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

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
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
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

Metabolic acidosis + metabolic alkalosis + respiratory disorder
- Example: Patient with DKA (metabolic acidosis) + vomiting (metabolic alkalosis) + pneumonia (respiratory acidosis) 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

Osmolal Gap Calculation
- Measured osmolality - calculated osmolality 2
- Elevated osmolal gap suggests toxic alcohol ingestion (methanol, ethylene glycol) 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
Serial ABG Monitoring
- Track response to treatment (hemodialysis, fomepizole, bicarbonate) 3
- Assess adequacy of ventilatory compensation 3

Clinical Algorithm for Toxic Ingestions

Step 1: Obtain ABG, basic metabolic panel, serum osmolality 2

Step 2: Calculate anion gap and osmolal gap 2

Step 3: If high AG + high osmolal gap → suspect toxic alcohol 2

Step 4: Initiate specific antidote therapy and consider hemodialysis 3

Step 5: Serial ABG monitoring every 2-4 hours until stabilized 3

Role of ABG in Resuscitation of Undifferentiated Shock

In patients with undifferentiated shock and impaired tissue perfusion, central venous blood gas analysis provides crucial information about tissue perfusion and metabolic status. 3

Initial Assessment

Arterial blood gas in stable patients; central venous blood gas in patients with impaired tissue perfusion 3
Assess for metabolic acidosis as marker of inadequate tissue perfusion 3
Base deficit >15 mmol/l indicates severe acidosis and increased risk of complications 4

Resuscitation Guidance

Volume Resuscitation
- In the absence of coma (Glasgow coma score <8), 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
Serial ABG Monitoring
- Monitor response to resuscitation by tracking pH, lactate, and base deficit 3
- Improving acidosis indicates adequate resuscitation 3
- Worsening or persistent acidosis despite adequate volume resuscitation suggests need for vasopressors or other interventions 4
Treatment Priorities
- If the patient is still shocked or if the shocked state returns, treatment of shock should take priority, since cerebral perfusion depends on adequate blood pressure 4
- Restoration of circulatory volume and tissue perfusion is the primary goal 5

Special Considerations in Shock

Metabolic acidosis resolves with correction of hypovolemia and treatment of underlying cause 4
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
The effectiveness of sodium bicarbonate to correct metabolic acidosis from septic shock is unsure, and acidosis may have protective effects 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

Evidence-Based Indications for Bicarbonate Therapy

Chronic Kidney Disease

Initiate sodium bicarbonate when serum bicarbonate falls below 22 mmol/L, with aggressive treatment required when levels drop below 18 mmol/L 1
Oral sodium bicarbonate (2-4 g/day or 25-50 mEq/day) divided into 2-3 doses 1
Target maintenance is serum bicarbonate ≥22 mmol/L at all times 1
Monthly monitoring of serum bicarbonate initially, then at least every 4 months once stable 1

Severe Acute Metabolic Acidosis

Consider bicarbonate therapy only when pH falls below 6.9-7.0 1, 5
In diabetic ketoacidosis, bicarbonate therapy is generally NOT indicated unless pH falls below 6.9-7.0 5
For cardiac arrest, rapid administration of 44.6-100 mEq of bicarbonate initially may be given, with subsequent doses of 44.6-50 mEq every 5-10 minutes as needed 1

Specific Clinical Scenarios

In malignant hyperthermia, sodium bicarbonate administration is considered at a low threshold, as low pH values are associated with poor outcomes 1
Sodium bicarbonate aids potassium reuptake into cells and alkalinizes urine in malignant hyperthermia 1

Contraindications and Cautions

Bicarbonate therapy should be avoided or used cautiously in several situations:

Advanced heart failure with volume overload 1
Severe hypertension poorly controlled 1
Significant edema 1
Diabetic ketoacidosis (unless pH <6.9) 5
Lactic acidosis from tissue hypoperfusion 5
Septic shock 5

Mechanisms of Potential Harm

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

Monitoring During Bicarbonate Therapy

Critical monitoring parameters include:

Serum bicarbonate levels 1
Blood pressure 1
Serum potassium 1
Fluid status 1
Arterial blood gases to assess pH and bicarbonate response 1
Ensure treatment doesn't cause hypertension or hyperkalemia 1

Treatment Goals

The treatment goal is to increase bicarbonate levels toward but not exceeding the normal range 1
In severe acute metabolic acidosis requiring bicarbonate, the goal is to achieve a pH of 7.2-7.3, not normalization 1
The goal of achieving a total CO₂ of approximately 20 mEq/L initially is appropriate 1

Alternative Therapies

Administration of 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

Etiology-Specific Bicarbonate Use

Diabetic Ketoacidosis

Focus on insulin therapy, fluid resuscitation, and electrolyte replacement as primary treatment 5
Continuous intravenous insulin is the standard of care for critically ill and mentally obtunded patients 5
Bicarbonate administration has not been shown to improve resolution of acidosis or time to discharge 5
For children with pH <6.9,1-2 mEq/kg IV of sodium bicarbonate can be given slowly 5

Severe Malaria

Metabolic acidosis resolves with correction of hypovolemia and treatment of anemia by adequate blood transfusion 4
No evidence supports sodium bicarbonate use 4

Chronic Kidney Disease with Decompensation

Correction of metabolic acidosis reduces protein catabolism and prevents muscle wasting 1
Correction improves albumin synthesis, increasing serum albumin levels 1
Correction prevents bone demineralization, improving bone histology 1
May reduce hospitalizations in patients with corrected acidosis 1

Dosing Considerations

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

Common Pitfalls

Do not use bicarbonate as first-line treatment for lactic acidosis or ketoacidosis 5
Do not delay definitive treatment (dialysis, insulin, fluid resuscitation) while attempting bicarbonate therapy 5
Avoid citrate-containing alkali salts in CKD patients exposed to aluminum salts, as they may increase aluminum absorption 5

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

Acute Respiratory Acidosis
- Low pH (<7.35) with elevated PCO2 (>45 mmHg) 7
- Minimal bicarbonate elevation (compensation takes 3-5 days) 1
- Results from hypoventilation leading to CO2 retention 7
Chronic Respiratory Acidosis
- Normal or near-normal pH with elevated PCO2 1
- Elevated bicarbonate (>28 mmol/L) as renal compensation 1
- A patient with normal pH and elevated bicarbonate (>28 mmol/L) has probably got long-standing hypercapnia 1
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, as it is maintaining a normal pH and is physiologically appropriate 1

Diagnostic Algorithm for Respiratory Disorders

Step 1: Obtain ABG

Assess pH, PCO2, and bicarbonate 1

Step 2: Determine primary disorder

If pH <7.35 and PCO2 >45: Respiratory acidosis 7
If pH >7.45 and PCO2 <35: Respiratory alkalosis 7

Step 3: Assess compensation

Calculate expected metabolic compensation 3
If bicarbonate is higher than expected: Chronic respiratory acidosis with renal compensation 1
If bicarbonate is lower than expected: Coexisting metabolic acidosis 3