Physiology Note - Acid Base Physiology
Dr Bijay KC
Associate Professor and ICU in-charge
Department of Critical Care
Kathmandu Medical College and Teaching Hospital
Life is a struggle, not against sin, not
against money power... but against hydrogen ions.
H. L.
Mencken
Acid–base balance is
the human body’s finest demonstration of homeostasis—an intricate dance between
lungs, kidneys, electrolytes, proteins, and cellular metabolism. Hydrogen ions
(H⁺), though tiny, exert enormous biological power. Their concentration is
regulated within an astonishingly narrow range because even minor shifts alter
enzyme kinetics, ionic gradients, cardiac contractility, vascular tone, and
cellular survival. In critical care, acid–base physiology is not abstract
theory—it is a continuous, dynamic reflection of tissue perfusion, respiratory
efficiency, renal integrity, metabolic status, and fluid choices.
1. The
Hydrogen Ion and pH: The Foundation
pH is the negative logarithm of hydrogen ion concentration: ( Figure 1)
pH
= –log([H⁺])
Normal arterial pH ranges from 7.35–7.45, corresponding to a hydrogen ion
concentration of roughly 36–44 nmol/L. The logarithmic scale means that a small
change in pH represents a dramatic shift in H⁺. Because H⁺ interacts with
nearly every
protein in the body,
pH is one of the most tightly regulated physiological variables.
2. The
Body’s Buffer Systems: First Line of Defense
A buffer is like a shock absorber—something that temporarily absorbs a
disturbance. When H⁺ rises or falls, buffers limit pH change, buying time for
the lungs and kidneys.
2.1 The Bicarbonate
Buffer System
The dominant extracellular buffer is the bicarbonate–carbonic acid system.
CO₂ + H₂O ↔ H₂CO₃ ↔ H⁺ + HCO₃⁻
The Henderson–Hasselbalch equation describes this relationship:
pH = 6.1 + log(HCO₃⁻ / (0.03 × PaCO₂))
This shows that pH depends on the ratio—not the absolute value—of bicarbonate
and CO₂. The lungs regulate CO₂, while the kidneys regulate bicarbonate.
Bicarbonate provides
about 85% of plasma buffering.
2.2 Hemoglobin
Buffering
Hemoglobin, rich in histidine, is an excellent H⁺ buffer—especially in venous
blood, where deoxygenated Hb’s buffering capacity is highest ( Figure 2). This is one
reason venous pH is slightly lower than arterial pH.
2.3 Protein and
Phosphate Buffers
Proteins and phosphates buffer intracellular compartments and renal tubular
fluid. Their role becomes more prominent during chronic disorders. (Figure 3)
Figure 3: The Phosphate Buffer
3. Respiratory
Regulation of Acid–Base
The lungs can alter pH within minutes by adjusting PaCO₂. CO₂, a volatile acid,
is produced continuously by cellular metabolism. Ventilation determines its
elimination.
• Hypoventilation → CO₂ retention → respiratory acidosis
• Hyperventilation → CO₂ washout → respiratory alkalosis
Central
chemoreceptors respond to pH changes in the CSF, while peripheral
chemoreceptors respond to PaO₂, PaCO₂, and pH. Chronic hypercapnia (e.g., COPD)
triggers renal compensation over 2–5 days, increasing bicarbonate retention.
4. Renal
Regulation: Long‑Term Control
The kidneys are the long‑term regulators of acid–base balance. They maintain pH
through:
4.1 Reabsorption of
Filtered Bicarbonate ( Figure 4)
The proximal tubule reabsorbs ~85–90% of filtered HCO₃⁻ using carbonic
anhydrase.
4.2 Hydrogen Ion
Secretion
H⁺ is secreted via:
• Na⁺/H⁺ exchange
• H⁺‑ATPase pumps
These mechanisms are essential in metabolic acidosis.
Figure 4: Reabsorption of filtered bicarbonate
4.3 Generation of New
Bicarbonate
Through ammonia genesis (NH₄⁺ creation) and titratable acid excretion, each H⁺
excreted generates one bicarbonate ion.
In AKI, these processes fail → metabolic acidosis.
Recovery from AKI can produce rebound alkalosis as retained bicarbonate is
cleared.
5.
Classification of Acid–Base Disorders
5.1 Metabolic Acidosis (↓HCO₃⁻)
Anion Gap (AG) = Na⁺ – (Cl⁻ + HCO₃⁻)
Normal: 8–12 mmol/L
High‑AG acidosis
(GOLDMARK):
• Glycols, Oxoproline, L‑lactate, D‑lactate, Methanol, Aspirin, Renal failure,
Ketoacidosis
Normal‑AG
(hyperchloremic) acidosis:
• Diarrhea, Saline overload, RTA, CA inhibitors, fistulas, adrenal
insufficiency
Delta‑delta analysis
helps detect mixed disorders.
Lactic acidosis is
the signature ICU metabolic acidosis—an early sign of tissue hypoxia or
mitochondrial dysfunction.
5.2 Metabolic
Alkalosis (↑HCO₃⁻)
Common causes:
• Vomiting/NG suction
• Diuretics
• Post‑hypercapnic alkalosis
• Mineralocorticoid excess
Chloride depletion
plays a key role. Urine chloride helps classification:
• <10 mmol/L → chloride‑responsive
• >20 mmol/L → chloride‑resistant
5.3 Respiratory
Acidosis
Due to hypoventilation from CNS depression, COPD, neuromuscular failure, or
high dead space.
Compensation:
• Acute: +1 mmol/L HCO₃⁻ for each 10 mmHg ↑ PaCO₂
• Chronic: +4 mmol/L per 10 mmHg ↑ PaCO₂
5.4 Respiratory
Alkalosis
Caused by hypoxemia, sepsis, pregnancy, anxiety, or mechanical
ventilation.
Consequences include decreased cerebral blood flow, hypocalcemia, and reduced
tissue oxygen delivery.
6.
Stewart’s Approach: Modern Physicochemical View
Peter Stewart reframed acid–base physiology using fundamental physical
chemistry. Instead of focusing on bicarbonate, he showed that pH is determined
by three independent variables:
1. PaCO₂
2. Strong Ion Difference (SID)
3. Total Weak Acids (Aᴛᴏᴛ)—mainly albumin and phosphate
Everything
else—including HCO₃⁻—is dependent on these.
6.1 Strong Ion
Difference (SID) ( Figure 5)
SID = (Na⁺ + K⁺ + Ca²⁺ + Mg²⁺) – (Cl⁻ + lactate⁻)
Normal SID ≈ 40–44 mmol/L
• ↓ SID → acidosis
• ↑ SID → alkalosis
ICU example: Normal
saline (SID = 0) lowers plasma SID, causing hyperchloremic acidosis.
6.2 Total Weak Acids
(Aᴛᴏᴛ)
Albumin is a weak acid.
• ↓ albumin → ↓ Aᴛᴏᴛ → metabolic alkalosis
• ↑ albumin → acidosis
This explains why
septic or cirrhotic patients often appear alkalotic despite critical illness.
6.3 Why Stewart
Matters
Stewart explains phenomena classical approaches cannot:
• Why saline causes acidosis
• Why hypoalbuminemia raises pH
• Why bicarbonate infusion may worsen intracellular acidosis
• Why two patients with identical HCO₃⁻ can have very different pH
7. Organ Consequences
of Acid–Base Disorders
Acidosis:
• ↓ myocardial contractility
• ↓ catecholamine responsiveness
• ↑ pulmonary vascular resistance
• K⁺ shifts → arrhythmias
Alkalosis:
• ↓ cerebral blood flow
• respiratory depression
• hypocalcemia → tetany
• left shift of oxygen dissociation curve → tissue hypoxia
8. Compensation Rules
at the Bedside
These help determine whether a disorder is simple or mixed.
• Winter’s formula for metabolic acidosis: PaCO₂ = 1.5 × HCO₃⁻ + 8 ± 2
• Metabolic alkalosis: PaCO₂ = 0.7 × HCO₃⁻ + 20 ± 5
• Acute respiratory disorders → minimal renal compensation
• Chronic disorders → larger renal shifts
9. Simple ICU
Approach to ABG Analysis
1. Check pH
2. Identify primary disorder
3. Check compensation
4. Calculate anion gap
5. Evaluate delta‑delta
6. Always correlate with clinical context
ABG interpretation
without clinical context is a map without terrain.
10. Cross‑Atlantic
Debate and Stewart’s Resolution
Boston and Copenhagen schools centered acid–base status on bicarbonate and base
excess. Stewart revealed that bicarbonate is not causal but reflective—a
dependent variable determined by strong ions, weak acids, and CO₂. His model
unified mechanisms that older systems could not explain and remains the
foundation of modern ICU acid–base analysis.
11. α-Stat and pH-Stat
Strategies in Acid–Base Management During Hypothermia (ICU Perspective)
Management of acid–base
physiology during hypothermia requires an understanding of how temperature
alters PaCO₂ and pH. As temperature decreases, CO₂ solubility increases,
leading to a fall in measured PaCO₂ and a rise in pH. Two interpretive
strategies exist to address this: α-stat
and pH-stat.
α-Stat is the default approach
used in most adult ICUs and cardiac operating rooms. With α-stat, arterial
blood gases are analyzed and interpreted at 37°C, irrespective of the patient’s
actual temperature. The resulting rise in pH and fall in PaCO₂ during cooling
are not corrected.
This approach preserves the normal dissociation state of histidine residues on
intracellular proteins—hence the term α-stat—and maintains intracellular charge
neutrality. Clinically, α-stat preserves
cerebral autoregulation, avoids excessive cerebral
vasodilation, and reduces the risk of cerebral microembolism during
cardiopulmonary bypass or hypothermia. It is therefore preferred for adult cardiac surgery, targeted
temperature management (TTM), neurocritical care, and moderate
hypothermia protocols.
pH-Stat, in contrast, uses temperature-corrected ABG analysis.
The goal is to maintain pH at 7.40 and PaCO₂ at 40 mmHg at the patient’s actual temperature.
Because cooling reduces PaCO₂, this strategy typically requires adding CO₂ (via
reducing ventilation or adding CO₂ to the sweep gas). The consequence is cerebral vasodilation,
increased cerebral blood flow, and more homogeneous brain cooling. pH-stat is
therefore advantageous in pediatric
cardiac surgery, deep
hypothermic circulatory arrest (DHCA), and situations where
maximal cerebral perfusion is desired. However, it can impair autoregulation
and increase cerebral embolic load.
In the ICU, the choice
between α-stat and pH-stat influences PaCO₂ targeting, cerebral hemodynamics,
and interpretation of ABGs in hypothermic patients. Understanding these
strategies ensures accurate acid–base analysis and optimizes neuroprotection
during therapeutic hypothermia or complex cardiac-critical care scenarios.
12. Final
Reflection: Acid–Base as the Ultimate Homeostatic Symphony
Acid–base physiology is the body's most elegant demonstration of decentralized
homeostasis. Without a central controller, lungs adjust ventilation, kidneys
fine‑tune ion balance, strong ions shift with fluids and metabolism, and weak
acids buffer quietly in the background. Like a well‑conducted orchestra, each
system responds moment‑to‑moment to maintain a range narrow enough to sustain
life. In the chaos of the ICU, this precision is a reminder of how exquisitely
designed our physiology is—robust yet delicate, adaptable yet exact.
13. Imortant reads:
A) www.derangedphysiology.com/acid
base physiology
B) www.litfl.com/acid
base
C) Stewart PA.
Modern quantitative acid-base chemistry. Can J Physiol Pharmacol. 1983
Dec;61(12):1444-61
D) Shaw I and
Gregory K.Acid–base
balance: a review of normal physiology” (BJA Education, 2022)
E) Barletta
et al. A Systematic
Approach to Understanding Acid-Base Disorders in the Critically Ill (Annals of Pharmacotherapy, 2024)
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