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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 depletionAdr

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 weaknessRespirat