsThis theoretically reduces free-water generation even without ADH.However, how important is this mechanism?ADH antagonists can largely reverse impaired water excretion in:Heart failureCirrhosisAdrenal insufficiency…without necessarily improving tissue perfusion.That argues that ADH is doing much of the work.Severity of Disease MattersThe tendency toward increased ADH and reduced distal delivery increases with the severity of effective volume depletion.Thus:Worse heart failure → greater risk of hyponatremiaWorse cirrhosis → greater risk of hyponatremiaHyponatremia generally does not occur until disease is relatively advanced.In heart failure, even Na <137 mEq/L is associated with reduced survival.A seemingly minor reduction in sodium may therefore reflect a major impairment in renal water excretion.Water Intake Still MattersThe severity of hyponatremia is strongly influenced by how much water the patient consumes.UltramarathonersMay lose 10–14 L of sweat.Sweat contains approximately 20–100 mEq/L of Na + K.Replacement fluids may contain carbohydrates but relatively little solute.Symptomatic hyponatremia can develop.Serum Na may fall below 120 mEq/L.CholeraSevere diarrhea from cholera may contain:Stool Na approximately 120–140 mEq/L.Low-solute replacement solutions increase the risk of hyponatremia.Concurrent Potassium DepletionPotassium depletion can worsen hyponatremia.K leaves cells to replenish extracellular potassium.Electroneutrality is partly maintained by Na moving into cells.This lowers extracellular Na concentration.Normally, falling plasma osmolality would suppress ADH and permit water excretion.If ADH remains elevated because of volume depletion, this compensatory mechanism is blocked.Giving KCl alone can therefore partially correct hyponatremia by reversing the transcellular cation exchange.Hard to believe Edelman isn’t invoked here.

ReferencesThis is the famous Edelman equation from JCI in 1958 by Isodore Edelman! Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water (not to be confused by Isildur House of Isildur - Tolkien GatewayJoel mentioned his slide deck on Edelman: https://pbfluids.com/wp-content/uploads/2023/04/QN_III-The-Edelman-Equation-full-lecture-from-2020-07-30.pdfThis is an excellent review (with great figures) on Osmotic homeostasis by Danziger and Zeidel in CJASN Joel and JC mentioned the work from Joseph Verbalis on hyponatremia- this is an excellent review that includes population data from NHANES plus striking images of the osteopenic bones in hyponatremic rats! Check this out! Hyponatremia‐induced osteoporosis - Verbalis - 2010 - Journal of Bone and Mineral Research - Wiley Online LibraryJoel and JC mentioned “reference 2” from the chapter by Kleeman and others on diuretic induced hyponatremia which invoked hypokalemia as an important player: Diuretic-Induced Hyponatremia | Annals of Internal MedicineWe couldn't help flirting with diarrhea a little Secretory diarrhoea: mechanisms and emerging therapies - PMCWe talked about cravings for those with salt losses and here’s one example Gitelman syndrome in a South African family presenting with hypokalaemia and unusual food cravings - PMCPBFluids classic: Saltiest Sodium. Dumbest DudeVolume Depletion versus Dehydration: How Understanding the Difference Can Guide Therapy here’s one of many articles that argues for choosing language wisely. Amy’s VOG references:PMC304149442321668418463004219516633374011 PMC3041494PMC128849993102222 42060832 41201721 32401639 Link to Goljian Physiology Spotify! Episode 2 is Fluid and Hemodynamics: https://open.spotify.com/show/1uD6090Kkg01b4zr2ouNiM?si=e7f609e0d9634840Outline: Chapter 22Introduction to Disorders of OsmolalityHyponatremia and hypernatremia are common clinical problemsReflect abnormalities of water balance that may or may not be accompanied by changes in Na balanceWater Distribution and Osmotic PressureTBW makes up 60% of lean body weight in men50% of lean body weight in women60% intracellular40% extracellularOne-fifth of extracellular water is in the intravascular spaceBreakdown70 kg manTBW = 42 L25 L intracellular17 L extracellular3 L of the 17 L is intravascularOsmotic forces determine the distribution of waterEach compartment has one major solute that holds water within the compartmentNa → extracellular compartmentK → intracellular compartmentPlasma proteins → plasma spaceUrea is an ineffective osmolePhysiologic Effects of Changes in Plasma OsmolalityFigure 22-1Na pulls water from the intracellular compartmentIncreases extracellular volumeDecreases intracellular volumeEven though Na is locked in the extracellular compartmentAdministering Na increases osmolality everywhere by changing water distributionIncreases extracellular volumeDecreases intracellular volumeExampleAdding 210 mEq Na to 17 L ECF would mathematically increase concentration by 12.5 mEq/L (210/17)Actually only raises serum Na by ~5Water moves from cellsNa remains trapped in ECFUltimately diluted in TBW210/42 L = 5 mEq/LAdding waterExpands both compartmentsDilutes osmolality in both compartmentsGiving isotonic salineExpands extracellular compartment onlyDoes not change intracellular volumeChanges in osmolality and intracellular volumeResponsible for symptoms of hypo- and hypernatremiaIn these examplesExtracellular volume is increasedSodium concentration may be high, low, or normalMeaning of Plasma Sodium ConcentrationNa, glucose, and urea are the primary extracellular osmolesGives osmolality calculationUnder normal conditionsGlucose and BUN contribute <10 mOsm/LThereforePlasma osmolality ≈ 2 × plasma NaHypernatremia represents hyperosmolalityHyponatremia usually reflects hypo-osmolalityException: hyperglycemiaPlasma Sodium Concentration and Total Body OsmolalityIf plasma Na reflects plasma osmolalityAnd plasma osmolality is in equilibrium with total body osmolalityThen plasma Na reflects total body osmolalitySinceTotal body osmolality = (ECF solutes + ICF solutes) / TBWAndNa and K (plus accompanying anions) are the major extracellular and intracellular solutesThenPlasma Na ≈ (Na + K) / TBWFigure 22-2Key Edelman figureLoss of potassiumK moves out of cellsTo maintain electroneutralityNa enters cellsLowers serum NaOr Cl leaves with KLowers intracellular osmolalityWater moves from cells to ECFDilutes serum NaOr extracellular H dissociates from buffers and enters cellsCombines with intracellular buffersNo net movement of soluteWater still leaves cellsSerum Na dilutedSuggests K loss is responsible for much diuretic-induced hyponatremia (Ref 2)DKA example0.45% NS with 40 mEq KCl is insufficient to correct hyperosmolalityHyponatremia and HypernatremiaCan result from alterations inNaKWaterUsually due to water abnormalitiesExceptionThiazidesLoss of both Na and K contributesToxicity of K prevents excess K from producing hypernatremiaDiarrheaIsosmotic to plasmaIonic composition variesSecretory diarrhea (cholera)Na + K approximately equals plasma NaCauses volume depletionDoes not cause hypernatremiaOsmotic diarrheaFecal Na + K between 30 and 110Nonreabsorbed solutes account for remainderCauses hypernatremiaDiarrheal illnessOften causes feverIncreases insensible lossesAlso stimulates ADH and thirstUsually water balance remains near normalInfants commonly become hypernatremicRegulation of Plasma OsmolalityDaily variation in water intake and loss alters plasma osmolalityWater intakeDrinkingWater content of foodWater of oxidationCarbohydrates metabolized to CO2 and H2OWater retention lowers plasma osmolalityWater lossUrineFecesSkinRespiratory tractWater loss raises plasma osmolalityWater intake and excretion are tightly regulatedOsmoreceptors in hypothalamusAfter water loadPlasma osmolality fallsADH release inhibitedUrinary water loss increasesHyperosmolalityStimulates thirstStimulates ADHIncreases water intakeDecreases water lossRegulation disrupted byNeurologic disordersHypothalamusPosterior pituitaryRenal disordersImpaired concentrating or diluting abilityNonosmotic stimuliVolume depletionOsmoregulation versus Volume RegulationTable 22-2Plasma osmolalityRatio of solute to waterExtracellular volumeDetermined by absolute amount of Na and waterTwo examplesExercising on a hot dayLoss of dilute sweat↑ Plasma osmolality (Na)↓ Extracellular volumeSIADH↓ Plasma osmolality (Na)↑ Extracellular volumeNice exercise at bottom of page 691Isotonic salineDoes not change osmolalityHypothalamus not activatedIncreased volume suppresses reninIncreases ANPWater loadInhibits ADHProduces dilute urineRapid restoration of volumeOnly transient volume expansionLittle effect on renin or ANPNaCl without waterExpands extracellular volumeStimulates renal NaCl lossAlso stimulates thirst and ADHProduces small volume of concentrated urineSimilar to intakeVolume Depletion versus DehydrationThey are not synonymsUrine Osmolality and Specific GravityRelation Between Intake and OutputSimply comparing ins and outs is inadequateComposition of fluids may differ markedlyReplacing urinary losses with free waterProduces hyponatremia

ReferencesBiff Palmer! Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023Josh what is sensed- pCO2 or pH and some exploration suggests that it is not settled! Sensing, physiological effects and molecular response to elevated CO2 levels in eukaryotes - PMC and this one with catchy title: Out of thin air: Sensory detection of oxygen and carbon dioxide - PMCIf anna does VOG on Haldane- we’ll need references The Response of Extracellular Hydrogen Ion Concentration to Graded Degrees of Chronic Hypercapnia: The Physiologic Limits of the Defense of pH - PMC (this is the correct reference for figure 20-3 reference). JC shared some info from Dr. Adrogue Josh mentioned potential differences between people with respect to oxygen sensors and this study of sherpas: [Association of polymorphisms of 1772 (C-->T) and 1790 (G-->A) in HIF1A gene with hypoxia adaptation in high altitude in Sherpas] and this excellent review: Sensing hypoxia: physiology, genetics and epigenetics - PMCVOG from Amy on renal failure with respiratory acidosis https://pubmed.ncbi.nlm.nih.gov/38936337/Joel and Roger mention these two perspectives on alkali therapy for respiratory acidosis the first from Adrogué and Madias, the second from David Goldfarb: Alkali Therapy for Respiratory Acidosis: A Medical Controversy - American Journal of Kidney DiseasesSodium bicarbonate therapy for acute respiratory acidosisJoel mentioned this paper: https://www.nejm.org/doi/pdf/10.1056/NEJM196607212750301 the “carbon dioxide response curve for chronic hypercapnia in man by Bracket, Wingo et al. NEJM 1969 Josh mentioned a study in female ewes that showed a chloride excretion. Acute renal response to rapid onset respiratory acidosis and followed up with this: No renal dysfunction or salt and water retention in acute mountain sickness at 4,559 m among young resting males after passive ascentThis was also studied by Pitts and Giebisch and others: THE EXTRARENAL RESPONSE TO ACUTE ACID-BASE DISTURBANCES OF RESPIRATORY ORIGIN - PMC giebisch and Pitts (the original paper says “with the technical assistance of mary ellen parks and martha MacLeod but on the JCI website, they remedied this and made Parks and MacLeod authors) Joel mentioned the negative Diablo trial Effect of Acetazolamide vs Placebo on Duration of Invasive Mechanical Ventilation Among Patients With Chronic Obstructive Pulmonary Disease: A Randomized Clinical TrialOutline: Chapter 20Respiratory AcidosisClinical disorder characterized byReduced arterial pHElevation of pCO2Variable increase in HCO3Increased pCO2 is also seen in metabolic alkalosisBut here it is appropriateAnd secondaryPATHOPHYSIOLOGY AND ETIOLOGYMetabolism generates 15,000 mmol of CO2 per dayCO2 is not an acid, butCombines with H2O to form H2CO3H2CO3 dissociates to HCO3 and H+Most H+ combines with intracellular buffersHemoglobin in RBCsHCO3 leaves the cell via the chloride exchangerNet resultCO2 generated is primarily carried in blood as HCO3Little change in pHProcess reverses in the alveoliAs H+Hb is oxygenated, H+ is releasedH+ combines with HCO3 to form H2CO3Carbonic anhydrase breaks H2CO3 into H2O and CO2CO2 is exhaledControl of VentilationAlveolar ventilationProvides oxygen for oxidative metabolismEliminates metabolically produced CO2Main stimuli for respirationReduced arterial pO2Increased pCO2Controlled in chemosensitive areas of the medullaRespond to CO2-induced changes in cerebral pHInitial hypoxic stimulation comes from carotid body chemoreceptorsFigure 20-1 is wildpCO2 is maintained within narrow limits despiteLarge daily CO2 loadVariable respiratory quotientVariable metabolic rateMinute ventilation rises 1–4 liters for every 1 mmHg rise in pCO2pO2 does not significantly stimulate ventilation until arterial pO2 <50–60 mmHgActually starts earlierIncreased ventilation lowers pCO2 which inhibits respirationIf pCO2 is fixed, pO2 of 70–80 mmHg will stimulate respirationFigure 20-2Development of HypercapniaBecause CO2 is such a potent respiratory stimulantRespiratory acidosis is usually due to decreased minute ventilationNot increased CO2 productionTable 20-1 lists causesCO2 retention in intrinsic pulmonary diseaseDue to ventilation/perfusion mismatchHypercapnia is beneficialAllows excretion of produced CO2 at lower minute ventilationConsequencesIncreased pCO2 decreases pHIncreased bone and cellular bufferingIncreased renal H secretionRaises serum HCO3Relationship Between Hypercapnia and HypoxemiaAll hypercapnic patients breathing room air have lower alveolar and arterial pO2Total alveolar partial pressures must equal atmospheric pressureHypoxemia generally occurs earlier and is more severe than hypercapniaCO2 diffuses 20× faster than O2Compensation by increasing ventilation in normal lung segmentsImproves CO2 eliminationCannot substantially increase O2 because Hb already saturatedAcute asthma exampleMucus plugging and bronchoconstriction cause hypoxemiaHypoxemia and mechanoreceptors stimulate ventilationProduces respiratory alkalosisRespiratory acidosis is a late findingRespiratory resistance risesMaximal minute ventilation fallspCO2 risesFirst normalizesThen becomes elevatedThereforeNormal pCO2 in acute asthma indicates severe diseaseGeneralization to other lung diseasesEven small increases in pCO2 indicate severe respiratory diseaseHypoxemia-induced hyperventilation delays hypercapniaBut there is 16-fold variability in sensitivity to hypoxemiaLess sensitive individuals develop respiratory acidosis more readilyRegulation of Ventilation in Chronic Respiratory AcidosisTwo common statementsRespiratory centers become less sensitive to CO2 over timeHypoxia becomes the primary respiratory stimulusInsensitivity to CO2Chemoreceptors primarily respond to pHChronic respiratory acidosis increases HCO3Therefore less pH change despite elevated pCO2Less respiratory stimulationWorsening hypercapnia and hypoxiaSimilarlyDiuretic-induced metabolic alkalosis suppresses ventilationDependence on hypoxemiaPatients with chronic respiratory acidosis rely on hypoxia to drive breathingLoss of CO2 stimulation due toRenal compensation raising HCO3Diuretics raising HCO3Making pH less dependent on pCO2Hypoxia drives ventilation when pO2 falls below ~80Makes oxygen administration potentially dangerousCan suppress respiratory driveOxygen also reverses hypoxic vasoconstrictionIncreases V/Q mismatchAcute Respiratory AcidosisBody poorly adapted to acute elevations in pCO2HCO3 cannot buffer H2CO3See Eq 20-4Must use hemoglobin and proteins as buffersSee Eq 20-5HCO3 rises 1 mEq/L for every 10 mmHg increase in pCO2ExamplepCO2 rises to 80HCO3 rises to 28pH falls to 7.17Without bufferingpH would be 7.10Not dramatically differentEtiologyAcute exacerbations of lung diseaseSevere asthmaPulmonary edemaDrug overdoseSleep apnea syndromesCentralObstructiveMixedChronic hypercapnia uncommon in isolated OSACO2 cleared during wakefulnessOSA + structural lung disease + obesityReduced daily alveolar ventilationPersistent CO2 retentionObesity hypoventilation syndromeMechanical ventilationInadequate respiratory rate can cause respiratory acidosisFixed ventilation means increased CO2 production can cause respiratory acidosisCardiac arrestSuggests sodium bicarbonateArterial ABG may miss severity due to poor pulmonary blood flowMixed venous blood may be better guideEnteral or parenteral overfeedingChronic Respiratory AcidosisAfter 3–5 daysHCO3 rises 3.5 mEq/L for every 10 mmHg rise in pCO2ExamplepCO2 = 804 × 3.5 = 14HCO3 should be 38pH ~7.30Allows tolerance of pCO2 values of 90–110Exogenous alkaliUnnecessaryUselessEasily excretedEtiologyCOPDGenetic variation in sensitivity to hypoxemia and CO2Blue bloatersLow response to CO2Hypoxia becomes primary respiratory stimulusPink puffersStrong CO2 responseTachypnea develops earlyCompensation for loss of lung tissuePickwickian syndromeObesity hypoventilation syndromeBook mistakenly says hyperventilationChest wall weight impairs breathingMore complex than thatWeight loss only helps some patientsProgesterone can improve conditionSuggests central respiratory defectMay coexist with OSAUnlike OSA, Pickwickian patients have chronic respiratory acidosisSYMPTOMSNeurologicHeadacheBlurred visionRestlessnessAnxietyCan progress toSomnolence (CO2 narcosis)TremorAsterixisDeliriumIncreased CSF pressurePapilledemaDue to increased cerebral blood flowSymptoms due to CSF acidemiaLess common in metabolic acidosisHCO3 crosses BBB poorlyLess common in chronic respiratory acidosisLess severe acidemiaArrhythmiasPeripheral vasodilationHypotensionParticularly when pH <7.1Cor pulmonalePeripheral edemaCan occur despite normal GFRSuggests relationship between respiratory acidosis and renal sodium handlingOr possibly hypoxiaDIAGNOSISLast full paragraph on page 659 discusses ambiguity of ABGsNicely doneFigure 20-6Two additional examplesBoth instructiveFinal sentence“In summary, the confidence bands are useful guides in the interpretation of acid-base measurements. However, this interpretation cannot proceed in a vacuum and must be correlated with a complete history and physical examination.”Use of the Alveolar-Arterial Oxygen GradientDerivation1 atmosphere = 760 mmHgWater vapor = 47 mmHgNitrogen = 563 mmHgLeaves ~150 mmHg oxygenNo net movement of water or nitrogenTherefore O2 + CO2 must account for remaining pressurePAO2 = PIO2 − PACO2Must multiply CO2 by 1.25 to account for respiratory quotientPAO2 = PIO2 − (1.25 × PACO2)Since CO2 diffuses rapidlyPACO2 ≈ PaCO2Normal valuesPIO2 = 150PaCO2 = 40PAO2 = 150 − (1.25 × 40)PAO2 = 100Normal A-a gradient5–10 mmHg in young adults15–20 mmHg in elderlyA-a gradient = PAO2 − PaO2Combined equationA-a gradient = PIO2 − (1.25 × PaCO2) − PaO2A-a gradient increased in intrinsic pulmonary diseaseOxygen has difficulty entering bloodMay also be increased in some extrapulmonary disordersNo explanation givenNormal A-a gradient argues against pulmonary diseaseSuggestsCentral hypoventilationPrimary metabolic alkalosisChest wall weaknessRespiratory muscle weaknessTREATMENTComplete discussion beyond scope of textAcute Respiratory AcidosisGive oxygen for hypoxiaCorrect underlying cause of hypercapniaOr intubateSodium bicarbonateRole not well definedMay help if pH <7.15Especially severe asthmatics on ventilatorsAvoid inPulmonary edemaCan worsen congestionCNS effectsDoes not protect CNS because HCO3 does not cross BBBIncreased pCO2Must monitor mixed venous pHLate metabolic alkalosisRare according to authorTromethamine (THAM)Binds hydrogenRapidly cleared by kidneys“THAM is of uncertain safety”Chronic Respiratory AcidosisGoalsAdequate oxygenationImprove effective alveolar ventilation if possibleRarely need to treat pH directlyBeware oxygenCan act as respiratory depressantDietary modificationsReduce carbohydratesImproves respiratory drive for unclear reasonsWeight reductionImproves respiratory mechanicsTarget pO2 60–65Reduces pulmonary vasoconstrictionReduces secondary polycythemiaMechanical ventilationLower pCO2 graduallyRapid correction can induce metabolic alkalosisSeizuresComaEffect of superimposed metabolic alkalosisMetabolic alkalosis depresses ventilationDiscontinue diureticsGive salineAcetazolamideAcetazolamide caveatsNeed appropriate bicarbonate target, not normalCan transiently increase pCO2 before diuretic effectMay be due to partial inhibition of carbonic anhydrase in RBCs needed for CO2 carrying capacity

ReferencesChapter 19, Part 3 August 30, 2023Biff Palmer’s Ted Talk-Why not? Biff Palmer at TEDxSMU 2013Anna mentioned this issue of lactic acidosis in a panic disorder: The Lactic Acid Response to Alkalosis in Panic Disorder | The Journal of Neuropsychiatry and Clinical NeurosciencesReminder of important clinical lesson: Lactate: panicking doctor or panicking patient? - PMCMelanie regaled the group with an excerpt (page 351) Cohen, J. J., Kassirer, J. P. (1982). Acid-base. United States: Little, Brown.Biff Palmer! Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023Melanie loves this study of chronic respiratory alkalosis on participants to traveled to the High ALpine research station on the Jungfraujoch in the Swiss Alps Chronic Respiratory Alkalosis — The Effect of Sustained Hyperventilation on Renal Regulation of Acid–Base Equilibrium | NEJM (and here’s a great picture: Services: Jungfraujoch Research Station - Climate and Environmental Physics (CEP)JC mentioned that there are cells in the carotid body which are called glomus cells Neurobiology of the carotid body.JC discussed respiratory alkalosis in cirrhosis and here’s a review he had melanie write that addresses this topic: Acid Base Disorders in Cirrhosis - Advances in Kidney Disease and Health and here are some reviews he likes: The hyperventilation of cirrhosis: progesterone and estradiol effects and Acid-base disturbance in patients with cirrhosis: relation to hemodynamic dysfunction and Blood-Brain Barrier Permeability Is Exacerbated in Experimental Model of Hepatic Encephalopathy via MMP-9 Activation and Downregulation of Tight Junction ProteinsThe finding of respiratory alkalosis in pregnancy is not a new concept. Here’s a study from 1962: Acid-base balance of arterial blood during pregnancy, at delivery, and in the puerperium - American Journal of Obstetrics & GynecologyMelanie reminded us of the Charlie Brown sad face that occurs after bicarbonate infusion and delay in bicarbonate movement to the CSF! Spinal-Fluid pH and Neurologic Symptoms in Systemic Acidosis | NEJM (part 2 of chapter 11)Josh mentioned this report from Andrew Tarulli (a great neurologist previously at BIDMC who has moved to Overlook Hospital in NJ) Central Neurogenic Hyperventilation: A Case Report and Discussion of Pathophysiology | Allergy and Clinical Immunology | JAMA NeurologyHe also mentioned this important transporters that affect the pH. The choroid plexus sodium-bicarbonate cotransporter NBCe2 regulates mouse cerebrospinal fluid pHRefractory Central Neurogenic Hyperventilation: A Novel Approach Utilizing Mechanical Dead SpaceOutline: Chapter 21Respiratory AlkalosisIncreased pH, low pCO2, variable reduction in HCO3Differentiate from metabolic acidosis where pH is decreased(but pCO2 and HCO3 are likewise decreased)PATHOPHYSIOLOGYPrimary decrease in pCO2 when effective alveolar ventilation is increased beyond that needed to eliminate daily CO2 productionHow does the body respond to hypocapniaMass actionReduction in H+ induced by hypocapnia can be minimized by lowering HCO3One: rapid cell bufferingTwo: later decrease in net renal acid secretion → lower HCO3These two strategies explain the difference between acute and chronic respiratory alkalosisAcute Respiratory AlkalosisWithin 10 minutes, H ions move into extracellular fluidH+ combines with HCO3 → fall in plasma HCO3Converted to CO2 and H2OH+ comes from intracellular buffersProtein, phosphate, hemoglobinH+ may also come from alkalemia-induced increase in cellular lactic acid production (1)⁉️Enough H+ enters ECF to lower HCO3 by 2 mEq for each 10 mmHg decrease in pCO2 (Fig 20-3)Example: pCO2 falls to 20HCO3 falls by 4 → ~20 mEq/LpH ~7.63Not very efficient at protecting pHWithout compensation pH would be ~7.70Chronic Respiratory AlkalosisCompensatory ↓ renal H secretionBegins within 2 hoursNot complete for 2–3 daysDue to parallel rise in tubular cell pHManifested byHCO3 lossDecreased NH4 in urine4 mEq drop in HCO3 for each 10 mmHg decrease in pCO2Example: pCO2 20 → HCO3 16 → pH ~7.53ETIOLOGYRespiration governed by two sets of chemoreceptorsCentral (respiratory center in brainstem)Peripheral (carotid bodies at bifurcation, aortic bodies at arch)Central chemoreceptorsStimulated by ↑ pCO2 or metabolic acidosisPeripheral chemoreceptorsStimulated by hypoxia (and acidosis)Thus hyperventilation can be produced byHypoxemiaAnemiaReduction in arterial pHOther stimuliPainAnxietyMechanoreceptorsDirect stimulation of respiratory centerTable 21-1HypoxemiaRespiratory response occurs in stagesStage 1Peripheral chemoreceptor activationHyperventilation → respiratory alkalosisIncreased cerebral pH inhibits central respiratory centerLimits hyperventilationNo significant hyperventilation until pO2 < 50–60 mmHgIf lung disease prevents pCO2 reductionHypoxia stimulates ventilation at PaO2 < 70–80 mmHgStage 2⁉️Persistent hypoxemia → ↓ HCO3Lowers pH toward normalRemoves alkalosis inhibitionAllows greater ventilatory responsePulmonary DiseaseCommon in pneumonia, PE, interstitial fibrosisAlso pulmonary edema (though acidosis more common)Hyperventilation may be due to hypoxemiaOften not corrected by oxygenOther contributorsMechanoreceptors in airways, lungs, chest wallSignals via vagus nerveJuxtacapillary receptors (interstitium)Irritant receptors (epithelium)Activated by inflammation or inhaled irritants(asthma, pneumonia)These contribute to dyspnea even without hypoxiaDirect Stimulation of Medullary Respiratory CenterCortical input (psychogenic hyperventilation)Retained amines in hepatic failure (not prostaglandins⁉️)Bacterial toxins (gram-negative sepsis)SalicylatesProgesterone (pregnancy, luteal phase)Persistent acid CSF after rapid correction of metabolic acidosisNaHCO3 raises extracellular pHPeripheral chemoreceptors reduce ventilation → ↑ pCO2CO2 crosses BBB rapidly, HCO3 does notBrain senses ↑ pCO2 → ↓ CSF pHParadoxical prolongation of hyperventilationNeurologic disordersPontine tumors → local acidosis → ↓ CSF pH → ↑ ventilationHypocapnia in acute cerebral accidentsMechanical VentilationOverventilation can cause respiratory alkalosisCorrect byIncreasing dead space (no explanation given 🤷🏻‍♂️)Decreasing tidal volumeDecreasing respiratory rateSYMPTOMSDue to increased CNS and peripheral nerve excitabilityLightheadednessAltered consciousnessParesthesias (extremities, circumoral)CrampsCarpopedal spasmSyncopeCardiacSupraventricular and ventricular arrhythmiasMechanismsImpaired cerebral functionIncreased membrane excitability↓ cerebral blood flow35–40% reduction if pCO2 drops by 20 mmHgPsychogenic hyperventilation symptomsDyspneaHeadacheChest painSymptoms more prominent in acute disease (rapid pH change)Electrolytes↓ phosphate (as low as 0.5–1.5 mg/dL)Due to intracellular shiftIncreased glycolysis → ↑ phosphorylated compoundsDIAGNOSISTachypneaBut could be acidosis or alkalosisConsider sepsisCompensation equations can be ambiguousExample: 7.48 / 20 / XX / 16Could be chronic respiratory alkalosisOr acute respiratory alkalosis + metabolic acidosis 😖Case 21-15-year-old with AMS, playing with aspirinTREATMENTUsually not necessaryDo NOT giveRespiratory depressantsHClPaper bag rebreathing↑ inspired CO2Can correct acute respiratory alkalosisIf chronic → may leave patient with metabolic acidosisCan treat with NaHCO3“Give a mouse a cookie” 😉

ReferencesChapter 19, Part 3 August 30, 2023Joel and Roger mentioned the most common cause seems to be Sjögren’s syndrome for an acquired distal RTA. We mentioned this in an earlier episode and referenced this example of an absence of the H+ ATPase, presumably from autoantibodies to this transporter. Here’s a case report: Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjogren's syndrome and distal renal tubular acidosis Joel mentioned this paper in the New England Journal of Medicine in which there were patients who had hyperkalemia with a distal RTA: Hyperkalemic Distal Renal Tubular Acidosis Associated with Obstructive Uropathy | NEJM in this setting, some patients  Anna mentioned this article on “ampho-terrible:” It’s the holes!!!    Yano T, Itoh Y, Kawamura E, Maeda A, Egashira N, Nishida M, Kurose H, Oishi R. Amphotericin B-induced renal tubular cell injury is mediated by Na+ Influx through ion-permeable pores and subsequent activation of mitogen-activated protein kinases and elevation of intracellular Ca2+ concentration. Antimicrob Agents Chemother. 2009 Apr;53(4):1420-6Josh mentioned this study on furosemide’s effect on the TAL: Furosemide-induced urinary acidification is caused by pronounced H+ secretion in the thick ascending limb Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an alternative to ammonium chloride - Kidney InternationalMelanie mentioned treatment of patients with cystinosis Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients | Clinical Kidney Journal | Oxford AcademicAmy shared her observations regarding base supplements including Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis - PubMed and Dosage of potassium citrate in the correction of urinary abnormalities in pediatric distal renal tubular acidosis patients - PubMedRoger mentioned that he has had good luck with Moonstone Nutrition drinks alkali citrates for kidney healthWe referred to David Goldfarb’s teaching on kidney stones in patients with acidification defects:  A Woman with Recurrent Calcium Phosphate Kidney Stones (we also referenced this in an earlier episode but this one is a fan favorite). Joel mentioned the concern of bone loss in distal RTA: Incomplete renal tubular acidosis in 'primary' osteoporosis and Abnormal distal renal tubular acidification in patients with low bone mass: prevalence and impact of alkali treatmentJC mentioned Ehlers-Danlos syndrome with renal tubular acidosis and medullary sponge kidneys. A report of a case and studies of renal acidification in other patients with the Ehlers-Danlos syndromeLety mentioned concerns of encrustation of stents in stone forming individuals Potassium Citrate as a Preventive Treatment for Double-J Stent Encrustation: A Randomized Clinical TrialJoel schooled us in toluene and the presentation which appears to be an RTA- https://journals.lww.com/JASN/Abstract/1991/02000/Glue_sniffing_and_distal_renal_tubular_acidosis_.3.aspxMelanie mentioned this work by Alan Yu’s lab on a mechanism of hypercalciuria Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease Furosemide/Fludrocortisone Test and Clinical Parameters to Diagnose Incomplete Distal Renal Tubular Acidosis in Kidney Stone Formers and an accompanying editorial by Goldfarb Refining Diagnostic Approaches in Nephrolithiasis: Incomplete Distal Renal Tubular AcidosisHere’s a nice piece on ifosfamide and phosphate from Josh New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2Here’s this crazy piece on excessive bicarbonate - Gas production after reaction of sodium bicarbonate and hydrochloric acidJosh points out that the pH can be important for inotropy:  An effect of pH upon epinephrine inotropic receptors in the turtle heartMel’s favorite from Halperin because of the pun: Renal tubular acidosis (RTA): recognize the ammonium defect and pHorget the urine pHAmy’s VOG on RTA and OsteoporosisKI Review on acidosis and bone health: Effects of acid on boneGuideline on congenital RTA: Distal renal tubular acidosis: ERKNet/ESPN clinical practice pointsAJKD article on acidosis and bone health: Serum Bicarbonate and Bone Mineral Density in US AdultsCitrate reversing CsA induced acidosis effects: Citrate reverses cyclosporin A-induced metabolic acidosis and bone resorption in ratsOutline: Chapter 19 Metabolic Acidosis part 3Renal Tubular AcidosisAcidosis from diminished net tubular acid secretionThree typesType 1 (Distal)Type 2 (Proximal)Type 4 (…)The acidosis of renal failure could be added to this groupBut NH4+ per nephron is normalThis is a problem of too few nephrons, not tubular acidosisNephrons able to maximally acidify the urineType 1 Distal RTADecrease in net H secretion in the collecting ductMinimal urine pH rises from 4.5 to 5.3HCO3 can fall below 10Three mechanismsDefect in H-ATPase found in cortex and medullaSjögren syndromeCan be genetic chloride bicarbonate exchangerThis pumps bicarbonate out basolateral membrane after it is generated in the splitting of water to form HDefect in cortical Na reabsorptionVoltage-dependent defectConcurrent K secretion defectFound in urinary obstruction and sickle cellVolume deficiency can decrease Na delivery to distal nephronDecreased amount of Na reabsorption can cause a reversible type 1 RTA of this typeIncreased membrane permeabilityAmphotericinpH of 5.0 is 250× plasmaTable 19-7Fractional excretion of bicarbonate in distal RTANormally negligible since bicarbonate can’t exist with pH down around 5In distal RTA it may be as high as 6.5; FEHCO3 is 3%If pH goes up over 7 this can rise to 5–10%Usually in infantsAs they age their urine pH falls a bitThis is called type 3Plasma KH-ATPase defects have low KPatients also have downregulation of H-K-ATPaseDownregulation of NaCl reabsorption in proximal tubuleDecreased filtered bicarbonate means less bicarbonate to absorb with Na, hence more Na excretion from proximal tubuleThis increases distal sodium delivery and increases aldosteroneVoltage defect also has decreased renal K clearance → hyperkalemiaDifferentiate from type 4 RTA by looking at urine pHLower in type 4Higher in voltage-dependent distal RTANephrocalcinosisHypercalciuria, hyperphosphatemia, nephrolithiasis, and nephrocalcinosis are frequentComes from bones buffering the acidosisKidney decreases reabsorption of these so they are lost in urineTwo other factorsLow urinary citrateHypokalemia drives thisAcidosis drives thisHigh urine pH (CaPhos stones)All corrected by correcting the metabolic acidosisIncomplete Type 1Defective urinary acidification but not acidemicIncreased proximal NH3 production lowers urinary HLow urinary citrateCan progress to complete type 1Etiology of Type 1Sjögren syndrome, rheumatoid arthritis19-8Clinical manifestationsStonesHypokalemiaGrowth defectsDiagnosisNAGMA and elevated urine pH5.3 in adults5.6 in childrenDifferentiate Type 1 vs Type 2Give bicarbonate drip1 mEq/kg/hrUrine pH remains high with Type 1Does not go up as it does with proximal Type 2Incomplete distal RTAGive acid load0.1 mmol/kgUrine pH remains >5.3 in classicFalls in normal patients (usually below 5)TreatmentTreat metabolic acidosisMinimize potassium lossReduce bone catabolismPrevent stonesAlkali requirementAdults: 1–2 mEq/kg/dayChildren: 4–14 mEq/kg/dayAlkaliSodium bicarbonateSodium citratePotassium citrate if hypokalemia persists despite correcting acidosisOr for calcium stone diseaseTreat hypokalemiaType 2 Proximal RTADecreased HCO3 reabsorption90% of bicarbonate reabsorption happens in proximal tubuleBicarbonate wasting starts normally at 26–28 mmol/L (Tm for bicarbonate)In RTA 2 the Tm falls to a lower level (maybe 17)Serum bicarbonate falls to 17 and stabilizesType 2 RTA is self-limitingTypically HCO3 around 14–20 Distal acidification intactCarbonic anhydrase inhibitor can block 80% of proximal HCO3 reabsorptionOnly 30% of filtered bicarbonate excreted due to distal H secretionTotal absence of proximal reabsorption results in HCO3 11–12Clinical difference in treatmentIn Type 2, giving bicarbonate and raising serum HCO3 above Tm → more wasted in urineFEHCO3 can reach 15% with normal serum HCO3Urine pH >7.5Below Tm, urine pH <5.3In Type 1, curve relating HCO3 excretion to plasma HCO3 similar to normal (with increased obligatory urine HCO3 due to higher urine pH)Defect in HCO3 reabsorptionCan be isolatedOr part of Fanconi syndromePathogenesis (three steps)Na-H exchange (apical membrane)Na-K-ATPase (basolateral membrane)Carbonic anhydraseIntracellularLuminalMultiple myeloma most common adult causeIfosfamideCan also cause phosphate wasting, NDI, and Type 1 RTAK balanceCommon but variableMild hypokalemia at baseline due to increased Na wasting → hyperaldosteronismWorse with bicarbonate therapyDistal delivery of nonreabsorbable anion increases obligate cation lossFigure 19-7Bone diseaseRickets (children), osteomalacia/osteopenia (adults)Up to 20%Phosphate wasting and vitamin D deficiency may contributeImpaired growthNo nephrocalcinosis or nephrolithiasisLower urine pHNonreabsorbable amino acids and organic anions bind calciumEtiology19-9Idiopathic and cystinosis (children)Carbonic anhydrase inhibitorsMultiple myelomaDiagnosisNAGMA and pH <5.3Look for Fanconi syndromeRaise serum HCO3 and watch urine pH riseFEHCO3 15–20%TreatmentCorrect acidosis to allow normal growthDifficult due to rapid urinary lossMay need 10–15 mEq/kg/dayHCO3 or citrateMore than 20 mEq HCO3 can cause stomach rupture from CO2 generationSmall dose thiazide to increase proximal Na reabsorption and HCO3 reabsorptionIdiopathic Type 2 may improve after yearsType 4 RTAAldosterone deficient or resistantNormally stimulates H secretion and K secretionLoss causes hyperkalemia and metabolic acidosisHyperkalemia antagonizes NH4 generationHigh K may outcompete NH4 on Na-K-2Cl in TALHLess ammonium recyclingLess NH3 available in collecting ductCorrecting hyperkalemia can correct acidosisMetabolic acidosis generally mildHCO3 >15Urine pH <5.3 (generally, not always)Mineralocorticoid can treat but causes hypertension and sodium retentionOften responds to loop diureticRhabdomyolysis can cause high anion gap metabolic acidosisSymptomsRespiratory compensation increases 4–8 fold → dyspneapH <7.0–7.1Fatal ventricular arrhythmiasReduced cardiac contractilityDecreased response to inotropesNeurologicalLethargy to comaMore related to CSF pH than plasmaLess neurologic symptoms than respiratory acidosisBBB more permeable to CO2 than HCO3Skeletal problemsDecreased growthKids/infants: anorexia, nausea, listlessnessTreatmentGeneral principlesCorrect with HCO3No alkali required for lactic or ketoacidosisGoal: pH >7.2Equations on page 629 need “log”Example: pH 7.1, pCO2 20, HCO3 6Raise HCO3 to 8 if pCO2 stays 20Raise to 10 if pCO2 risesParagraph “regardless…” highlights risks of bicarbonateBicarbonate deficitDeficit = HCO3 space × HCO3 deficit per literHCO3 space50% body weight (normal)60% (mild–moderate acidosis)70% (severe, HCO3 <8–10)Example: 70 kg, raise HCO3 6→10 using 0.7 space = 196 mEqRough guideline; does not account for ongoing acid productionEarly large bump in bicarbonateDrifts down as bicarbonate moves intracellularlyPlasma potassiumK depletion can cause metabolic acidosisMetabolic acidosis increases K“Normal” K may mask depletion (see DKA)Beware correcting acidosis in hypokalemiaHeart failureBicarbonate comes with sodium loadComment that bicarbonate moves into cellBut Na remains extracellularDialysis can be used

ReferencesChapter 19, Part 12Metabolic acidosis  June 14, 2023ReferencesChapter 19, Part 2Roger mentioned MELAS syndrome MELAS syndrome: Clinical manifestations, pathogenesis, and treatment optionsJosh mentioned this blog on lactate- Understanding lactate in sepsis & Using it to our advantageWe discussed the Warburg effect The Warburg Effect: How Does it Benefit Cancer Cells? - PMC and here’s a case from skeleton key- Skeleton Key Group Case #28: Mysterious Acidosis in Cancer - Renal Fellow NetworkOtto Warburg won the Nobel Prize in Physiology and Medicine in 1931 for describing how animal tumors produce large quantities of lactic acid (Wikipedia)Joel calls it the Lactate saline reflex, but the accepted term of art is Lacto-Bolo reflex The origins of the Lacto-Bolo reflex: the mythology of lactate in sepsisBuffer agents do not reverse intramyocardial acidosis during cardiac resuscitation.Josh mentioned this article the BICAR-ICU Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial - The LancetRoger shared 3 quotes to make the point that there has been little movement in our knowledge the past 40 years:Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study from Cooper in the AnnalsLactic Acidosis and Bicarbonate Therapy | Annals of Internal Medicine from Robert HollanderLactic acidosis from Nick MadiasJosh mentioned the use of sodium bicarbonate for CKD Eubicarbonatemic Hydrogen Ion Retention and CKD Progression - Kidney Medicine  (Madias) Bicarbonate therapy for prevention of chronic kidney disease progression (from Wesson),  Sodium Bicarbonate Prescription and Extracellular Volume Increase: Real‐world Data Results from the AlcalUN StudyAmy’s VoG on metabolic acidosis/KDIGO guidelinesVery nice JASN review that describes the mechanisms of how metabolic acidosis leads to CKD progressionFirst description by THE Dr. Bright1930 Lancet description of benefit2009 RCT that the 2012 KDIGO guidelines sort of based their 2b recommendations off of2020 BiCARB Study2021 META AnalysisWe discussed methanol toxicity : Case Study: Methanol Poisoning from Adulterated Liquor | Food Safety, Acute methyl alcohol poisoning: a review based on experiences in an outbreak of 323 cases and josh poking at the osmolar gap: PulmCrit- Toxicology dogmalysis: the osmolal gap and shared these guidelines: METHANOL | extrip-workgroup and Roger loves this: Urine fluorescence using a Wood's lamp to detect the antifreeze additive sodium fluorescein: a qualitative adjunctive test in suspected ethylene glycol ingestionsFrom China to Panama, a Trail of Poisoned Medicine - The New York Times (diethylene glycol) . The Accidental Poison That Founded the Modern FDA - The AtlanticOutline: Chapter 19 Metabolic AcidosisEtiologies and DiagnosisLactic AcidosisPyruvate → lactate (LDH; NADH → NAD+)Normal production: 15–20 mmol/kg/dayMetabolized in liver/kidney → pyruvate → glucose or TCANormal lactate: 0.5–1.5 mmol/L; acidosis if > 4–5 mmol/LCauses:↑ production: hypoxia, redox imbalance, seizures, exercise↓ utilization: shock, hepatic hypoperfusionMalignancy, alcoholism, antiretroviralsD-lactic acidosisShort bowel/jejunal bypassGlucose → D-lactate (not metabolized by LDH)Symptoms: confusion, ataxia, slurred speechSpecial assay neededTx: bicarb, oral antibioticsTreatmentUnderlying causeBicarb controversial: may worsen intracellular acidosis, overshoot alkalosis, ↑ lactateTarget pH > 7.1; prefer mixed venous pH/pCO2Ketoacidosis (Chapter 25 elaborates)FFA → TG, CO2, H2O, ketones (acetoacetate, BHB)Requires:↑ lipolysis (↓ insulin)Hepatic preference for ketogenesisCauses:DKA (glucose > 400)Fasting ketosis (mild)Alcoholic ketoacidosisPoor intake + EtOH → ↓ gluconeogenesis, ↑ lipolysisMixed acid-base (vomiting, hepatic failure, NAGMA)Congenital organic acidemias, salicylatesDiagnosis:AG, osmolar gap (acetone, glycerol)Ketones: nitroprusside only detects acetone/acetoacetateBHB can be 90% of total (false negative)Captopril → false positiveTreatment:Insulin +/- glucoseRenal Failure↓ excretion of daily acid loadGFR < 40–50 → ↓ ammonium/TA excretionBone buffering stabilizes HCO3 at 12–20 mEq/LSecondary hyperparathyroidism helps with phosphate bufferingAlkali therapy controversial in adultsIngestionsSalicylatesSymptoms at >40–50 mg/dLEarly: respiratory alkalosis → Later: metabolic acidosisTreatment: bicarb, dialysis (>80 mg/dL or coma)MethanolMetabolized to formic acid → retinal toxicityOsmolar gap elevatedTx: bicarb, ethanol/fomepizole, dialysisEthylene glycol→ glycolic/oxalic acid → renal failureSame treatment + thiamine/pyridoxineOtherToluene, sulfur, chlorine gas, hyperalimentation (arginine, lysine)GI Bicarbonate LossDiarrhea, bile/pancreatic drainage → loss of alkaline fluidsUreterosigmoidostomy → Cl-/HCO3- exchange in colonCholestyramine → Cl- for HCO3-

ReferencesPart 2, March 1, 2023The 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 - PMCMelanie 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 - SurgeryThis is an interesting case that Melanie mentioned with the help of Stew Lecker Trust the Patient: An Unusual Case of Metabolic Alkalosis - PMCGot 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 ZonesHere 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 - PMCNotes for Melanie’s VOG on reference 47: Maladaptive renal response to secondary hypercapnia in chronic metabolic alkalosisFrom Biff Palmer Figure 4- Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023 - American Journal of Kidney DiseasesAnna’s VOG-  GI composition of cats or somethingOutline: Chapter 18Metabolic AlkalosisElevation of arterial pH, increased plasma HCO3, and compensatory hypoventilationHigh HCO3 may be compensatory for respiratory acidosisHCO3 > 40 indicates metabolic alkalosisPathophysiology: Two Key QuestionsHow do patients become alkalotic?Why do they remain alkalotic?Generation of Metabolic AlkalosisLoss of H+ ionsGI loss: vomiting, GI suction, antacidsRenal loss: diuretics, mineralocorticoid excess, hypercalcemia, post-hypercapniaAdministration of bicarbonateTranscellular shiftK+ loss → H+ shifts intracellularlyIntracellular acidosisRefeeding syndromeContraction alkalosisSame HCO3, smaller extracellular volume → increased [HCO3]Seen in CF (sweating), illustrated in Fig 18-1Common theme: hypochloremia is essential for maintenanceMaintenance of Metabolic AlkalosisKidneys normally excrete excess HCO3Example: Normal subjects excrete 1000 mEq NaHCO3/day with minor pH changeImpaired HCO3 excretion required for maintenanceTable 18-2Mechanisms of MaintenanceDecreased GFR (less important)Increased tubular reabsorptionProximal tubule (PT): reabsorbs 90% of filtered HCO3TALH and distal nephron manage the restContributing factors:Effective circulating volume depletionEnhances HCO3 reabsorptionAng II increases Na-H exchangeIncreased tubular [HCO3] enables more H+ secretionDistal nephron HCO3 reabsorptionStimulated by aldosterone (↑ H-ATPase, ↑ Na reabsorption)Negative luminal charge impedes H+ back-diffusionChloride depletionReduces NaK2Cl activity → ↑ renin → ↑ aldosteroneLuminal H-ATPase co-secretes Cl → low Cl increases H+ secretionCl-HCO3 exchanger needs Cl gradient → low Cl impairs HCO3 secretionKey conclusion: Cl depletion > volume depletion in perpetuating alkalosisAlbumin corrects volume but not alkalosisNon-N Cl salts correct alkalosis without fixing volumeHypokalemiaStimulates H+ secretion and HCO3 reabsorptionTranscellular shift (H/K exchange) → intracellular acidosisH-K ATPase reabsorbs K and secretes HSevere hypokalemia reduces Cl reabsorption → ↑ H+ secretionImportant with mineralocorticoid excessRespiratory CompensationHypoventilation: 0.7 mmHg PCO2 ↑ per 1 mEq/L HCO3 ↑PCO2 can exceed 60Rise in PCO2 increases acid excretion (limited effect on pH)EpidemiologyGI Hydrogen LossGastric juice: high HCl, low KClStomach H+ generation → blood HCO3Normally recombine in duodenumVomiting/antacids prevent recombination → alkalosisAntacids (e.g., MgOH)Mg binds fats, leaves HCO3 unbound → alkalosisRenal failure impairs excretionCation exchange resins (SPS, MgCO3) → same effectCongenital chloridorrheaHigh fecal Cl-, low pH → metabolic alkalosisPPI may help by reducing gastric Cl loadRenal Hydrogen LossMineralocorticoid excess & hypokalemiaAldosterone → H+ ATPase stimulation, Na+ reabsorption → negative lumen → ↑ H+ secretionDiuretics (loop/thiazide)Volume contractionSecondary hyperaldosteronismIncreased distal flow and H+ lossPosthypercapnic alkalosisChronic respiratory acidosis → ↑ HCO3Rapid correction (ventilation) → unopposed HCO3 → alkalosisGradual CO2 correction neededMaintenance: hypoxemia, Cl lossLow chloride intake (infants)Na+ reabsorption must exchange with H+/K+H+ co-secretion with Cl impaired if Cl is lowHigh dose carbenicillinHigh Na+ load without ClNonresorbable anion → hypokalemia, alkalosisHypercalcemia↑ Renal H+ secretion & HCO3 reabsorptionCan contribute to milk-alkali syndromeRarely causes acidosis via reduced proximal HCO3 reabsorptionIntracellular H+ ShiftHypokalemiaCommon cause and effect of metabolic alkalosisH+/K+ exchange → intracellular acidosis → ↑ H+ excretionRefeeding SyndromeRapid carb reintroduction → cellular shiftNo volume contraction or acid excretion increaseRetention of BicarbonateRequires impaired excretion to become significantOrganic anions (lactate, acetate, citrate, ketoacids)Metabolism → CO2 + H2O + HCO3Citrate in blood transfusion (16.8 mEq/500 mL)8 units → alkalosis riskCRRT + citrate anticoagulantSodium bicarbonate therapyRebound alkalosis possible with acid reversal (e.g., ketoacidosis)Extreme cases: pH up to 7.9, HCO3 up to 70Contraction AlkalosisNaCl and water loss without HCO3Seen in vomiting, diuretics, CF sweatMild losses neutralized by intracellular buffersSymptomsOften asymptomaticFrom volume depletion: dizziness, weakness, crampsFrom hypokalemia: polyuria, polydipsia, weaknessFrom alkalosis (rare): paresthesias, carpopedal spasm, lightheadednessMore common in respiratory alkalosis due to rapid pH shift across BBBPhysical exam not usually helpfulClues: signs of vomitingDiagnosisHistory is keyIf unclear, suspect:Surreptitious vomitingCFSecret diuretic useMineralocorticoid excessUse urine chlorideTable 18-3: urine Na is misleading in alkalosisTable 18-4: urine chemistry changes with complete HCO3 reabsorptionVomiting: low urine Na, K, Cl + acidic urineSufficient NaCl intake prevents this stageExceptions to low urine Cl:Severe hypokalemiaTubular defectsCKDDistinguishing from respiratory acidosisUse pH as guideCaution with typo (duplicate pCO2)A-a gradient might helpTreatmentCorrect K+ and Cl− deficiency → kidneys self-correctUpper GI losses: add H2 blockersSaline-responsive alkalosisTreat with NaClMechanisms:Reverse contraction componentReduce Na+ retention → promote NaHCO3 excretion↑ distal Cl delivery → enable HCO3 secretion via pendrinMonitor urine pH: from 5.5 → 7–8 with therapyGive K+ with Cl, not phosphate, acetate, or bicarbonateSaline-resistant alkalosisSeen in edematous states or K+ depletionEdema (CHF, cirrhosis): use acetazolamide, HCl, dialysisAcetazolamide: may ↑ CO2 via RBC carbonic anhydrase inhibitionMineralocorticoid excess: K+ + K-sparing diuretic (use caution)Severe hypokalemia:eNaC Na+ reabsorption must be countered by H+ if no K+Corrects rapidly with K+ replacementRestores saline responsivenessRenal failure: requires dialysis

ReferencesChapter 19, Part 1 Metabolic acidosis  June 14, 2023American Society of Nephrology | Medical Students - Kidney TREKS this is the program that Josh mentioned at Mount Desert Island! Effects of pH on Potassium: New Explanations for Old Observations - PMC here’s the review melanie from Peter Aronson that clarifies the fact that there are no H+-K+ antiporters outside the kidney but rather coupled transport-We discussed whether we like “Winter’s formula” Quantitative Displacement of Acid-Base Equilibrium in Metabolic Acidosis | Annals of Internal Medicine Dr. R. W. Winters was charged with larceny https://www.nytimes.com/1982/05/16/nyregion/ex-columbia-u-doctor-charged-with-larceny.htmlJCI - The Maladaptive Renal Response to Secondary Hypocapnia during Chronic HCl Acidosis in the Dog this was a classic experiment exploring the respiratory response to an infusion of HCl but the animals were maintained in a high pCO2 milieu (not generalizable to humans!)Here’s the thoughtful Pulmcrit post (by Josh Farkas)  that Josh mentioned regarding correction of anion gap for hypoalbuminemia: Mythbusting: Correcting the anion gap for albumin is not helpfulJC mentioned that the anion gap does change in cirrhosis when the albumin is very low but using the correction factor may not change the clinical findings Acid-base disturbance in patients with cirrhosis: relation to hemodynamic dysfunctionDiagnostic Importance of an Increased Serum Anion Gap | NEJM Melanie mentioned the work of Patricia Gabow on the anion gap. In this review, she refers to work that she had done to try to identify all the organic anions in the anion gap but it falls short. Also, check out this critical look at the delta/delta: The Δ Anion Gap/Δ Bicarbonate Ratio in Lactic Acidosis: Time for a New Baseline?Roger mentioned near drowning in the Dead Sea and the unusual electrolytes in that instance. Near-Drowning in the Dead Sea: A Retrospective Observational Analysis of 69 PatientsWe discussed this classic NEJM article by Daniel Batlle The Use of the Urinary Anion Gap in the Diagnosis of Hyperchloremic Metabolic AcidosisAmy mentioned this review from  Uribarri  and Oh in JASN on the urine anion gap: The Urine Anion Gap: Common MisconceptionsJoel has a great blog post on the urine osmolar gap. urine osmolar gap – Precious Bodily Fluids Anna’s VoG on the bicarb deficit:  Kurtz, I Acid-Base Case Studies, 2nd Edition. Trafford Publishing 2004.  And the Fernandez paper that derived a better equationReference for Josh’s VoG: Key enzyme in charge of ketone reabsorption of renal tubular SMCT1 may be a new target in diabetic kidney diseaseSevere anion gap acidosis associated with intravenous sodium thiosulfate administrationUnexpectedly severe metabolic acidosis associated with sodium thiosulfate therapy in a patient with calcific uremic arteriolopathySodium Thiosulfate Induced Severe Anion Gap Metabolic AcidosisSodium Thiosulfate and the Anion Gap in Patients Treated by HemodialysisOutline: Chapter 19 Metabolic AcidosisOverviewLow arterial pHReduced HCO3Compensatory hyperventilation (↓ pCO2)Bicarb < 10 strongly suggests metabolic acidosis (renal compensation for respiratory alkalosis does not go that low)PathophysiologyH+ + HCO3- <=> H2CO3 <=> CO2 + H2OAcidosis results from H+ addition or HCO3 lossResponse to Acid LoadExtracellular bufferingExample: Add 12 mmol H+/L → HCO3 falls from 24 → 12 → pH drops to 7.1 (40 to 80 nmol/L)Intracellular and bone buffering55–60% buffered intracellularly and in bone12 mEq/L acid load only reduces serum HCO3 by ~5 mEq/LH+ into cells → K+ out (hyperkalemia)Notably in diarrhea or renal failureLess effect with organic acidosis (e.g., DKA, lactic acidosis)Respiratory compensationStimulates chemoreceptors → ↑ tidal volume (more than RR)Decreases pCO2, increases pHBegins within 1–2 hours; peaks at 12–24 hoursWinters formula alternative: for every 1 mEq ↓ HCO3, pCO2 ↓ by 1.2Chronic: respiratory compensation is blunted by renal adaptationRenal hydrogen excretion50–100 mEq/day acid generated from diet90% filtered HCO3 reabsorbed in PTAcid secreted:10–40 mEq via titratable acid (TA)30–60 mEq via NH3/NH4 (can ↑ to 250 mEq in acidosis)TA: phosphate (DKA → ketones act as TA)Max excretion up to 500 mEq/day in severe acidosisGeneration of Metabolic AcidosisMechanismsInability to excrete H+ (slow)Addition of H+ or loss of HCO3 (rapid)Anion Gap (AG)Normal: 5–11 (falling due to rising Cl-)Mostly due to negatively charged proteins (albumin)Adjust for albumin: AG ↓ 2.5 per 1 g/dL albumin ↓Revised: AG = unmeasured anions - unmeasured cations↑ AG = addition of unmeasured anions (e.g., lactate, ketones)Hyperchloremic acidosis: ↓ HCO3 replaced by ↑ Cl (normal AG)Delta–Delta AnalysisAdjust AG for albuminNormal ΔAG:ΔHCO3 = 1.6:1 (early 1:1)<1 → high + normal AG acidosisOther causes of AG variationHigh AG without acidosis: hemoconcentration, alkalosisLow AG: hypoalbuminemia, ↑ unmeasured cations (lithium, IgG, lab artifact)Urine Anion Gap (UAG)Normal = ~0; should be very negative (< -20) in acidosisType 1 & 4 RTA → UAG positive or near zeroInvalid in ketoacidosis or volume depletion (Na retention → ↓ distal acidification)Urine Osmolal GapEstimate NH4+ via osmolar gapRequires urine Na, K, glucose, ureaEtiologies and DiagnosisLactic AcidosisPyruvate → lactate (LDH; NADH → NAD+)Normal production: 15–20 mmol/kg/dayMetabolized in liver/kidney → pyruvate → glucose or TCANormal lactate: 0.5–1.5 mmol/L; acidosis if > 4–5 mmol/LCauses:↑ production: hypoxia, redox imbalance, seizures, exercise↓ utilization: shock, hepatic hypoperfusionMalignancy, alcoholism, antiretroviralsD-lactic acidosisShort bowel/jejunal bypassGlucose → D-lactate (not metabolized by LDH)Symptoms: confusion, ataxia, slurred speechSpecial assay neededTx: bicarb, oral antibioticsTreatmentUnderlying causeBicarb controversial: may worsen intracellular acidosis, overshoot alkalosis, ↑ lactateTarget pH > 7.1; prefer mixed venous pH/pCO2Ketoacidosis (Chapter 25 elaborates)FFA → TG, CO2, H2O, ketones (acetoacetate, BHB)Requires:↑ lipolysis (↓ insulin)Hepatic preference for ketogenesisCauses:DKA (glucose > 400)Fasting ketosis (mild)Alcoholic ketoacidosisPoor intake + EtOH → ↓ gluconeogenesis, ↑ lipolysisMixed acid-base (vomiting, hepatic failure, NAGMA)Congenital organic acidemias, salicylatesDiagnosis:AG, osmolar gap (acetone, glycerol)Ketones: nitroprusside only detects acetone/acetoacetateBHB can be 90% of total (false negative)Captopril → false positiveTreatment:Insulin +/- glucoseRenal Failure↓ excretion of daily acid loadGFR < 40–50 → ↓ ammonium/TA excretionBone buffering stabilizes HCO3 at 12–20 mEq/LSecondary hyperparathyroidism helps with phosphate bufferingAlkali therapy controversial in adultsIngestionsSalicylatesSymptoms at >40–50 mg/dLEarly: respiratory alkalosis → Later: metabolic acidosisTreatment: bicarb, dialysis (>80 mg/dL or coma)MethanolMetabolized to formic acid → retinal toxicityOsmolar gap elevatedTx: bicarb, ethanol/fomepizole, dialysisEthylene glycol→ glycolic/oxalic acid → renal failureSame treatment + thiamine/pyridoxineOtherToluene, sulfur, chlorine gas, hyperalimentation (arginine, lysine)GI Bicarbonate LossDiarrhea, bile/pancreatic drainage → loss of alkaline fluidsUreterosigmoidostomy → Cl-/HCO3- exchange in colonCholestyramine → Cl- for HCO3-Renal Tubular Acidosis (RTA)Type 1 (Distal)↓ H+ secretion in collecting duct → urine pH > 5.3Etiologies: Sjögren, RA, amphotericinFeatures: nephrocalcinosis, stones, hypokalemiaDiagnosis: NAGMA, persistent ↑ urine pHTreatment: alkali (1–2 mEq/kg/d adults; 4–14 kids), K+ if neededType 2 (Proximal)↓ HCO3 reabsorptionBicarb threshold reduced → self-limitedCauses: multiple myeloma, Fanconi, ifosfamideFeatures: rickets/osteomalacia, no stones, pH variableDiagnosis: NAGMA, pH < 5.3, high FE HCO3 when HCO3 loadedTreatment: alkali (10–15 mEq/kg/d), thiazidesType 4Aldo deficiency/resistance → hyperkalemia + mild acidosisK+ inhibits NH4 generationTx: correct K+, consider loop diureticsSymptomsHyperventilation (dyspnea)pH < 7.0–7.1 → arrhythmias, ↓ contractilityNeurologic: lethargy → coma (CSF pH driven)Skeletal growth issues in childrenTreatment PrinciplesNo alkali needed for keto/lactic acidosis unless pH < 7.2Bicarbonate DeficitDeficit = HCO3 space * (desired - actual HCO3)HCO3 space: 50–70% of body weightWatch for:K+ shifts: beware hypokalemia when correcting acidosisNa+ load in CHFDialysis if necessary