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