Lactate physiology and diagnostic evaluation

Introduction

By 1900, many physicians had noted metabolic acidosis in patients who were critically ill. In 1925, Clausen identified increased lactate along with acidosis in these patients, which gave rise to the condition of “lactic acidosis,” although later work showed the lactate and acid were produced in entirely separate biochemical reactions, as described recently in a review ( ) . In 1964, Broder and Weil observed that lactate levels above 4 mmol/L were associated with poor outcomes in patients with shock, as cited in a review by Andersen et al. ( ) . While a decreased supply of oxygen to cells caused by inadequate cardiac, pulmonary, or circulatory function is well recognized as a cause of increased blood lactate, other causes have more recently become appreciated, such as mitochondrial dysfunction. Together, these causes of hyperlactatemia have led to very large increases in lactate testing in critical care.

Over the past 35 years, the measurement of blood lactate has evolved from a test regarded as having little clinical value to a highly valuable tool in monitoring general metabolic function. The annual test volume at Duke Medical Center for blood lactate has increased from approximately 2000 tests in 1985, to 10,000 in 1995, to 30,000 in 2005, and is now over 60,000. Reasons for this increase started in 1986 when a pediatric cardiac surgeon began to use blood lactate for monitoring the status of pediatric patients during open-heart surgery. This continued with use during extracorporeal membrane oxygenation (ECMO) procedures ( ) , and further with use in evaluating patients in the ED, including trauma patients and those with chest pain, and as a criterion for admission to a higher level of care. Over the last 10–15 years, major increases in lactate testing have resulted from official guidelines recommending lactate measurement for evaluating sepsis and for monitoring the effectiveness of therapy in patients with sepsis ( ) .

Physiology and metabolism

Lactate is converted from pyruvate in the cytoplasm of most cells, with the highest levels produced in muscle cells. In the process of glycolysis, which is always an anaerobic process, glucose is converted to pyruvate. In cells with no mitochondria such as erythrocytes, glycolysis is the only pathway for producing ATP. With an adequate supply of oxygen to cells with functional mitochondria, pyruvate is converted to acetyl CoA by pyruvate dehydrogenase with the essential cofactor thiamine, then enters the Krebs cycle and is eventually metabolized by the very complex process of oxidative phosphorylation to produce CO ₂ and large amounts of ATP. Under these conditions, a relatively small amount of pyruvate is converted to lactate, so blood lactate remains within normal intervals. Whether pyruvate is converted to Acetyl CoA or to lactate depends on the proportions of NAD ⁺ and NADH. With adequate oxygen in the mitochondria, more NAD ⁺ is produced, which favors the conversion of pyruvate to Acetyl CoA. However, if oxygen supply is inadequate, or in cells with no mitochondria (such as erythrocytes), levels of NADH are increased, which favors the conversion of pyruvate to lactate by the enzyme lactate dehydrogenase. These processes are shown in Fig. 9.1 . Contrary to common belief, the production of lactate from pyruvate does not produce acid, but actually consumes acid in the reaction:

The continual production of NAD ⁺ is necessary for the production of ATP, either by the highly efficient process of oxidative phosphorylation in mitochondria or from the inefficient process in the cytosol where pyruvate is converted to lactate.

This anaerobic production of lactate is far less efficient, ultimately producing much less ATP and large amounts of lactate, which diffuses into the blood. Hydrogen ions also accumulate from the degradation of ATP to ADP in the reaction:

Thus, the concentration of lactate in the blood becomes a clinical marker for numerous pathologic processes such as cardiac and circulatory insufficiency (shock, trauma, coagulopathy, etc.), sepsis, pulmonary disease or dysfunction, and various types of drug or toxin overdoses, including exposure to carbon monoxide or cyanide.

Lactate is mainly metabolized by the liver (around 60%) and kidney (around 30%), and the rate of lactate clearance in the normal liver exceeds the rate of lactate production of other tissues ( ) . Because it is usually associated with damage to the liver, kidney, or mitochondria, diminished clearance of lactate often indicates a poorer outcome ( ) .

Causes of hyperlactatemia

Lactate concentrations are commonly elevated in acutely ill patients, notably in sepsis and septic shock, trauma, cardiac and pulmonary insufficiencies, during and after cardiac surgery, and other types of ischemia due to cardiac arrest or circulatory problems ( ) . Consequently, blood lactate measurements are frequently used to evaluate the initial condition of the patient and to monitor the effectiveness of therapy. In addition to the traditional view that elevated blood lactate is caused by an oxygen deficit to tissues, elevated lactate can also result from mitochondrial dysfunction. While this includes the rare cases of cyanide poisoning, mitochondrial dysfunction is an important contributor in sepsis, where several factors associated with sepsis inhibit mitochondrial function and elevate blood lactate: inflammation, cytokines, platelet and endothelial activators, tissue necrosis factor, etc. Some common uses of blood lactate measurements include the following:

• In neonates during and after open-heart surgery for congenital heart disease ( ) ;

• To evaluate patients who may require ECMO and for monitoring their progress;

• For triage in an ED setting to determine which patients need more immediate care and for monitoring the effectiveness of therapy;

• In trauma patients, early identification of increased blood lactate followed by aggressive resuscitation improves survival. Although published nearly 30 years ago, the principles of lactate interpretation have stood the test of time. Survival was very high (98%–100%) in patients whose blood lactate normalized within 24 h; was 75%–80% in patients whose blood lactate normalized in 24–48 h; but relatively poor in patients whose blood lactate could not be normalized by 48 h ( ) . A study of intubated trauma patients in the ED found that both serum lactate and end-tidal p CO ₂ correlated with hospital mortality ( ) .

• During open-heart surgery, patients are cooled to reduce oxygen consumption. However, this can also cause perfusion abnormalities (vasoconstriction and shunting) that can lead to tissue hypoxia. Along with the anesthesia and drugs, these can cause problems with oxygen metabolism that leads to increased blood lactate. Thus, blood lactate measurements have become a means to monitor such patients.

• Pulmonary embolism, often associated with deep-vein thrombosis, is a major cause of hospitalization or mortality, with elevated blood lactate levels correlated to both a high mortality rate and prothrombotic fibrin properties ( ) .

• Identification of high-risk ICU patients needing more aggressive therapy. Patients who responded to treatment by reduction in lactate to less than 1.0 mmol/L, had a mortality less than 7%.

• In cirrhotic patients, blood lactate typically increases with the severity of cirrhosis. The increased blood lactate appears related to accelerated glycolysis in the splanchnic region coupled with reduced capacity to metabolize lactate in the liver ( ) .

• In goal-directed therapy for sepsis, blood lactate measurements (lactate >2.0 mmol/L) have become an essential component of “sepsis bundles” for detecting higher-risk patients ( , ) . Blood lactate is elevated in some patients with sepsis who have no evidence of hypoperfusion or tissue hypoxia. As noted earlier, several factors associated with sepsis can elevate lactate, including inflammation, cytokines, platelet and endothelial activators, and tissue necrosis factor.

• As a summary statement, blood lactate concentrations evaluate the complex metabolic state of the patient experiencing surgery, trauma, sepsis, anesthesia, hypothermia, some drugs, inflammation, coagulopathies, etc.

Table 9.1 lists several causes of elevated blood lactate concentrations ( ) .

Blood lactate in sepsis

As noted earlier, several factors associated with sepsis inhibit mitochondrial function and elevate blood lactate: inflammation, cytokines, platelet and endothelial activators, tissue necrosis factor, etc. Blood lactate can be used as a marker for evaluating and monitoring the complex circulatory, cellular, and metabolic disturbances that occur in sepsis patients. Monitoring blood lactate is now included in the “sepsis bundles” used as guidelines for improving outcomes in sepsis and septic shock. These bundles have evolved over the years, with the most important revision in 2018 that the 3-h and 6-h bundles have been combined into a single “Hour-1 bundle” ( , ) . Sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction in sepsis may now be evaluated by an increase in the Sequential Organ Failure Assessment (SOFA) score of two points or more ( ) .

Septic shock is defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure (MAP) ≥65 mmHg and lactate >2 mmol/L (>18 mg/dL) in the absence of hypovolemia ( ) . Table 9.2 summarizes the changing definitions of sepsis, and Fig. 9.2 shows the progression of a systemic infection to sepsis and septic shock along with the associated changes in lactate and other physiologic parameters.

Table 9.2

Summary of the changing definitions of sepsis.

Sepsis category	SEP-1/SEP-2 (∼2005)	SEP-3 (2016)
Sepsis	2 of 4 SIRS criteria AND suspected infection	SOFA score >2 + suspected infection
Severe sepsis	Sepsis + organ failure + hypoperfusion or hypotension	This category has been eliminated
Septic shock	Lactate >4 mmol/L Systolic BP <90 mmg or MAP <70 mmHg and not responsive to fluids	Vasopressors required to maintain MAP above 65 mmHg, and lactate >2 mmol/L without hypovolemia