Channel Your Enthusiasm

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

References
Chapter 19, Part 3 August 30, 2023Biff Palmer’s Ted Talk-Why not? Biff Palmer at TEDxSMU 2013
Anna 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 Neurosciences
Reminder of important clinical lesson: Lactate: panicking doctor or panicking patient? - PMC
Melanie 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 2023
Melanie 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 Proteins
The 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 & Gynecology
Melanie 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 Neurology
He also mentioned this important transporters that affect the pH. The choroid plexus sodium-bicarbonate cotransporter NBCe2 regulates mouse cerebrospinal fluid pH
Refractory Central Neurogenic Hyperventilation: A Novel Approach Utilizing Mechanical Dead Space
Outline: Chapter 21
Respiratory Alkalosis
Increased pH, low pCO2, variable reduction in HCO3
Differentiate from metabolic acidosis where pH is decreased
(but pCO2 and HCO3 are likewise decreased)
PATHOPHYSIOLOGY
Primary decrease in pCO2 when effective alveolar ventilation is increased beyond that needed to eliminate daily CO2 production
How does the body respond to hypocapnia
Mass action
Reduction in H+ induced by hypocapnia can be minimized by lowering HCO3
One: rapid cell buffering
Two: later decrease in net renal acid secretion → lower HCO3
These two strategies explain the difference between acute and chronic respiratory alkalosis
Acute Respiratory Alkalosis
Within 10 minutes, H ions move into extracellular fluid
H+ combines with HCO3 → fall in plasma HCO3
Converted to CO2 and H2O
H+ comes from intracellular buffers
Protein, phosphate, hemoglobin
H+ 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 20
HCO3 falls by 4 → ~20 mEq/L
pH ~7.63
Not very efficient at protecting pH
Without compensation pH would be ~7.70
Chronic Respiratory Alkalosis
Compensatory ↓ renal H secretion
Begins within 2 hours
Not complete for 2–3 days
Due to parallel rise in tubular cell pH
Manifested by
HCO3 loss
Decreased NH4 in urine
4 mEq drop in HCO3 for each 10 mmHg decrease in pCO2
Example: pCO2 20 → HCO3 16 → pH ~7.53
ETIOLOGY
Respiration governed by two sets of chemoreceptors
Central (respiratory center in brainstem)
Peripheral (carotid bodies at bifurcation, aortic bodies at arch)
Central chemoreceptors
Stimulated by ↑ pCO2 or metabolic acidosis
Peripheral chemoreceptors
Stimulated by hypoxia (and acidosis)
Thus hyperventilation can be produced by
Hypoxemia
Anemia
Reduction in arterial pH
Other stimuli
Pain
Anxiety
Mechanoreceptors
Direct stimulation of respiratory center
Table 21-1
Hypoxemia
Respiratory response occurs in stages
Stage 1
Peripheral chemoreceptor activation
Hyperventilation → respiratory alkalosis
Increased cerebral pH inhibits central respiratory center
Limits hyperventilation
No significant hyperventilation until pO2 < 50–60 mmHg
If lung disease prevents pCO2 reduction
Hypoxia stimulates ventilation at PaO2 < 70–80 mmHg
Stage 2⁉️
Persistent hypoxemia → ↓ HCO3
Lowers pH toward normal
Removes alkalosis inhibition
Allows greater ventilatory response
Pulmonary Disease
Common in pneumonia, PE, interstitial fibrosis
Also pulmonary edema (though acidosis more common)
Hyperventilation may be due to hypoxemia
Often not corrected by oxygen
Other contributors
Mechanoreceptors in airways, lungs, chest wall
Signals via vagus nerve
Juxtacapillary receptors (interstitium)
Irritant receptors (epithelium)
Activated by inflammation or inhaled irritants
(asthma, pneumonia)
These contribute to dyspnea even without hypoxia
Direct Stimulation of Medullary Respiratory Center
Cortical input (psychogenic hyperventilation)
Retained amines in hepatic failure (not prostaglandins⁉️)
Bacterial toxins (gram-negative sepsis)
Salicylates
Progesterone (pregnancy, luteal phase)
Persistent acid CSF after rapid correction of metabolic acidosis
NaHCO3 raises extracellular pH
Peripheral chemoreceptors reduce ventilation → ↑ pCO2
CO2 crosses BBB rapidly, HCO3 does not
Brain senses ↑ pCO2 → ↓ CSF pH
Paradoxical prolongation of hyperventilation
Neurologic disorders
Pontine tumors → local acidosis → ↓ CSF pH → ↑ ventilation
Hypocapnia in acute cerebral accidents
Mechanical Ventilation
Overventilation can cause respiratory alkalosis
Correct by
Increasing dead space (no explanation given 🤷🏻‍♂️)
Decreasing tidal volume
Decreasing respiratory rate
SYMPTOMS
Due to increased CNS and peripheral nerve excitability
Lightheadedness
Altered consciousness
Paresthesias (extremities, circumoral)
Cramps
Carpopedal spasm
Syncope
Cardiac
Supraventricular and ventricular arrhythmias
Mechanisms
Impaired cerebral function
Increased membrane excitability
↓ cerebral blood flow
35–40% reduction if pCO2 drops by 20 mmHg
Psychogenic hyperventilation symptoms
Dyspnea
Headache
Chest pain
Symptoms more prominent in acute disease (rapid pH change)
Electrolytes
↓ phosphate (as low as 0.5–1.5 mg/dL)
Due to intracellular shift
Increased glycolysis → ↑ phosphorylated compounds
DIAGNOSIS
Tachypnea
But could be acidosis or alkalosis
Consider sepsis
Compensation equations can be ambiguous
Example: 7.48 / 20 / XX / 16
Could be chronic respiratory alkalosis
Or acute respiratory alkalosis + metabolic acidosis 😖
Case 21-1
5-year-old with AMS, playing with aspirin
TREATMENT
Usually not necessary
Do NOT give
Respiratory depressants
HCl
Paper bag rebreathing
↑ inspired CO2
Can correct acute respiratory alkalosis
If chronic → may leave patient with metabolic acidosis
Can treat with NaHCO3
“Give a mouse a cookie” 😉

References
Chapter 19, Part 3 August 30, 2023
Joel 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):1420-6
Josh 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 International
Melanie mentioned treatment of patients with cystinosis Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients | Clinical Kidney Journal | Oxford Academic
Amy 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 - PubMed
Roger mentioned that he has had good luck with Moonstone Nutrition drinks alkali citrates for kidney health
We 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 treatment
JC 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 syndrome
Lety mentioned concerns of encrustation of stents in stone forming individuals Potassium Citrate as a Preventive Treatment for Double-J Stent Encrustation: A Randomized Clinical Trial
Joel 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.aspx
Melanie 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 Acidosis
Here’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 2
Here’s this crazy piece on excessive bicarbonate - Gas production after reaction of sodium bicarbonate and hydrochloric acid
Josh points out that the pH can be important for inotropy: An effect of pH upon epinephrine inotropic receptors in the turtle heart
Mel’s favorite from Halperin because of the pun: Renal tubular acidosis (RTA): recognize the ammonium defect and pHorget the urine pH
Amy’s VOG on RTA and Osteoporosis
KI Review on acidosis and bone health: Effects of acid on bone
Guideline on congenital RTA: Distal renal tubular acidosis: ERKNet/ESPN clinical practice points
AJKD article on acidosis and bone health: Serum Bicarbonate and Bone Mineral Density in US Adults
Citrate reversing CsA induced acidosis effects: Citrate reverses cyclosporin A-induced metabolic acidosis and bone resorption in rats

Outline: Chapter 19 Metabolic Acidosis part 3
Renal Tubular Acidosis
Acidosis from diminished net tubular acid secretion
Three types
Type 1 (Distal)
Type 2 (Proximal)
Type 4 (…)
The acidosis of renal failure could be added to this group
But NH4+ per nephron is normal
This is a problem of too few nephrons, not tubular acidosis
Nephrons able to maximally acidify the urine
Type 1 Distal RTA
Decrease in net H secretion in the collecting duct
Minimal urine pH rises from 4.5 to 5.3
HCO3 can fall below 10
Three mechanisms
Defect in H-ATPase found in cortex and medulla
Sjögren syndrome
Can be genetic chloride bicarbonate exchanger
This pumps bicarbonate out basolateral membrane after it is generated in the splitting of water to form H
Defect in cortical Na reabsorption
Voltage-dependent defect
Concurrent K secretion defect
Found in urinary obstruction and sickle cell
Volume deficiency can decrease Na delivery to distal nephron
Decreased amount of Na reabsorption can cause a reversible type 1 RTA of this type
Increased membrane permeability
Amphotericin
pH of 5.0 is 250× plasma
Table 19-7
Fractional excretion of bicarbonate in distal RTA
Normally negligible since bicarbonate can’t exist with pH down around 5
In 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 infants
As they age their urine pH falls a bit
This is called type 3
Plasma K
H-ATPase defects have low K
Patients also have downregulation of H-K-ATPase
Downregulation of NaCl reabsorption in proximal tubule
Decreased filtered bicarbonate means less bicarbonate to absorb with Na, hence more Na excretion from proximal tubule
This increases distal sodium delivery and increases aldosterone
Voltage defect also has decreased renal K clearance → hyperkalemia
Differentiate from type 4 RTA by looking at urine pH
Lower in type 4
Higher in voltage-dependent distal RTA
Nephrocalcinosis
Hypercalciuria, hyperphosphatemia, nephrolithiasis, and nephrocalcinosis are frequent
Comes from bones buffering the acidosis
Kidney decreases reabsorption of these so they are lost in urine
Two other factors
Low urinary citrate
Hypokalemia drives this
Acidosis drives this
High urine pH (CaPhos stones)
All corrected by correcting the metabolic acidosis
Incomplete Type 1
Defective urinary acidification but not acidemic
Increased proximal NH3 production lowers urinary H
Low urinary citrate
Can progress to complete type 1
Etiology of Type 1
Sjögren syndrome, rheumatoid arthritis
19-8
Clinical manifestations
Stones
Hypokalemia
Growth defects
Diagnosis
NAGMA and elevated urine pH
5.3 in adults
5.6 in children
Differentiate Type 1 vs Type 2
Give bicarbonate drip
1 mEq/kg/hr
Urine pH remains high with Type 1
Does not go up as it does with proximal Type 2
Incomplete distal RTA
Give acid load
0.1 mmol/kg
Urine pH remains >5.3 in classic
Falls in normal patients (usually below 5)
Treatment
Treat metabolic acidosis
Minimize potassium loss
Reduce bone catabolism
Prevent stones
Alkali requirement
Adults: 1–2 mEq/kg/day
Children: 4–14 mEq/kg/day
Alkali
Sodium bicarbonate
Sodium citrate
Potassium citrate if hypokalemia persists despite correcting acidosis
Or for calcium stone disease
Treat hypokalemia
Type 2 Proximal RTA
Decreased HCO3 reabsorption
90% of bicarbonate reabsorption happens in proximal tubule
Bicarbonate 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 stabilizes
Type 2 RTA is self-limiting
Typically HCO3 around 14–20
Distal acidification intact
Carbonic anhydrase inhibitor can block 80% of proximal HCO3 reabsorption
Only 30% of filtered bicarbonate excreted due to distal H secretion
Total absence of proximal reabsorption results in HCO3 11–12
Clinical difference in treatment
In Type 2, giving bicarbonate and raising serum HCO3 above Tm → more wasted in urine
FEHCO3 can reach 15% with normal serum HCO3
Urine pH >7.5
Below Tm, urine pH <5.3
In 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 reabsorption
Can be isolated
Or part of Fanconi syndrome
Pathogenesis (three steps)
Na-H exchange (apical membrane)
Na-K-ATPase (basolateral membrane)
Carbonic anhydrase
Intracellular
Luminal
Multiple myeloma most common adult cause
Ifosfamide
Can also cause phosphate wasting, NDI, and Type 1 RTA
K balance
Common but variable
Mild hypokalemia at baseline due to increased Na wasting → hyperaldosteronism
Worse with bicarbonate therapy
Distal delivery of nonreabsorbable anion increases obligate cation loss
Figure 19-7
Bone disease
Rickets (children), osteomalacia/osteopenia (adults)
Up to 20%
Phosphate wasting and vitamin D deficiency may contribute
Impaired growth
No nephrocalcinosis or nephrolithiasis
Lower urine pH
Nonreabsorbable amino acids and organic anions bind calcium
Etiology
19-9
Idiopathic and cystinosis (children)
Carbonic anhydrase inhibitors
Multiple myeloma
Diagnosis
NAGMA and pH <5.3
Look for Fanconi syndrome
Raise serum HCO3 and watch urine pH rise
FEHCO3 15–20%
Treatment
Correct acidosis to allow normal growth
Difficult due to rapid urinary loss
May need 10–15 mEq/kg/day
HCO3 or citrate
More than 20 mEq HCO3 can cause stomach rupture from CO2 generation
Small dose thiazide to increase proximal Na reabsorption and HCO3 reabsorption
Idiopathic Type 2 may improve after years
Type 4 RTA
Aldosterone deficient or resistant
Normally stimulates H secretion and K secretion
Loss causes hyperkalemia and metabolic acidosis
Hyperkalemia antagonizes NH4 generation
High K may outcompete NH4 on Na-K-2Cl in TALH
Less ammonium recycling
Less NH3 available in collecting duct
Correcting hyperkalemia can correct acidosis
Metabolic acidosis generally mild
HCO3 >15
Urine pH <5.3 (generally, not always)
Mineralocorticoid can treat but causes hypertension and sodium retention
Often responds to loop diuretic
Rhabdomyolysis can cause high anion gap metabolic acidosis
Symptoms
Respiratory compensation increases 4–8 fold → dyspnea
pH <7.0–7.1
Fatal ventricular arrhythmias
Reduced cardiac contractility
Decreased response to inotropes
Neurological
Lethargy to coma
More related to CSF pH than plasma
Less neurologic symptoms than respiratory acidosis
BBB more permeable to CO2 than HCO3
Skeletal problems
Decreased growth
Kids/infants: anorexia, nausea, listlessness
Treatment
General principles
Correct with HCO3
No alkali required for lactic or ketoacidosis
Goal: pH >7.2
Equations on page 629 need “log”
Example: pH 7.1, pCO2 20, HCO3 6
Raise HCO3 to 8 if pCO2 stays 20
Raise to 10 if pCO2 rises
Paragraph “regardless…” highlights risks of bicarbonate
Bicarbonate deficit
Deficit = HCO3 space × HCO3 deficit per liter
HCO3 space
50% body weight (normal)
60% (mild–moderate acidosis)
70% (severe, HCO3 <8–10)
Example: 70 kg, raise HCO3 6→10 using 0.7 space = 196 mEq
Rough guideline; does not account for ongoing acid production
Early large bump in bicarbonate
Drifts down as bicarbonate moves intracellularly
Plasma potassium
K depletion can cause metabolic acidosis
Metabolic acidosis increases K
“Normal” K may mask depletion (see DKA)
Beware correcting acidosis in hypokalemia
Heart failure
Bicarbonate comes with sodium load
Comment that bicarbonate moves into cell
But Na remains extracellular
Dialysis can be used

References
Chapter 19, Part 12
Metabolic acidosis June 14, 2023
References
Chapter 19, Part 2
Roger mentioned MELAS syndrome MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options
Josh mentioned this blog on lactate- Understanding lactate in sepsis & Using it to our advantage
We 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 Network
Otto 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 sepsis
Buffer 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 Lancet
Roger 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 Annals
Lactic Acidosis and Bicarbonate Therapy | Annals of Internal Medicine from Robert Hollander
Lactic acidosis from Nick Madias
Josh 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 Study
Amy’s VoG on metabolic acidosis/KDIGO guidelines
Very nice JASN review that describes the mechanisms of how metabolic acidosis leads to CKD progression
First description by THE Dr. Bright
1930 Lancet description of benefit
2009 RCT that the 2012 KDIGO guidelines sort of based their 2b recommendations off of
2020 BiCARB Study
2021 META Analysis
We 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 ingestions
From China to Panama, a Trail of Poisoned Medicine - The New York Times (diethylene glycol) . The Accidental Poison That Founded the Modern FDA - The Atlantic
Outline: Chapter 19 Metabolic Acidosis
Etiologies and Diagnosis
Lactic Acidosis
Pyruvate → lactate (LDH; NADH → NAD+)
Normal production: 15–20 mmol/kg/day
Metabolized in liver/kidney → pyruvate → glucose or TCA
Normal lactate: 0.5–1.5 mmol/L; acidosis if > 4–5 mmol/L
Causes:
↑ production: hypoxia, redox imbalance, seizures, exercise
↓ utilization: shock, hepatic hypoperfusion
Malignancy, alcoholism, antiretrovirals
D-lactic acidosis
Short bowel/jejunal bypass
Glucose → D-lactate (not metabolized by LDH)
Symptoms: confusion, ataxia, slurred speech
Special assay needed
Tx: bicarb, oral antibiotics
Treatment
Underlying cause
Bicarb controversial: may worsen intracellular acidosis, overshoot alkalosis, ↑ lactate
Target pH > 7.1; prefer mixed venous pH/pCO2
Ketoacidosis (Chapter 25 elaborates)
FFA → TG, CO2, H2O, ketones (acetoacetate, BHB)
Requires:
↑ lipolysis (↓ insulin)
Hepatic preference for ketogenesis
Causes:
DKA (glucose > 400)
Fasting ketosis (mild)
Alcoholic ketoacidosis
Poor intake + EtOH → ↓ gluconeogenesis, ↑ lipolysis
Mixed acid-base (vomiting, hepatic failure, NAGMA)
Congenital organic acidemias, salicylates
Diagnosis:
AG, osmolar gap (acetone, glycerol)
Ketones: nitroprusside only detects acetone/acetoacetate
BHB can be 90% of total (false negative)
Captopril → false positive
Treatment:
Insulin +/- glucose
Renal Failure
↓ excretion of daily acid load
GFR < 40–50 → ↓ ammonium/TA excretion
Bone buffering stabilizes HCO3 at 12–20 mEq/L
Secondary hyperparathyroidism helps with phosphate buffering
Alkali therapy controversial in adults
Ingestions
Salicylates
Symptoms at >40–50 mg/dL
Early: respiratory alkalosis → Later: metabolic acidosis
Treatment: bicarb, dialysis (>80 mg/dL or coma)
Methanol
Metabolized to formic acid → retinal toxicity
Osmolar gap elevated
Tx: bicarb, ethanol/fomepizole, dialysis
Ethylene glycol
→ glycolic/oxalic acid → renal failure
Same treatment + thiamine/pyridoxine
Other
Toluene, sulfur, chlorine gas, hyperalimentation (arginine, lysine)
GI Bicarbonate Loss
Diarrhea, bile/pancreatic drainage → loss of alkaline fluids
Ureterosigmoidostomy → Cl-/HCO3- exchange in colon
Cholestyramine → Cl- for HCO3-