Lactate (plasma/whole blood/CSF/fetal scalp/Fluid)

1 Name and description of analyte

1.1 Name of analyte

Lactate

1.2 Alternative names

Lactic acid and lactate can sometimes be used interchangeably.

1.3 Description of analyte

Glycolysis produces an intermediate metabolite, pyruvate. Under aerobic conditions,

pyruvate is converted to acetyl CoA which enters the Kreb's (tricarboxylic acid or citrate)

cycle. Under anaerobic conditions, pyruvate is converted by lactate dehydrogenase (LDH) to

lactic acid. At physiological pH, lactic acid almost completely dissociates to lactate and

hydrogen ions. Lactate then feeds into the Cori cycle. Lactate exists in two isomers: L-lactate

and D-lactate. Current lactate measurements only include L-lactate (the primary isomer

produced in humans), which will be the focus of this monograph. Note that D-lactate is

responsible for a rare type of lactic acidosis associated in particular with short bowel

syndrome, see 3.2.

1.4 Function of the analyte

Lactate is produced by most tissues in the human body. Under anaerobic conditions, lactate

is an end product of glycolysis and feeds into the Cori cycle as a substrate for

gluconeogenesis.

2 Sample requirements and precautions

2.1 Medium in which measured

 Lactate can be measured in plasma; whole blood measurements are now widely

available using blood gas analysers and hand-held instruments.

 Lactate can also be measured in CSF samples.

 Fetal scalp samples are used during labour to assess distressed fetuses.

 Ascitic fluid can be used to measure lactate.

2.2 Precautions re sampling handling

Glycolysis continues in vitro after phlebotomy. Because erythrocytes do not contain

mitochondria, the pyruvate formed cannot enter the TCA cycle. However, the reduction of

pyruvate to lactate continues. The resulting decrease in blood [glucose] is paralleled by an

increase in [lactate]. This increase is significant at approximately 0.7mmol/L/h. Sampling

protocols include sodium fluoride and potassium oxalate as preservatives, keeping the

blood on ice until centrifugation, and separation within a maximum of 15 mins. It has been

suggested that ice is not required for samples collected into sodium fluoride tubes; stability

has been shown to be acceptable for up to 8 h. WHO stability guidelines state that lactate is

unstable in blood at room temperature but once separated is stable in plasma for 8 h at

room temperature or three days at 4–8°C.

Measurement of lactate using a blood gas analyser requires a venous sample taken into a

heparinised syringe. Analysis can usually be carried out promptly at point of care; stability is

therefore rarely an issue. If a delay is to occur, storage on ice can limit the effect; however,

this will have an effect on other analytes such as potassium or pO

CSF samples should also be taken into sodium fluoride potassium oxalate tubes, however

most kit inserts state that CSF samples can be used as obtained.

3 Summary of clinical applications and limitations of measurement

3.1 Applications

Lactate measurements are used:

 to determine the presence of lactic acidosis

 to aid in the diagnosis of pyruvate metabolism defects present in the first 48 hours of

life.

 in the initial investigation of suspected sepsis

 to help monitor hypoxia and response to treatment

 in the case of fetal scalp blood samples, to help diagnose fetal hypoxia if there is an

abnormal fetal heart rate pattern during labour

 in the case of CSF, to help distinguish between viral and bacterial meningitis

3.2 Limitations

Most commercially available lactate assays measure L-lactate. However, there are several

conditions in which D-lactate can become increased. D-lactate assays are available. Recent

studies have demonstrated increased concentrations of D-lactate in diabetes and in

infection, ischemia, and trauma, suggesting that D-lactate might be used as a biomarker in

these conditions. However, to further explore the use of D-lactate in this context, there is a

need of an improved method for its analysis.

4 Analytical considerations

4.1 Analytical methods

Lactate can be measured by enzymatic, colorimeteric or electrochemical methods. Lactate

can be measured on typical laboratory main analyzers but point of care instruments are now

becoming widely available.

675 mV

Lactate oxidase

LOD

POD

1. Enzymatic methods

One of the first lactate methods for rapid lactate measurement was the duPont aca, which used self-

contained reaction packets to measure lactate in plasma by an enzymatic colorimetric method.

Lactate dehydrogenase (LDH) oxidized lactate to pyruvate with simultaneous reduction of NAD

NADH, which was monitored bichromatically at 340 nm (NADH absorbance) and 383 nm

(background absorbance).

A frequently used enzymatic assay for lactate uses lactate oxidase. Lactate is oxidized to pyruvate

and hydrogen peroxide by lactate oxidase (LOD). A coloured product is produced by the reaction of

peroxidase (POD), hydrogen peroxide, 4 -aminoantipyrine (4-AA) and a hydrogen donor, N-ethyl-N-

(2-hydroxy-3-sulfopropyl)-3-methylaniline (TOOS). The coloured product is measured

photometrically. The colour intensity is proportional to the concentration of lactate in the sample

under examination.

Lactate + O

Pyruvate + H

+ 4-AA + TOOS Chromogen + 2H

2. Dry-slide methods

Multi-layered slides coated on a polyester support are used. After centrifugation, plasma is

deposited on the slide. As the sample penetrates into the chemical layers, lactate in the sample is

oxidized by LOD to pyruvate and hydrogen peroxide (H

). The H

then oxidizes dye precursors

which are measured by reflectance spectrophotometry. These methods cannot analyze whole blood,

but require plasma from blood collected in a tube containing sodium fluoride/potassium oxalate.

3. Electrochemical sensors

The principle of measurement is based on diffusion of lactate from the whole-blood sample through

a membrane that both screens out interfering substances and oxidizes lactate to pyruvate. A

platinum electrode then oxidizes the H

generated in this reaction. The current generated is

proportional to the lactate concentration. The typical reaction sequence is:

Lactate + O

Pyruvate + H

+ O

+ 2e

4.2 Reference method

There is currently no reference method for lactate measurement.

4.3 Reference material

Not determined.

4.4 Interfering substances

Interference from indices such as haemolysis, lipaemia and bilirubin may vary depending on

the method of choice. The following is the interference associated with the enzymatic LOD

method:

 bilirubin: none of significance up to 274 μmol/L bilirubin

 hemolysis: none of significance up to 5.0 g/L haemoglobin

 lipemia: none of significance up to 11.3 mmol/L triglyerides

 ascorbate: none of significance up to 568 μmol/L

4.5 Sources of error

Incorrect sample handling, as detailed in section 2.2, may cause a spuriously elevated

[lactate].

The ethylene glycol metabolites glycolate and glyoxylic acid have been shown to falsely

elevate L-lactate results due to cross-reactivity with the oxidase enzyme. This is most

commonly found in blood gas analysers, but not is the methods on routine chemistry

analyzers.

The use of the ‘lactate gap’ can help differentiate ethylene glycol poisoning from lactic

acidosis. The term ‘lactate gap’ is used to describe a difference between a lactate result

from a point of care instrument to one provided by the main laboratory method. This

usually occurs as a result of interference in one of the methods from the ethylene glycol

metabolites.

Note: A true increase in [lactate] can occur in ethylene glycol poisoning and should not be

ignored as it may add prognostic value.

5 Reference intervals and variance

5.1.1 Reference interval (adults): 0.5– .8 mmol/L

5.1.2 Reference interval (children): 1–12 months 1.1–2.3 mmol/L

1– y 0.8–1.5 mmol/L

7–15 y 0.6–0.9 mmol/L

CSF reference intervals: neonate 1.1–6.7 mmol/L

3–10 days 1.1–4.4 mmol/L

>10 days 1.1 – 2.8 mmol/L

Adult 1.1 – 2.4 mmol/L

5.1.3 Extent of variation

5.1.3.1 Interindividual CV: 27.2 %

5.1.3.2 Intraindividual CV: 16.7%

5.1.3.3 Index of individuality: 1.6

5.1.3.4 CV of method: typically <5%

5.1.3.5 Critical difference: 1.5 mmol/L

5.1.4 Sources of variation

The main source of variation is likely to be due to pre-analytical factors. [Lactate]

increases after exercise or physical activity, therefore this should be avoided prior to

sampling.

6. Clinical uses of measurement and interpretation of results

6.1 Indications and interpretation

1 Investigation of inborn errors of metabolism and causes of congenital lactic acidosis.

Of the inborn errors of metabolism [lactate] is raised in pyruvate dehydrogenase (PDH)

deficiency and Krebs cycle defects as well as in mitochondrial disorders. The [lactate] to

[pyruvate] ratio is used to distinguish between PDH and other causes of congenital lactic

acidosis. However, it is thought that the usefulness of this is limited for values of

[lactate] >5.0 mmol/L.

2 Assessment of critically ill patients and prognosis

Hyperlactataemia is common among the critically ill and has important implications for

morbidity and mortality. [Lactate] >5mmol/L in association with acidosis (pH <7.35, [H

]

>45 nmol/L), carries a mortality of 80%. Admission lactate ≥2 mmol/L has been shown to

be a significant predictor of mortality in adults in intensive care units (ICU). Lactate

concentrations have a role in risk-stratification of patients in the emergency department

(ED).

3 Diagnosing sepsis

The use of lactate as a method to detect severe sepsis and septic shock and as a

rationale for further therapies was evaluated in the 2012 Surviving Sepsis Campaign

Guidelines. The guidelines committee recommended the quantitative resuscitation of a

patient with sepsis-induced shock, defined as tissue hypoperfusion (hypotension

persisting after initial fluid challenge or blood lactate concentration ≥4 mmol/L).

4 Lactate-directed therapy

Recent studies have advocated the use of lactate-directed therapy in post-cardiac

surgery patients. Targeting a 20% decrease in [lactate] over a 2 h period seems to be

associated with reduced in-hospital mortality. However the relevance of lactate-directed

therapy needs to be investigatee by more studies.

5 CSF Lactate

CSF lactate is used to help distinguish between bacterial meningitis (BM) from acute

asceptic meningitis (AM). Values > 6 mmol/L are regarded as being indicative of BM, 4–6

mmol/L found in partially treated meningitis and <2 mmol/L in AM.

6 Fetal scalp lactate

During labour, the aim is to identify fetuses at risk for severe adverse outcome so as to

be able to intervene before damage has occurred. Upon identification of an abnormal

fetal heart rate, fetal scalp samples are taken to measure pH. However, it has been

suggested that the use of lactate measurements may facilitate earlier diagnosis,

primarily because a much smaller volume of blood is required for the new handheld

lactate meters than for blood gas analyzers. A suggested clinical guideline for scalp

blood determination and management is as follows:

7. Fluid lactate

Lactate has been used along with pH to help differentiate bacterial peritonitis from

uncomplicated ascites. However it is not as accurate as leucocyte counts and elevated

[Lltate] has been found in malignant and tuberculous ascites. It has also been suggested that

a value for {peritoneal fluid [lactate] - plasma [lactate] ≥1.5mmmol/L} can help separate

patients with viscous perforation, gangrenous intestine, peritonitis or intraabdominal

abscess from other conditions producing acute abdominal issues. The evidence for clinical

utility in this context is, however, limited.

6.2 Confounding factors

As reported in section 4.5

7. Causes of abnormal results

7.1 High Values

High [lactate] can determine indicate to the presence of a lactic acidosis. However, any form

of shock or tissue hypoperfusion will result in elevated [lactate]. In general, lactate elevation

may be caused by increased production, decreased clearance, or a combination of both.

7.1.1 Causes

Causes of a high lactate can be broadly classified into hypoperfusion driven and non-

hypoperfusion driven.

Hypoperfusion driven

Non-hypoperfusion driven

Shock

Seizure

Post-cardiac arrest

Malignancy

Regional ischemia (e.g. mesenteric ischemia)

Thiamin deficiency

Haemorrhagic shock

Drugs e.g. metformin, salicylate

Trauma (particularly related to blood loss)

DKA

Mitochondrial disease

Liver/renal dysfunction

Lactate (mmol/L)

Description

Management

<4.2

Normal

Continue labour

4.2–4.8

Preacidaemia

Repeat 20–30mins later

>4.8

Acidaemia

Consider delivery

7.1.2 Investigations

The following algorithm is a suggested approach to investigate increased [lactate].

This investigation will be mostly clinical but the following laboratory tests will aid the

diagnosis:

 blood gas measurement

 full blood count

 blood cultures

 CRP

 urea, creatinine and ‘electrolytes’

 blood clotting screen.

7.2 Low values

Low lactate values are not clinically significant

7.2.1 Causes

Not applicable

7.2.2 Investigations

Not applicable

7.3 Notes

It is important is recognise that while a high [lactate] may indicate the presence of lactic

acidosis, it is not always associated with it. See 7.1.

8. Performance

8.1 Sensitivities, specificities

Plasma [lactate] of 0–2.4, 2.5–3.9 and ≥4 mmol/L have been associated with mortalities of

4.9% (95% CI: 3.5% – 6.3%), 9.0% (95% CI: 5.6% – 12.4%) and 28.4% (95% CI: 21% –36%)

respectively.

Elevated [lactate] values are 96% sensitive and 38% specific for mesenteric ischemia.

↑[Lactate]

Evaluate for

tissue

hypoperfusion

Evaluate for

local tissues

ischemia

Stop offending

agents

Consider

Thiamin

deficiency

Consider

anaerobic

muscle activity

Consider other

metabolic

derangements

CSF lactate is a useful tool in the early diagnosis of bacterial meningitis with high sensitivity

(92%) and specificity (99%) as well as in differentiating bacterial from viral meningitis.

Sensitivities and specificities for ascetic fluid lactate are approximately 90% using a cut-off

of 4.4mmol/L, with a positive predictive value of 62%.

Fetal scalp blood lactate has been shown to be superior in predicting hypoxic ischaemic

encephalopathy (HIE), with a sensitivity of 67% and a specificity of 93% in predicting

moderate to severe HIE versus 49% and 93% respectively for pH.

9. Systematic reviews and guidelines

9.1 Systematic reviews

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;19:74.

Lewis CT, Naumann DN, Crombie N, Midwinter MJ. Prehospital point-of-care lactate

following trauma: A systematic review. Journal of trauma and acute care surgery, 2016

81:748-55

Vincent J-L, Quintairos e Silva A, Couto Jr L, Taccone FS. The value of blood lactate kinetics in

critically ill patients: a systematic review, Crit Care, 2016; 20:257.

Huy NT, Thao NT Diept DT et al. Cerebrospinal fluid lactate concentration to distinguish

bacterial from aseptic meningitis: a systematic review and meta-analysis. Critical Care

2010,14:R240.

9.2 Guidelines

Sepsis: recognition, diagnosis and early management, NICE guideline, published: 13 July

2016 www.nice.org.uk/guidance/ng51

Dellinger RP, Levy MM, Carlet TM et al. Surviving Sepsis Campaign: International Guidelines

for Management of Severe Sepsis and Septic Shock: 2012, J Crit Care Med 2013; 41:580-637.

Sepsis Management . Irish Health Service National Clinical Guideline No. 6, ISSN 2009-6259,

Published November 2014.

10. Links

10.1 Related analytes

Glucose

Ketones

CRP

10.2 Related tests

Blood gases

Author: Ms Kelly McCarthy

Date Completed: 04.2017

Date Revised: