- product of anaerobic glycolysis which reflects type A (oxygen delivery) or type B (altered metabolism) causes
- 50% eliminated by liver
- accumulation leads to lactic acidosis
- normal range: 0.6-1.8mmol/L
- hyperlactaemia: a level from 2 to 5 mmol/L
- severe lactic acidosis: > 5 mmol/L
- high mortality with lactate > 8mmol/L
- normal production is 20 mmols/kg/day, enters the circulation and undergoes hepatic and renal metabolism (Cori cycle)
- all tissues can produce lactate under anaerobic conditions
Relationship of lactate to pyruvate
Pyruvate + NADH <-> Lactate + NAD+ + H+
- catalysed by lactate dehydrogenase
- pyruvate and lactate are in equilibrium
- lactic acid has a pK value of about 4 so it is fully dissociated into lactate and H+ at body pH (i.e. it is a ‘strong ion’)
Tissues Producing Excess Lactate
- at rest, the tissues which normally produce excess lactate are:
- (i) skin – 25% of production
- (ii) red cells – 20%
- (iii) brain – 20%
- (iv) muscle – 25% (
- v) gut – 10%
- during heavy exercise, the skeletal muscles contribute most of the much increased circulating lactate
- during pregnancy, the placenta is an important producer of lactate (can pass to fetus as well)
- major source in sepsis and ARDS is the lung
Lactate metabolism and elimination
- lactate is metabolised predominantly in the liver (60%) and kidney (30%)
- the heart can also use lactate for ATP production
- 50% is converted into glucose (gluconeogenesis) and 50% into CO2 and water (citric acid cycle)
- this results in no net acid accumulation but requires aerobic metabolism
- the small amount of lactate that is renally filtered (180mmol/day) is fully reabsorbed
- lactic acidosis can occur due to: (i) excessive tissue lactate production (ii) impaired hepatic metabolism of lactate (large capacity to clear)
- clinically there is often a combination of the above to produce a persistent lactic acidosis
CAUSES (Cohen & Woods classification)
Type A – Inadequate Oxygen Delivery
- anaerobic muscular activity (sprinting, generalised convulsions)
- tissue hypoperfusion (shock, cardiac arrest, regional hypoperfusion -> mesenteric ischaemia)
- reduced tissue oxygen delivery (hypoxaemia, anaemia) or utilisation (CO poisoning)
Type B – No Evidence of Inadequate Tissue Oxygen Delivery
- B1: associated with underlying diseases
- LUKE: leukaemia, lymphoma
- TIPS: thiamine deficiency, infection, pancreatitis, short bowel syndrome
- FAILURES: hepatic, renal, diabetic failures
- B2: associated with drugs & toxins
- nitroprusside infusion
- ethanol intoxication in chronic alcoholics
- anti-retroviral drugs
- lactate-based dialysate in RRT
- congenital forms of lactic acidosis with various enzyme defects — e.g. pyruvate carboxylase deficiency, glucose-6-phosphatase and fructose-1,6-bisphosphatase deficiencies, oxidative phosphorylation enzyme defects)
- B3: associated with inborn errors of metabolism
Causes in sepsis
- Endogenous catecholamine release and use of adrenaline as an inotrope
- Circulatory failure due to hypoxia and hypotension
- Cytopathic hypoxia – widespread microvascular shunting and mitochondrial failure
- Inhibition of pyruvate dehydrogenase (PDH) by endotoxin
- Coexistent liver disease
- plasma lactate level
- once documented the cause must be found and treated appropriately
- D lactate is isomer of lactate produced by intestinal bacterial and not by humans — it is not detected on standard lactate assays — a bed side test may be able to be developed to help with diagnosis of mesenteric ischaemia
COLLECTION OF LACTATE SAMPLES
- venous samples are equivalent to arterial in clinical practice
- do not need to take off tourniquet when collecting venous lactate sample (unless protracted search for venous access, in which case take tourniquet off for 20 seconds before taking sample)
- result will be unchanged if left for 15 minutes at room temperature (otherwise put on ice)
- repeat lactate if elevated in 4 hours or sooner if change in condition
- (i) diagnose and correct the underlying condition
- (ii) restore adequate tissue oxygen delivery
- (iii) ensure appropriate compensatory hyperventilation where possible
Use of bicarbonate
- two randomised controlled studies of bicarbonate in lactic acidosis and shock found no beneficial effects on cardiac function or any other effects of pH correction.
- alternatives to NaHCO3: carbicarb, dichloroacetate, Tris/THAM
- only real justification in the treatment of lactic acidosis: — severe pulmonary hypertension and right heart failure to optimized right ventricular function — severe IHD where lactic acidosis is thought to be an arrythmogenic risk.
- Adverse effects (see sodium bicarbonate use)
- peritoneal dialysis is not useful in removing lactate when using bicarbonate buffered
- haemofiltration: it remains a useful marker of clinical disease progression in patients on bicarbonate buffered haemofiltration
EVIDENCE FOR LACTATE LEVELS AND LACTATE CLEARANCE
- lactate levels proportional to mortality
- lactate ≥ 4 is associated with poorer outcome regardless of whether it is from sepsis or not (some exceptions e.g. salbutamol toxicity, seizure)
- lactate clearance non-inferior to ScVO2 monitoring (Jones, JAMA, 2010)
- poor lactate clearance prognositically bad in trauma (Abramson, D, Journal of Trauma, 1998)
- Lactate is the best means to screen for occult severe sepsis (occult sepsis is when the patient’s blood pressure and mental status are good, but the patient is still at high risk of death (1 in 5 patients in the Rivers trial had MAP >100, half of these had high lactate)
- EGDT useful in patients with hyperlactaemia but titrating treatment to enhance oxygen delivery against lactate concentration not good (Jansen, Am J Respir Critical Care Med, 2010)
- lactate gap = lactate (measured by oxidase method) – laboratory lactate (dehydrogenase method)
- some point of care analysers (e.g. Radiometer 700) cannot distinguish between lactate and glycolate
- laboratory analysers, and some point of care analysers (e.g. iSTAT and Bayer) show minimal elevations in lactate in the presence of glycolate
- glycolate accumulates in ethylene glycol toxicity
References and Links
- CCC — Lactic Acidosis Evaluation
- CCC — Lactate Clearance vs ScvO2 Monitoring in Severe Sepsis
- CCC — Metformin-associated Lactic Acidosis (MALA)
- CCC — D-Lactic acidosis
- Abramson D, Scalea TM, Hitchcock R, Trooskin SZ, Henry SM, Greenspan J. Lactate clearance and survival following injury. J Trauma. 1993 Oct;35(4):584-8; discussion 588-9. PubMed PMID: 8411283.
- Bakker J, Nijsten MW, Jansen TC. Clinical use of lactate monitoring in critically ill patients. Ann Intensive Care. 2013 May 10;3(1):12. doi: 10.1186/2110-5820-3-12. PubMed PMID: 23663301; PubMed Central PMCID: PMC3654944.
- Brindley PG, Butler MS, Cembrowski G, Brindley DN. Falsely elevated point-of-care lactate measurement after ingestion of ethylene glycol. CMAJ. 2007 Apr 10;176(8):1097-9. PubMed PMID: 17420492; PubMed Central PMCID: PMC1839775.
- Fuller BM, Dellinger RP. Lactate as a hemodynamic marker in the critically ill. Curr Opin Crit Care. 2012 Jun;18(3):267-72. doi: 10.1097/MCC.0b013e3283532b8a. Review. PubMed PMID: 22517402; PubMed Central PMCID: PMC3608508.
- Gibot S. On the origins of lactate during sepsis. Crit Care. 2012 Sep 10;16(5):151. [Epub ahead of print] PubMed PMID: 22979942; PubMed Central PMCID: PMC3682245.
- Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, Willemsen SP, Bakker J; LACTATE study group. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010 Sep 15;182(6):752-61. doi: 10.1164/rccm.200912-1918OC. Epub 2010 May 12. PubMed PMID: 20463176.
- Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb 24;303(8):739-46. doi: 10.1001/jama.2010.158. PubMed PMID: 20179283; PubMed Central PMCID: PMC2918907.
- Kruse O, Grunnet N, Barfod C. Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review. Scand J Trauma Resusc Emerg Med. 2011 Dec 28;19:74. doi: 10.1186/1757-7241-19-74. Review. PubMed PMID: 22202128; PubMed Central PMCID: PMC3292838.
- Marik PE, Bellomo R. Lactate clearance as a target of therapy in sepsis: A flawed paradigm. OA Critical Care 2013 Mar 01;1(1):3. [Free Full Text]
- Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. PubMed PMID: 11794169. [Fulltext]
- Shah AD, Wood DM, Dargan PI. Understanding lactic acidosis in paracetamol (acetaminophen) poisoning. Br J Clin Pharmacol. 2011 Jan;71(1):20-8. doi: 10.1111/j.1365-2125.2010.03765.x. PubMed PMID: 21143497; PubMed Central PMCID: PMC3018022.
FOAM and web resources
- Acid Base Physiology — Lactic acidosis
- ALIEM — Lactic Acidosis and Beta Agonist Therapy in Asthma (2013)
- EMCrit Podcast 37 – Lactate in Sepsis (with Lactate FAQ)
- ICN — The Myth of Lactic Acidosis by Marek Nalos (2014)
Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health, a Clinical Adjunct Associate Professor at Monash University, and the Chair of the Australian and New Zealand Intensive Care Society (ANZICS) Education Committee. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.
After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.
He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE. He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of LITFL.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.
His one great achievement is being the father of two amazing children.
On Twitter, he is @precordialthump.