Definitions

When pH_a (arterial blood pH) differs from 7.4 +/- 0.02 (or the [H⁺] differs from 40 +/- 2 nEq/L) there occurs acidemia (pH_a < 7.38, [H⁺] > 42 nEq/L) or alkalemia (pH_a   > 7.42,  [H⁺] < 38 nEq/L).

If the pH_a change is due primarily to a change in P_aCO2, there is respiratory acidosis (P_aCO2 > 42 mmHg) or respiratory alkalosis (P_aCO2 < 38 mmHg).

When the pH_a change is due primarily to a change in [HCO₃^-] from its normal value of 24 mM, there is metabolic acidosis ([HCO₃^-] < 22 mM) or metabolic alkalosis ([HCO₃^-] > 26 mM).

Note:  -emia refers to changes in blood;  acidosis and alkalosis refer to pathophysiologic processes that lead to pH changes in blood

(A) Metabolic acidosis: pH < 7.38; HCO₃^- < 22 mM; P_aCO2 1 mmHg decrease per 1 mM decrease in HCO₃^- (acute or chronic)

Causes:

Metabolic acidosis is the most frequent acid-base imbalance and may be due to:

(1) Extrarenal loss of bicarbonate, with hyperchloremia and increased urinary excretion of NH₄⁺ (evident as high urinary cation gap:   [Cl^-] - [Na⁺] - [K⁺] >> 0)

(2) Urinary loss of HCO₃^- (alkaline urine, with high bicarbonate, and little NH₄⁺ and thus no urine cation gap)

(3) Accumulation of organic anions (lactacidosis, ketoacidosis) with large plasma anion gap (due to organic anions, [Na⁺]+[K⁺]-[Cl^-]-[HCO₃^-]>>15), abundant urinary NH₄⁺ but no urinary cation gap (NH₄⁺ is excreted with organic anions so that there is a large urinary osmolar gap: U_osm - 2([Na⁺]+[K⁺]) - [urea] - [glucose] >>0. Only lactacidosis can develop in minutes (as in shock).

(4) Decreased kidney production of HCO₃^- (hyperchloremia, no plasma anion gap, and low urinary excretion of ammonium, (urinary cation gap =0); severe chronic renal failure may result in metabolic acidosis with increased plasma anion gap (due to high plasma [P_i]) and low urinary NH₄⁺ excretion.

Compensations:

(1) Immediate buffering by reaction with ECF HCO₃^- represents ~40% of rapid (~2 hrs) buffering of acid. HCl + NaHCO₃ => NaCl+ H₂CO₃ + CO₂ + H₂O

(2) Respiratory compensation. A low pH_a stimulates V_A, so P_aC02 decreases minimizing the decrease in pH_a.  For each 1 mM decrease in [HCO₃^-] a 1 mmHg drop in P_aC02 is expected.

Note:  Because of respiratory compensation for metabolic acidosis, P_aCO2 is expected to be below its normal range or (P_aCO2 < 38 mmHg).  If , because of disease, there is no respiratory compensation, then P_aCO2 will be normal or elevated, and the respiratory system is contributing to the acidemia (see Respiratory Acidosis below)..

(3) Tissue phase.  Entry of H⁺ into cells accounts for ~60% of rapid (~2 h) buffering of poorly permeable acids (HCl or H₂SO₄). This phase is capable of buffering 100% of the acid by 24 h, and is due to the following ion exchanges and buffering of H⁺ by cell proteins and HCO₃^-:

(a) Na⁺ in the ICF for H⁺ from the ECF;  occurs in most tissues including bone; accounts for 65% of the entry of protons into the ICF (and bone).

(b) ICF K⁺ for ECF H⁺; accounts for 25% of the entry of H⁺ into the ICF. May result in hyperkalemia (6-7 mEq/L) that affects muscle and nerve cells and induces cardiac arrythmias.

(c) ECF Cl^- for ICF HC0₃^-; accounts for 10% of the ICF buffering of H⁺; reduces ICF HC0₃^- and intracellular pH;   occurs mostly in red cells where Hb buffers excess H⁺.

(4) Renal phase.  Generation of bicarbonate through urinary excretion of ammonium and titratable acids, restores the depleted cell HCO₃^- and buffer base reserves over 2-3 days. Manifest only in chronic stage.

(B) Metabolic alkalosis: pH_a > 7.42; [HCO₃^-] > 26 mM; P_aCO₂ 0.75 mmHg increase for each 1 mM increase in [HCO₃^-] (chronic or acute)

Causes:

(1) Loss of gastric juice (vomiting, suction)

(2) Side effect of diuretics and other forms of ECFV contraction.

(3) Hyperaldosteronism of volume depletion promotes renal H⁺ secretion, generation and retention of HCO₃^-.

(4) In hypokalemia, K⁺ shifts out of cells in exchange for H⁺, inducing extracellular alkalosis and intracellular acidosis.

Compensations:

(1) Respiratory.  As pH_a increases, V_A is depressed and P_aCO2 increases (P_aCO2 > 42 mmHg). This normalizes blood pH but is limited by ensuing hypoxia. For each 1 mM rise in HCO₃^- there is expected a 0.75 mmHg rise in P_aCO2;  if this does not occur, there is a respiratory tendency to alkalosis.

(2) Cell ionic exchanges.  Some 25% of the bicarbonate load is neutralized by H⁺ derived from intracellular buffers that exchange the H⁺ for extracellular Na⁺.  In addition, ~2% of extracellular HCO₃^- enters red cells in exchange for Cl^-.

(3) Metabolic. Increases in endogenous organic acid production neutralize ~5 % of an acute HCO₃^-  load. High pH_a increases production of lactic and citric acids which decrease [HCO₃^-]. High blood pH stimulates glycolysis and inhibits the citric acid cycle.

(4) Renal excretion of HCO₃^- rises when its concentration in plasma increases. Lowering of [HCO₃^-]_pl is limited by high renal reabsorption rate stimulated by high P_aCO2, by ECF volume contraction, by hyperaldosteronism, by K⁺ depletion, and by hypochloremia. These tend to perpetuate the high [HCO₃^-]_pl. Beta-intercalated cells in CCD secrete bicarbonate, increasing its urinary excretion.

(C) Respiratory alkalosis: pH > 7.44; P_aCO2 < 38 mm Hg; [HCO₃^-] decreases (<24 mM) by 0.5 mM (chronic) or 0.1 mM (acute) per each 1 mmHg drop in P_aC02

Cause:  Alveolar hyperventilation (altitude, hysteria, aspirin excess)

Compensations

(1) Cell buffers.  In the acute state there is a 0.1 mM decrease in [HCO₃^-] for each mmHg decrease in P_aCO2. This decrease is due to enhanced dissociation of H⁺ from cell buffers when the [H⁺]_i decreases due to the low P_aCO2. Cell H⁺ exchange for ECF Na⁺ and K⁺ and react with the ECF HCO₃^-, reducing its concentration. Some extracellular HCO₃^- enters cells in exchange for Cl^- and is titrated by H⁺ dissociating from the cell buffers.

In the chronic state, there is a 0.5 mM decrease in [HCO₃^-] for each one mmHg decrease in PaCO₂. This is due to:

(2) Renal compensation due to increased HCO₃^- excretion associated with the low P_aCO2, which decreases HCO₃^- reabsorption. Urinary excretion of NH₄⁺ and titratable acid are  transiently reduced, leading to accumulation of metabolic and dietary acids which help reduce ECF [HCO₃^-] ([HCO₃^-] < 22 mM). Eventually urinary HCO₃^- excretion ceases and excretion of NH4⁺ and titratable acid resumes.

(3) Metabolic compensation by increased production of lactic and citric acids that react with and reduce [HCO₃^-]_ecf

(D) Respiratory acidosis: pH < 7.38; P_aC02 > 42 mm Hg; [HCO₃^-] increases (>24 mM) by 0.25 mM (chronic) or 0.05 mM (acute) per each 1 mmHg rise in P_aC02

Cause: Alveolar hypoventilation

Compensations:

(1) Fast cell ion exchanges.  An acute small rise in [HCO₃^-]_pl is due to exchange of ECF H⁺ for ICF (or bone) Na⁺ (37%) or for ICF K⁺ (13%) and to exchange of ECF Cl^- for ICF (red cells) HCO₃^- (30%). These rapid ionic exchanges are associated with CO₂ buffering by intracellular proteins. For each 1 mmHg increment in P_aCO2 there is a small acute 0.05 mM increment in HCO₃^-.

(2) Metabolic.  Reduced production of lactic acid contributes about 5% to the acute increase in [HCO₃^-]_pl.

(3) Renal. Increased HCO₃^- reabsorption stimulated by high P_aCO2 prevents urinary loss of bicarbonate.
In the transition to the chronic stage (1-3 days), enhanced renal NH₄⁺, and titratable acid excretion contribute to further increase [HCO₃^-] in ECF and ICF above normal ([HCO₃^-] > 26 mM), returning pH towards normal. As the pH stimulus decreases, renal NH₄⁺ and titratable acid excretion subside. Renal reabsorption of bicarbonate remains elevated as long as the P_aCO2 is high.

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