Lactic acidosis

Lactic acidosis is a serious medical condition characterized by the excessive accumulation of lactic acid in the bloodstream, leading to a decrease in blood pH and metabolic acidosis. It is typically defined as a serum lactate concentration exceeding 4 mmol/L, often accompanied by an arterial blood pH below 7.35 and a plasma bicarbonate level less than 20 mmol/L.^[1] This buildup occurs when the body's tissues produce more lactate than can be cleared, primarily due to impaired oxygen delivery or utilization, and it is a common complication in critically ill patients.^[1]^[2] Lactic acidosis is classified into two main types based on underlying mechanisms. Type A lactic acidosis results from tissue hypoxia or hypoperfusion, such as in cases of septic shock, cardiogenic shock, severe anemia, or carbon monoxide poisoning, where inadequate oxygen supply leads to anaerobic metabolism and lactate production.^[1] In contrast, Type B lactic acidosis occurs without evident hypoxia and is associated with conditions like liver or kidney failure, malignancies, or medications such as metformin and nucleoside reverse transcriptase inhibitors used in HIV treatment.^[1]^[2] Additional causes include intense exercise, convulsions, or inborn errors of metabolism, though these are often transient.^[2] Clinically, lactic acidosis presents with symptoms that vary depending on the severity and underlying cause, including nausea, vomiting, abdominal pain, rapid or deep breathing (Kussmaul respirations), weakness, fatigue, and altered mental status.^[1]^[2] In severe cases, patients may exhibit hypotension, oliguria, tachycardia, or coma, with mortality rates increasing significantly when pH falls below 7.2 or lactate exceeds 7 mmol/L.^[1] Diagnosis involves measuring serum lactate levels via arterial or venous blood gas analysis, alongside calculation of the anion gap (typically >12 mEq/L, adjusted for hypoalbuminemia), to confirm the presence of metabolic acidosis and rule out other causes.^[1] Management focuses on identifying and treating the underlying etiology, such as administering fluids and vasopressors for shock or discontinuing offending medications.^[1] Supportive measures include oxygen therapy, mechanical ventilation if respiratory failure occurs, and in refractory cases, hemodialysis to remove lactate and correct acid-base imbalances.^[1] Bicarbonate therapy is used cautiously and only in extreme acidosis (pH <7.1-7.2) due to potential risks like intracellular acidosis.^[1] Early recognition and intervention in an intensive care setting are crucial, as lactic acidosis signals high morbidity and mortality in acute settings.^[1]

Definition and Classification

Definition

Lactic acidosis is a metabolic disorder characterized by the accumulation of lactate in the bloodstream, leading to a decrease in blood pH and bicarbonate levels. It is typically defined as a serum lactate concentration exceeding 4 mmol/L, accompanied by an arterial pH below 7.35 and a serum bicarbonate level below 20 mEq/L. This condition reflects an imbalance between lactate production and clearance, often resulting from impaired tissue oxygenation or metabolic dysfunction.^[1] The concept of lactate buildup during anaerobic metabolism, which underlies lactic acidosis, emerged from early 20th-century biochemical research, including the 1929 description of the Cori cycle by Carl Ferdinand Cori and Gerty Theresa Cori, who demonstrated how lactate produced in muscles is transported to the liver for reconversion to glucose, preventing excessive accumulation under hypoxic conditions.^[3] Lactic acidosis is distinguished from respiratory acidosis, which stems from carbon dioxide retention and elevated partial pressure of arterial carbon dioxide (PaCO₂), by its metabolic origin involving a high anion gap without primary ventilatory impairment. It also differs from other metabolic acidoses, such as ketoacidosis, where the elevated anion gap arises from ketone bodies rather than lactate.^[4] In the general population, the incidence of lactic acidosis remains low, estimated at 0.5% to 3.8% among hospitalized patients with internal diseases. However, it is far more prevalent in critically ill individuals, with hyperlactatemia (lactate ≥5 mmol/L) observed in about 13.6% of intensive care unit (ICU) admissions overall, rising to over 50% in cases of severe sepsis or septic shock, where it serves as a marker of disease severity and is associated with substantially increased mortality risk.^[1]^[5]^[6]

Types

Lactic acidosis is traditionally classified into Type A and Type B based on the underlying pathophysiology related to tissue oxygenation, a system proposed by Cohen and Woods in their seminal 1976 monograph.^[7] Type A lactic acidosis is characterized by the presence of clinical evidence of tissue hypoperfusion or hypoxia, leading to increased lactate production due to anaerobic metabolism; common examples include shock states and cardiac arrest, which account for the majority of cases encountered in intensive care settings.^[7]^[1] In contrast, Type B lactic acidosis occurs in the absence of overt hypoxia or hypoperfusion and is further subdivided into three subtypes: B1, associated with underlying systemic diseases such as malignancy or liver failure; B2, linked to drugs or toxins including metformin, ethanol, and salicylates; and B3, resulting from inborn errors of metabolism like mitochondrial disorders.^[7]^[8] D-lactic acidosis is a distinct variant primarily arising in short bowel syndrome where bacterial fermentation produces D-lactate and is generally associated with Type B mechanisms.^[9] A 2020 study highlighted hyperlactatemia without metabolic acidosis as a separate prognostic entity in critically ill individuals, associated with increased mortality independent of acid-base status.^[10]

Clinical Features

Signs and Symptoms

Lactic acidosis presents with a spectrum of clinical manifestations that vary based on severity and underlying conditions, often reflecting tissue hypoperfusion and metabolic derangement. In mild cases, symptoms may be subtle or absent, while progression to severe acidosis leads to multisystem involvement.^[1] Early symptoms commonly include nausea, vomiting, abdominal pain, fatigue, and myalgias, which can precede more overt signs and are frequently observed in conditions like metformin-associated lactic acidosis. These gastrointestinal and musculoskeletal complaints arise as nonspecific indicators of metabolic stress. As the condition advances, cardiorespiratory signs emerge, such as tachypnea with Kussmaul breathing (deep, rapid respirations as a compensatory response to acidosis), tachycardia, and hypotension, particularly in cases of significant hypoperfusion.^[11]^[12]^[1] Neurological effects typically manifest as confusion and lethargy, progressing to coma in severe cases with pH below 7.2, reflecting the impact of acidemia on cerebral function. Physical examination often reveals cool extremities due to peripheral vasoconstriction, hyperventilation, and signs of organ dysfunction such as acute kidney injury evidenced by oliguria. These findings underscore the systemic nature of advanced lactic acidosis.^[12]^[1]^[12] Mild hyperlactatemia, with lactate levels below 5 mmol/L, is often asymptomatic and discovered incidentally during routine evaluations, without accompanying acidosis or clinical features. In contrast, symptomatic cases exceeding this threshold correlate with the progression described above and may be confirmed through blood tests showing elevated lactate and reduced pH.^[1]^[12]

Causes

Lactic acidosis is broadly classified into Type A, associated with clinical evidence of tissue hypoperfusion or hypoxia, and Type B, occurring in the absence of such evidence.^[1]^[8] Type A lactic acidosis arises from conditions that impair oxygen delivery to tissues. Common causes include circulatory failure, such as cardiogenic or septic shock and severe hemorrhage leading to hypovolemic shock.^[1]^[8] Severe anemia, where hemoglobin levels drop below 5 g/dL, reduces oxygen-carrying capacity and contributes to lactate accumulation.^[8] Carbon monoxide poisoning binds to hemoglobin, preventing oxygen transport and mimicking hypoxic states.^[8] Intense exercise, particularly in untrained individuals or during prolonged high-intensity efforts, can also trigger Type A lactic acidosis due to localized muscle hypoxia.^[8] Type B lactic acidosis encompasses a diverse array of etiologies without overt hypoxia. It is further categorized into subtypes based on underlying mechanisms, though these do not involve tissue oxygen deprivation.^[1] Type B1 causes involve associated diseases that either increase lactate production or impair its clearance. Malignancies, such as lymphomas and leukemias, often lead to elevated lactate through rapid tumor cell metabolism.^[1]^[8] Liver cirrhosis and severe hepatic dysfunction hinder lactate metabolism by reducing hepatic clearance capacity.^[8] Renal failure, particularly acute kidney injury, limits lactate excretion and metabolism.^[8] Pancreatitis, often linked to alcohol use, is another contributor through inflammatory processes affecting lactate handling.^[8] Type B2 causes include medications, toxins, and nutritional factors. Certain medications, such as metformin especially in the setting of renal impairment, and nucleoside reverse transcriptase inhibitors used in HIV treatment, are well-documented triggers.^[1]^[8] Toxins like cyanide, which inhibits mitochondrial respiration, and ethylene glycol, metabolized to toxic acids, can induce lactic acidosis.^[1]^[8] Alcohol intoxication, particularly from ethanol, disrupts lactate metabolism and is a frequent cause.^[8] Type B3 causes are rare and stem from inborn errors of metabolism. Genetic disorders such as pyruvate dehydrogenase deficiency impair the conversion of pyruvate to acetyl-CoA, leading to lactate buildup. Glucose-6-phosphatase deficiency (von Gierke disease), which impairs gluconeogenesis and leads to pyruvate accumulation and lactate buildup, is another example.^[8]^[7] Iatrogenic factors, such as the accumulation of propylene glycol from prolonged intravenous lorazepam infusions or linezolid administration, can result in osmotic effects and lactate elevation.^[1]

Pathophysiology

Lactate Metabolism

Lactate is primarily produced through anaerobic glycolysis in various tissues, such as skeletal muscle and erythrocytes, where glucose is metabolized to pyruvate, which is then converted to lactate by the enzyme lactate dehydrogenase (LDH).^[13] This process allows for the regeneration of NAD⁺, essential for continued glycolysis under conditions of limited oxygen availability.^[14] The formation of lactate is regulated by the NADH/NAD⁺ ratio in the cell, which reflects the redox state and energy demands. LDH catalyzes the reversible reaction:

\text{Pyruvate} + \text{NADH} + \text{H}^{+} \xrightarrow{\text{LDH}} \text{Lactate} + \text{NAD}^{+}

This equilibrium favors lactate production when NADH levels are high, as occurs during intense metabolic activity.^[14]^[13] Lactate produced in peripheral tissues is transported via the bloodstream to the liver, where it participates in the Cori cycle, a key metabolic pathway for its utilization and recycling. In the liver, lactate is converted back to pyruvate by LDH and subsequently to glucose through gluconeogenesis, which can be released into circulation for reuse by other tissues.^[15] This cycle maintains glucose homeostasis and prevents excessive lactate accumulation under normal conditions.^[13] Clearance of lactate occurs mainly through aerobic metabolism in the liver and kidneys. The liver accounts for approximately 60-70% of lactate clearance, oxidizing it to pyruvate, which enters the tricarboxylic acid cycle to produce CO₂ and energy, or using it for gluconeogenesis.^[16]^[17] The kidneys contribute 20-30% to this process, similarly converting lactate to pyruvate for oxidation or gluconeogenesis, particularly during periods of increased lactate load.^[18]^[16] In healthy individuals, arterial lactate levels are maintained at 0.5-1 mmol/L, reflecting a balance between production and clearance. Daily lactate production is estimated at 20-25 mmol/kg of body weight, primarily from glycolytic activity in resting and active tissues.^[1]^[19]

Mechanisms of Acidosis

Lactic acidosis arises primarily from an imbalance where lactate production exceeds its clearance, leading to accumulation of lactate and associated protons in the extracellular fluid. This disruption in lactate homeostasis results in metabolic acidemia, characterized by a low blood pH and reduced bicarbonate levels. The condition is broadly classified into Type A, driven by tissue hypoxia, and Type B, associated with non-hypoxic factors, though both involve derangements in metabolic pathways.^[1] Increased lactate production occurs when cellular energy demands shift to anaerobic glycolysis due to hypoxia or hypoperfusion, as seen in conditions like septic or cardiogenic shock. Under these circumstances, oxygen scarcity impairs mitochondrial oxidative phosphorylation, overwhelming the activity of pyruvate dehydrogenase (PDH), the enzyme that converts pyruvate to acetyl-CoA for the Krebs cycle. Consequently, pyruvate is redirected to lactate via lactate dehydrogenase (LDH) to regenerate NAD⁺, allowing glycolysis to continue for limited ATP production. The net biochemical reaction can be summarized as:

\text{Glucose} \rightarrow 2 \text{ Lactate} + 2 \text{ H}^{+}

This process yields a net production of protons alongside lactate, contributing directly to acid load.^[8] Decreased lactate clearance exacerbates the imbalance, particularly when hepatic or renal function is compromised. The liver accounts for approximately 60-70% of lactate metabolism through gluconeogenesis or oxidation, while the kidneys handle 20-30%; both processes require adequate ATP and perfusion. In states such as shock-induced hypoperfusion or liver failure, reduced blood flow limits these organs' capacity to uptake and oxidize lactate, leading to its systemic accumulation.^[1] The development of acidosis is not solely due to lactate itself, which functions as a conjugate base rather than a direct acid. Instead, the protons co-produced during anaerobic glycolysis and the subsequent dissociation of lactic acid (lactate⁻ + H⁺) drive the acid-base disturbance. These protons are buffered primarily by bicarbonate (HCO₃⁻), resulting in its consumption and a fall in plasma pH, often manifesting as a high anion gap metabolic acidosis.^[8] Secondary effects can further complicate the acid-base profile. During recovery phases, as lactate levels decline with fluid resuscitation, a hyperchloremic metabolic acidosis may emerge due to chloride-rich solutions diluting bicarbonate. In Type B lactic acidosis, mitochondrial dysfunction—such as from biguanide toxicity or malignancies—impairs PDH and electron transport, promoting lactate generation without overt hypoxia.^[1] Recent research from the 2020s highlights the role of inflammation in amplifying these mechanisms, particularly in sepsis. Pro-inflammatory cytokines, such as TNF-α and IL-6, upregulate glycolytic enzymes in immune and endothelial cells, boosting lactate production independently of hypoxia. This inflammatory-driven metabolic reprogramming sustains hyperlactatemia and contributes to immune dysregulation in septic states.^[20]

Diagnosis

Laboratory Findings

Diagnosis of lactic acidosis relies on laboratory confirmation of metabolic acidosis with elevated lactate levels. Arterial blood gas (ABG) analysis typically reveals a low pH below 7.35, indicating acidemia, along with reduced bicarbonate levels under 20 mEq/L, consistent with a metabolic process.^[1]^[21] Elevated serum lactate exceeding 4 mmol/L in this context confirms the diagnosis, distinguishing it from mere hyperlactatemia where lactate surpasses 2 mmol/L without acidosis.^[1]^[21] The anion gap is calculated using the formula AG = Na⁺ - (Cl⁻ + HCO₃⁻), with normal values ranging from 8 to 12 mEq/L. An elevated anion gap above 12 mEq/L (or up to 16 mEq/L in some laboratory references) signals a high anion gap metabolic acidosis, attributable to unmeasured anions like lactate; correction for hypoalbuminemia is recommended by adding 2.5 mEq/L for every 1 g/dL decrease in albumin below 4 g/dL to enhance accuracy.^[1]^[21] Lactate measurement is preferably performed on arterial blood as the gold standard, though venous samples are commonly used for initial screening and are typically about 1 mmol/L higher than arterial levels, with mean differences reported between 0.18 and 1.06 mmol/L. Laboratory assays provide precise quantification, while point-of-care methods offer rapid results but require validation against central lab standards for reliability.^[21]^[22] Additional laboratory tests support the diagnosis and help identify underlying causes. Lactate dehydrogenase (LDH) levels are often elevated, particularly in malignancy-associated cases, serving as a supportive marker. Glucose concentrations are usually normal or low, reflecting potential hypoperfusion or metabolic derangements, while ketone measurements may be checked to exclude alternative acidoses like diabetic ketoacidosis.^[23]^[1] Bedside point-of-care lactate testing using handheld devices or strips enables rapid screening in emergencies, such as suspected sepsis, reducing turnaround time from over 50 minutes to under 35 minutes compared to central laboratory processing and facilitating timely intervention.^[21]^[24]

Differential Diagnosis

The differential diagnosis of lactic acidosis primarily encompasses other causes of high anion gap metabolic acidosis, as well as conditions that may present with similar clinical features of acidosis and tissue hypoperfusion but differ in etiology and laboratory confirmation.^[1] Key considerations include ketoacidosis, uremic acidosis, and toxin-induced acidoses, which must be excluded through targeted testing to avoid misdiagnosis.^[1] Diabetic ketoacidosis and alcoholic ketoacidosis are common mimics, characterized by high anion gap metabolic acidosis due to ketone production rather than lactate accumulation.^[1] These are distinguished by the detection of serum or urine ketones (e.g., beta-hydroxybutyrate) and, in diabetic ketoacidosis, elevated blood glucose levels typically exceeding 250 mg/dL, whereas alcoholic ketoacidosis often occurs in the setting of recent alcohol bingeing with normal or low glucose.^[1] Other high anion gap acidoses include uremic acidosis from acute or chronic kidney failure, identified by elevated blood urea nitrogen and creatinine levels, and toxin-induced forms such as salicylate poisoning or ingestion of methanol and ethylene glycol.^[1] These are differentiated via serum toxin levels (e.g., salicylate concentrations typically >40-50 mg/dL indicating toxicity) and calculation of the osmolar gap, which is often increased in alcohol-related intoxications.^[1]^[25] Conditions mimicking lactic acidosis include sepsis without substantial lactate elevation, thiamine deficiency presenting as refractory acidosis, and bowel ischemia.^[1] Sepsis may simulate lactic acidosis through systemic inflammation and hypoperfusion but can be clarified by cultures and procalcitonin levels when lactate remains below 2 mmol/L; thiamine deficiency, a type B lactic acidosis cause, impairs pyruvate metabolism and is suspected in malnourished patients, confirmed by clinical response to intravenous thiamine administration.^[26] Bowel ischemia elevates lactate due to local hypoperfusion and is distinguished by abdominal pain, leukocytosis, and confirmatory imaging such as CT angiography.^[27] Low anion gap alternatives, such as hyperchloremic metabolic acidosis, arise from non-lactate sources like excessive normal saline resuscitation and are identified by a normal anion gap (<12 mEq/L) with elevated chloride levels and absent lactate rise.^[28] A structured diagnostic approach begins with calculation of the anion gap from electrolytes; an elevated gap (>12-16 mEq/L, corrected for albumin) prompts immediate serum lactate measurement to confirm lactic acidosis.^[1] If lactate accounts for less than the full gap, evaluate for coexisting disorders via ketone testing, renal function assessment, toxin screening, and, if ischemia is suspected, targeted imaging like CT for bowel evaluation.^[1]

Treatment

General Principles

The management of lactic acidosis centers on supportive measures to optimize tissue perfusion and oxygenation, alongside targeted interventions for the underlying etiology, such as sepsis or hypoxia. Initial resuscitation prioritizes the ABCs—airway, breathing, and circulation—to stabilize the patient and prevent further lactate accumulation. Oxygen supplementation is administered to improve systemic oxygenation, particularly in cases of hypoxemia contributing to type A lactic acidosis.^[1] Fluid resuscitation forms a cornerstone of therapy, with intravenous crystalloids administered to restore intravascular volume and enhance perfusion, targeting a mean arterial pressure of at least 65 mm Hg. Balanced crystalloids, such as lactated Ringer's solution, are preferred over normal saline to minimize the risk of hyperchloremic metabolic acidosis from excessive chloride load. In septic shock, an initial bolus of 30 mL/kg is recommended within the first 3 hours, followed by dynamic reassessment using parameters like lactate clearance or passive leg raise testing.^[1]^[29] Ongoing monitoring of serial arterial lactate levels is essential to evaluate treatment efficacy and guide adjustments, with a target reduction of greater than 20% within 2 hours indicating adequate resuscitation response. Routine use of sodium bicarbonate is not recommended due to risks including paradoxical intracellular acidosis, CO2 retention, and potential worsening of hemodynamics; it should be reserved for severe cases with pH below 7.1 to 7.2 and impaired ventilation, where it may be titrated cautiously to raise pH toward 7.2. If fluid resuscitation fails to maintain perfusion, vasopressors are initiated, with norepinephrine as the first-line agent in septic shock to support mean arterial pressure without excessive vasoconstriction.^[30]^[31]^[1]

Specific Therapies

Specific therapies for lactic acidosis target the underlying etiology, classified as Type A (associated with tissue hypoxia) or Type B (without overt hypoxia, subdivided into B1 due to underlying diseases and B2 due to drugs or toxins). In Type A lactic acidosis, interventions focus on correcting hypoxia and restoring tissue perfusion. For sepsis-related cases, source control is paramount, involving prompt administration of broad-spectrum antibiotics and surgical intervention to eliminate the infection source, as delays in source control correlate with higher lactate levels and mortality. Mechanical ventilation is indicated for respiratory failure contributing to hypoxia, improving oxygenation and reducing lactate production through better alveolar recruitment and CO2 clearance. In severe anemia exacerbating oxygen delivery deficits, blood transfusion to achieve a hemoglobin level of 7-9 g/dL is recommended to enhance oxygen-carrying capacity and mitigate acidosis. For Type B1 lactic acidosis, treatment addresses the comorbid condition. In malignancy-associated cases, such as those linked to hematologic cancers, chemotherapy or targeted therapies like rituximab for lymphoma aim to reduce tumor burden and normalize lactate production. Liver failure contributing to impaired lactate clearance may benefit from extracorporeal liver support systems, such as the Molecular Adsorbent Recirculating System (MARS), which has shown reductions in serum lactate by adsorbing toxins and improving hepatic function in acute-on-chronic liver failure. Renal impairment as a cause requires dialysis, particularly hemodialysis, to enhance lactate elimination and correct acid-base disturbances when glomerular filtration rate falls below 10-15 mL/min. Type B2 lactic acidosis necessitates removal or reversal of the precipitant. Discontinuation of offending agents is first-line; for metformin-induced cases, immediate withholding and supportive measures are essential, with resolution often occurring within 24-48 hours in mild instances. In severe metformin-associated lactic acidosis, hemodialysis is recommended to enhance elimination of metformin and correct acidosis, particularly when pH is ≤7.0 or lactate exceeds 20 mmol/L.^[32] In toxin exposures like ethylene glycol poisoning, fomepizole inhibits alcohol dehydrogenase to block toxic metabolite formation, thereby halting lactate accumulation from glycolic acid. Thiamine supplementation (100-500 mg intravenously) is essential for deficiency states, such as in alcoholics, as it activates pyruvate dehydrogenase and shifts metabolism away from lactate production. Advanced therapies are employed for refractory cases. Extracorporeal membrane oxygenation (ECMO) supports severe cardiogenic shock by providing circulatory and respiratory assistance, allowing myocardial recovery and lactate normalization in critically ill patients. Continuous renal replacement therapy (CRRT) facilitates lactate clearance at rates up to 50-70 mL/min, superior to intermittent dialysis for unstable patients with hyperlactatemia. Emerging therapies in the 2020s include dichloroacetate, which activates pyruvate dehydrogenase to promote lactate oxidation to pyruvate, showing preliminary reductions in lactate levels in small trials for mitochondrial disorders, though it remains investigational and not standard due to potential neurotoxicity.

Prognosis

Factors Affecting Outcome

The outcome of lactic acidosis is influenced by several clinical and laboratory factors that determine its severity and potential reversibility. Initial serum lactate levels exceeding 4 mmol/L are associated with increased mortality risk, reflecting significant metabolic derangement and tissue hypoperfusion. Similarly, arterial pH below 7.2 indicates severe acidemia, which correlates with significantly higher mortality compared to milder cases, as it exacerbates hemodynamic instability and organ dysfunction. Persistent lactate elevation despite initial resuscitation further worsens prognosis, signaling ongoing production or impaired clearance, often leading to multi-organ failure.^[33]^[1] Comorbid conditions play a critical role in modulating prognosis, with advanced age serving as a non-modifiable risk factor that amplifies mortality when combined with elevated lactate, due to reduced physiological reserve and delayed recovery. Multi-organ failure, quantified by a Sequential Organ Failure Assessment (SOFA) score greater than 10, is a strong predictor of adverse outcomes, as it denotes widespread systemic involvement and higher in-hospital death rates. Underlying malignancy, particularly in type B lactic acidosis, portends an extremely poor prognosis, with survival often limited to weeks even with intervention, owing to the Warburg effect driving relentless lactate production.^[34]^[35]^[36] The response to therapy is a key modifiable determinant of survival, where rapid lactate clearance exceeding 10-20% per hour following resuscitation indicates effective restoration of perfusion and metabolism, correlating with improved outcomes and up to fivefold higher odds of survival. In contrast, clearance below 10% at 6-8 hours predicts higher mortality, emphasizing the need for timely cause-directed interventions. Type-specific factors also affect prognosis: type A lactic acidosis carries higher mortality if underlying hypoxia or shock remains unresolved, whereas type B cases fare better with reversible causes, such as prompt drug withdrawal in metformin-associated toxicity.^[37]^[33]^[1] Socioeconomic elements, including delayed presentation in resource-limited settings, contribute to poorer outcomes by hindering early recognition and intervention, as lactic acidosis may go undetected without routine point-of-care testing in rural or low-income areas.^[38]

Mortality Rates

Lactic acidosis in hospitalized patients is associated with substantial mortality, typically ranging from 20% to 50%, depending on severity and underlying conditions. In cases of severe hyperlactatemia (lactate ≥10 mmol/L), particularly in the context of septic shock, mortality rates approach 80%, as evidenced by multiple studies highlighting the prognostic impact of extreme lactate elevations.^[39]^[40] In intensive care unit (ICU) settings, in-hospital mortality for patients with lactic acidosis is approximately 35-40%, based on recent analyses of critically ill cohorts from 2015 onward, with one single-center study reporting a 34.5% 90-day mortality rate among those with elevated lactate levels. Mortality varies by type: Type A lactic acidosis, linked to tissue hypoperfusion, generally carries a higher mortality risk than Type B, which may have better outcomes when the underlying etiology is promptly addressed. For example, in metformin-associated lactic acidosis, mortality has improved to around 25% with prompt intervention including hemodialysis.^[41]^[42]^[43]^[44] Outcomes have improved with interventions such as early goal-directed therapy, exemplified by the legacy of the Rivers protocol, which demonstrated a reduction in mortality from 46.5% to 30.5% in severe sepsis and septic shock through targeted resuscitation. Post-2020, patients with lactic acidosis complicating COVID-19-associated acute respiratory distress syndrome (ARDS) experienced elevated mortality rates, often exceeding 40%, due to compounded inflammatory and hypoxic stresses. Among survivors, long-term risks persist, with approximately 30% facing hospital readmission within one year, primarily driven by comorbidities and recurrent infections in sepsis-related cases.^[45]^[46]

Lactic Acidosis in Animals

In Reptiles

In reptiles, lactic acidosis often arises as a physiological adaptation during periods of anaerobic metabolism, such as prolonged apnea in diving species like sea turtles or during brumation in terrestrial forms. For instance, freshwater turtles such as Chrysemys picta can endure weeks to months of anoxic submergence at low temperatures (around 3–10°C), accumulating plasma lactate concentrations up to 145 mmol/L without experiencing fatal acidosis, thanks to their remarkable tolerance for metabolic depression and buffering capacity.^[47]^[48] This adaptation allows ectothermic reptiles to survive hypoxic conditions, like underwater foraging or overwintering, where oxygen debt leads to reliance on glycolysis for energy, producing lactate as a byproduct.^[49] Pathologically, lactic acidosis in reptiles manifests prominently in capture myopathy, a stress-induced syndrome in wild individuals during handling or pursuit, which triggers intense anaerobic muscle activity, rapid lactate buildup, hyperthermia, rhabdomyolysis, and potentially death. In green sea turtles (Chelonia mydas), for example, manual restraint or forced submergence during capture elevates blood lactate to levels exceeding 20 mmol/L, contributing to cardiovascular strain and metabolic collapse if prolonged.^[50]^[51] In captive reptiles, bacterial septicemia—often from Salmonella or Pseudomonas species—represents another key cause, leading to systemic hypoperfusion, tissue hypoxia, and secondary lactic acidosis as part of the sepsis response.^[52]^[53] Reptiles exhibit unique adaptations for managing lactic acidosis, including slow but effective lactate clearance primarily through renal excretion and urinary output, with additional diffusion across permeable skin in some species aiding minor elimination. In anoxic turtles, lactate is excreted via the kidneys and bladder urine, often complexed with calcium to form soluble calcium lactate, facilitating its removal without overwhelming the system.^[54] pH buffering relies heavily on endogenous stores of calcium carbonate in mineralized tissues like the shell and skeleton, which release Ca²⁺ and Mg²⁺ ions to neutralize protons, preventing severe extracellular acidosis even at lactate peaks of 50–200 mmol/L.^[55]^[56] These mechanisms contrast with faster mammalian clearance via hepatic gluconeogenesis, allowing reptiles to tolerate prolonged acid loads at the cost of delayed recovery.^[57] Clinical management of lactic acidosis in reptiles prioritizes minimizing ongoing stress to halt further lactate production, as handling exacerbates the condition. Supportive measures include cooling to reduce metabolic rate in hyperthermic cases like capture myopathy, aggressive hydration via fluids to enhance perfusion and excretion, and environmental stabilization in quiet, dark enclosures.^[58]^[59] Sodium bicarbonate therapy should be used cautiously and is reserved for severe cases with close monitoring of blood gases. Antibiotics and supportive care for underlying septicemia are essential in captives, but overall prognosis hinges on early intervention to prevent cardiac or renal complications.^[60] Research on lactic acidosis in reptiles remains limited, with most foundational studies on physiological tolerance conducted before 2020, focusing on model species like turtles.

In Ruminants

Lactic acidosis in ruminants, particularly cattle and sheep, primarily arises from acute ruminal fermentation disorders triggered by grain overload or sudden ingestion of highly fermentable carbohydrates, such as grains or silage with elevated sugar content.^[61]^[62] This condition, often termed ruminal lactic acidosis, occurs when animals unaccustomed to high-concentrate diets consume excessive amounts—typically 10–20 kg of grain in cattle—leading to rapid starch breakdown by rumen bacteria.^[61] Poorly fermented silage can exacerbate risks in dairy and feedlot operations due to variable fermentation quality.^[63] The pathophysiology involves a sharp decline in ruminal pH below 5.5, shifting the microbial flora toward lactate-producing species like Streptococcus bovis, which generate both L- and D-lactate isomers.^[61]^[62] This overproduction—reaching lactate concentrations >10 mmol/L in ruminal fluid—overwhelms absorption and buffering capacities, resulting in systemic absorption of D-lactate, metabolic acidosis, dehydration, and rumen atony.^[62] The D-lactate form is particularly neurotoxic, contributing to encephalopathy, while the acidic environment induces rumenitis and secondary complications like laminitis.^[62] Blood gas analysis reveals a mixed metabolic acidosis with elevated anion gap.^[61] Clinical symptoms manifest rapidly, including depression, incoordination, diarrhea, and dehydration, progressing to ataxia, recumbency, and collapse in severe cases.^[61]^[62] Neurological signs, such as ataxia from D-lactate encephalopathy, are prominent, alongside cardiovascular instability (heart rate >120 bpm) and abdominal distension.^[62] Laminitis develops in survivors due to inflammatory responses.^[61] Diagnosis relies on history of dietary indiscretion, clinical presentation, and ruminal fluid analysis showing pH <5.5 and lactate >10 mmol/L, often via rumenocentesis.^[61]^[62] Fecal examination for undigested grain and blood gases confirming acidosis support the findings.^[61] Treatment varies by severity: mild cases receive oral alkalinizing agents and antibiotics to modulate rumen flora, while severe ones necessitate intravenous fluids (e.g., 5% sodium bicarbonate at 5 L/450 kg body weight), rumen lavage, or surgical rumenotomy to remove toxic contents.^[61]^[62] Prevention emphasizes gradual adaptation to concentrate feeds over 2–3 weeks and bunk management to avoid gorging.^[61] Recent approaches include probiotics like Megasphaera elsdenii to stabilize pH and reduce lactate producers.^[62] Economically, ruminal lactic acidosis is prevalent in feedlot cattle, second only to respiratory diseases, causing reduced growth, treatment costs, and 5–10% mortality in severe outbreaks.^[62] As of 2025, annual economic losses from subacute ruminal acidosis in the North American dairy industry are estimated at 5–10 billion USD, while acute cases contribute through complications like liver abscesses, costing approximately 256 million USD in US beef feedlots.^[64]^[65]