GENERAL MEDICINE/REVIEW ARTICLE

Demystifying Lactate in the Emergency

Department
Gabriel Wardi, MD, MPH*; Jessica Brice, MD; Matthew Correia, MD; Dennis Liu, MD; Michael Self, MD; Christopher Tainter, MD

*Corresponding Author. E-mail: [email protected].

The role of lactic acid and its conjugate base, lactate, has evolved during the past decade in the care of patients in the emergency
department (ED). A recent national sepsis quality measure has led to increased use of serum lactate in the ED, but many causes for
hyperlactatemia exist outside of sepsis. We provide a review of the biology of lactate production and metabolism, the many causes of
hyperlactatemia, and evidence on its use as a marker in prognosis and resuscitation. Additionally, we review the evolving role of
lactate in sepsis care. We provide recommendations to aid lactate interpretation in the ED and highlight areas for future research.
[Ann Emerg Med. 2019;-:1-12.]

0196-0644/$-see front matter

Copyright © 2019 by the American College of Emergency Physicians.
https://doi.org/10.1016/j.annemergmed.2019.06.027

INTRODUCTION conditions and cause a metabolic acidosis.4-7 We will refer

Lactate measurement in the emergency department to L-lactate as lactate unless otherwise specified.
(ED) is a source of both guidance and confusion. Although
lactate can be a useful tool when interpreted correctly, Physiologic Function of Lactate
improper interpretation can mislead clinicians and result in In times of both rest and exercise, lactate serves 2
inappropriate care and unnecessary therapies. Our important functions: maintaining blood glucose by acting
understanding of lactate has developed considerably since it as a carbon substrate for gluconeogenesis, and acting as an
was first isolated in sour milk by Swedish chemist Carl oxidizable agent that can be shuttled from areas of high
Wilhelm Scheele in 1780.1 Since then, lactic acid and its glycolysis and glycogenolysis activity to areas of high
conjugate base, lactate, have become integral parts of the cellular respiration to engage in oxidative phosphorylation.8
diagnostic, therapeutic, and prognostic management of Lactate uptake and use is increased in the heart and brain
patients in the ED. However, significant controversy and under times of metabolic stress, including sepsis and shock,
misinterpretation surround the use of lactate, particularly in with the heart using lactate for up to 60% of its metabolic
light of more recent national sepsis quality measures. We demand, and the brain up to 25%.9,10 The myocardium
provide a review of the physiologic description of lactate oxidizes lactate as a carbon source for oxidative
and its application in the ED. phosphorylation and is a net consumer of lactate. During
states of moderate exercise, myocardial uptake of lactate
Chemistry increases proportionally with the workload.11,12 Similarly,
Lactic acid is an organic a-hydroxy acid with the neurons and astrocytes in the brain will take up lactate and
chemical formula CH3CH(OH)COOH. With a pKa of oxidize it as a fuel source to generate energy both at rest and
3.86, lactic acid readily deprotonates a hydrogen ion to during times of hypoglycemia, exercise, and
form its conjugate base, the lactate ion. At physiologic pH cardiopulmonary resuscitation.13
in human beings, the ratio between the lactate ion and
lactic acid is approximately 3,000:1, so the lactate anion is Lactate Homeostasis
commonly referred to as “lactate.”2 Lactate exists as 2 Traditionally, lactate has been viewed as an end product
stereoisomers: L-(þ)-lactate and D-(–)-lactate. L-lactate of anaerobic metabolism largely in skeletal muscle, a
composes nearly the entirety of lactate present in human concept known as the “oxygen debt model” that was
beings because mammalian cells exclusively contain L- pioneered in the 1920s.14 In the setting of decreased
lactate dehydrogenase, the enzyme that converts pyruvate oxygen availability, pyruvate is produced from glucose
to lactate. In normal physiologic states, D-lactate is through glycolysis and then reduced to lactate by L-lactate
produced in nanomolar concentrations in mammalian dehydrogenase. This reaction allows nicotinamide adenine
cells.3 However, it may accumulate in certain pathologic dinucleotide (reduced) to be oxidized to nicotinamide

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Demystifying Lactate in the Emergency Department Wardi et al

adenine dinucleotide (oxidized), which serves as a necessary oxidation.19 The glucose created through gluconeogenesis
oxidizing agent in the generation of adenosine triphosphate is then released back into circulation to be redistributed
(Figure 1).15 In this conventional perspective, lactate was through the body. Several factors are associated with
considered simply a metabolic waste product generated as a decreased hepatic clearance, including acidosis, underlying
cost for resupplying the cell with nicotinamide adenine cirrhosis, and hypoperfusion.20 Renal clearance accounts
dinucleotide (oxidized). for approximately 25% to 30% of lactate removal.21 The
More contemporary understanding recognizes lactate as majority occurs in the renal cortex, where cells will take up
a key player both in energy use and oxidation/reduction lactate and then either oxidize it for energy or use it for
reactions, even under aerobic conditions.16 Several studies gluconeogenesis to create glucose to be exported back to the
have demonstrated that lactate was produced by glycolysis renal medulla or systemic circulation. Only an estimated
at rest when skeletal muscle was fully oxygenated and 10% of renal clearance is through actual urinary excretion.
during periods of activity in which the anaerobic threshold
had not been reached.17 The proinflammatory cytokine Classification of Lactic Acidosis
milieu with increased catecholamine levels, often observed A “lactic acidosis” refers specifically to an elevated serum
in sepsis or other states of physiologic stress, causes an lactate level with a pH less than or equal to 7.35.22 In
increased metabolic state. Glucose use is increased, and so is contrast, hyperlactatemia has several definitions, but most
the presence of transporters and enzymes that are associated commonly refers to a serum lactate level greater than or
with glycolysis and lactate metabolism.9 Increased equal to 2 mmol/L, regardless of pH.23 In 1976, Cohen
glycolysis leads to an increased concentration of pyruvate, and Woods24 categorized lactic acidosis into 2 groups (type
which exceeds the oxidative capacity of the tricarboxylic A and B) based on the presence or absence of clinical
acid cycle cycle and is subsequently converted to lactate. evidence of tissue hypoxia, and provided a useful
framework to develop management strategies (Table 1).
Metabolism The cause of lactic acidosis may be multifactorial and might
The average lactate turnover rate at a physiologically not exclusively fall into either type A or B.
steady state is approximately 20 mmol/kg per day.18 The Type A lactic acidosis is defined by lactate accumulation
liver metabolizes approximately 70% to 75% of circulating in the setting of poor tissue perfusion or oxygenation.
lactate.19 This typically occurs in periportal hepatocytes, Common clinical entities leading to type A lactic acidosis
where lactate is used for either gluconeogenesis or, less so, include shock, cardiac arrest, severe hypoxemia, severe
anemia, regional tissue hypoperfusion, or excessive
muscular contraction. In these scenarios, oxygen demand
outstrips the available oxygen supply, either systemically or
regionally, leading to lactate accumulation. Type B lactic
acidosis refers to lactate elevation in the absence of cellular
hypoxia. Common causes of type B lactate accumulation in
the ED include medications (eg, albuterol, epinephrine) or
underlying disease process states (eg, sepsis, malignancy,
end-stage liver disease, diabetic ketoacidosis).
Accumulation of D-lactate leading to an acidosis is rare
and more difficult to recognize because measuring it requires
a separate analytic test. In short bowel syndrome, decreased
digestion of carbohydrates leads to the presence of sugars in
the colon. Bacteria then ferment these sugars to create D-
lactate and additionally convert L-lactate to D-lactate.2,4
Diabetic ketoacidosis and propylene glycol administration
have also been associated with D-lactate buildup.

LABORATORY EVALUATION
Methods for Lactate Measurement
Figure 1. Biochemical pathway of glucose showing creation of Standard measurement of lactate typically occurs either
lactate. through enzymatic spectrophotometry or electrode-based

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Wardi et al Demystifying Lactate in the Emergency Department

Table 1. Classification of elevated lactate level as defined by Cohen and Woods.24

Type Cause Clinical Scenarios
A Lactate accumulation in the setting of poor tissue perfusion or
hypoxia (either regional or global)
Global: Shock (cardiogenic, obstructive, distributive, hypovolemic) or
profound hypotension, severe anemia, cardiac arrest, trauma, burns,
carbon monoxide, cyanide
Regional: Limb or mesenteric ischemia, localized trauma or burns,
compartment syndrome, necrotizing soft tissue infection,
microcirculatory dysfunction*
Exertional: Convulsions or seizure, increased work of breathing,
strenuous exercise
B Lactate accumulation in the absence of clinical evidence of
tissue hypoperfusion or hypoxia
B1 Lactate elevation associated with underlying disease process Malignancy, sepsis, thiamine deficiency, liver failure, renal insufficiency,
pheochromocytoma, diabetic and alcoholic ketoacidosis
B2 Lactate elevation caused by a drug or toxin Metformin, acetaminophen, b2-agonists (including albuterol,
epinephrine), sympathomimetics, theophylline, nucleoside reverse-
transcriptase inhibitors, alcohol, toxic alcohols, propofol, cyanide,
carbon monoxide
B3 Lactate elevation caused by congenital errors of metabolism Pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency,
glucose-6-phosphatase deficiency, congenital mitochondriopathies

*Area of ongoing research.

amperometry. Both methods correlate extremely well when Difference Between Arterial and Venous Lactate
done properly. After blood is drawn, RBC metabolism Results
continues to generate lactate, particularly if significant Arterial and peripheral venous lactate values correlate very
delays exist before analysis. This undesirable elevation can well when the results fall within normal limits; however, mild
be diminished by immediately cooling the blood sample or discrepancies arise with hyperlactatemia.31-36 Central lactate
by use of a “gray top” collection tube, which contains values correlate extremely well with arterial values at all
sodium fluoride, a preservative that inhibits cellular levels.37 Arterial and central blood samples represent lactate
metabolism.25 However, a specimen analyzed within 15 that is systemically circulated, whereas venous samples reflect
minutes from drawing blood will have minimal distortion the local milieu, thus explaining the small discrepancies
of lactate, even if no method to prevent additional between these sites. However, drawing arterial blood can be
metabolism is performed.26 Whole blood and finger-stick painful, time consuming, and challenging in certain patient
samples can be analyzed with electrode-based amperometry populations. It is therefore appropriate, particularly in
at the bedside, providing a point-of-care lactate level, whose patients without an arterial line, to start with and trend
values correlate well with standard assays and provide peripheral venous samples.
results significantly quicker.27,28
Effect of Lactated Ringer’s Solution on Serum Lactate
Effect of Tourniquet Use on Lactate Lactated Ringer’s solution is a commonly administered
There has been concern that tourniquet use may elevate resuscitation fluid that may improve patient-centered
local lactate levels by leading to transient ischemia and outcomes compared with normal saline solution,
subsequent anaerobic metabolism. An older study involving particularly in septic patients.38-40 Each liter of lactated
arterial tourniquet application in the operating room to Ringer’s solution contains 28 to 29 mmol of sodium
induce ischemia resulted in a linear increase in serum lactate. In a 70-kg adult, approximately 1,400 mmol (20
lactate level, up to 206% of baseline values, after 75 mmol/kg) of lactate is metabolized daily. To our
minutes of tourniquet application.29 However, the knowledge, there is no published evidence that a bolus of
application of a venous tourniquet does not significantly lactated Ringer’s solution significantly increases lactate
alter venous lactate levels.26,30 compared with normal saline solution, although transient

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Demystifying Lactate in the Emergency Department Wardi et al

elevations can be observed, particularly if venipuncture microscopic vascular dysfunction to illness severity,
occurs in the immediate vicinity of the lactated Ringer’s elevated lactate levels, and worsened outcomes.56,58,59
solution infusion site.41,42 In patients with liver failure or Further study is needed to determine the importance of
significant hepatic hypoperfusion, there may be an increase microcirculatory dysfunction in sepsis and potential
in serum lactate level because of an inability of the liver to therapies to correct it.
metabolize the additional lactate burden.43
Anaerobic Metabolism in Sepsis
Although tissue hypoxia and resultant anaerobic
LACTATE IN SEPSIS metabolism will result in increased lactate production, this
Among its many uses as a diagnostic test, lactate level has relationship has been challenged as the primary cause of
long been used as a marker of resuscitation, for risk hyperlactatemia in sepsis. Certain septic patients develop
stratification, and as a mortality prediction tool in sepsis. vasopressor-dependent hypotension, yet never experience
Despite a commonly held belief that elevated lactate levels an elevated lactate level.59,60 Another subset of septic
in sepsis occur as a consequence of anaerobic metabolism patients develops hyperlactatemia with associated high
from tissue malperfusion, there is mounting evidence that mortality, yet lacks hypotension.61 Additionally, if
this may not be the primary source of lactate production, anaerobic metabolism from tissue hypoxia were the main
particularly in patients without overt shock physiology. source of lactate in sepsis, we would expect to see several
Indeed, accelerated aerobic glycolysis from adrenergic stress things. First, interventions to increase oxygen delivery
is now thought to be a significant cause of hyperlactemia in should consistently decrease lactate levels. However, several
septic patients, with additional contributions from studies have failed to support this.62,63 Furthermore,
impaired clearance, medication effects, microcirculatory studies evaluating tissue hypoxia in sepsis and septic shock
dysfunction, and tissue malperfusion.44-47 Cytopathic have found no evidence of cellular hypoxia. In fact, muscle
hypoxia and direct mitochondrial impairment have been and mucosal pO2 is often elevated in sepsis.46,64-66 Tissues
proposed as another cause, although the exact mechanism with an adequate oxygen supply should not generate lactate,
remains incompletely understood and further research is yet the lung is a major source of lactate in sepsis.50,51
required.48,49
Lactate in “Occult Hypoperfusion” and “Cryptic
Anatomic Location of Lactate Generation in Sepsis Shock”
The specific anatomic site of lactate generation in septic The terms “occult hypoperfusion” and “cryptic shock”
patients remains controversial. The 2 regions suspected to have been used to describe patients with elevated lactate
generate the majority of lactate in sepsis are the lungs and levels and normal blood pressure, and reflect their relatively
skeletal muscle. The strongest evidence comes from the high mortality rate. Indeed, in the initial early goal-directed
lungs as generators of lactate in sepsis.50-53 One hypothesis therapy trial, one of the inclusion criteria was serum lactate
is that neutrophil b2-receptor stimulation by endogenous level greater than or equal to 4 mmol/L, regardless of blood
catecholamines causes significant lactate production, which pressure.67 In patients with suspected infection, elevated
is further substantiated by the large number of these lactate levels were associated with increased 28-day
receptors found in the lungs.54 Muscle tissue has been mortality regardless of blood pressure, and used the term
shown to have significantly higher lactate levels than “occult hypoperfusion” to describe this subset of patients,
supplying arteries in septic shock.46 An additional source of which had previously been used for patients with traumatic
lactate elevation in sepsis is leukocyte glycolysis. Like other injuries and heart failure syndromes.68-70 Later, Puskarich
tissues, inflammatory cells undergo accelerated aerobic et al61 showed that septic patients with cryptic shock,
glycolysis during sepsis and have a markedly increased defined as a lactate level greater than or equal to 4 mmol/L
lactate output, similar to that which occurs in the lungs.54 without hypotension, and those with “overt” shock,
Microcirculatory dysfunction has been proposed as a defined as hypotension after a fluid challenge, had similar
source of lactate in sepsis. Proinflammatory cytokines lead mortality after protocolized therapy.
to endothelial and hematologic cell dysfunction, causing
heterogeneous areas of low or slow flow at the capillary- LACTATE IN OTHER CONDITIONS
venule-arteriole level. This leads to scattered areas of tissue A recent study evaluated patients admitted with a lactate
hypoxia despite normal macrocirculatory parameters.55-57 level greater than 4 mmol/L and found 23.2% of cases were
Using dark-field microscopy to visualize the from infection, 20% from seizures, and the remaining from
microcirculation, investigators have linked the density of causes unrelated to infection.71

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Wardi et al Demystifying Lactate in the Emergency Department

Trauma, Burns, and Inhalational Injuries sepsis, or history of gastric bypass surgery are at particular
Elevated lactate levels in patients with traumatic injuries risk for hyperlactatemia as a result of thiamine deficiency.88
are associated with increased mortality.72-74 Lactate Recent studies have shown that the administration of
elevation has classically been attributed to global intravenous thiamine to septic patients is associated with
hypoperfusion in the setting of hemorrhagic shock, or faster lactate clearance and decreased mortality, particularly
regionally, as in the case of arterial vessel injury. However, those with underlying thiamine deficiency or alcohol use
much as in sepsis, additional mechanisms, such as disorders.89-92
accelerated glycolysis, cause hyperlactatemia during
hemorrhage.75,76 An elevated initial serum lactate level may Toxins and Medications
occur in patients with occult hypoperfusion and can be Although lactate elevation in the majority of toxicities is
used as both a prognostic indictor and a marker of thought to be primarily due to a type B lactic acidosis, the
resuscitation.77,78 A failure to clear lactate in trauma underlying mechanisms for lactate production are often
patients has been shown to be a strong independent complex and multifactorial. Mechanisms include inhibition
predictor of mortality, as well as length of stay in the of oxidative phosphorylation or mitochondrial damage, b2-
hospital and ICU, and a risk factor for the development of adrenergic stimulation, shock states, increased muscle
infection, regardless of the initial presenting vital signs.79 activity, seizures, renal failure, and hepatic toxicity. Table 2
Lactate serves as a prognostic indicator of infectious provides a more comprehensive list of medications and
complications, organ dysfunction, and mortality, and as a toxins associated with lactate elevation.93
marker of resuscitation in patients with burns and
Acetaminophen. Lactate elevation has been proposed to
inhalational injuries.80,81 Lactate levels greater than or
be caused by 2 mechanisms in patients with acetaminophen
equal to 2 mmol/L and the failure to clear an elevated
toxicity. Animal models have shown that large
lactate level have been associated with mortality in previous
acetaminophen ingestions directly inhibit the
studies and may outperform base excess.82 It may be
mitochondrial electron transport chain before any
reasonable, according to published evidence, to use lactate
laboratory evidence of hepatotoxicity.94,95 Later, lactate
normalization as a goal in the fluid resuscitation of these
elevation occurs as a result of increased N-acetyl-p-
patients, although additional evidence is needed before
benzoquinone imine production, the toxic metabolite
widespread adoption of this approach.83
associated with liver injury. Lactate elevation in acute liver
failure portends a poor prognosis.94
Seizures, Convulsions, and Extreme Exertion
Seizures are known to cause hyperlactemia as a result of b2-Agonists (albuterol, epinephrine). b-Agonists have
local muscle tissue hypoxia and resultant anaerobic been shown to result in lactate elevation primarily through
metabolism.84 One study evaluating 157 patients with accelerated glycolysis, even in fully aerobic conditions.32
generalized tonic-clonic seizure showed that 84.7% had The association between albuterol and lactate elevation was
elevated lactate levels, with a median of 3.64 mmol/L but with initially limited to case reports; however, recent data
levels as high as 17 mmol/L.85 Patients with hyperlactemia suggest it is likely a relatively common phenomenon. A
caused solely by seizures should have rapid clearance within 1 study evaluating 105 children admitted with severe asthma
to 2 hours after the seizure resolution.71,86 There has been no exacerbation reported that 83% had a lactate level greater
correlation between degree of lactate elevation and outcome.71 than 2.2 mmol/L and 45% had lactate levels greater than 5
Patients with extreme exertion or agitation, particularly those mmol/L.96 Lactate elevations associated with albuterol
in physical restraints, develop hyperlactatemia through a typically resolve quickly after completion of therapy.97
similar mechanism. An observational study found that 95% of Epinephrine also causes an elevated lactate level through a
collapsed Boston Marathon runners had an average lactate similar mechanism.75,76,98 Previous investigations into the
level of 3.45 mmol/L.87 use of epinephrine in septic shock have found that survivors
have higher lactate levels in the first hours of resuscitation
Thiamine Deficiency compared with nonsurvivors.99
Thiamine is an essential cofactor in the conversion from Carbon monoxide and cyanide. Carbon monoxide
pyruvate to acetyl coenzyme A. A deficiency in thiamine will reversibly binds to hemoglobin with approximately 200 to
therefore result in an inability of pyruvate to enter the 300 times the affinity of oxygen, resulting in decreased
tricarboxylic acid cycle and rather undergo anaerobic arterial oxygen delivery. Furthermore, it binds to
metabolism, leading to elevated lactate levels (Figure 1). cytochrome A, inhibiting oxidative phosphorylation.100,101
Patients with long-term alcohol use, poor nutritional status, Lactate elevation in pure carbon monoxide poisoning is

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6 Annals of Emergency Medicine Table 2. Toxins associated with hyperlactatemia (adopted from Andersen et al93).

Demystifying Lactate in the Emergency Department

Toxin or Medication Mechanism of Lactate Elevation Recommended Therapy or Antidote Comments
Abrin Protein inhibitor and causes direct cellular damage, Supportive care Toxic component of jequirity beans
with resultant hepatotoxicity causing poor
clearance, seizures
Acetaminophen Multiple mechanisms, including direct inhibition of N-acetyl cysteine, aggressive supportive care, Most common cause of acute liver failure in developed
electron transport chain (in the absence of liver transplantation if indicated countries
hepatotoxicity), impaired clearance after direct
hepatocyte toxicity because of increased NAPQI
production
Albuterol b2-Receptor activation N/A Lactate elevation associated with albuterol resolves after
completion of therapy.
Carbon monoxide Reversibly binds to hemoglobin with approximately Decontamination, hyperbaric oxygen, Lactate elevation in pure carbon monoxide poisoning is
200–300 times the affinity of oxygen, resulting in supportive care typically mild, but has been shown to correlate with the
decreased arterial oxygen content. Binds to severity of toxicity. High lactate levels should raise
cytochrome A, inhibiting oxidative phosphorylation. suspicion for cyanide toxicity.
Cyanide Impairment of oxidative phosphorylation by inhibiting Decontamination. Antidotes include Lactate levels >10 mmol/L are highly concerning for
complex IV in the electron transport train hydroxycobalamin and sodium thiosulfate concomitant cyanide poisoning. Animal models have
with sodium nitrate. shown that cyanide levels and lactate levels are largely
directly correlated.
Ethanol Increased NADH to NADþ ratio Supportive care Often increased by a secondary cause, such as sepsis or
thiamine deficiency
Metformin Inhibits gluconeogenesis, thereby decreasing NADþ Cessation of metformin; may require dialysis.
levels. Newer evidence suggests metformin may Supportive care.
poison mitochondrial transport chain.
Nucleoside reverse- Suspected from poor clearance because of liver injury; Supportive care. Cessation of offending agent. Examples include didanosine, stavudine, and lamivudine.
transcriptase inhibitor animal models have shown impaired mitochondrial
function.
Propofol Exact mechanism is unclear. Several animal studies Removal of propofol, dialysis, supportive care Characterized by bradycardia, lactic acidosis, hyperkalemia,
have suggested a mitochondrial process and cardiovascular compromise, hepatic steatosis,
include uncoupling of oxidative phosphorylation, rhabdomyolysis, renal injury, and lipemia. Rare except in
oxidation of cytochromes, and inactivation of cases of prolonged high doses of propofol infusion.
complex II/III/coenzyme Q.
Ricin Protein inhibitor and causes direct cellular damage, Supportive care Toxic component of castor bean
with resultant hepatotoxicity causing poor
Volume

clearance, seizures
Sodium azide When combined with acid, it forms hydrazoic acid, Supportive care A white powder used as a reagent in car air bags and
-,

which is highly toxic and causes direct inhibition of laboratory preservatives

no.

oxidative phosphorylation. Seizures.

Sodium fluoroacetate
-

Inhibits the Krebs cycle, thus impairing aerobic Supportive care Highly toxic and currently licensed for use only against

Wardi et al
metabolism. Seizures. coyotes in the United States
: -
2019
Wardi et al Demystifying Lactate in the Emergency Department

typically mild, but has been shown to correlate with the

VPA levels do not correlate with severity of overdose. Lactate

reduce blood pressure in cardiac surgery and hypertensive

hyperexcitability. Causes inhibition of antagonistic muscle

crises. Toxicity typically occurs in long duration of therapy

Acute ingestions of >1 g or 15 mg/kg are associated with

Supportive care. Recovery is likely if the patient A rodenticide but has also been implicated in cocaine and
An arterial and venous vasodilator typically used to rapidly

severity of toxicity.101-103 Cyanide toxicity is most

toxicity. Oftentimes the result of other causes, such as

groups in the spinal cord, resulting in severe extensor

levels usually elevated mildly unless a seizure occurs.

Lactate levels can be falsely elevated in ethylene glycol
commonly observed with concomitant carbon monoxide
laxatives. Inhibits glycine, which results in CNS poisoning after smoke inhalation injuries. Cyanide impairs

kidney injury, thiamine deficiency, and sepsis.

oxidative phosphorylation by inhibiting complex IV in the

toxicity in adults or children, respectively.

and in patients with renal insufficiency.

electron transport train. Animal models have shown that

cyanide levels and lactate levels are closely correlated.104

NAPQI, N-acetyl-p-benzoquinone imine; NADH, nicotinamide adenine dinucleotide (reduced); NADþ, nicotinamide adenine dinucleotide (oxidized); CNS, central nervous system; VPA, valproic acid.
Lactate levels greater than 10 mmol/L are highly
concerning for concomitant cyanide poisoning.105
Ethanol. Acute ethanol intoxication causes an elevated
lactate level primarily through an increased nicotinamide
adenine dinucleotide (reduced) to nicotinamide adenine
dinucleotide (oxidized) ratio, which favors the creation of
spasms.

lactate. Underlying comorbidities, such as liver

impairment, renal disease, or thiamine deficiency, can also
lead to lactate elevation.
Metformin. Metformin increases peripheral glucose
Supportive care. Benzodiazepines for agitation.
Immediate cessation of sodium nitroprusside;

Most cases are self-limited and resolve with

uptake, thereby inhibiting gluconeogenesis and decreasing

fomepizole or dialysis in accordance with
Supportive care. Toxic alcohols may require
Multidose activated charcoal. Supportive

the availability of nicotinamide adenine dinucleotide

same therapy as for cyanide toxicity

(oxidized), which is necessary to covert lactate to pyruvate.

removal of VPA. Supportive care.

In acute overdose, profoundly elevated lactate levels have

time of ingestion and toxicity.
survives longer than 24 h.

been observed but are not correlated with prognosis.106

Renal impairment with a glomerular filtration rate less than
60 is thought to increase the risk for development of
hyperlactatemia.107
measures.

PROGNOSTIC VALUE AND LACTATE

CLEARANCE
Elevated lactate levels and an inability to clear lactate are
and releases cyanide ions during this process, thus
Reacts with oxyhemoglobin to form methemoglobin

associated with a worse prognosis in many conditions,

Seizures, cardiogenic shock, and catecholamine-

Direct damage from metabolites to hepatocytes

induced activation of b2-adrenergic receptors

particularly in sepsis, trauma, hemorrhage, shock, and

cardiac arrest.108-111 In a prospective cohort study of ED
results in impaired clearance, seizures.

patients with infection, mortality rates increased with

increasing lactate levels, with an initial lactate level greater
Muscle spasms and convulsions

Increased NADH to NADþ ratio

than or equal to 4 mmol/L associated with a 28%

inhospital mortality rate.112 In a separate study of patients
causing lactate elevation

with severe sepsis, this relationship was found to be

b2-Receptor activation

independent of shock state.113 Unsurprisingly, increasing

lactate concentrations in septic shock are also associated
with increasing inhospital mortality, even without signs of
overt shock.69,114 However, despite the emphasis on
specific lactate-level cutoffs found in current definitions
and Centers for Medicare and Medicaid Services
recommendations, mortality and poor prognosis are
associated with even mildly elevated lactate values.115 Thus,
(methamphetamine,
Sodium nitroprusside

Sympathomimetics

lactate may be best thought of as a continuous rather than

cocaine, etc)

dichotomous variable in regard to prognostication and risk

Toxic alcohols
Theophylline
Strychnine

stratification.
A decrease in lactate concentrations during
VPA

resuscitation is associated with improved mortality.116-118

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Demystifying Lactate in the Emergency Department Wardi et al

Although there is no clear target percentage decrease or sample, the first decision point is to determine whether
time frame to decrease lactate level, achieving a “normal” there is concern for shock or hypoperfusion. Any patient
lactate level quickly appears to be a reasonable goal; there with hyperlactatemia and evidence of circulatory shock and
is no consensus at this point.117,118 Although earlier general hypoperfusion clearly benefits from resuscitation to
studies evaluated protocoled lactate measurements in the restore adequate tissue perfusion. Patients with evidence of
care of septic patients and showed noninferiority to regional hypoperfusion (eg, limb or mesenteric ischemia)
targeting central venous oxygen saturation levels, a similar require emergency intervention to restore perfusion to the
benefit in mortality was associated with simply measuring affected region, and an elevated lactate level may help guide
more than one lactate level in the ED.116,119 Some authors providers to an accurate and timely diagnosis. In patients
have suggested that measuring lactate itself has mortality who lack overt shock or hypoperfusion, an elevated lactate
benefits, but it is more likely that early measurement of level should be interpreted in the context of the patient’s
lactate is a marker of timely and appropriate care.117 More medical history, medication list, or any exposures. As we
recently, a large randomized controlled trial showed that a described earlier, hyperlactatemia can also occur from
resuscitation strategy targeting peripheral perfusion overproduction, impaired clearance, or a combination of
compared with lactate normalization did not reduce all- both in the absence of tissue malperfusion. Common
cause 28-day mortality.120 medications administered in the ED (eg, albuterol) and
brief episodes of extreme exertion can result in
hyperlactatemia that typically clears quickly without any
HOW TO USE LACTATE IN THE ED intervention. Septic patients may have an elevated lactate
The diagnostic utility of lactate in the ED is diverse: it level from accelerated glycolysis caused by adrenergic stress
functions as a marker of resuscitation, identifies patients and may benefit from resuscitation, particularly if there is
with occult hypoperfusion, and provides prognostic legitimate concern for occult shock. Patients with renal
information. Figure 2 provides a framework to guide failure and cirrhosis will have higher lactate levels than
appropriate interpretation and use of lactate level. counterparts without these conditions. Oncology patients,
Assuming an appropriately collected and analyzed lactate particularly those with hematologic malignancy, often have

Figure 2. ---

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Wardi et al Demystifying Lactate in the Emergency Department

elevated lactate levels from tumor turnover, rather than All authors attest to meeting the four ICMJE.org authorship criteria:
infection or hypoperfusion. (1) Substantial contributions to the conception or design of the
work; or the acquisition, analysis, or interpretation of data for the
Any test showing an elevated lactate level should be
work; AND (2) Drafting the work or revising it critically for important
repeated. Lactate clearance is associated with improved intellectual content; AND (3) Final approval of the version to be
outcomes and successful resuscitation, and risk stratifies published; AND (4) Agreement to be accountable for all aspects of
patients with cardiac arrest, shock, or hypoperfusion. A the work in ensuring that questions related to the accuracy or
failure to clear lactate should cause providers to pause and integrity of any part of the work are appropriately investigated and
then reevaluate the elevated lactate level to determine resolved.
whether additional resuscitation or therapies are needed. In Funding and support: By Annals policy, all authors are required to
certain instances, such as in patients beginning to receive disclose any and all commercial, financial, and other relationships
epinephrine, an increase in lactate level is associated with in any way related to the subject of this article as per ICMJE conflict
of interest guidelines (see www.icmje.org). Dr. Wardi has received a
increased survival. Patients at risk for thiamine deficiency speaker’s fee from Thermo Fisher for work unrelated to this topic.
may require the administration of thiamine to help clear He is on the editorial board of PEER and received grant support
lactate. In patients who are anticipated to rapidly clear from the National Foundation of Emergency Medicine.
lactate without any intervention, a failure to do so should Publication dates: Received for publication May 11, 2019.
prompt a reanalysis of the current presentation to ensure no Revisions received June 18, 2019, and June 26, 2019. Accepted
other processes are present. for publication June 26, 2019.
Lactate levels may also provide false reassurance because
not all patients with hypoperfusion will generate elevated
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