Lactic acid is produced in physiologically normal processes, and as a common finding in disease states. When increased production is comorbid with decreased clearance, the severity of the clinical course escalates. Importantly, the effects of severely elevated levels of lactic acid can have profound hemodynamic consequences and can lead to death. Serum lactate levels can be both a marker for risk as well as a therapeutic target. The higher the level and the longer the time to normalization of elevated serum lactate, the greater the risk of death.
Clinicians should be aware that hyperlactatemia can occur in the presence of adequate tissue perfusion and oxygenation. Lactic acidosis on the other hand usually occurs in the presence of inadequate tissue perfusion, abnormalities in carbohydrate metabolism and with the use of certain medications.
Lactic acid is normally produced in excess by about 20 mmol/kg/day, which enters the bloodstream. It is then metabolized mostly via the liver and the kidney. Some tissues can use lactate as a substrate and oxidize it to carbon dioxide (C02) and water, but only the liver and kidney have the necessary enzymes to utilize lactate for the process of gluconeogenesis.
The tissues which normally produce excess lactic acid include the skin, red cells, brain tissue, muscle, and the gastrointestinal (GI) tract. During heavy exercise, it is the skeletal muscles which produce the most excess circulating lactate, which normalizes in the absence of impaired hepatic metabolism. In general, elevated lactate can be the result of increased production, decreased clearance, or both.
Pyruvate production as a result of glycolysis gets shunted into two main metabolic pathways. Under aerobic conditions, it enters the citric acid cycle after having been converted to acetyl-CoA by pyruvate dehydrogenase, and a series of reactions occur to form ATP and NADH, which goes on to the process of oxidative phosphorylation which produces the majority of ATP in a cell. However, under anaerobic conditions, pyruvate generated from glycolysis channels into the Cori cycle or lactic acid cycle.
In the lactic acid cycle, pyruvate is converted to lactate, and NAD+ is regenerated from NADH. Subsequently, the NAD+ gets utilized in glycolysis to generate two molecules of ATP per molecule of glucose. Excess lactate gets shuttled to the liver, to undergo gluconeogenesis.
Pathologic and persistent lactic acidosis occurs when a combination of two variables coexist. That is, there is excessive production of lactate which exceeds the liver’s capacity to metabolize it. For example, excessive lactate production from severe convulsions concomitant with impaired hepatic metabolic capabilities such as can occur with cirrhosis, hypothermia, sepsis, severe hypovolemia, severe hypotension, or some combination of these factors, can lead to severe lactic acidosis.
Medications and toxins that cause lactic acidosis:
Lactic acidosis is among the most common concerns for those caring for critically ill patients. However, clinical studies of this problem have been somewhat sparse, with most studies being retrospective, or prospective with small sample sizes.
Jung and colleagues conducted a multi-center, prospective analysis in 2011.
Jung et al. found that severe lactic acidosis occurred in 6% of the studied population of 2550 patients. Eighty-three percent of those patients were treated with vasopressors, and mortality was 57% in this group with a pH of 7.09 (plus or minus 0.11) and high lactic acid values. The severity of lactatemia and the time for the lactic acidosis to correct were linked to survival. The higher the level and the longer the time for normalization, the greater the mortality.
Shock and severe lactic acidosis (pH less than 7.2) are often comorbid, and this carries a mortality rate of about 50%. No survival has been reported for severe lactic acidosis with shock when the pH had fallen under 7.0. Interestingly, this contrasts to lactic acidosis associated with non-shock states, as in metformin-induced lactic acidosis producing pH values of 7.0 where observed mortality was only 25%.
Normal lactate levels are less than two mmol/L, with hyperlactatemia defined as lactate levels between 2 mmol/L and 4 mmol/L. Severe levels of lactate are 4 mmol/L or higher. Other definitions for lactic acidosis include pH less than or equal to 7.35 and lactatemia greater than 2 mmol/L with a partial pressure of carbon dioxide (PaC02) less than or equal to 42 mmHg.
High levels of lactate are associated with increased risk of death independent of organ failure and shock. Patients with mildly elevated and intermediate levels along with sepsis have higher rates of in-hospital 30-day mortality. Lactic acidosis can cause a reduction of cardiac contractility and vascular hyporesponsiveness to vasopressors through various mechanisms. However, as no causal relationship between lactic acidosis has been established, severe cases are more of a precipitator than a direct causal factor as pertains to mortality. Indeed, lactic acidosis likely contributes to a worsening of underlying comorbidities, and therefore its impact on mortality.
Shock associated lactic acidosis is the primary, but not exclusive, cause of metabolic acidosis in the shock state. Shock is defined as a clinical state of acute circulatory failure with inadequate oxygen utilization and/or delivery by the cells which results in cellular dysoxia or hypoxia. Clinicians usually consider that metabolic acidosis with a pH less than 7.2 has a deleterious effect on hemodynamics and requires supportive care.
Lactic acidosis is characterized as being one of two types. Type-A lactic acidosis is due to hypoperfusion and hypoxia, which occurs when an oxygen consumption/delivery mismatch occurs, with resulting anaerobic glycolysis. Examples of type-A lactic acidosis include all shock states (septic, cardiogenic, hypovolemic, obstructive), regional ischemia (limb, mesenteric), seizures/convulsions, and severe cases of shivering.
Type-B lactic acidosis is defined as not having to do with tissue hypoxia or hypoperfusion. While perhaps less common as compared to type-A lactic acidosis, both type-A and type-B share the fundamental problem of the inability of mitochondria to process the amount of pyruvate with which it is presented. Thus alternative metabolic pathways for pyruvate, as described in the lactic acid cycle, become activated which results in excessive levels of lactate. Examples of type-B lactic acidosis are liver disease, malignancy, medications (metformin, epinephrine), total parenteral nutrition, HIV, thiamine deficiency, mitochondrial myopathy, congenital lactic acidosis, trauma, excessive exercise, diabetic ketoacidosis, and ethanol intoxication.
Lactate is an endogenous non-toxic molecule and an energetic substrate of gluconeogenesis. Based upon the Stewart-Fencl physicochemical approach to acid-base modification, all strong acids such as lactic acid are completely dissociated at physiological pH in water. Thus, protons are generated with a commensurate drop in pH depending on the level of excess production and decreased metabolic clearance of lactate.
The drop in intracellular pH causes membrane transporters to extrude lactate and hydrogen ions (H+) to maintain physiologic intracellular pH. The resulting accumulation of extracellular lactate and protons subsequently lowers the extracellular pH. Thus, while any accumulation of lactate results in lactic acidosis, it is again, the combination of excessive accumulation with a diminished metabolic clearance which is by far the most serious.
While the onset of acidosis can be rapid, it may also be progressive over several days. A careful history should be performed to evaluate the various potential causes of the shock that could contribute to lactic acidosis. As well, a detailed medical history should be taken, including the ingestion of drugs or toxins. When the patient is unable, then the patient's family should be consulted, with the underlying goal of elucidating any causative factors in the development of the patient's lactic acidosis.
Remember lactic acidosis can occur after exercise or due to certain medications. In addition, children with a deficiency of pyruvate dehydrogenase may develop lactic acidosis following an upper respiratory tract infection.
No distinctive features are unique to lactic acidosis. Signs and symptoms will be greatly dependent on the underlying etiology. Patients in whom lactic acidosis is present are typically critically ill, and shock states such as hypovolemic, septic, or cardiogenic are frequently seen.
On examination, clinical signs of tissue hypoperfusion are often present. Severe hypotension, altered mental status, oliguria, and tachypnea may be present. Fever greater than 38.5 C is often present when the septic shock is the cause of the lactic acidosis. Kussmaul respirations, a deep breathing pattern, may be seen as the body attempts to compensate for the metabolic acidosis.
In any patient suspected of having a metabolic acidosis, serum electrolytes should be drawn, and arterial blood gas analysis performed. If the anion gap is elevated or there are other reasons to suspect that lactic acidosis may be present, serum lactate should also be drawn. An anion gap is considered to be high when over 12 mE/L.
The anion gap is defined as follows:
Sodium + Unmeasured cations = Chloride + Bicarbonate + Unmeasured anions. Rearranged, and we get Anion gap = Sodium – (Chloride + Bicarbonate).
In the absence of unmeasured anions (such as Lactate), the anion gap is typically considered approximately 4 mEq/L to 12 mEq/L as there are always unmeasured anions in the blood, such as phosphate and importantly, albumin.
High levels of plasma lactate will almost always produce an anion gap metabolic acidosis. However, lower levels of lactate may show a normal anion gap metabolic acidosis. As well, hypoalbuminemia, which is often seen in critical illness, may obscure the results of an anion gap calculation, since albumin is the largest unmeasured anion in the normal state. In other words, in an otherwise high anion gap metabolic acidosis, the anion gap may appear normal if the patient also has underlying hypoalbuminemia.
Consideration of the cause of lactic acidosis is a crucial step in its treatment. For example, if the lactic acidosis is secondary to mesenteric ischemia, then surgery may be warranted. If the cause is convulsions from seizure activity, then treating the seizure is a critical step in treatment. Further supportive care must then be individualized.
As causes of lactic acidosis are myriad, and thus treatment methods can be highly diverse, we will focus on type-A lactic acidosis secondary to septic shock, a common and serious medical condition. There has been a large focus of treatment involving lactic acidosis associated with a septic shock which has been undertaken by the Surviving Sepsis Campaign (SSC). According to the SSC, septic shock is sepsis that results in tissue hypoperfusion, with vasopressor-requiring hypotension and elevated lactate levels.
Infection management is an important step in addressing septic shock. Administering broad-spectrum antibiotics within 1 hour of sepsis recognition is important, and should be considered an ideal goal. Notably, this should occur after blood is drawn and sent to the lab for identifying the offending pathogen(s). Additionally, anatomic source control as rapidly as possible is recommended.
For patients with septic shock, it is recommended to provide 30 ml/kg of crystalloid within 3 hours of initial assessment, with additional fluids based upon frequent reassessment. Assessing fluid responsiveness using dynamic variables [central venous pressure (CVP), mean arterial pressure (MAP), and mixed venous saturation (SV02)] is recommended. Targets for resuscitation are a MAP of 65 mmHg with no specific SV02 or CVP recommendations based upon updated guidelines from 2016. However, frequent reassessment is always recommended, taking into consideration other comorbidities and the overall clinical picture.
The requirement for the use of vasopressors becomes necessary as a differentiating factor between severe sepsis, and septic shock (which is unresponsive to fluid therapy alone). The initial vasopressor of choice is norepinephrine. If MAP target is not achieved at this point, then adding “shock dose” vasopressin, dosed at 0.03 U/min is considered, at which point corticosteroids may also be considered. If MAP target is still not achieved, then it is recommended to begin epinephrine therapy at 20 mcg/min to 50 mcg/min, and intravenous corticosteroids should be started. Finally, if a MAP of greater than 65 mmHg is still not achieved, then the addition of phenylephrine at 200 mcg/min to 300 mcg/min should be considered.
The administration of alkali remains controversial and may not improve hemodynamics. Tromethamine can be used as a buffering agent as it does not lead to generation of carbon dioxide. However, there are no good data to indicate that it improves prognosis.
Hemodialysis is sometimes used to manage severe lactic acidosis, especially in patients with renal failure. Unfortunately, in the vast majority of cases, lactic acidosis is caused by inadequate tissue perfusion and so the perfusion has to be improved first.
In patients with sepsis-induced ARDS, a low tidal volume and low plateau pressure ventilator strategy should be utilized. Target tidal volumes should be no greater than 6 ml/kg predicted body weight. Plateau pressures less than 30 cm of water is recommended.
The prognosis of patients depends on the cause and level of lactate. Very high levels of lactate during shock are associated with a high mortality rate. Early diagnosis is the key.
In summary, lactic acidosis is a common problem with a host of causes, both physiologic and pathophysiologic. Due to of its potential for severity, and impact on mortality, a thorough and in-depth understanding of the nuances is important for clinicians. While general guidelines exist for the treatment and management of the myriad of causes, as always, treatment must be individualized, and other comorbidities taken into consideration.
Because there are many causes of lactic acidosis, the condition is best managed by an interprofessional team that consists of a surgeon, endocrinologist, internist, intensivist, ICU nurses and a pharmacist.
The key feature is to determine the primary cause. The pharmacist should ensure that the patient is on no medication that is causing the lactic acidosis. Secondly, because most other cases are due to inadequate perfusion, the patient should be resuscitated, hydrated and may even require mechanical ventilation. Some patients with mesenteric ischemia may require surgery. Close monitoring by nurses is vital. Almost every organ system can be affected by lactic acidosis and clinicians needs to assess laboratory data and evaluate the patient repeatedly to ensure that perfusion is not compromised. Patients with diabetes who are prescribed metformin should be educated by the pharmacist about the signs and symptoms of lactic acidosis. Even though rare, a change in medication is recommended.
The outcomes of patients with lactic acidosis depend on the cause, patient age, other comorbidities, ARDS, multiorgan failure and response to treatment, but an interprofessional team approach will offer the best outcomes.
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