What is metabolic acidosis, its pathophysiology, systemic effects, etiology, and approach to assessment and management?

Metabolic Acidosis: Comprehensive Overview

Introduction and Definition

Metabolic acidosis is a primary reduction in serum bicarbonate (<22 mmol/L) associated with blood pH <7.35, where the body attempts compensation by increasing ventilation to eliminate CO2. 1

• Metabolic acidosis develops when the kidney's mechanisms for maintaining acid-base homeostasis are overwhelmed or impaired, occurring in situations such as rapid production of nonvolatile acids, abnormally high bicarbonate losses, and impaired acid excretion by the kidney 2
• Low serum bicarbonate concentrations almost always indicate metabolic acidosis 1
• The normal serum bicarbonate range is 22-26 mmol/L, though more recent evidence suggests 23-30 mEq/L to avoid missing acid-base disorders 1

Pathophysiology

The kidney maintains acid-base homeostasis through elimination of protons and reabsorption/generation of bicarbonate; metabolic acidosis occurs when these mechanisms fail. 2

Primary Mechanisms

• In Chronic Kidney Disease, the kidneys' impaired ability to excrete hydrogen ions and synthesize ammonia leads to acid accumulation in the body 1
• Western dietary patterns with high animal protein, cereal, and grain consumption combined with low fruit and vegetable intake create an imbalance between nonvolatile acids and available alkali 1
• Animal proteins contain sulfur-containing amino acids that produce nonvolatile acids during metabolism 1
• A fall in extracellular and intracellular pH affects cellular function via different mechanisms, requiring treatment directed at improving both parameters 3

Compensatory Response

• The body attempts to compensate for metabolic acidosis by increasing ventilation to eliminate CO2 1
• Patients with severe acidosis may self-ventilate their PCO2 to very low levels as compensation for the metabolic acidosis 4
• When initiating mechanical ventilation in these patients, great care must be taken to avoid a rapid rise of PCO2, even to normal levels, before acidosis has been partly corrected 4

Systemic Effects of Acidosis

Acute metabolic acidosis is associated with increased morbidity and mortality through multiple organ system effects. 3

Cardiovascular Effects

• Depressive effects on cardiovascular function and facilitation of cardiac arrhythmias 3
• Hypotension (systolic blood pressure <80 mm Hg or <70 mm Hg if <1 year) complicates about 25% of cases presenting with severe acidosis (base deficit >15 mmol/l) 4
• Acidosis directly stimulates endothelial cell secretion of endothelin 1, which enhances sodium-hydrogen exchanger 3 activity, increasing luminal hydrogen ion secretion 1

Metabolic and Nutritional Effects

• Protein catabolism is increased, leading to muscle wasting and malnutrition 1
• Correction of acidemia has been associated with increased serum albumin and decreased protein degradation rates 1
• Acidosis increases oxidation of branched chain amino acids 5
• Correction of metabolic acidosis increases essential amino acid concentrations, promoting cellular influx and decreasing efflux of branched chain amino acids 1

Bone and Mineral Effects

• Bone demineralization occurs, contributing to renal osteodystrophy 1
• Chronic metabolic acidosis alters the homeostatic relationships between blood ionized calcium, PTH, and 1,25(OH)₂D₃, leading to bone dissolution 1
• Maintaining serum bicarbonate ≥22 mmol/L is associated with normal bone biopsy results, versus mixed osteodystrophy at levels <20 mmol/L 1

Growth and Development

• Growth retardation in children with CKD may occur due to chronic metabolic acidosis 1
• In children with renal tubular acidosis, normalization of serum bicarbonate is important for normal growth parameters 5

Immune and Inflammatory Effects

• Stimulation of inflammation and suppression of the immune response 3

Electrolyte Disturbances

• Acidosis causes hyperkalemia due to transcellular shift of potassium 5
• Hyperkalaemia may complicate cases with severe metabolic acidosis at admission 4

Etiology

Determining the presence or absence of an anion gap is the first step in ascertaining the etiology of metabolic acidosis. 2

High Anion Gap Metabolic Acidosis

Lactic Acidosis

• Lactic acidosis evolves from various conditions, either with or without systemic hypoxia 6
• Lactic acidosis due to tissue hypoxia requires primary focus on improving oxygen delivery 7

Ketoacidosis

• Diabetic ketoacidosis: bicarbonate of 15-18 mmol/L indicates mild DKA, while levels below 15 mmol/L indicate moderate to severe DKA 1
• The primary goal in DKA is restoring circulatory volume and tissue perfusion, along with resolution of ketoacidosis and correction of electrolyte imbalances 5

Renal Failure

• Acute kidney injury with severe acidosis (pH <7.20) represents refractory acidosis requiring urgent intervention 5
• In CKD stages 3-5, serum bicarbonate levels should be measured to monitor for metabolic acidosis 1

Toxic Ingestions

• The presence or absence of an osmolal gap, urine pH, and serum potassium levels may be useful in certain settings 2

Normal Anion Gap (Hyperchloremic) Metabolic Acidosis

Gastrointestinal Losses

• Abnormally high bicarbonate losses through gastrointestinal tract 2

Renal Tubular Acidosis

• Impaired acid excretion by the kidney 2

Iatrogenic Causes

• Unbalanced electrolyte preparations can induce hyperchloremic metabolic acidosis 6
• Hyperchloremic acidosis potentially worsens kidney-related outcome parameters 6

Recovery Phase

• Recovery from diabetic ketoacidosis can cause acidosis with a normal anion gap 1

Approach to Assessment

Appropriate evaluation of acute metabolic acidosis includes assessment of acid-base parameters, including pH, partial pressure of CO2 and HCO3- concentration in arterial blood in stable patients, and also in central venous blood in patients with impaired tissue perfusion. 3

Initial Laboratory Assessment

1. Arterial Blood Gas Analysis

   • Confirm metabolic acidosis (pH <7.35, bicarbonate <22 mmol/L) 1
   • Assess PCO2 to evaluate respiratory compensation 1
   • In patients with impaired tissue perfusion, central venous blood gas may be more appropriate 3

2. Serum Bicarbonate and Anion Gap

   • Calculate the serum anion gap: (Na+) - (Cl- + HCO3-) 2
   • Calculate the change from baseline (delta anion gap) to detect organic acidoses 3
   • This enables detection of organic acidoses, a common cause of severe metabolic acidosis, and aids therapeutic decisions 3

3. Additional Laboratory Tests

   • Serum electrolytes, particularly potassium 5
   • Blood glucose to exclude hypoglycemia 4
   • Serum osmolality to calculate osmolal gap if toxic ingestion suspected 2
   • Urine pH in certain settings 2
   • Lactate level if lactic acidosis suspected 6
   • Ketones if diabetic ketoacidosis suspected 1

Clinical Assessment

• Assess conscious level using AVPU scale (Alert, responds to Voice, responds to Pain, or Unresponsive) or Glasgow coma scale 4
• Evaluate hemodynamic status: blood pressure, heart rate, capillary refill time (≥2 seconds is a reasonable prognostic indicator) 4
• Assess volume status: signs of volume depletion such as orthostatic hypotension, decreased skin turgor, and elevated BUN/creatinine ratio 1
• Urine output of <1 ml/kg/hour, in the absence of urinary retention or established renal failure, indicates impaired renal perfusion secondary to hypovolemia 4

Systematic Approach Algorithm

Step 1: Confirm metabolic acidosis

• pH <7.35 and HCO3- <22 mmol/L 1

Step 2: Calculate anion gap

• High anion gap (>12): Consider lactic acidosis, ketoacidosis, renal failure, toxic ingestions 2
• Normal anion gap: Consider GI losses, RTA, iatrogenic causes, recovery phase of DKA 1, 2

Step 3: Assess severity

• Bicarbonate ≥22 mmol/L: Monitor without pharmacological intervention 1
• Bicarbonate 18-22 mmol/L: Consider oral alkali supplementation 1
• Bicarbonate <18 mmol/L: Initiate pharmacological treatment 1
• pH <7.20: Consider urgent intervention including possible dialysis 5
• pH <6.9-7.0: Consider bicarbonate therapy in specific contexts 1, 5

Step 4: Identify underlying cause

• History, physical examination, and targeted laboratory tests 2

Step 5: Initiate cause-specific treatment

• Address underlying etiology as primary intervention 5

Triple Disorder

A triple disorder exists when three primary acid-base disturbances occur simultaneously, requiring careful analysis of expected compensation versus observed values.

Recognition Approach

• Calculate expected compensation for the primary disorder 3
• If the observed values differ significantly from expected compensation, consider additional primary disorders 3
• Measure arterial blood gases to determine pH and PaCO2 for complete acid-base assessment 1

Common Triple Disorder Scenarios

1. Metabolic acidosis + metabolic alkalosis + respiratory disorder

   • Example: Patient with DKA (metabolic acidosis) + vomiting (metabolic alkalosis) + pneumonia (respiratory acidosis) 2

2. Detection Strategy

   • Calculate delta anion gap and compare to delta bicarbonate 3
   • If delta AG ≠ delta HCO3-, consider coexisting metabolic alkalosis or additional metabolic acidosis 3

Clinical Pitfall

• Failing to recognize triple disorders can lead to inappropriate treatment, as the pH may appear near-normal despite severe underlying derangements 3

Role of ABG in Toxicology

The presence or absence of an osmolal gap, combined with anion gap analysis and ABG findings, is crucial for identifying toxic ingestions causing metabolic acidosis. 2

Key Toxicological Applications

1. Osmolal Gap Calculation

   • Measured osmolality - calculated osmolality 2
   • Elevated osmolal gap suggests toxic alcohol ingestion (methanol, ethylene glycol) 2

2. Anion Gap Analysis

   • High anion gap metabolic acidosis with elevated osmolal gap: Consider methanol, ethylene glycol 2
   • High anion gap without osmolal gap elevation: Consider salicylate toxicity, other organic acidoses 2

3. Serial ABG Monitoring

   • Monitor arterial or venous blood gases to assess response to treatment 1
   • Track pH trends to guide antidote administration and supportive care 3

Specific Toxins

• Metformin: The incidence of metformin-associated acute metabolic acidosis is actually quite low 6
• Salicylates: May cause mixed respiratory alkalosis and metabolic acidosis 2

Role of ABG in Resuscitation of Undifferentiated Shock

In patients with undifferentiated shock, ABG analysis guides resuscitation by identifying metabolic acidosis severity, assessing tissue perfusion, and monitoring response to interventions.

Initial Assessment

• Central venous blood gas may be more appropriate than arterial in patients with impaired tissue perfusion 3
• Severe acidosis (base deficit >15 mmol/l) complicates about 25% of shock cases and correlates with hypotension 4

Resuscitation Guidance

1. Volume Resuscitation

   • In the absence of coma, volume resuscitation with 20-40 ml/kg of either 0.9% saline or 4.5% human albumin solution safely corrects hemodynamic features of shock 4
   • Volume resuscitation should proceed cautiously and be stopped once signs of circulatory failure have been reversed 4
   • For any patient with persisting features of shock despite 40 ml/kg of fluid, elective intubation and ventilation, and placement of a central venous catheter to guide further fluid management is recommended 4

2. Shock with Coma

   • In patients presenting in coma with shock, human albumin solution should be considered the resuscitation fluid of choice 4
   • A more cautious approach to volume expansion is advised in comatose patients 4

3. Monitoring Adequacy of Resuscitation

   • Serial ABGs track improvement in pH and lactate clearance 3
   • Base deficit improvement indicates successful resuscitation 4
   • Urine output of <1 ml/kg/hour indicates impaired renal perfusion and is a good non-invasive guide to fluid management 4

Treatment Priorities

• Treatment of shock should take priority, since cerebral perfusion depends on adequate blood pressure 4
• The primary focus for lactic acidosis due to tissue hypoxia is improving oxygen delivery 7
• Sodium bicarbonate should not be used to treat metabolic acidosis arising from tissue hypoperfusion in sepsis; instead focus treatment on restoring tissue perfusion with fluid resuscitation and vasopressors 5

Common Pitfalls

• Avoid using hypotonic fluids (e.g., glucose solutions) for fluid resuscitation 5
• Avoid using dopamine in an attempt to improve renal function 5
• Do not use furosemide unless hypervolemia, hyperkalemia, and/or renal acidosis are present 5

Role of Sodium Bicarbonate

Treatment of metabolic acidosis must be directed at the underlying cause rather than routine bicarbonate administration, as sodium bicarbonate has not demonstrated mortality benefit in most acute organic acidoses and may worsen intracellular acidosis. 5

When NOT to Use Bicarbonate

1. Diabetic Ketoacidosis

   • Bicarbonate therapy is generally NOT indicated in DKA unless pH falls below 6.9-7.0 1, 5
   • Primary treatment should focus on insulin therapy and fluid resuscitation, which corrects the underlying ketoacidosis 5
   • Bicarbonate administration has not been shown to improve resolution of acidosis or time to discharge in DKA 5

2. Lactic Acidosis from Tissue Hypoperfusion

   • Sodium bicarbonate should not be used to treat metabolic acidosis arising from tissue hypoperfusion in sepsis 5
   • Focus treatment on restoring tissue perfusion with fluid resuscitation and vasopressors 5
   • The effectiveness of sodium bicarbonate to correct metabolic acidosis from septic shock is unsure, and acidosis may have protective effects 5

3. Severe Malaria

   • Metabolic acidosis resolves with correction of hypovolemia and treatment of anemia by adequate blood transfusion 5
   • No evidence supports sodium bicarbonate use in severe malaria 4, 5

When to Consider Bicarbonate

Bicarbonate therapy should be considered in specific clinical scenarios with severe acidemia, but only after addressing the underlying cause.

1. Chronic Kidney Disease

   • Oral sodium bicarbonate supplementation is the initial treatment for CKD-related metabolic acidosis when serum bicarbonate falls below 22 mmol/L 1
   • Pharmacological intervention is strongly recommended when bicarbonate drops below 18 mmol/L 1
   • Typical dosing: 0.5-1.0 mEq/kg/day divided into 2-3 doses, or 2-4 g/day (25-50 mEq/day) 1
   • Target maintenance is serum bicarbonate ≥22 mmol/L at all times 1

2. Severe Acidemia (pH <6.9-7.0)

   • In DKA, bicarbonate administration is considered only when pH < 6.9 5
   • For children with DKA and pH <6.9,1-2 mEq/kg IV of sodium bicarbonate can be given slowly 5
   • The goal of bicarbonate therapy is to achieve a pH of 7.2-7.3, not normalization 1

3. Acute Kidney Injury with Severe Acidosis

   • Hemodialysis is the definitive treatment for patients with severe acidosis (pH <7.20) and acute kidney injury 5
   • Dialysis should not be delayed while attempting medical management 5

Dosing and Administration

For CKD patients requiring bicarbonate:

• Initial dose: 2-4 g/day (25-50 mEq/day) divided into 2-3 doses 1
• For dialysis patients: Higher dialysate bicarbonate concentrations (38 mmol/L) combined with oral supplementation 1
• For peritoneal dialysis: Higher dialysate lactate or bicarbonate levels plus oral sodium bicarbonate 1

For acute severe acidemia:

• Rapid administration of 44.6-100 mEq of bicarbonate initially may be given in cardiac arrest 1
• Subsequent doses of 44.6-50 mEq every 5-10 minutes as needed 1
• Measure arterial blood gases to assess pH and bicarbonate response 1

Monitoring During Bicarbonate Therapy

• Monitor serum bicarbonate, blood pressure, serum potassium, and fluid status regularly after initiating treatment 1
• Monthly monitoring of serum bicarbonate initially, then at least every 4 months once stable 1
• Ensure treatment doesn't cause hypertension or hyperkalemia 1
• Monitor electrolytes, particularly potassium levels, as acidosis causes hyperkalemia due to transcellular potassium shift 5

Potential Adverse Effects

• Administration of bicarbonate solutions may worsen intracellular acidosis 5, 3
• Reduction in ionized calcium 5, 3
• Production of hyperosmolality 5, 3
• Increased carbon dioxide production with subsequent intracellular acidosis 6
• Oral sodium bicarbonate does not significantly increase blood pressure, body weight, or hospitalizations when used appropriately 1

Contraindications and Cautions

• Be cautious or avoid sodium bicarbonate in patients with advanced heart failure with volume overload 1
• Avoid in severe hypertension poorly controlled 1
• Avoid in significant edema 1
• Citrate-containing alkali salts should be avoided in CKD patients exposed to aluminum salts as they may increase aluminum absorption 1, 5

Alternative Therapies

• Tris(hydroxymethyl)aminomethane (THAM) improves acidosis without producing intracellular acidosis and its value as a form of base is worth further investigation 3
• Selective sodium-hydrogen exchanger 1 (NHE1) inhibitors have been shown to improve hemodynamics and reduce mortality in animal studies of acute lactic acidosis 3
• Dichloroacetate reduces lactic acidosis in African children, but effect on mortality unknown 4

Benefits of Correction in CKD

Correction of metabolic acidosis in CKD provides multiple clinical benefits:

1. Nutritional Benefits

   • Reduces protein catabolism, prevents muscle wasting and malnutrition 1
   • Improves albumin synthesis, increasing serum albumin levels 1
   • May promote weight gain, increasing body weight and mid-arm circumference 1

2. Bone Health

   • Prevents bone demineralization, improving bone histology 1
   • Reduces secondary hyperparathyroidism progression 1

3. CKD Progression

   • May slow CKD progression 1
   • Reduces hospitalizations in patients with corrected acidosis 1

4. Growth in Children

   • Pediatric clinicians may choose to treat milder acidosis (bicarbonate >18 mmol/L) more aggressively to optimize growth and bone health 1

Approach to Respiratory Disorders

Respiratory acidosis is characterized by elevated PaCO2 (>46 mmHg), and in chronic respiratory acidosis, the kidneys retain bicarbonate to buffer the acidity, resulting in high bicarbonate levels as a compensatory mechanism, not the primary disorder. 1

Distinguishing Respiratory from Metabolic Disorders

1. Acute Respiratory Acidosis

   • Low blood pH (<7.35) with elevated CO2 levels 7
   • Results from hypoventilation leading to CO2 retention 7
   • Minimal bicarbonate elevation (compensation takes days) 1

2. Chronic Respiratory Acidosis

   • Elevated PaCO2 (>46 mmHg) 1
   • Kidneys retain bicarbonate over time to buffer chronically elevated CO2 1
   • Normal pH with elevated bicarbonate (>28 mmol/L) indicates long-standing hypercapnia with complete renal compensation 1

3. Compensated Chronic Respiratory Acidosis

   • Normal pH with elevated bicarbonate (>28 mmol/L) and elevated PCO2 (>45 mmHg) indicates long-standing hypercapnia with complete renal compensation 1
   • The elevated bicarbonate is protective and should not be treated directly 1

Diagnostic Approach

To differentiate between primary metabolic alkalosis and compensatory response to chronic respiratory acidosis:

• Assess arterial blood gas (ABG) to determine pH and PaCO2 1
• Significantly elevated PaCO2 (>46 mmHg) indicates chronic respiratory acidosis 1
• A patient with normal pH and elevated bicarbonate (>28 mmol/L) probably has long-standing hypercapnia 1

Management of Chronic Respiratory Acidosis

The elevated bicarbonate in chronic respiratory acidosis is physiologically appropriate and should not be treated; instead, focus on managing the underlying respiratory disorder. 1

1. Oxygen Management

   • Target oxygen saturation of 88-92% in patients with chronic hypercapnia, rather than attempting to correct the bicarbonate level 1
   • Prior to blood gas availability, use 24% Venturi mask at 2-3 L/min or nasal cannulae at 1-2 L/min, or 28% Venturi mask at 4 L/min 1
   • Avoid excessive oxygen therapy, as PaO2 above 10.0 kPa (75 mmHg) increases the risk of worsening respiratory acidosis in patients with hypercapnic respiratory failure 1
   • Careful oxygen therapy is essential, as excessive oxygen can worsen hypercapnia in certain conditions like COPD 7

2. Monitoring

   • Serial blood gases are essential to detect transition from compensated to decompensated respiratory acidosis 1
   • Repeat blood gases at 30-60 minutes after any change in oxygen therapy or if clinical deterioration occurs 1
   • Measure blood gases on arrival for any acute illness in patients with baseline compensated respiratory acidosis 1

3. Addressing Underlying Respiratory Disorder

   • For COPD exacerbations: Optimize bronchodilators, corticosteroids, and antibiotics if indicated 1
   • Consider non-invasive ventilation (NIV) if pH falls below 7.35 despite medical management 1
   • About 20% of patients with acute exacerbations of COPD have respiratory acidosis 7
   • For obesity hypoventilation syndrome: Consider weight loss, positive airway pressure therapy (CPAP/BiPAP), and treatment of concurrent obstructive sleep apnea 1

4. Mechanical Ventilation

   • Mechanical ventilation may be required in acute respiratory acidosis to improve ventilation and reduce CO2 levels 7
   • Initiate NIV early if pH falls below 7.35 1
   • For patients with severe baseline hypercapnia (PCO2 >55 mmHg), consider prophylactic NIV in the immediate postoperative period 1

Special Clinical Scenarios

1. Postoperative Management

   • Maintain target oxygen saturation 88-92% in the postoperative period for patients with chronic hypercapnia 1
   • Consider prophylactic NIV for patients with severe baseline hypercapnia 1

2. Acute Decompensation

   • If pH falls below 7.35 despite medical management, initiate non-invasive ventilation 1
   • Patients with persisting features of shock despite fluid resuscitation warrant elective intubation and ventilation 4

Bicarbonate Therapy in Respiratory Acidosis

• Bicarbonate therapy is NOT indicated for compensated chronic respiratory acidosis with normal pH 1
• May be considered if severe acute metabolic acidosis develops (pH <7.1) from a separate process 1
• The goal of bicarbonate therapy is to achieve a pH of 7.2-7.3, not normalization, and only in the context of treating the acute metabolic component 1

Management of Contraction Alkalosis in Respiratory Patients

For patients with chronic hypercapnia who develop contraction alkalosis from diuretics:

• Acetazolamide can be used to reduce bicarbonate buffering capacity, allowing for continued necessary diuresis for heart failure without worsening alkalosis 1
• Carbonic anhydrase inhibitors promote urinary bicarbonate loss, directly lowering elevated HCO3 levels 1
• Diuretics should not be stopped abruptly in acute heart failure, as the patient still needs decongestion 1
• Monitor potassium levels closely when starting acetazolamide, as it can cause hypokalemia 1

Common Pitfalls in Respiratory Acidosis Management

1. Ventilation Initiation

   • When initiating ventilation in patients with severe acidosis, great care should be taken to avoid a rapid rise of PCO2, even to normal levels, before acidosis has been partly corrected 4
   • Patients with severe acidosis may self-ventilate their PCO2 to very low levels as compensation 4

2. Oxygen Therapy

   • Excessive oxygen can worsen hypercapnia in COPD and other chronic respiratory conditions 1, 7
   • Always target 88-92% oxygen saturation in chronic hypercapnia 1

3. Misidentifying the Primary Disorder

   • Elevated bicarbonate in chronic respiratory acidosis is compensatory, not a primary metabolic alkalosis requiring treatment 1
   • Focus on the underlying respiratory disorder, not the bicarbonate level 1