Acid-Base Balance and Homeostasis

Acid-Base Balance

• Optimal function of cellular enzymes and metabolic processes requires a tightly regulated pH.
• Normal pH range: 7.35 to 7.45

Acid-Base Homeostasis

• Maintains blood hydrogen ion concentration [H+] near normal.
• Manages daily acidic/alkaline loads from food intake and metabolism.
• Achieved through three mechanisms:
  • Extracellular bicarbonate and intracellular protein buffering systems.
  • Pulmonary regulation of PaCO2: Eliminates carbonic acid via the lungs as CO2.
  • Renal reclamation/excretion: Reclaims or excretes HCO3- and excretes acids like ammonium.

Role of Lungs and Kidneys

• Lungs and kidneys maintain a normal acid-base balance.
• Carbon dioxide (CO2), generated during normal metabolism, is a weak acid.
• Lungs excrete CO2 to prevent increases in blood CO2 partial pressure (Pco2).
• CO2 production varies with the body's metabolic needs.
• Pulmonary response to CO2 changes involves central sensing of Pco2.
  • Ventilation increases/decreases to keep Pco2 normal (35-45 mm Hg).

Role of Kidneys

• Kidneys excrete endogenous acids.
• Adults produce 1 to 2 mEq/kg/day of hydrogen ions.
• Children produce 2 to 3 mEq/kg/day of hydrogen ions.
• Hydrogen ions from endogenous acid production are neutralized by bicarbonate, which can lower bicarbonate concentration.
• Kidneys regenerate bicarbonate by secreting hydrogen ions.
  • This maintains serum bicarbonate within the normal range of 20-28 mEq/L.

Clinical Significance of Acid-Base Balance

• Disturbances in acid-base equilibrium commonly occur in various illnesses.
• Common in critical care medicine.
• Severe derangements impact organ systems like:
  • Cardiovascular: Arrhythmias and impaired contractility
  • Neurologic Coma and seizures
  • Pulmonary: Dyspnea, impaired oxygen delivery, respiratory fatigue
  • Renal: Hypokalemia
• Acid-base status changes affect pharmacokinetics (drug clearance and protein binding) and pharmacodynamics.

Clinical Assessment

• Acidemia: pH is below normal (
• Acidosis: Pathologic process that increases hydrogen ion concentration
• Alkalosis: Pathologic process that decreases hydrogen ion concentration

Simple Acid-Base Disorders

• A simple acid-base disorder involves a single primary disturbance.
• Respiratory compensation occurs during a simple metabolic disorder.
  • Pco2 decreases in metabolic acidosis.
  • Pco2 increases in metabolic alkalosis.
• Decreasing pH in metabolic acidosis increases ventilatory drive, lowering Pco2.
• Decreased CO2 concentration elevates pH.
• Respiratory compensation for metabolic issues occurs rapidly, within 12-24 hours.

Primary Respiratory Process Compensation

• A primary respiratory process leads to slower metabolic compensation via the kidneys.
• Kidneys respond to a respiratory acidosis:
  • Increasing hydrogen ion excretion
  • Increasing bicarbonate generation
  • Elevating serum bicarbonate concentration
• Kidneys compensate for respiratory alkalosis by:
  • Increasing bicarbonate excretion
  • Decreasing serum bicarbonate concentration
• Metabolic compensation by the kidneys takes 3-4 days.

Compensatory Changes

• A small, rapid change in bicarbonate concentration occurs during a primary respiratory process.
• Expected metabolic compensation for a respiratory issue depends on whether the process is acute or chronic.

Mixed Acid-Base Disorders

• More than one primary acid-base disturbance is present.
• Infants with bronchopulmonary dysplasia may have both:
  • Respiratory acidosis from chronic lung disease
  • Metabolic alkalosis from diuretics.
• Compensation is expected in a simple disorder.
• Mixed acid-base disorders are present when patients do not have the appropriate compensation.

Metabolic Acidosis

• Metabolic acidosis occurs frequently in hospitalized children.
• Diarrhea is the most common cause.
• Metabolic acidosis suggests a narrow differential diagnosis for unknown medical problems.

Causes of Metabolic Acidosis

• Normal Anion Gap:
  • Diarrhea
  • Renal tubular acidosis
  • Urinary tract diversions
  • Posthypocapnia
  • Ammonium chloride intake
• Increased Anion Gap:
  • Lactic acidosis (shock)
  • Ketoacidosis (diabetic, starvation, or alcoholic)
  • Kidney failure
  • Poisoning (e.g., ethylene glycol, methanol, or salicylates)
  • Inborn errors of metabolism

Diarrhea and Bicarbonate Loss

• Diarrhea results in bicarbonate loss from the body.
• Bicarbonate loss in stool depends on diarrhea volume and bicarbonate concentration.
  • Stool bicarbonate concentration increases with severe diarrhea.
• Volume depletion resulting from diarrhea causes losses of sodium and water.
  • Can exacerbate acidosis by causing hypoperfusion (shock) and lactic acidosis.

Renal Tubular Acidosis (RTA)

• Three forms of RTA exist:
  • Distal (type I)
  • Proximal (type II)
  • Hyperkalemic (type IV)

Distal RTA

• Children with distal RTA may experience:
  • Hypokalemia
  • Hypercalciuria
  • Nephrolithiasis
  • Nephrocalcinosis
• Rickets is a less common finding.
• Failure to thrive, which develops from from chronic metabolic acidosis, is the most common complaint.
• Autosomal dominant and autosomal recessive forms exist.
• The autosomal dominant form is relatively mild.
• The autosomal recessive distal RTA is more severe.
  • Often linked to deafness due to a defect in the gene for H+-ATPase.
  • The gene is present in the kidney and inner ear.
• Distal RTA may be secondary to:
  • Medications
  • Congenital or acquired renal disease
• Patients cannot acidify their urine.
  • Urine pH is typically greater than 5.5, even with existing metabolic acidosis.

Proximal RTA

• Proximal RTA rarely presents by itself.
• Proximal RTA is often a part of Fanconi syndrome, a generalized dysfunction of the proximal tubule.
• Fanconi syndrome causes:
  • Glycosuria
  • Aminoaciduria
  • Excessive urinary losses of phosphate and uric acid.
• It also results in renal wasting of bicarbonate.

Chronic Hypophosphatemia

• More clinically significant because it leads to rickets in children.
• Rickets or failure to thrive may be the presenting complaint.
• Fanconi syndrome cases are usually secondary to an underlying genetic disorder.
  • Most commonly cystinosis
• Fanconi syndrome can be caused by toxic medications like ifosfamide or valproate.
• Ability to acidify urine remains intact in proximal RTA.
  • Untreated patients typically have a urine pH less than 5.5.
• Bicarbonate therapy increases bicarbonate losses in urine and raises urine pH.

Hyperkalemic RTA

• Renal excretion of acid and potassium is impaired.
• Caused by an absence of aldosterone, or the kidney's inability to respond to it.

Lactic Acidosis

• Commonly occurs when inadequate oxygen delivery to tissues leads to anaerobic metabolism.
• Results in excess production of lactic acid.
• Secondary causes:
  • Shock
  • Severe anemia
  • Hypoxemia
• Severe lactic acidosis results from Inborn errors of carbohydrate metabolism.
• Can result from:
  • Diabetes mellitus
  • Renal failure

Metabolic Acidosis from Toxic Ingestions

• Toxic ingestions Metabolic acidosis:
  • Acute salicylate intoxication
  • Ethylene glycole
  • Methanol

Clinical Manifestations of Metabolic Acidosis

• The underlying disorder usually produces most of the signs and symptoms in children with mild/moderate cases.
• Clinical manifestations are related to the degree of acidemia.
  • Patients with respiratory compensation and less severe acidemia have fewer manifestations.
  • Patients with concomitant respiratory acidosis have more manifestations.
• At serum pH less than 7.20 risk of arrhythmias are increased and impaired cardiac contractility occurs.
  • Especially in the presence of underlying heart disease or predisposing electrolyte disorders
• Acidemia diminishes cardiovascular response to catecholamines, potentially exacerbating hypotension in children with shock or volume deletion.
• Acidemia causes vasoconstriction of the pulmonary vasculature.
  • Problematic in newborns with persistent fetal circulation.
• The normal respiratory response (compensatory hyperventilation) to metabolic acidosis may be subtle with mild cases.
  • Increased respiratory effort is discernible if acidemia worsens.
• Chronic metabolic acidosis causes failure to thrive.

Diagnosis of Metabolic Acidosis

• Plasma anion gap is useful in evaluating patients.
• Patients are divided into two diagnostic groups: normal anion gap and increased anion gap.
• Anion gap is calculated using the following formula: Na - Cl - HCO3

Interpreting the Anion Gap

• A normal anion gap falls between 3 and 11.
• A decrease of 1 g/dL in albumin concentration decreases the anion gap by roughly 4 mEq/L.
• Less commonly, increases in unmeasured cations such as calcium, potassium, or magnesium also decreases the anion gap.
• Lowering unmeasured cations is a rare cause of increasing the anion gap.

Treatment of Metabolic Acidosis

• The most effective therapeutic approach for patients is correction of the underlying disorder.
• Acid-base balance is normalized by:
  • Administering insulin in diabetic ketoacidosis.
  • Restoring adequate perfusion in lactic acidosis.
• Bicarbonate therapy is reserved for irreparable conditions, such as:
  • Renal tubular acidosis (RTA)
  • Chronic renal failure

Metabolic Alkalosis

• Causes are divided into two categories based on urinary chloride levels.
• Alkalosis in patients with low urinary chloride is maintained by volume depletion.
  • Described as "chloride responsive" because volume repletion with fluids containing sodium chloride and potassium chloride corrects the alkalosis.
• Emesis, which results in hydrochloride and volume depletion, is a leading cause.

Chloride Responsive Alkalosis (Urinary Chloride <15 mEq/L)

• Gastric losses (emesis or nasogastric suction)
• Pyloric stenosis
• Diuretics (loop or thiazide)
• Chloride-losing diarrhea
• Chloride-deficient formula
• Cystic fibrosis (sweat losses of chloride)
• Posthypercapnia (chloride loss during respiratory acidosis)

Chloride Resistant Alkalosis (Urinary Chloride >20 mEq/L)

• High Blood Pressure:
  • Adrenal adenoma or hyperplasia
  • Glucocorticoid-remediable aldosteronism
  • Renovascular disease
  • Renin-secreting tumor
  • 17Alfa-Hydroxylase deficiency
  • 11Beta-Hydroxylase deficiency
  • Cushing syndrome
  • 1 1 Beta-Hydrorysteroid dehydrogenase deficiency
  • Licorice ingestion
  • Liddle syndrome
• Normal Blood Pressure:
  • Gitelman syndrome
  • Bartter syndrome
  • Base administration

Clinical Manifestations of Metabolic Alkalosis

• Symptoms are linked electrolyte disturbances and/or underlying disease.
• Hypokalemia is often present.
  • Can be severe in diseases causing this condition.
• Children with chloride-responsive alkalosis often show symptoms of volume depletion.
• Children with chloride-unresponsive alkalosis may have symptoms related to hypertension.
• Alkalemia can induce:
  • Arrhythmias
  • Hypoxia secondary to hypoventilation
  • Decrease cardiac output

Diagnosis of Metabolic Alkalosis

• Urinary chloride concentration is the most helpful diagnostic test.
• Medical history usually suggests a diagnosis.
• The following should be considered when there is no obvious explanations:
  • Bulimia
  • Surreptitious diuretic use
  • genetic disorders like Bartter or Gitelman syndrome.

Treatment of Metabolic Alkalosis

• Treatment is based on both the severity and the underlying etiology.
• Mild metabolic alkalosis (HCO3<32mEq/L) usually requires no intervention.
• Patients with chloride – responsive metabolic alkalosis benefit from correction of hypokalemia.
  • Volume repletion with sodium and potassium chloride
• Aggressive volume repletion can be contraindicated.
  • Mild volume depletion is medically necessary for a child receiving diuretic therapy.
• Volume repletion is contraindicated for chloride-resistant causes associated with hypertension
  • It exacerbates hypertension and does not repair the alkalosis.
• Treatment focuses on eliminating/blocking the action of excess mineralocorticoids.
• Therapy includes supplementation of potassium and potassium-sparing diuretics.
• Used in treating Bartter syndrome and Gitelman syndrome.

Respiratory Acid-Base Disturbances

• Respiratory acidosis involves decreased effectiveness of the lungs in removing CO2.
• Causes are either pulmonary or non-pulmonary.

Causes of Respiratory Acidosis

• Central nervous system depression (encephalitis or narcotic overdose)
• Disorders of the spinal cord, peripheral nerves, or neuromuscular junction (botulism or Guillain-Barre syndrome)
• Respiratory muscle weakness (muscular dystrophy)
• Pulmonary disease (pneumonia or asthma)
• Upper airway disease (laryngospasm)

Respiratory Alkalosis

• Inappropriate reduction in blood CO2 concentration.
• Variety of stimuli can increase ventilatory drive and cause the condition.

Causes of Respiratory Alkalosis

• Hypoxemia or tissue hypoxia (carbon monoxide poisoning or cyanotic heart disease)
• Lung receptor stimulation (pneumonia or pulmonary embolism)
• Central stimulation (anxiety or brain tumor)
• Mechanical ventilation
• Hyperammonemias

Treatment of Respiratory Acid-Base Disorders

• Treatment focuses on correcting the underlying disorder.
• Mechanical ventilation may be necessary for children with refractory respiratory acidosis.