Lactic acidosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Lactic acidosis is a condition caused by the buildup of lactic acid in the body. It leads to acidification of the blood (acidosis), and is considered a distinct form of metabolic acidosis.

The cells produce lactic acid when they use glucose for energy in the absence of adequate oxygen. If too much lactic acid stays in the body, the balance tips and the person begins to feel ill. The signs of lactic acidosis are deep and rapid breathing, vomiting, and abdominal pain. Lactic acidosis may be caused by diabetic ketoacidosis or liver or kidney disease, as well as some forms of medication (most notably the anti-diabetic drug metformin). Some anti-HIV drugs (antiretrovirals) warn doctors in their prescribing information to regularly watch for symptoms of lactic acidosis caused by mitochondrial toxicity.

The main treatment for lactic acidosis is to correct the medical problem that causes the condition.

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Lactic acid was first found and described in sour milk by Karl Wilhelm Scheele (1742–1786) in 1780. The German physician–chemist Johann Joseph Scherer (1841–1869) was the first to demonstrate the presence of lactic acid in human blood in 1843 and 1851. His 1843 case reports are the first description of lactic acid in human blood post-mortem and as a pathological finding in septic and haemorrhagic shock. Carl Folwarczny, an Austrian physician, was the first to demonstrate lactic acid in blood in a living patient in 1858.

• In 1843, Scherer highlighted in his book that lactic acid was present in patients of puerperal fever and not in healthy people. He was of the mind that lactic acid was formed in blood during breakdown of tissue in puerperal fever and other severe diseases. Thus, lactic acid was recorded in human blood for the first time and was associated for the first time with symptoms of septic and haemorrhagic shock.
• in 1858, Carl Folwarczny drew blood from a leukaemia patient during life and analysed it according to Scherer’s method, which tested positive for lactic acid. In 1863, Folwarczny described that lactic acid can be found in the blood of patients with leukaemia, septicaemia (pyaemia) and related conditions such as puerperal fever.
• Georg Salomon proved in 1878 that lactic acid was also present in the blood of patients who were suffering and died from other diseases. He studied blood obtained during autopsy from cadavers, but also blood from patients obtained by bloodletting or cupping, and in some cases he compared the blood before and after death. He was able to demonstrate lactic acid in the blood of patients suffering from leukaemia, (pernicious) anaemia, congestive heart failure, chronic obstructive pulmonary disease, pleuritis, pericarditis, pneumonia and several solid malignant tumours.
• Walter Morley Fletcher (1873–1933) and Frederick Gowland Hopkins (1861–1947), in their 1907 paper demonstrated that anaerobic formation of lactic acid occurs simultaneously with muscle contraction, and is removed aerobically (depending on the availability of oxygen).
• In 1925, Clausen identified that buildup of lactic acid in blood underlies acid-base disorders.
• In 1961, Huckabee established that lactic acidosis frequently accompanies severe illnesses and it can be attributed to widespread tissue hypoxia.
• In 1976, Cohen and Woods classified the lactic acidosis according to the presence or absence of adequate tissue oxygenation.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saud Khan M.D.

Lactic acidosis is classified as type A and type B according to the root cause being either a shortage of oxygen or other metabolic/acquired factors respectively.

The Cohen-Woods classification (1976) categorizes causes of lactic acidosis as follows:

• Type A: Decreased perfusion or oxygenation: Occurs due to an oxygen demand/supply mismatch, causing anaerobic glycolysis. Examples include all shock states (septic, cardiogenic, hypovolemic, obstructive), regional ischemia (limb, mesenteric), seizures/convulsions, and severe cases of shivering.
• Type B: Defined as not having to do with tissue hypoxia or hypoperfusion.
  • B1: Underlying diseases (sometimes causing type A) such as liver disease, malignancy, HIV, thiamine deficiency, diabetic ketoacidosis.
  • B2: Medication or intoxication example metformin, epinephrine, total parenteral nutrition, ethanol.
  • B3: Inborn error of metabolism, such as mitochondrial myopathy, congenital lactic acidosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Lactic acidosis occurs when cells make lactic acid faster than it can be metabolized. ^{[1] [2]} Both overproduction of lactate, or reduced metabolism, lead to acidosis. Normal lactate levels are less than 2 mmol/L, lactate levels between 2 mmol/L and 4 mmol/L are defined as hyperlactatemia. Severe hyperlactatemia is a level of 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.

After glycolysis, pyruvate is shunted into two main pathways.

• Under aerobic conditions, it is converted to acetyl-CoA by pyruvate dehydrogenase, then enters the citric acid cycle and a series of reactions occur to form ATP (Adenosine Triphosphate) and NADH (nicotinamide adenine dinucleotide), which goes into oxidative phosphorylation, producing the majority of ATP in a cell.

• Anaerobic conditions result in pyruvate channeling into the Cori cycle (lactic acid cycle), where pyruvate is converted to lactate, to regenerate NAD+ from NADH. The NAD+ generated can now be utilized in glycolysis again, forming two molecules of ATP per molecule of glucose. The lactate produced gets sent to the liver, for gluconeogenesis^[3].

Acid generation on the cellular level is dictated by the ratio of NAD+ and NADH. These molecules help maintain the intracellular pH by influencing the ratio of pyruvate to lactate. Therefore, an increased NADH concentration results in an increased lactate level. Causes of increased NADH include a hypoxic state, ingestion and oxidation of large amounts of ethanol.

In the lactic acidosis associated with shock, a marked increase in lactate production driven by catecholamine stimulation of glycolysis is a key mechanism. A similar process is likely responsible for the lactic acidosis that occurs when high doses of inhaled beta agonists are used to treat severe asthma.^[4] There are types of lactic acidosis based on the process that leads to an increased lactate level. Type A is is due to hypovolemia leading to hypoxia, type B involves an offending drug (metformin has been associated^[5]) or toxin.^[6]

Normally, there is a very high metabolic potential for lactate utilization, as demonstrated in patients with grand mal seizures^[7] which is not utilized in acidosis states. This difference may be due to decreased lactate clearance in hypovolemic disorders such as shock, where lactic acidosis occurs despite a mild increase in lactate formation^[8].

Lactic acidosis is an underlying process in the development of rigor mortis. Tissue in the muscles of the deceased resort to anaerobic metabolism and significant amounts of lactic acid are released into the muscle tissue. This along with the loss of ATP causes the muscles to grow stiff.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Lactic acidosis is one of the most common causes of high anion gap metabolic acidosis and is usually associated with a serum lactate levels above 4 mmol/L. Reduced oxygen tension shunts glycolysis towards pyruvate production, which in turn leads to lactate accumulation since pyruvate can no longer undergo aerobic metabolism.

Life-threatening causes include conditions which result in death or permanent disability within 24 hours if left untreated.

• Cardiac arrest
• Mesenteric ischemia
• Sepsis
• Shock

• Alcoholism
• Carbon monoxide poisoning
• Cyanide poisoning
• Exercise
• Grand mal seizure
• Hypoglycemia
• Hypoxemia
• Malignancy
• Metformin
• Pheochromocytoma
• Pulmonary edema
• Salicylate intoxication
• Stavudine
• Zidovudine

Causes by Organ System developed by WikiDoc.org, Copyleft 2013

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Saud Khan M.D.

Lactic acidosis must be differentiated from other diseases that cause elevated lactate Any shock state or dysfunction of the metabolic pathway responsible for lactate clearance or production can underlie lactic acidosis. A few are:

• Inborn errors of metabolism
• Cardiogenic shock
• Cardiogenic pulmonary edema

Lactic acidosis should be differentiated from:

• Any shock state
• SIRS; lactate may be 2-5 mEq/L
• Thiamine deficiency
• D-lactic acidosis
• Seizures
• Infarcted colon
• Hepatic failure
• Malignancy
• Heavy exercise
• Albuterol and other beta agonists
• Toxicologic Causes:
  • Cyanide
  • Carbon Monoxide
  • Metformin use in diabetics
  • Didanosine
  • Stavudine
  • Zidovudine
  • Linezolid
  • Strychnine
  • Rotenone (Fish Poison)
  • Phospine (rodenticide)
  • INH (if patient seizes)
  • Valproate
  • Hydrogen Sulfide
  • Nitroprusside (cyanide)
  • Ricin & Castor Beans
  • Propofol
  • Sympathomimetics (cocaine, methamphetamine)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saud Khan M.D.

Lactic acidosis is a common event in the high dependency units of a hospital, however the exact prevalence is difficult to estimate, as it usually occurs in critically ill patients.

Incidence

Among type 2 diabetics, lactic acidosis is a rare event, with an estimated incidence of 4.3 cases per 100,000 person-years in metformin users. The occurrence in type 2 diabetes is alarming as the mortality can be up to 50%. A secondary analysis of more than 41,000 person-years in type 2 diabetes showed that the incidence of LA in diabetic patients not exposed to metformin was between 9.7 and 16.7 per 100,000 person-years.

Lactic acidosis often occurs in patients with acute severe asthma, most likely due to fatiguing respiratory muscles and subsequent inadequate oxygen delivery to the muscles and liver ischemia. Severe lactic acidosis also occurs in sedated mechanically ventilated patients without respiratory muscle activity.

Hyperlactatemia is also associated with antiretroviral therapy. In a large study, incidence was found to be 18.3 per 1000 person-years with antiretroviral therapy and 35.8 per 1000 person-years for stavudine (d4T) regimens.

Case Fatality Rate

• Jung et al. found that of the studied population of 2550 patients, severe lactic acidosis occurred in 6% . Among those treated with vasopressors, mortality was 57%, with a pH of 7.09 (+-0.11) and high lactic acid values. 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%.
• Patients who have an arterial lactate level of more than 5 mmol/L and a pH of less than 7.35 are critically ill and have a very poor prognosis. Multicenter trials have shown a mortality rate of 75% in these patients.
• A stepwise logistic regression model identified serum lactate, anion gap acidosis, phosphate, and age as independent predictors of mortality in patients with lactic acidosis compared to patients with metabolic acidosis.
• In patients with suspected sepsis, lactate levels between 2.0 and 3.9 mmol/L were associated with a moderate-to-high risk of mortality, independent of the patients blood pressure.
• Overall, there is a high mortality rate (70%) among patients with a serum lactate level greater than 2 mmol/L which persists after 24 hours with an associated acidemia.^[1][2][3][4]

Gender

The prevalence and incidence of lactic acidosis does not vary by gender.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Saud Khan M.D.

Common risk factors in the development of lactic acidosis are:

• Diabetics taking metformin and SGLT2 inhibitors, especially in conjunction with active COVID-19^[1]
• Underlying sepsis
• Septic, cardiogenic or haemorrhagic shock

Lactic acidosis predisposing factors are reported to include:

• Acute kidney injury
• Previous history of lactic acidosis
• Hypovolemia
• Hemodynamic instability due to infection or other causes
• Seizure
• Concurrent liver disease
• Alcohol abuse
• Acute heart failure/Myocardial infarction
• Shock due to any cause

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Saud Khan M.D.

Lactic acidosis may occur rapidly within minutes or gradually, over a period of days, depending on the underlying cause. Treating the cause of the metabolic disturbance relieves symptoms which are nonspecific, and may include disorientation, muscle pains, nausea, jaundice, shallow breathing or rapid heart rate. Common complications of lactic acidosis include arrythmias, loss of consciousness, organ failure and death. Benign causes, such as temporary elevations of lactate after exercise, are harmless, however, if it occurs as part of an underlying systemic disease, it can lead to significantly worse outcomes.

Underlying sepsis or any type of shock in a critically ill patient may lead to hyperlactaemia, which is an independent predictor of death. 80% of the patients die in intensive care when their serum lactate values reach >10 mmol/l, and if the severe lactic acidosis persists for 48 hours, mortality is 100%^[1]. Increased lactate levels require immediate diagnostic work-up and classification.

The determination of the lactate serum concentrations, and close follow-up is recommended in the first hour of admission for a patient with suspected sepsis^[2]. In addition, blood cultures, broad-spectrum antibiotics, fluid resuscitation and vasopressor administration are recommended within the first hour. Increased lactate levels (≥4 mmol/l) along with refractory hypotension warrant large amounts of crystalloids, and rate of infusion must be managed according to lactate clearance. Factors affecting lactate metabolism must be monitored, for example liver function impairment reduces clearance. High lactate levels on admission are associated with organ failure and mortality in patients with liver disease.

If left untreated, Type A severe lactic acidosis (lactate>4mmol/L) prognosis is usually poor. in septic shock, mortality is directly linked to both initial levels of lactate in the blood and the rate of removal of acid from the blood.

Complications that can develop as a result of lactic acidosis are:

• Cardiac arrythmia
• Change in mental state
• Organ damage/failure
• Increasing myocardial suppression due to low blood pH. Further hypoperfusion and multiorgan failure leading to even higher levels of lactate, which ultimately may lead to death.

In patients with baseline lactate levels above 5 mmol/l, their 12-hour lactate clearance is monitored for a predictive prognosis for survival with greater clearance signifying better prognosis (lower levels of lactate lead to better outcomes), while the absolute lactate level is an independent predictor for the severity of the underlying disease even after correction^[3].

In patients with lactic acidosis linked to underlying malignancy, removal of tumor(s) leads to correction of lactate levels.

In patients with lactic acidosis caused by alcoholic ketoacidosis, administration of thiamine and dextrose is required along with rapid volume resuscitation, with literature showing no benefit of withholding dextrose till thiamine is administered, especially in hypoglycemic patients.

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