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Acidosis and Alkalosis¶

Chapter 58 | Part 2 – Cardinal Manifestations & Presentation · Part 2 – Cardinal Manifestations & Presentation · Chapter 58

Key Clinical Points¶

Systemic arterial pH is maintained between 7.35 and 7.45 via chemical buffering, respiratory, and renal mechanisms.
Anion Gap (AG) = Na+ - (Cl- + HCO-); normal range is 6–12 mmol/L (average ~10).
Winter's equation for metabolic acidosis: Paco2 = (1.5 × [HCO3-]) + 8 ± 2.
Bicarbonate therapy in DKA is reserved for severe acidemia (pH <7.00) or evidence of shock.
Salicylate clearance increases fivefold with urine alkalinization (pH >7.5).
Osmolar gap (>10–15 mmol/kg H2O) indicates unmeasured solutes like ethanol, ethylene glycol, or methanol.
Lactic acidosis is categorized as Type A (hypoperfusion) or Type B (aerobic/metabolic disorders).
High-AG acidosis is caused by ketoacids, lactate, toxins, or renal failure; non-AG (hyperchloremic) acidosis involves bicarbonate loss (e.g., diarrhea).
Mixed acid-base disorders are identified when delta values (ΔAG and ΔHCO3-) do not match.
Bicarbonate target in DKA is [HCO3-] of 10–12 mmol/L and pH of approximately 7.20.

DEFINITION & CLASSIFICATION¶

• Acid-Base Homeostasis: Systemic arterial pH is maintained between 7.35 and 7.45 ◦ Maintained by extracellular/intracellular chemical buffering + respiratory and renal regulation. • Henderson-Hasselbalch Equation:

Definition (Harrison's 22e): pH = pK' + log([HCO3-] / (0.03 × PCO2)) ◦ pK' value: 6.1 ◦ Standard steady-state Paco2: ~40 mmHg • Anion Gap (AG): Definition (Harrison's 22e): AG = Na+ – (Cl− + HCO−) ◦ Normal range: 6–12 mmol/L (average ~10) ◦ Components of normal AG: anionic proteins (albumin), phosphate, sulfate, and organic anions.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Metabolic Acidosis Etiologies: ◦ High-Anion Gap (High-AG) Acidosis: → Caused by accumulation of non-chloride-containing acids. → Categories include: Lactic acidosis, Ketoacidosis, Toxins, and Renal failure. ◦ Non-Anion Gap (Non-AG/Hyperchloremic) Acidosis: → Characterized by normal AG and hyperchloremia. → Causes: Bicarbonate loss from GI tract (diarrhea), renal tubular acidosis, or other non-metabolizable anions in kidney failure. • Lactic Acidosis Types: ◦ Type A: Due to poor tissue perfusion (shock, cardiac failure, severe anemia). ◦ Type B: Due to aerobic disorders (malignancy, diabetes, kidney/liver failure, toxins). • Ketoacidosis: ◦ Diabetic Ketoacidosis (DKA): Increased fatty acid metabolism + ketoacid accumulation. ◦ Alcoholic Ketoacidosis: Associated with alcohol abuse. ◦ Starvation Ketoacidosis. • Toxic Alcohol Intoxication: ◦ Ethylene glycol, Methanol, Propylene glycol. ◦ Note: Isopropyl alcohol typically does not increase AG unless severe hypotension/lactic acidosis occurs.

Respiratory Disorders¶

• Respiratory Alkalosis: → Causes: CNS stimulation (pain, anxiety, fever), Hypoxemia (high altitude, pneumonia), Drugs (salicylates, pregnancy), and others. • Respiratory Acidosis: → Causes: Central (drugs, stroke), Airway (obstruction, asthma), Parenchyma (emphysema, ARDS), Neuromuscular (myasthenia, scoliosis).

CLINICAL FEATURES¶

• Metabolic Acidosis Effects: ◦ Respiratory: Characteristic increase in ventilation. ◦ Cardiac: Potential depression of intrinsic contractylene; however, inotropic function may be normal due to catecholamine release. ◦ Vascular: Peripheral arterial vasodilation and central arterial venoconstriction → decreased compliance → risk of pulmonary edema. ◦ CNS: Depression, headache, lethargy, stupor, or coma. ◦ Metabolic: Potential glucose intolerance.

DIFFERENTIAL DIAGNOSIS¶

• Identifying Mixed Disorders: ◦ Comparison of Δ values: → ΔAG = patient's AG - 10 → ΔHCO3- = 25 - patient's [HCO3-] → If ΔAG > ΔHCO3-, a mixed disorder (e.g., high-AG acidosis + metabolic alkalosis) is likely. • Identifying High-AG vs. Non-AG: → Presence of metabolic acidosis + normal AG + hyperchloremia = non-AG acidosis. → High-AG indicates accumulation of acids like lactate, ketoacids, or toxins.

DIAGNOSTIC APPROACH¶

Initial Collection: Obtain arterial blood gas (ABG) and venous electrolytes simultaneously.
Verification: Compare calculated [HCO3-] from ABG with measured value on electrolyte panel; must agree within ±2 mmol/L.
Anion Gap Assessment: → Calculate AG = Na+ - (Cl- + HCO-). → Correct for hypoalbuminemia: Add 2.5 mmol/L for every 1 g/dL below 4.5 g/dL. → High AG is present if AG > 10 mEq/L.
Identify High-AG Causes (Table 58-4): → Lactic acidosis (Diabetic, Alcoholic, Starvation, Kidney failure). → Toxins (Ethylene glycol, Methanol, Salicylates, Propylene glycol). → Ketoacidosis.
Identify Non-AG Causes (Table 58-5): → GI bicarbonate loss (Diarrhea, fistula). → Renal acidosis (RTA, hypokalemia).
Predict Compensation (Table 58-1): → Metabolic Acidosis: Paco2 = (1.5 imes [HCO3-]) + 8 ± 2. → Respiratory Alkalosis (Acute): [HCO3-] will ↓ 0.2 mmol/L per mmHg ↓ in Paco2.
Compare Delta Values: → Compare ΔAG and ΔHCO3- to identify mixed disorders.
Electrolyte Comparison: Compare change in [Cl-] with change in [Na+] on the electrolyte panel.

MANAGEMENT & TREATMENT¶

Bicarbonate Therapy (General): → Reserved for severe acidemia or when no "potential" HCO3- exists. → Target: Slowly increase plasma [HCO3-] to 22 mmol/L; avoid overcorrection.
Diabetic Ketoacidosis (DKA) Management: → Criteria for Bicarbonate: Adult patients with severe acidemia (pH <7.00) or evidence of shock. → Dosage: Slow infusion of 50 meq NaHCO3 in 300 mL saline over 30–45 min during initial 1–2 h. → Monitoring: Monitor for hypokalemia; avoid bolus administration. → Goals: Increase [HCO3-] to 10–12 mmol/L and pH to ≈7.20 (not to normal).
Salicylate Management: → Urine alkalinization: Target pH >7.5 → increases clearance fivefold. → Hemodialysis: Perform if AKI prevents rapid clearance.
Toxic Alcohol Management: → Ethylene Glycol/Methanol: Fomepizole and hemodialysis. → Propylene Glycol: Monitor for accumulation in patients receiving frequent IV preparations.
Lactic Acidosis Management: → Primary goal: Correct underlying cause (e.g., restore perfusion). → Caution: Avoid excessive NaHCO3 as it may increase lactate production via phosphofructokinase stimulation.

KEY PEARLS & HIGH-YIELD POINTS¶

• Albumin Correction: Always check serum albumin; if <4.5 g/dL, add 2.5 mmol/L to the AG for every 1 g/dL below normal. • Osmolar Gap: A gap >10–15 mmol/kg H2O is a critical indicator of unmeasured solutes (ethanol, ethylene glycol, methanol). • Winter's Equation: Used to determine if a patient has a concurrent respiratory disorder in the setting of metabolic acidosis. • Bicarbonate Caution: In DKA, do not aim for normal [HCO3-] or pH; target 10–12 mmol/L and ≈7.20 respectively.

Reference Tables¶

TABLE 58-1 Prediction of Compensatory Responses to Simple Acid-Base Disturbances and Pattern of Changes DISORDER…¶

Harrison's 22e, p.367

DISORDER	PREDICTION OF COMPENSATION	RANGE OF VALUES
		PH	HCO– 3	Paco 2
Metabolic acidosis	Paco = (1.5 × HCO–) + 8 ± 2 2 3 or Paco will ↓ 1.25 mmHg per mmol/L ↓ in 2 [HCO–] 3 or Paco = [HCO–] + 15 2 3	Low	Low	Low
	Paco will ↑ 0.75 mmHg per mmol/L ↑ in 2 [HCO–] 3 or Paco will ↑ 6 mmHg per 10 mmol/L ↑ in 2 [HCO–] 3 or Paco = [HCO–] + 15 2 3	High	High
Respiratory alkalosis		High	Low	Low
Acute	[HCO–] will ↓ 0.2 mmol/L per mmHg ↓ 3 in Paco 2
Chronic	[HCO–] will ↓ 0.4 mmol/L per mmHg ↓ 3 in Paco 2
		Low	High
	[HCO–] will ↑ 0.1 mmol/L per mmHg ↑ 3 in Paco 2
	[HCO–] will ↑ 0.4 mmol/L per mmHg ↑ 3 in Paco 2

TABLE 58-2 Clinical Examples of Mixed Acid-Base Disorders Mixed Metabolic and Respiratory Metabolic…¶

Harrison's 22e, p.368

Mixed Metabolic and Respiratory
Metabolic acidosis—respiratory alkalosis
Key: High-AG metabolic acidosis; prevailing Paco below predicted value
2
(Table 58-1)
Example: Na+, 140; K+, 4.0; Cl−, 106; HCO−, 14; AG, 20; Paco, 24; pH, 7.39
3 2
(etiology: lactic acidosis, sepsis in ICU)
Metabolic acidosis—respiratory acidosis
Key: High-AG metabolic acidosis; prevailing Paco above predicted value
2
(Table 58-1)
Example: Na+, 140; K+, 4.0; Cl−, 102; HCO−, 18; AG, 20; Paco, 42; pH, 7.25
3 2
(etiology: severe pneumonia or pulmonary edema)
Metabolic alkalosis—respiratory alkalosis
Key: Paco does not increase as predicted; pH higher than expected
2
Example: Na+, 140; K+, 4.0; Cl−, 91; HCO−, 33; AG, 16; Paco, 38; pH, 7.56
3 2
(end-stage liver disease with ascites in patient receiving diuretics)
Metabolic alkalosis—respiratory acidosis
Key: Paco higher than predicted; pH normal although both Paco and
2 2
HCO− abnormal
3
Example: Na+, 140; K+, 3.5; Cl−, 88; HCO−, 42; AG, 10; Paco, 67; pH, 7.42
3 2
(COPD in patient receiving diuretics)
Mixed Metabolic Disorders
Metabolic acidosis—metabolic alkalosis
Key: Only detectable if in patient with high-AG acidosis; ΔAG (10) >> ΔHCO (0)
3
Example: Na+, 140; K+, 3.0; Cl−, 95; HCO−, 25; AG, 20; Paco, 40; pH, 7.42 (uremia
3 2
with vomiting)
Metabolic acidosis—metabolic acidosis
Key: Mixed high-AG—normal-AG acidosis; ΔHCO– accounted for by combined
3
change in ΔAG and ΔCl−
Example: Na+, 135; K+, 3.0; Cl−, 110; HCO−, 10; AG, 15; Paco, 25; pH, 7.20
3 2
(diarrhea and lactic acidosis, toluene toxicity, treatment of diabetic
ketoacidosis)

TABLE 58-3 Steps in Accurate Diagnosis of Acid-Base Disorders

1. Obtain arterial blood gas (ABG) and venous electrolytes simultaneously.
  2. Calculated [HCO−] on ABG and measured value on electrolyte panel should
  3
  be approximately same; if not, suspect lab error or sampling error.
  3. Assess anion gap (AG); correct to albumin concentration of 4.5 g/dL if
  hypoalbuminemia; high AG present if AG >10 mEq/L.
  4. Known causes of high-AG acidosis (Table 58-4; ketoacidosis, lactic acid
  acidosis, advanced kidney disease, or toxic alcohol ingestion).
  5. Known causes of nongap acidosis (Table 58-5; bicarbonate loss from
  gastrointestinal tract, renal tubular acidosis).
  6. Estimate predicted compensatory response (Table 58-1).
  7. Compare delta values (ΔAG and ΔHCO−).
  3
  8. Compare change in [Cl−] with change in [Na+] on the electrolyte panel.
  s

TABLE 58-4 Causes of High-Anion Gap Metabolic Acidosis Lactic acidosis Ketoacidosis¶

Harrison's 22e, p.369

Lactic acidosis	Toxins
Ketoacidosis	Ethylene glycol
Diabetic	Methanol
Alcoholic	Salicylates
Starvation	Propylene glycol
	Pyroglutamic acid (5-oxoproline)
	Kidney failure (acute and chronic)

TABLE 58-5 Causes of Non–Anion Gap Acidosis I. Gastrointestinal bicarbonate loss¶

Harrison's 22e, p.372

I. Gastrointestinal bicarbonate loss
A. Diarrhea
B. External pancreatic or small-bowel drainage/fistula
C. Diversion of ureter: ureterosigmoidostomy, jejunal loop, ileal loop
D. Drugs
1. Calcium chloride (acidifying agent)
2. Magnesium sulfate (diarrhea)
3. Cholestyramine (bile acid diarrhea)
II. Renal acidosis
A. Hypokalemia
1. Proximal RTA (type 2 RTA)
Drug-induced: acetazolamide, topiramate
Inherited: (a) autosomal recessive missense mutation of SLCA4
(encodes for basolateral NBCe1) (accompanied by ocular
abnormalities); (b) autosomal dominant mutation of NHE3 (apical Na+/H+
exchanger) (rare; associated with short stature)
2. Distal (classic) RTA (type 1 RTA)
Drug-induced: amphotericin B, ifosfamide
Inherited: defect of ATP6V1B1 (encodes for basolateral HCO–/Cl–
3
exchanger of distal tubule and collecting duct)
B. Hyperkalemia
1. Generalized distal nephron dysfunction (type 4 RTA)
a. Selective aldosterone deficiency
b. Mineralocorticoid resistance (PHA I, autosomal dominant)
c. Voltage defect (PHA I, autosomal recessive, and PHA II)
d. Hyporeninemic hypoaldosteronism
e. Tubulointerstitial disease
C. Normokalemia
1. Chronic progressive kidney disease
III. Drug-induced hyperkalemia (with CKD)
A. Potassium-sparing diuretics (amiloride, triamterene, spironolactone,
eplerenone)
B. Trimethoprim
C. Pentamidine
D. ACE-Is and ARBs
E. Nonsteroidal anti-inflammatory drugs
F. Calcineurin inhibitors
G. Heparin in critically ill patients
IV. Other
A. Acid loads (ammonium chloride, IV hyperalimentation [uncommon])
B. Loss of potential bicarbonate: ketosis with ketone excretion
C. Expansion acidosis (rapid saline administration)
D. Hippurate
E. Cation exchange resins

TABLE 58-6 Causes of Metabolic Alkalosis I. Exogenous HCO – loads¶

Harrison's 22e, p.374

I. Exogenous HCO– loads
3
A. Acute alkali administration
B. Milk-alkali syndrome
II. Effective ECFV depletion, normal or low BP (with orthostasis), K+ deficiency,
and secondary hyperreninemic hyperaldosteronism
A. Gastrointestinal origin
1. Vomiting
2. Gastric aspiration
3. Congenital chloridorrhea
4. Gastrocystoplasty
5. Villous adenoma
B. Renal origin
1. Diuretic use (thiazides and loop diuretics)
2. Posthypercapnic state
3. Hypercalcemia/hypoparathyroidism
4. Recovery from lactic acidosis or ketoacidosis
5. Nonreabsorbable anion administration (e.g., IV penicillin, carbenicillin)
6. Mg2+ deficiency
7. K+ depletion
8. Bartter’s syndrome (loss-of-function mutations of transporters and ion
channels in TALH)
9. Gitelman’s syndrome (loss-of-function mutation of Na+-Cl–
cotransporter in DCT and collecting duct)
III. ECFV expansion, hypertension, K+ deficiency, and mineralocorticoid excess
A. High renin
1. Renal artery stenosis
2. Accelerated hypertension
3. Renin-secreting tumor
4. Estrogen therapy
B. Low renin
1. Primary aldosteronism
a. Adenoma
b. Hyperplasia
c. Carcinoma
2. Adrenal enzyme defects
a. 11β-Hydroxylase deficiency
b. 17α-Hydroxylase deficiency
3. Cushing’s syndrome or disease
4. Other
a. Licorice
b. Carbenoxolone
c. Chewer’s tobacco
IV. Gain-of-function mutation of sodium channel in DCT (ENaC)
with ECFV expansion, hypertension, K+ deficiency, and
hyporeninemic-hypoaldosteronism
A. Liddle’s syndrome

TABLE 58-7 Respiratory Acid-Base Disorders I. Alkalosis¶

Harrison's 22e, p.375

I. Alkalosis
A. Central nervous system stimulation
1. Pain
2. Anxiety
3. Fever
4. Cerebrovascular accident
5. Meningitis, encephalitis
6. Tumor
7. Trauma
B. Hypoxemia or tissue hypoxia
1. High-altitude acclimatization
2. Pneumonia, pulmonary edema
3. Aspiration
4. Severe anemia
C. Drugs or hormones
1. Pregnancy, progesterone
2. Salicylates
3. Cardiac failure
D. Stimulation of chest receptors
1. Hemothorax
2. Flail chest
3. Cardiac failure
4. Pulmonary embolism
E. Miscellaneous
1. Septicemia
2. Hepatic failure
3. Mechanical hyperventilation
4. Heat exposure
5. Recovery from metabolic acidosis
II. Acidosis
A. Central
1. Drugs (anesthetics, morphine, sedatives)
2. Stroke
3. Infection
B. Airway
1. Obstruction
2. Asthma
C. Parenchyma
1. Emphysema
2. Pneumoconiosis
3. Bronchitis
4. Adult respiratory distress syndrome
5. Barotrauma
D. Neuromuscular
1. Poliomyelitis
2. Kyphoscoliosis
3. Myasthenia
4. Muscular dystrophies
E. Miscellaneous
1. Obesity
2. Hypoventilation
3. Permissive hypercapnia