Lactic Acidosis – Causes, Symptoms, Treatment

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.[rx][rx][rx]

Lactic acidosis is typically the result of an underlying acute? or chronic? medical condition, medication, or poisoning. The symptoms are generally attributable to these underlying causes but may include nausea?, vomiting?, Kussmaul breathing (labored and deep), and generalized weakness?.

Types of Lactic Acidosis

There are two types of lactic acidosis, Type A and Type B:

• Type A lactic acidosis – is caused by tissue hypoperfusion resulting from hypovolemia, cardiac failure, sepsis, or cardiopulmonary arrest.
• Type B lactic acidosis – is caused by impairment of cellular functioning and localized? areas of tissue hypoperfusion.

The Cohen-Woods classification categorizes causes of lactic acidosis as:^[rx]

• Type A: Decreased tissue oxygenation (e.g., from decreased blood flow)
• Type B
  • B1: Underlying diseases (sometimes causing type A)
  • B2: Medication or intoxication
  • B3: Inborn error of metabolism

Causes of Lactic Acidosis

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 that 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.[rx][rx][rx]

Diagnosis? of Lactic Acidosis

History and Physical

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 lactic acidosis. Kussmaul respirations, a deep breathing pattern, may be seen as the body attempts to compensate for the metabolic acidosis.[rx][rx][rx][rx]

Evaluation

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.

Treatment of Lactic Acidosis

Consideration of the cause of lactic acidosis is a crucial step in its treatment. For example, if 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.

If elevated lactate is present in acute illness, supporting the oxygen supply and blood flow are key initial steps.^[rx] Some vasopressors (drugs that augment the blood pressure) are less effective when lactate levels are high, and some agents that stimulate the beta-2 adrenergic receptor can elevate the lactate further.^[rx]

Direct removal of lactate from the body (e.g. with hemofiltration or dialysis) is difficult, with limited evidence for benefit; it may not be possible to keep up with the lactate production.^[rx]

Limited evidence supports the use of sodium bicarbonate solutions to improve the pH (which is associated with increased carbon dioxide generation and may reduce the calcium levels).^[rx][rx]

Lactic acidosis caused by inherited mitochondrial disorders (type B3) may be treated with a ketogenic diet and possibly with dichloroacetate (DCA),^[rx] although this may be complicated by peripheral neuropathy and has a weak evidence base.^[rx]

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 the 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 the 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 the 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.