Lactic Acidosis

Etiology

Lactic acid is typically produced in excess at a rate of about 20 mmol/kg per day and enters the bloodstream, where it is primarily metabolized by the liver and kidneys. While some tissues can use lactate as a substrate and oxidize it to carbon dioxide (CO₂) and water, only the liver and kidneys possess the necessary enzymes for gluconeogenesis from lactate. The tissues that typically produce excess lactic acid include the skin, red blood cells, brain tissue, muscles, and the gastrointestinal tract. During intense exercise, skeletal muscles are the primary source of elevated circulating lactate, which usually returns to normal levels if hepatic metabolism is unimpaired.

Elevated lactate levels may result from increased production, decreased clearance, or a combination of both. Lactic acidosis is classified into 2 types—type A and type B.

Type A Lactic Acidosis 

Type A lactic acidosis occurs due to tissue hypoperfusion and hypoxia, leading to an imbalance between oxygen delivery and consumption. This condition shifts cellular metabolism toward anaerobic glycolysis, redirecting pyruvate metabolism toward the production of lactate.

Common causes of type A lactic acidosis include:

• Shock states: Septic, cardiogenic, hypovolemic, and obstructive
• Regional ischemia: Mesenteric or limb ischemia
• Cardiopulmonary arrest

These conditions are often associated with high mortality and require immediate correction of the underlying circulatory or respiratory compromise.[5] Early recognition and targeted intervention are essential for improving patient outcomes and reducing the risk of irreversible organ damage. 

Type B Lactic Acidosis

Type B lactic acidosis occurs without evidence of tissue hypoxia or hypoperfusion. Although less common than type A, both types share a fundamental issue—the mitochondria's inability to adequately metabolize excess pyruvate. This metabolic bottleneck activates alternative pathways, such as the lactic acid cycle, leading to elevated lactate levels.

Examples of conditions and factors associated with type B lactic acidosis include:

• Biguanide therapy [6]
• Malignancies such as leukemia, lymphoma, and solid tumors [7]
• Alcoholism (ethanol intoxication)
• Toxic alcohols, including methanol and ethylene glycol poisoning
• HIV infection
• Thiamine deficiency [8]
• Medications and drug-induced mitochondrial dysfunction, including:
  • Propofol
  • Nucleoside reverse transcriptase inhibitors
  • Linezolid
  • Valproate
  • Acetaminophen
  • Beta-adrenergic agonists
  • Isoniazid
  • Salicylates
  • Sulfasalazine
• Liver disease
• Congenital lactic acidosis
• Trauma
• Excessive exercise
• Cyanide poisoning

D-lactic acidosis is a rare but clinically significant subtype of lactic acidosis, typically observed in patients with short bowel syndrome or other forms of gastrointestinal malabsorption. In these individuals, undigested glucose and starch are fermented by colonic bacteria into various organic acids, including D-lactic acid—an isomer that humans metabolize poorly. Systemic absorption of D-lactate can lead to elevated plasma levels and metabolic acidosis.

Other causes of D-lactic acidosis include:

• High-dose intravenous infusions of propylene glycol (commonly used as a solvent in intravenous medications)
• Diabetic ketoacidosis [9]

Pathologic and persistent lactic acidosis occurs when 2 factors coexist—excessive lactate production and impaired hepatic clearance. When lactate production exceeds the liver's capacity for metabolism, lactic acidosis becomes more severe. For example, a patient experiencing excessive lactate production due to severe convulsions, coupled with impaired hepatic metabolic function, such as in cases of cirrhosis, hypothermia, sepsis, severe hypovolemia, or hypotension, is at significant risk of developing severe lactic acidosis.[10][11] Please see StatPearls' companion resource, "Glycogen Storage Disease Type I," for more information.

Epidemiology

Lactic acidosis is one of the most common metabolic complications encountered in critically ill patients. Despite its clinical significance, large-scale, high-quality studies remain limited. Most available data come from retrospective or small prospective studies, resulting in widely varying incidence and prevalence estimates depending on the patient population and diagnostic criteria used.

In a multicenter prospective study by Jung et al, severe metabolic or mixed acidemia—defined as a plasma pH of less than 7.20 within 24 hours of intensive care unit (ICU) admission—was observed in 6% of 2550 patients.[12] Among these patients, 83% required vasopressor support, and ICU mortality reached 57%. The average pH was 7.09 ± 0.11, accompanied by significantly elevated lactate levels.

Notably, the severity of hyperlactatemia and the time required for lactate normalization were independently associated with mortality. In contrast to absolute pH values, delayed resolution of lactic acidosis was a stronger predictor of poor outcomes. The use of sodium bicarbonate varied across centers and was not associated with improved survival.[12]

In patients with type 2 diabetes, incidence estimates of lactic acidosis vary significantly depending on the diagnostic thresholds applied. For instance, using a pH of less than 7.35 and lactate levels greater than or equal to 2.0 mmol/L, a population-based study reported an incidence of 391 per 100,000 person-years.[13] Among those treated with metformin, the incidence ranged from 9 to 10.37 per 100,000 person-years, depending on the study design and time period. A separate study on metformin-associated lactic acidosis reported 19.46 cases per 100,000 patient-years, while another described an incidence of 1 case per 2000 hospital admissions.[14]

Among patients with diabetic ketoacidosis, lactic acidosis appears to be highly prevalent, observed in up to 68% of cases in 1 study.[15] In individuals with HIV, particularly those receiving nucleoside reverse transcriptase inhibitors, an incidence of 19 per 1000 person-years has been reported when lactate levels exceeded 5 mmol/L alongside low bicarbonate or CO₂ levels.[16]

More broadly, among hospitalized patients with internal diseases, the prevalence of lactic acidosis has ranged from 0.5% to 3.8%, depending on clinical definitions and patient comorbidities.[17] Significantly, the definitions of lactic acidosis vary considerably across studies, with pH thresholds ranging from 6.9 to 7.35 and lactate cutoffs spanning 2.0 to 18.4 mmol/L. This variability underscores the need for standardized diagnostic criteria to enhance consistency in reporting, facilitate comparisons across populations, and improve the interpretation of research findings.

Pathophysiology

A clear understanding of the biochemistry of lactate generation and metabolism is essential for grasping the pathogenesis of lactic acidosis. In most patients, both lactate overproduction and impaired clearance contribute to elevated serum levels. Cellular lactate production is closely linked to the cell's redox state, which is reflected by the cytoplasmic ratio of oxidized to reduced nicotinamide adenine dinucleotide (NAD+/NADH).[18]

The enzyme lactate dehydrogenase catalyzes the interconversion of pyruvate and lactate, stereospecific for the L-isomer (L-lactate), the predominant form synthesized and metabolized in humans. Although D-lactate is not a major component of normal mammalian metabolism, it can be produced in significant amounts by certain bacteria and yeast, particularly within the gastrointestinal tract.

In healthy individuals, approximately 15 to 20 mmol/kg/d of lactic acid is produced, primarily through glucose metabolism via the glycolytic pathway. Under normal physiological conditions, this production is balanced by equivalent utilization, maintaining lactate homeostasis.

After glycolysis, pyruvate, the end product, is metabolized through 1 of 2 main pathways, as mentioned below.

• Aerobic metabolism: Pyruvate is converted to acetyl coenzyme A (acetyl-CoA) by pyruvate dehydrogenase, which then enters the citric acid cycle (Krebs cycle), supporting adenosine triphosphate (ATP) production through oxidative phosphorylation.

• Anaerobic metabolism: In the absence of sufficient oxygen, pyruvate is shunted into the lactic acid cycle (Cori cycle), where it is reduced to lactate, regenerating NAD+ from NADH. The restored NAD+ supports continued glycolysis, enabling the cell to produce 2 ATP molecules per 1 glucose molecule. The excess lactate generated is subsequently transported to the liver for the gluconeogenesis process.[19]

Maintaining the balance between lactate production and clearance is critical for metabolic stability. Disruption in either pathway can lead to pathological lactic acidosis.

Toxicokinetics

Lactate is an endogenous, nontoxic molecule that functions as a metabolic byproduct and an energetic substrate for gluconeogenesis. According to the Stewart-Fencl physicochemical approach to acid-base balance, all strong acids, including lactic acid, are fully dissociated at physiological pH in aqueous solution. This complete dissociation releases protons, contributing to a decrease in pH proportional to the extent of lactate overproduction and the degree of impaired metabolic clearance.

A drop in intracellular pH activates membrane transporters to expel lactate and hydrogen ions (H?) in an effort to preserve physiological intracellular pH homeostasis. This results in the accumulation of lactate and protons in the extracellular space, further lowering extracellular pH.

While any accumulation of lactate can lead to lactic acidosis, the combination of excessive production and impaired metabolic clearance poses the most significant clinical risk. The dual mechanism underlies the most severe and potentially life-threatening forms of lactic acidosis.[20]

History and Physical

The onset of acidosis can be rapid, but it may also progress gradually over several days. A comprehensive clinical history is essential for identifying potential causes of shock that may contribute to lactic acidosis. This includes evaluating recent illnesses, injuries, or surgical procedures, as well as assessing signs of infection, trauma, or organ dysfunction. A thorough medication and toxin exposure history is also essential, including over-the-counter drugs, prescription medications, and illicit substances. If the patient is unable to provide this information, family members or caregivers should be consulted to help identify any contributing factors.

Notably, lactic acidosis may occur following intense exercise or as a result of certain medications. Children with pyruvate dehydrogenase deficiency are also at risk of developing lactic acidosis in response to stressors such as an upper respiratory tract infection. No pathognomonic signs are specific to lactic acidosis, and the clinical presentation largely depends on the underlying cause. Patients are typically critically ill, with shock states, such as hypovolemic, septic, or cardiogenic shock, commonly observed.

On physical examination, signs of tissue hypoperfusion are often apparent, including severe hypotension, altered mental status, oliguria, and tachypnea. In cases of septic shock, fever exceeding 38.5?°C is often observed. Kussmaul respirations—a deep, labored breathing pattern—may develop as the body attempts to compensate for metabolic acidosis by increasing respiratory rate and depth.[21][22][23] Please see StatPearls' companion resource, "Melas Syndrome," for more information.

Evaluation

For any patient suspected of metabolic acidosis, obtaining serum electrolytes and performing an arterial blood gas analysis are essential. If the anion gap is elevated or if clinical signs suggest lactic acidosis, measuring serum lactate levels is recommended. An anion gap is typically considered elevated when it exceeds 12 mEq/L.

The anion gap is calculated using the following formula:

Anion gap= Sodium – (Chloride + Bicarbonate)

This equation reflects the difference between the primary measured cations and anions in the blood. In the absence of unmeasured anions, such as lactate, the normal range for the anion gap is typically 4 to 12 mEq/L. This range accounts for naturally occurring unmeasured anions, including phosphate and, notably, albumin.

Elevated plasma lactate levels almost always result in an anion gap metabolic acidosis. However, lower lactate concentrations can still lead to a normal anion gap metabolic acidosis. Hypoalbuminemia, commonly seen in critically ill patients, can affect the accuracy of an anion gap calculation. As albumin is the most significant contributor among unmeasured anions, low albumin levels can mask the presence of an anion gap acidosis, making the gap appear deceptively normal.

To improve diagnostic accuracy in such cases, a corrected anion gap can be calculated using the formula:

Corrected anion gap= Anion gap + (2.5 × [Normal albumin – Measured albumin in g/dL])

This adjustment accounts for the effect of hypoalbuminemia and enhances the sensitivity of the anion gap as a diagnostic tool in metabolic acidosis.[24] It is beneficial in critically ill patients, where standard anion gap measurements may fail to reflect significant underlying acid-base abnormalities.

Treatment / Management

Addressing the underlying cause of lactic acidosis is crucial for effective management of the condition. For instance, if the acidosis is due to mesenteric ischemia, prompt surgical intervention may be necessary. In cases caused by seizure activity, controlling seizures should be the immediate priority. After initial stabilization, supportive care should be tailored to the patient's specific clinical needs.

Given the wide range of potential causes and the diversity of therapeutic strategies, this section will focus on type A lactic acidosis secondary to septic shock, which is a common and life-threatening condition. The Surviving Sepsis Campaign defines septic shock as sepsis accompanied by tissue hypoperfusion, vasopressor-dependent hypotension, and elevated lactate levels.

Hospitals and healthcare systems are encouraged to implement performance improvement programs to effectively manage sepsis. These programs should include routine screening of high-risk, acutely ill patients and adherence to evidence-based treatment protocols. Early infection control is central to effective management. Broad-spectrum antibiotics should be administered within 1 hour of sepsis recognition, ideally after obtaining blood cultures. Additionally, anatomical source control should be pursued promptly.

In patients with septic shock, 30 mL/kg of intravenous crystalloids should be administered within the first 3 hours, followed by clinical reassessment to guide additional fluid therapy. Dynamic markers such as mean arterial pressure (MAP), central venous pressure, and mixed venous oxygen saturation should be used to evaluate fluid responsiveness. The recommended MAP target is 65 mm Hg or greater, although this may require adjustment based on comorbidities and the patient's overall clinical condition.

If hypotension persists after fluid resuscitation, vasopressors should be initiated, with norepinephrine as the first-line agent. If MAP goals remain unmet, vasopressin at 0.03 U/min may be added, and the use of corticosteroids should be considered. Epinephrine (20–50 mcg/min) can be initiated for additional hemodynamic support. If hypotension remains refractory, phenylephrine (200–300 mcg/min) may be considered a last-line agent.

In patients with sepsis-induced acute respiratory distress syndrome (ARDS), a lung-protective ventilation strategy is advised. This includes using low tidal volumes (≤6 mL/kg predicted body weight) and maintaining plateau pressures below 30 cm H₂O. For individuals with moderate-to-severe ARDS, prone positioning for more than 12 hours per day is recommended to improve oxygenation and outcomes.

Additional best practices for managing sepsis and septic shock include implementing a restrictive transfusion strategy, providing pharmacological venous thromboembolism prophylaxis in the absence of contraindications, and initiating insulin therapy when blood glucose exceeds 180 mg/dL (10 mmol/L) to maintain glycemic control. These interventions are part of a comprehensive sepsis care bundle that has been shown to improve patient outcomes.[25]

The use of alkalinizing agents, such as sodium bicarbonate, remains a topic of controversy. Routine bicarbonate administration in the setting of lactic acidosis and shock is not recommended and may be associated with worse outcomes.[26] However, emerging evidence supports a selective role for bicarbonate infusion in patients with acute kidney injury and a pH greater than 7.2 after initial resuscitation. Nevertheless, data remain limited, and further studies are needed to clarify its potential benefits for this subgroup.[27](B2)

Hemodialysis may be considered in severe lactic acidosis, especially in patients with renal failure. However, as most cases are due to tissue hypoperfusion, restoring adequate perfusion remains the priority. In cases of metformin-associated lactic acidosis, early initiation of dialysis (within 6 hours) and a preference for hemodialysis over peritoneal dialysis are associated with improved 30-day survival rates.[28]

Differential Diagnosis

Lactic acidosis has a broad differential diagnosis, including conditions ranging from tissue hypoperfusion and sepsis to drug toxicity and inborn errors of metabolism. A systematic approach is essential for identifying the underlying cause, as prompt and targeted management relies on accurate diagnosis.

Shock States (Type A Lactic Acidosis)

• Septic shock 
• Cardiogenic shock
• Hypovolemic shock 
• Obstructive shock 
• Regional ischemia 

Tissue Hypoxia Without Shock

• Severe anemia
• Respiratory failure with hypoxemia
• Carbon monoxide or cyanide poisoning

Non-Hypoxic Causes (Type B Lactic Acidosis)

• Medications and toxins
  • Metformin
  • Propofol
  • Linezolid
  • Isoniazid,
  • Valproate
  • Nucleoside reverse transcriptase inhibitors
  • Ethanol
  • Methanol
  • Ethylene glycol
• Malignancy (especially hematological malignancies such as leukemia and lymphoma)
• Thiamine deficiency
• Inborn errors of metabolism
  • Pyruvate dehydrogenase deficiency
  • Mitochondrial disorders
• Liver failure
• Seizures or strenuous exercise 

Other High Anion Gap Metabolic Acidosis Causes 

• Ketoacidosis
  • Diabetic
  • Alcoholic
  • Starvation
• Renal failure
• Toxin ingestion
  • Salicylates
  • Methanol
  • Ethylene glycol
  • Paraldehyde
• D-lactic acidosis 

Prognosis

The prognosis of lactic acidosis varies considerably depending on the underlying etiology, comorbidities, and severity of the acid-base disturbance. Reported mortality rates range from 17.3% to as high as 88%, with the highest rates observed in cases of severe metabolic acidosis, particularly in critically ill or septic patients. In general, mortality in lactic acidosis is closely associated with lower arterial pH, higher lactate concentrations, the need for vasopressors, and delayed correction of acidosis.

In specific contexts, such as metformin-associated lactic acidosis, outcomes are generally more favorable, particularly when early hemodialysis is initiated within 6 hours of admission.[28] In contrast, the indiscriminate use of sodium bicarbonate therapy in cases of general lactic acidosis has been associated with increased mortality.[26]

Prognostic indicators associated with increased mortality include:

• A pH of less than 7.2
• Lactate levels more than 7 mmol/L
• Blood bicarbonate less than 12 mmol/L
• Advanced age
• High Acute Physiology and Chronic Health Evaluation II (APACHE II) or Sequential Organ Failure Assessment (SOFA) scores
• Delayed dialysis in metformin-associated lactic acidosis
• Mechanical ventilation and ICU admission requirements

These findings highlight the importance of early diagnosis, targeted management based on the underlying cause, and cautious consideration of interventions such as bicarbonate therapy and renal replacement strategies.

Complications

Lactic acidosis can lead to a range of severe complications, particularly if not promptly identified and treated. Severe acidemia impairs cardiac contractility, reduces the responsiveness of catecholamines, and can lead to arrhythmias and hypotension, thereby exacerbating tissue hypoperfusion. This also contributes to multiple organ dysfunction, including acute kidney injury, hepatic impairment, and altered mental status. In critically ill patients, lactic acidosis often serves as a marker of underlying shock or organ failure, significantly increasing the risk of mortality. If prolonged or untreated, it can also complicate ventilatory management and diminish the effectiveness of resuscitative efforts.