Edited by Sophia Ambruso

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
1. 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