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References
This is the thiazide induced hyponatremia reference mentioned by Friedman: Thiazide-Induced Hyponatremia: Reproducibility by Single Dose Rechallenge and an Analysis of Pathogenesis
This 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 analysis
And 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 - PMC
Here’s the abstract that Amy mentioned: Abstract P174: Incidence of Hyponatremia on Spironolactone in Patients With a Prior Episode of Chlorthalidone-Induce Hyponatremia
We mentioned the issue of solute intake again and this favorite reference: Impact of solute intake on urine flow and water excretion
Joel 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 myxedema
Amy mentioned this reference: The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: results of a large prospective single-centre study
Some 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 insipidus
Here’s a reference on fetal vs maternal sodium gradient: Fetal diuretic responses to maternal hyponatremia: contribution of placental sodium gradient | Journal of Applied Physiology
Roger mentions the nephrogenic syndrome of antidiuresis: Nephrogenic Syndrome of Inappropriate Antidiuresis - PMC
The NEJM manuscript looking at water dilution in schizophrenia: Mechanisms of Altered Water Metabolism in Psychotic Patients with Polydipsia and Hyponatremia
Tragic case of water loading Woman dies after being in water-drinking contest - Los Angeles Times
The case report that Josh mentioned: Self-induced water intoxication without predisposing illness
Roger 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=1
And here’s an instructive case: Electrolyte Abnormalities in a Man With Plasma Cell Leukemia - American Journal of Kidney Diseases
Amy’s VoG on Legionella and Hyponatremia
association with hyponatremia
first 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 criteria
sensitivity 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 hypophosphatemia
https://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 — Hyponatremia
Diuretics
Mild 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 Hyponatremia
The 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 depletion
Potassium depletion
Direct inhibition of urinary dilution through decreased NaCl reabsorption
If 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 Different
Loop 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/L
Plasma Na <110 mEq/L
This 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 Failure
Renal failure impairs the ability to maximally dilute urine after a water load.
Potential mechanism:
Osmotic diuresis in the remaining nephrons
Severe hyponatremia is relatively uncommon when patients remain non-oliguric.
Risk increases as GFR approaches zero.
SYNDROME OF INAPPROPRIATE ADH SECRETION
Introduction
SIADH is:
Common
Associated with a wide range of clinical conditions
Characterized by nonphysiologic ADH activity
An unusual physiologic state in which water excretion is impaired while Na excretion remains relatively intact
See Table 23-3.
Pathogenesis
See 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 retention
Sodium excretion
…produces hyponatremia.
In chronic SIADH, sodium loss may become as important as or more important than the initial water retention.
Potassium Loss
Hyponatremia causes cellular swelling.
Cells adapt by ejecting intracellular solutes, including:
Potassium
The released potassium is subsequently excreted by the kidney.
Chronic Adaptation
A new steady state develops over approximately a couple of weeks.
At steady state:
Na intake = Na output
Contributing mechanisms include:
Relative ADH resistance
Reduced urine osmolality
Reduced aquaporin expression
Importantly, water ingestion remains essential. Without water intake, SIADH cannot produce hyponatremia.
Patterns of ADH Secretion in SIADH
Four patterns are described.
Type A — Erratic ADH Secretion
ADH secretion is essentially independent of osmotic regulation.
Type B — Reset Osmostat
ADH 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 ADH
ADH regulation appears normal around normal plasma osmolality.
But ADH cannot be completely suppressed when plasma osmolality falls.
Type D — Normal Measured ADH
Possible explanations:
Increased renal sensitivity to ADH
Another unidentified antidiuretic factor
Acid-Base and Potassium Balance in SIADH
Interesting 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 SIADH
SIADH can result from:
Increased hypothalamic ADH production
Ectopic ADH production
Potentiation of ADH’s renal effect
Exogenous ADH or related hormones
CNS / Neuropsychiatric Disease
Neuropsychiatric disorders can promote ADH release:
Directly
Through cortical neuronal pathways stimulating the hypothalamus
Examples:
Approximately 20% of patients with subarachnoid hemorrhage
Approximately 20–35% after transsphenoidal pituitary surgery
Adrenal insufficiency may contribute following pituitary surgery.
Psychiatric patients may have abnormalities at several levels:
Water intake
ADH secretion
Renal responsiveness to ADH
Again, much water intake is habitual rather than thirst-driven.
HIV
Hyponatremia has been reported in approximately 40% of patients with HIV infection.
Potential mechanisms include:
Volume depletion
Adrenal insufficiency
SIADH
Pneumocystis pneumonia
Malignancy
CNS disease
Drugs
Many drugs have been associated with SIADH, although most only rarely produce clinically significant hyponatremia.
Cyclophosphamide
Increases 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.
Chlorpropamide
Oral hypoglycemic agent.
Increases NaCl reabsorption in the TAL.
Increases sensitivity to ADH.
NSAIDs
Increase 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 Disease
Associated conditions include:
Pneumonia
Asthma
Atelectasis
Emphysema
Pneumothorax
Tuberculosis
Acute respiratory failure
Possible 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 Surgery
Transient SIADH may occur for 2–5 days after major surgery.
Pain afferents can directly stimulate hypothalamic ADH secretion.
Ectopic ADH Production
Classic association:
Small-cell carcinoma of the lung
Exogenous ADH and Oxytocin
Oxytocin:
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 bleeding
DDAVP for:
Nocturia
Platelet dysfunction
Central diabetes insipidus
Idiopathic SIADH
Occasionally no cause is identified.
Consider:
Occult malignancy
Temporal arteritis
These patients may have low serum uric acid because of increased urinary uric acid clearance.
CEREBRAL SALT WASTING
Rare syndrome associated with cerebral disease, particularly:
Subarachnoid hemorrhage
Phenotype:
Hyponatremia
High urine Na
Low serum uric acid
Volume depletion
Volume depletion is the key proposed distinction from SIADH.
A theoretical factor released from the injured brain may cause:
Renal salt wasting
Uric acid wasting
BNP has been proposed as one candidate.
ADRENAL INSUFFICIENCY
Hyponatremia is common in adrenal insufficiency.
Separating the contributions of:
Cortisol deficiency
Volume 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 ↑
HYPOTHYROIDISM
Hypothyroidism is often listed in the differential diagnosis of hyponatremia, but it is actually a rare cause of clinically significant hyponatremia.
RESET OSMOSTAT
Patients fulfill many criteria for SIADH but regulate osmolality around a lower set point.
Described in:
Hypovolemic states
Psychosis
Chronic malnutrition
Pregnancy
Possible mechanisms include:
Baroreceptor-mediated ADH stimulation
Altered cellular metabolism in malnutrition
Pregnancy-related hormonal effects
During pregnancy, hCG may promote release of ovarian relaxin.
Potential mechanisms:
Vasodilation → relative effective volume depletion
Direct effects on osmoreceptor regulation
PRIMARY POLYDIPSIA
Occurs in approximately 7% of patients with schizophrenia.
Clinical clues:
Weight gain during the day from water accumulation
Excessive water drinking
Dry mouth from medications
There 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/kg
Symptomatic hyponatremia after drinking 3–4 L of water while anxiously awaiting a drug test
Severe cases often involve stacked etiologies:
Primary polydipsia
Thiazides
Antipsychotics
Nausea-induced ADH
Stress-induced ADH
Low-solute intake / beer potomania
PSEUDOHYPONATREMIA AND NON-HYPOOSMOLAR HYPONATREMIA
Normal Plasma Osmolality
Classic Pseudohyponatremia
Normally, approximately 930 mL of each liter of plasma is water.
With severe:
Hyperlipidemia
Hyperproteinemia
…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 / Hysteroscopy
Absorption of non-electrolyte irrigation solutions can produce complex abnormalities.
Probably historical enough to skip?
Hyponatremia With Increased Plasma Osmolality
Hyperglycemia
Interesting 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.
Mannitol
Mannitol can cause hyperosmolar hyponatremia.
The amount of circulating mannitol can be estimated using the osmolar gap.
IVIG
Some IVIG preparations contain maltose, which can accumulate and contribute to hyperosmolar hyponatremia.

Roger’s Hydrogen to pH table

References
December 19, 2023
Joel had a patient with severe hypothyroidism and hyponatremia- case report
Mel 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 unit
JC 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.1986.02140200045024
Here’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 rate
We 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/NEJMoa043901
Amy’s VOG on Gastric Secretions
Dr. 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 secretions
From 1961! https://pubmed.ncbi.nlm.nih.gov/13714620/
From 1959! https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/expphysiol.1960.sp001428
Secretions (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_Edition
Basic Facts of Body Water and Ions (see page 96) https://link.springer.com/book/10.1007/978-3-662-38375-9
Chapter 23: Hypoosmolar States — Hyponatremia
PATHOPHYSIOLOGY
Plasma Sodium and Plasma Osmolality
Plasma 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 Hyponatremia
Two questions provide a useful framework:
How do patients develop hyponatremia?
Why do they remain hyponatremic?
Generation of Hyponatremia
Either 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 Hyponatremia
The 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, or
Serum 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 Excretion
Free-water excretion depends on two processes:
Generation of dilute tubular fluid
NaCl 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 fluid
Requires 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:
SIADH
Decreased effective circulating volume
Important exceptions include:
Oliguric kidney failure
Primary polydipsia
Low-solute intake / “tea and toast” physiology? Not discussed here.
Using Urine Osmolality as an ADH Readout
Urine 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 Much
Assume:
Daily solute load = 400 mOsm
Daily water intake = 2 L
If the kidney can dilute urine to 200 mOsm/kg:
400 mOsm ÷ 200 mOsm/kg = 2 L urine
All 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 urine
That 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.
ETIOLOGY
See 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 Depletion
Effective 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 Depletion
Loss of both:
Intravascular fluid
Interstitial fluid
Potential sources:
GI tract
Kidneys
Skin
Other Causes of Reduced Effective Circulating Volume
Decreased vascular resistance
Example: advanced liver disease
Reduced cardiac output
Example: heart failure
Why Effective Volume Depletion Causes Hyponatremia
Effective volume depletion affects:
Thirst
Potassium balance
Water excretion
ADH
Hypovolemia sensed through arterial baroreceptors is a potent non-osmotic stimulus for ADH secretion.
Reduced Delivery to the Diluting Segments
Volume depletion can also cause:
Reduced GFR
Increased proximal Na reabsorption
Reduced fluid delivery to the diluting segments
This theoretically reduces free-water generation even without ADH.
However, how important is this mechanism?
ADH antagonists can largely reverse impaired water excretion in:
Heart failure
Cirrhosis
Adrenal insufficiency
…without necessarily improving tissue perfusion.
That argues that ADH is doing much of the work.
Severity of Disease Matters
The tendency toward increased ADH and reduced distal delivery increases with the severity of effective volume depletion.
Thus:
Worse heart failure → greater risk of hyponatremia
Worse cirrhosis → greater risk of hyponatremia
Hyponatremia 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 Matters
The severity of hyponatremia is strongly influenced by how much water the patient consumes.
Ultramarathoners
May 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.
Cholera
Severe diarrhea from cholera may contain:
Stool Na approximately 120–140 mEq/L.
Low-solute replacement solutions increase the risk of hyponatremia.
Concurrent Potassium Depletion
Potassium 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.

References
This 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 Gateway
Joel 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.pdf
This 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 Library
Joel 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 Medicine
We couldn't help flirting with diarrhea a little Secretory diarrhoea: mechanisms and emerging therapies - PMC
We 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 - PMC
PBFluids classic: Saltiest Sodium. Dumbest Dude
Volume 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:
PMC3041494
42321668
41846300
42195166
33374011
PMC3041494
PMC12884999
3102222
42060832
41201721
32401639
Link to Goljian Physiology Spotify! Episode 2 is Fluid and Hemodynamics: https://open.spotify.com/show/1uD6090Kkg01b4zr2ouNiM?si=e7f609e0d9634840

Outline: Chapter 22
Introduction to Disorders of Osmolality
Hyponatremia and hypernatremia are common clinical problems
Reflect abnormalities of water balance that may or may not be accompanied by changes in Na balance
Water Distribution and Osmotic Pressure
TBW makes up 60% of lean body weight in men
50% of lean body weight in women
60% intracellular
40% extracellular
One-fifth of extracellular water is in the intravascular space
Breakdown
70 kg man
TBW = 42 L
25 L intracellular
17 L extracellular
3 L of the 17 L is intravascular
Osmotic forces determine the distribution of water
Each compartment has one major solute that holds water within the compartment
Na → extracellular compartment
K → intracellular compartment
Plasma proteins → plasma space
Urea is an ineffective osmole
Physiologic Effects of Changes in Plasma Osmolality
Figure 22-1
Na pulls water from the intracellular compartment
Increases extracellular volume
Decreases intracellular volume
Even though Na is locked in the extracellular compartment
Administering Na increases osmolality everywhere by changing water distribution
Increases extracellular volume
Decreases intracellular volume
Example
Adding 210 mEq Na to 17 L ECF would mathematically increase concentration by 12.5 mEq/L (210/17)
Actually only raises serum Na by ~5
Water moves from cells
Na remains trapped in ECF
Ultimately diluted in TBW
210/42 L = 5 mEq/L
Adding water
Expands both compartments
Dilutes osmolality in both compartments
Giving isotonic saline
Expands extracellular compartment only
Does not change intracellular volume
Changes in osmolality and intracellular volume
Responsible for symptoms of hypo- and hypernatremia
In these examples
Extracellular volume is increased
Sodium concentration may be high, low, or normal
Meaning of Plasma Sodium Concentration
Na, glucose, and urea are the primary extracellular osmoles
Gives osmolality calculation
Under normal conditions
Glucose and BUN contribute <10 mOsm/L
Therefore
Plasma osmolality ≈ 2 × plasma Na
Hypernatremia represents hyperosmolality
Hyponatremia usually reflects hypo-osmolality
Exception: hyperglycemia
Plasma Sodium Concentration and Total Body Osmolality
If plasma Na reflects plasma osmolality
And plasma osmolality is in equilibrium with total body osmolality
Then plasma Na reflects total body osmolality
Since
Total body osmolality = (ECF solutes + ICF solutes) / TBW
And
Na and K (plus accompanying anions) are the major extracellular and intracellular solutes
Then
Plasma Na ≈ (Na + K) / TBW
Figure 22-2
Key Edelman figure
Loss of potassium
K moves out of cells
To maintain electroneutrality
Na enters cells
Lowers serum Na
Or Cl leaves with K
Lowers intracellular osmolality
Water moves from cells to ECF
Dilutes serum Na
Or extracellular H dissociates from buffers and enters cells
Combines with intracellular buffers
No net movement of solute
Water still leaves cells
Serum Na diluted
Suggests K loss is responsible for much diuretic-induced hyponatremia (Ref 2)
DKA example
0.45% NS with 40 mEq KCl is insufficient to correct hyperosmolality
Hyponatremia and Hypernatremia
Can result from alterations in
Na
K
Water
Usually due to water abnormalities
Exception
Thiazides
Loss of both Na and K contributes
Toxicity of K prevents excess K from producing hypernatremia
Diarrhea
Isosmotic to plasma
Ionic composition varies
Secretory diarrhea (cholera)
Na + K approximately equals plasma Na
Causes volume depletion
Does not cause hypernatremia
Osmotic diarrhea
Fecal Na + K between 30 and 110
Nonreabsorbed solutes account for remainder
Causes hypernatremia
Diarrheal illness
Often causes fever
Increases insensible losses
Also stimulates ADH and thirst
Usually water balance remains near normal
Infants commonly become hypernatremic
Regulation of Plasma Osmolality
Daily variation in water intake and loss alters plasma osmolality
Water intake
Drinking
Water content of food
Water of oxidation
Carbohydrates metabolized to CO2 and H2O
Water retention lowers plasma osmolality
Water loss
Urine
Feces
Skin
Respiratory tract
Water loss raises plasma osmolality
Water intake and excretion are tightly regulated
Osmoreceptors in hypothalamus
After water load
Plasma osmolality falls
ADH release inhibited
Urinary water loss increases
Hyperosmolality
Stimulates thirst
Stimulates ADH
Increases water intake
Decreases water loss
Regulation disrupted by
Neurologic disorders
Hypothalamus
Posterior pituitary
Renal disorders
Impaired concentrating or diluting ability
Nonosmotic stimuli
Volume depletion
Osmoregulation versus Volume Regulation
Table 22-2
Plasma osmolality
Ratio of solute to water
Extracellular volume
Determined by absolute amount of Na and water
Two examples
Exercising on a hot day
Loss of dilute sweat
↑ Plasma osmolality (Na)
↓ Extracellular volume
SIADH
↓ Plasma osmolality (Na)
↑ Extracellular volume
Nice exercise at bottom of page 691
Isotonic saline
Does not change osmolality
Hypothalamus not activated
Increased volume suppresses renin
Increases ANP
Water load
Inhibits ADH
Produces dilute urine
Rapid restoration of volume
Only transient volume expansion
Little effect on renin or ANP
NaCl without water
Expands extracellular volume
Stimulates renal NaCl loss
Also stimulates thirst and ADH
Produces small volume of concentrated urine
Similar to intake
Volume Depletion versus Dehydration
They are not synonyms
Urine Osmolality and Specific Gravity
Relation Between Intake and Output
Simply comparing ins and outs is inadequate
Composition of fluids may differ markedly
Replacing urinary losses with free water
Produces hyponatremia

References
Biff Palmer! Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023
Josh 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 - PMC
If 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 - PMC
VOG 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 Diseases
Sodium bicarbonate therapy for acute respiratory acidosis
Joel 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 ascent
This 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 Trial

Outline: Chapter 20
Respiratory Acidosis
Clinical disorder characterized by
Reduced arterial pH
Elevation of pCO2
Variable increase in HCO3
Increased pCO2 is also seen in metabolic alkalosis
But here it is appropriate
And secondary
PATHOPHYSIOLOGY AND ETIOLOGY
Metabolism generates 15,000 mmol of CO2 per day
CO2 is not an acid, but
Combines with H2O to form H2CO3
H2CO3 dissociates to HCO3 and H+
Most H+ combines with intracellular buffers
Hemoglobin in RBCs
HCO3 leaves the cell via the chloride exchanger
Net result
CO2 generated is primarily carried in blood as HCO3
Little change in pH
Process reverses in the alveoli
As H+Hb is oxygenated, H+ is released
H+ combines with HCO3 to form H2CO3
Carbonic anhydrase breaks H2CO3 into H2O and CO2
CO2 is exhaled
Control of Ventilation
Alveolar ventilation
Provides oxygen for oxidative metabolism
Eliminates metabolically produced CO2
Main stimuli for respiration
Reduced arterial pO2
Increased pCO2
Controlled in chemosensitive areas of the medulla
Respond to CO2-induced changes in cerebral pH
Initial hypoxic stimulation comes from carotid body chemoreceptors
Figure 20-1 is wild
pCO2 is maintained within narrow limits despite
Large daily CO2 load
Variable respiratory quotient
Variable metabolic rate
Minute ventilation rises 1–4 liters for every 1 mmHg rise in pCO2
pO2 does not significantly stimulate ventilation until arterial pO2 <50–60 mmHg
Actually starts earlier
Increased ventilation lowers pCO2 which inhibits respiration
If pCO2 is fixed, pO2 of 70–80 mmHg will stimulate respiration
Figure 20-2
Development of Hypercapnia
Because CO2 is such a potent respiratory stimulant
Respiratory acidosis is usually due to decreased minute ventilation
Not increased CO2 production
Table 20-1 lists causes
CO2 retention in intrinsic pulmonary disease
Due to ventilation/perfusion mismatch
Hypercapnia is beneficial
Allows excretion of produced CO2 at lower minute ventilation
Consequences
Increased pCO2 decreases pH
Increased bone and cellular buffering
Increased renal H secretion
Raises serum HCO3
Relationship Between Hypercapnia and Hypoxemia
All hypercapnic patients breathing room air have lower alveolar and arterial pO2
Total alveolar partial pressures must equal atmospheric pressure
Hypoxemia generally occurs earlier and is more severe than hypercapnia
CO2 diffuses 20× faster than O2
Compensation by increasing ventilation in normal lung segments
Improves CO2 elimination
Cannot substantially increase O2 because Hb already saturated
Acute asthma example
Mucus plugging and bronchoconstriction cause hypoxemia
Hypoxemia and mechanoreceptors stimulate ventilation
Produces respiratory alkalosis
Respiratory acidosis is a late finding
Respiratory resistance rises
Maximal minute ventilation falls
pCO2 rises
First normalizes
Then becomes elevated
Therefore
Normal pCO2 in acute asthma indicates severe disease
Generalization to other lung diseases
Even small increases in pCO2 indicate severe respiratory disease
Hypoxemia-induced hyperventilation delays hypercapnia
But there is 16-fold variability in sensitivity to hypoxemia
Less sensitive individuals develop respiratory acidosis more readily
Regulation of Ventilation in Chronic Respiratory Acidosis
Two common statements
Respiratory centers become less sensitive to CO2 over time
Hypoxia becomes the primary respiratory stimulus
Insensitivity to CO2
Chemoreceptors primarily respond to pH
Chronic respiratory acidosis increases HCO3
Therefore less pH change despite elevated pCO2
Less respiratory stimulation
Worsening hypercapnia and hypoxia
Similarly
Diuretic-induced metabolic alkalosis suppresses ventilation
Dependence on hypoxemia
Patients with chronic respiratory acidosis rely on hypoxia to drive breathing
Loss of CO2 stimulation due to
Renal compensation raising HCO3
Diuretics raising HCO3
Making pH less dependent on pCO2
Hypoxia drives ventilation when pO2 falls below ~80
Makes oxygen administration potentially dangerous
Can suppress respiratory drive
Oxygen also reverses hypoxic vasoconstriction
Increases V/Q mismatch
Acute Respiratory Acidosis
Body poorly adapted to acute elevations in pCO2
HCO3 cannot buffer H2CO3
See Eq 20-4
Must use hemoglobin and proteins as buffers
See Eq 20-5
HCO3 rises 1 mEq/L for every 10 mmHg increase in pCO2
Example
pCO2 rises to 80
HCO3 rises to 28
pH falls to 7.17
Without buffering
pH would be 7.10
Not dramatically different
Etiology
Acute exacerbations of lung disease
Severe asthma
Pulmonary edema
Drug overdose
Sleep apnea syndromes
Central
Obstructive
Mixed
Chronic hypercapnia uncommon in isolated OSA
CO2 cleared during wakefulness
OSA + structural lung disease + obesity
Reduced daily alveolar ventilation
Persistent CO2 retention
Obesity hypoventilation syndrome
Mechanical ventilation
Inadequate respiratory rate can cause respiratory acidosis
Fixed ventilation means increased CO2 production can cause respiratory acidosis
Cardiac arrest
Suggests sodium bicarbonate
Arterial ABG may miss severity due to poor pulmonary blood flow
Mixed venous blood may be better guide
Enteral or parenteral overfeeding
Chronic Respiratory Acidosis
After 3–5 days
HCO3 rises 3.5 mEq/L for every 10 mmHg rise in pCO2
Example
pCO2 = 80
4 × 3.5 = 14
HCO3 should be 38
pH ~7.30
Allows tolerance of pCO2 values of 90–110
Exogenous alkali
Unnecessary
Useless
Easily excreted
Etiology
COPD
Genetic variation in sensitivity to hypoxemia and CO2
Blue bloaters
Low response to CO2
Hypoxia becomes primary respiratory stimulus
Pink puffers
Strong CO2 response
Tachypnea develops early
Compensation for loss of lung tissue
Pickwickian syndrome
Obesity hypoventilation syndrome
Book mistakenly says hyperventilation
Chest wall weight impairs breathing
More complex than that
Weight loss only helps some patients
Progesterone can improve condition
Suggests central respiratory defect
May coexist with OSA
Unlike OSA, Pickwickian patients have chronic respiratory acidosis
SYMPTOMS
Neurologic
Headache
Blurred vision
Restlessness
Anxiety
Can progress to
Somnolence (CO2 narcosis)
Tremor
Asterixis
Delirium
Increased CSF pressure
Papilledema
Due to increased cerebral blood flow
Symptoms due to CSF acidemia
Less common in metabolic acidosis
HCO3 crosses BBB poorly
Less common in chronic respiratory acidosis
Less severe acidemia
Arrhythmias
Peripheral vasodilation
Hypotension
Particularly when pH <7.1
Cor pulmonale
Peripheral edema
Can occur despite normal GFR
Suggests relationship between respiratory acidosis and renal sodium handling
Or possibly hypoxia
DIAGNOSIS
Last full paragraph on page 659 discusses ambiguity of ABGs
Nicely done
Figure 20-6
Two additional examples
Both instructive
Final 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 Gradient
Derivation
1 atmosphere = 760 mmHg
Water vapor = 47 mmHg
Nitrogen = 563 mmHg
Leaves ~150 mmHg oxygen
No net movement of water or nitrogen
Therefore O2 + CO2 must account for remaining pressure
PAO2 = PIO2 − PACO2
Must multiply CO2 by 1.25 to account for respiratory quotient
PAO2 = PIO2 − (1.25 × PACO2)
Since CO2 diffuses rapidly
PACO2 ≈ PaCO2
Normal values
PIO2 = 150
PaCO2 = 40
PAO2 = 150 − (1.25 × 40)
PAO2 = 100
Normal A-a gradient
5–10 mmHg in young adults
15–20 mmHg in elderly
A-a gradient = PAO2 − PaO2
Combined equation
A-a gradient = PIO2 − (1.25 × PaCO2) − PaO2
A-a gradient increased in intrinsic pulmonary disease
Oxygen has difficulty entering blood
May also be increased in some extrapulmonary disorders
No explanation given
Normal A-a gradient argues against pulmonary disease
Suggests
Central hypoventilation
Primary metabolic alkalosis
Chest wall weakness
Respiratory muscle weakness
TREATMENT
Complete discussion beyond scope of text
Acute Respiratory Acidosis
Give oxygen for hypoxia
Correct underlying cause of hypercapnia
Or intubate
Sodium bicarbonate
Role not well defined
May help if pH <7.15
Especially severe asthmatics on ventilators
Avoid in
Pulmonary edema
Can worsen congestion
CNS effects
Does not protect CNS because HCO3 does not cross BBB
Increased pCO2
Must monitor mixed venous pH
Late metabolic alkalosis
Rare according to author
Tromethamine (THAM)
Binds hydrogen
Rapidly cleared by kidneys
“THAM is of uncertain safety”
Chronic Respiratory Acidosis
Goals
Adequate oxygenation
Improve effective alveolar ventilation if possible
Rarely need to treat pH directly
Beware oxygen
Can act as respiratory depressant
Dietary modifications
Reduce carbohydrates
Improves respiratory drive for unclear reasons
Weight reduction
Improves respiratory mechanics
Target pO2 60–65
Reduces pulmonary vasoconstriction
Reduces secondary polycythemia
Mechanical ventilation
Lower pCO2 gradually
Rapid correction can induce metabolic alkalosis
Seizures
Coma
Effect of superimposed metabolic alkalosis
Metabolic alkalosis depresses ventilation
Discontinue diuretics
Give saline
Acetazolamide
Acetazolamide caveats
Need appropriate bicarbonate target, not normal
Can transiently increase pCO2 before diuretic effect
May be due to partial inhibition of carbonic anhydrase in RBCs needed for CO2 carrying capacity