Lactate

Lactate is the end product of anaerobic glycolysis, formed when pyruvate is reduced by lactate dehydrogenase. Skeletal muscle, gut, skin, red cells and brain produce it, and the liver and, to a lesser extent, the kidney clear it. It is measured as L-lactate by lactate oxidase on a blood gas analyser or a laboratory analyser. A raised level shows that production exceeds clearance, from tissue hypoperfusion, hypoxia, hepatic or mitochondrial dysfunction, or drug and toxin effects.

It is a time critical test in shock, sepsis and unexplained acidosis. The initial level and its change with treatment predict outcome better than vital signs alone.

Hyperlactataemia is found in roughly a quarter to a half of patients admitted with sepsis. In sepsis cohorts a level over 4 mmol/L carries a hospital mortality of about 30 to 40%.

Indications. Suspected sepsis, shock of any cause, cardiac arrest, major trauma and haemorrhage, severe asthma, prolonged seizures, acute abdominal pain with suspected mesenteric ischaemia, unexplained high anion gap acidosis, suspected poisoning (metformin, cyanide, carbon monoxide, toxic alcohols), neonatal asphyxia, suspected inborn error of metabolism, and monitoring of resuscitation.

Specimen. Arterial, venous or free flowing capillary blood. For a blood gas analyser, use a heparinised syringe and analyse within 15 minutes. For the laboratory, use a fluoride oxalate tube on ice, separated within 15 to 30 minutes. Limit tourniquet time to 1 minute and avoid fist clenching. A venous sample is adequate in most patients, and arterial sampling is not needed for lactate alone.

Reference range. 0.5 to 2.0 mmol/L (4.5 to 18 mg/dL) at rest. Multiply mmol/L by 9.0 to give mg/dL.

Categories.

• Under 2.0 mmol/L: normal.
• 2.0 to 3.9 mmol/L: hyperlactataemia, often without acidosis.
• 4.0 mmol/L or more: marked hyperlactataemia. Lactic acidosis is present when the pH is under 7.35 with a low bicarbonate and a raised anion gap.
• Over 10 mmol/L: very high mortality and needs immediate senior review.

Sepsis. A level over 2 mmol/L in suspected infection indicates hypoperfusion. A level that persists over 2 mmol/L after adequate fluid resuscitation with a vasopressor requirement defines septic shock. A level of 4 mmol/L or more, or hypotension, needs immediate resuscitation. The level is repeated within 2 to 4 hours, and a fall of at least 10% over 2 hours is associated with lower mortality.

Lactate to pyruvate ratio. Normally about 10 to 1. A ratio over 25 to 1 indicates hypoxic or redox driven production. A high lactate with a normal ratio suggests pyruvate dehydrogenase deficiency and needs specialist metabolic assessment.

Type A: inadequate oxygen delivery. Septic, cardiogenic, haemorrhagic and hypovolaemic shock, cardiac arrest, severe hypoxaemia, severe anaemia, carbon monoxide poisoning, cyanide poisoning, regional ischaemia (mesenteric ischaemia, acute limb ischaemia, compartment syndrome), severe asthma, and generalised seizures or extreme exertion (which clear within 1 to 2 hours).

Type B: impaired metabolism without hypoperfusion.

• Disease: liver failure (reduced clearance), haematological malignancy and solid tumours (aerobic glycolysis), thiamine deficiency (beriberi, alcohol dependence, parenteral nutrition), diabetic ketoacidosis, severe malaria (over 5 mmol/L marks severe disease), and HIV.
• Drugs and toxins: metformin (accumulation in kidney failure), linezolid, nucleoside reverse transcriptase inhibitors (stavudine, didanosine, zidovudine), propofol infusion syndrome, adrenaline and salbutamol (beta-2 stimulation of glycolysis), isoniazid, nitroprusside (cyanide), ethanol, toxic alcohols, large paracetamol overdose, and propylene glycol carriers of lorazepam and other infusions.
• Inherited: pyruvate dehydrogenase deficiency, mitochondrial disease, glycogen storage disease type I, fructose-1,6-bisphosphatase deficiency, and organic acidaemias.

D-lactic acidosis. Gut bacterial D-lactate in short bowel syndrome or after jejunoileal bypass causes episodes of confusion, ataxia and slurred speech with a high anion gap acidosis and a normal L-lactate. Routine assays do not detect D-lactate, so a specific assay is needed.

Metformin associated lactic acidosis. Lactate over 5 mmol/L with a pH under 7.35 in a patient on metformin, usually with kidney injury. Mortality is about 30 to 50%. Haemodialysis is indicated for lactate over 20 mmol/L, a pH of 7.0 or less, or failure to improve, and also removes metformin.

Clues to the cause.

• Cold peripheries, raised troponin and pulmonary oedema: cardiogenic shock.
• Fever, raised inflammatory markers and a source: sepsis.
• Pain out of proportion to examination with a normal abdomen and rising lactate: mesenteric ischaemia.
• Lactate with hypoglycaemia and a raised ammonia in a child: inherited metabolic disease.
• Lactate with high osmolar gap: toxic alcohols or propylene glycol.
• High lactate with normal perfusion and a drug history: type B.

Critical values and findings needing immediate action. Triggers vary by laboratory.

• Lactate of 4 mmol/L or more, or any value over 2 mmol/L with hypotension or altered consciousness.
• Rising lactate despite treatment.
• Lactate with pH under 7.2 or bicarbonate under 10 mmol/L.
• Lactate with suspected mesenteric ischaemia, limb ischaemia or compartment syndrome, which needs urgent surgical review.
• Lactate in suspected poisoning with cyanide, carbon monoxide or metformin.

Interferences and pitfalls.

• Delay in unseparated blood raises the result through glycolysis, because red cells and leucocytes continue to produce lactate.
• A prolonged tourniquet, fist clenching and struggling raise the result.
• Glycolate from ethylene glycol cross-reacts with lactate oxidase on some blood gas analysers and gives a falsely high lactate. A result on the blood gas analyser that is far higher than the laboratory value suggests ethylene glycol poisoning.
• Lactate containing fluids raise lactate modestly, and more in liver failure.
• Adrenaline type drugs and beta agonists raise lactate in the absence of hypoperfusion.
• A normal lactate does not exclude shock, early mesenteric ischaemia or sepsis.
• Lactate rises with labour, exercise and seizures, and falls over hours when the stimulus ends.

Special groups.

• Neonates: a cord arterial lactate over 4 mmol/L with a pH under 7.0 supports significant intrapartum hypoxia, and over 6 mmol/L carries a higher risk of encephalopathy. A raised lactate with hypoglycaemia or hyperammonaemia suggests an inborn error of metabolism.
• Pregnancy and labour: lactate rises in labour, and the obstetric context is needed for interpretation.
• Children: inborn errors of metabolism and thiamine deficiency are important causes.
• Older adults: mesenteric ischaemia and metformin accumulation are common causes.
• Regions with a high burden of malaria and HIV: severe malaria and nucleoside analogue toxicity are leading causes.

Follow up tests. Venous or arterial blood gas, anion gap, osmolar gap, glucose, blood ketones, urea and electrolytes, liver function tests, creatine kinase, troponin, ECG, echocardiography, blood cultures, carboxyhaemoglobin, cyanide level, toxic alcohol levels, metformin level, paracetamol level, thiamine level, D-lactate, pyruvate, plasma amino acids, urinary organic acids, malaria film, HIV viral load, CT of the abdomen when mesenteric ischaemia is suspected, mitochondrial genetic testing.