J Extra Corpor Technol.

2017;49:7–15
The Journal of ExtraCorporeal Technology

Review Article

Hyperlactatemia and Cardiac Surgery

Jonathon Minton, MB, ChB, FANZCA;* David A. Sidebotham, MB, ChB, FANZCA†

*Department of Anesthesia and Perioperative Medicine, The Alfred Hospital, Melbourne, Australia; and; †Department of
Cardiothoracic Anesthesia and the Cardiovascular Intensive Care Unit, Auckland City Hospital, Auckland, New Zealand

Presented at the Perfusion Downunder Meeting, Queenstown, New Zealand, August 18–20, 2016.

Abstract: The normal blood lactate level is 0–2 mmol/L, and a associated with adverse outcome and probably arises as a con-
value above 3–5 mmol/L is variably used to define hyperlacta- sequence of both hypoxic (e.g., microcirculatory shock) and non-
temia. In cardiac surgical patients, hyperlactatemia can arise hypoxic (accelerated aerobic metabolism) mechanisms. By contrast,
from both hypoxic and non-hypoxic mechanisms. The major late-onset hyperlactatemia is a benign, self-limiting condition that
non-hypoxic mechanism is likely stress-induced accelerated aero- typically arises within 6-12 hours of ICU admission and spontane-
bic metabolism, in which elevated lactate results from a mass ously resolves within 24 hours. Late onset hyperlactatemia occurs in
effect on the lactate/pyruvate equilibrium. The lactate/pyruvate the absence of any evidence of global or regional tissue hypoxia.
ratio is normal (<20) in this circumstance. Hyperlactatemia can The mechanism of late onset hyperlactatemia is not understood.
also result from impaired global or regional oxygen delivery, in Hyperlactatemia is a common accompaniment to treatment with
which case the lactate/pyruvate ratio is typically elevated (>20). β2-agonists such as epinephrine. Epinephrine-induced hyperlacta-
Lactate is a strong anion that is virtually fully dissociated at physio- temia is thought to be due to accelerated aerobic metabolism and
logical pH. As such, increased lactate concentration reduces the requires no specific intervention. Irrespective of the cause, the pres-
strong ion difference and exerts an acidifying effect on the blood. ence of hyperlactatemia should trigger a search for remedial causes
Hyperlactatemia in cardiac surgery patients has been categorized as of impaired tissue oxygenation, bearing in mind that normal—or
either early or late onset. Early-onset hyperlactatemia is that which even supranormal—indices of global oxygen delivery may exist
develops in the operating room or very early following intensive despite regional tissue hypoperfusion. Keywords: acidosis, lactate,
care unit (ICU) admission. Early-onset hyperlactatemia is strongly cardiac surgery, outcome. J Extra Corpor Technol. 2017;49:7–15

Hyperlactatemia occurs in 10–20% of patients following The purpose of this article is to review lactate metabolism
cardiac surgery and is associated with increased mortality in health and critical illness with an emphasis on cardiac
and morbidity (1,2). Clinically, elevated blood lactate surgical patients. In addition, an approach to investigating
concentration is frequently used as a marker of tissue and treating patients with hyperlactatemia is described.
hypoxia. However, lactate metabolism during the peri-
operative period is complex, dynamic, and incompletely
understood. The causes of perioperative hyperlactatemia NORMAL LACTATE METABOLISM
are varied and include hypoxic as well as non-hypoxic
causes (1,3–6). Lactate (CH3CH(OH)CO−2 ) is the conjugate base of
lactic acid. Lactic acid has a pKa of 3.86, meaning it is vir-
tually fully ionized at physiological pH. Lactate occurs in
Received for publication October 6, 2016; accepted December 1, 2016. two optical isomeric forms: levo (L) and dextro (D). The
Address correspondence to: David A. Sidebotham, MB, ChB, FANZCA,
Department of Cardiothoracic Anesthesia and the Cardiovascular Inten- endogenous form of lactate is predominantly L-lactate.
sive Care Unit, Auckland City Hospital, Auckland, New Zealand. E-mail: D-lactate is produced by certain bacterial microorganisms,
[email protected] including those in the gastrointestinal tract, but is not pro-
The senior author has stated that the authors have reported no material,
financial, or other relationship with any healthcare-related business or duced by mammalian cells. Only L-lactate is considered in
other entity whose products or services are discussed in this paper. this review, as this is the form of lactate that is responsible

Article available at https://ject.edpsciences.org or https://doi.org/10.1051/ject/201749007

8 J. MINTON AND D.A. SIDEBOTHAM

for perioperative hyperlactatemia and is the form that is pyruvate dehydrogenase, blocking entry of pyruvate to the
measured clinically. citric acid cycle.
To understand the mechanisms responsible for hyper-
lactatemia, it is necessary to have a working knowledge
of normal lactate metabolism. LACTATE DEHYDROGENASE AND THE
CORI CYCLE

GLYCOLYSIS The second mechanism for the regeneration of NAD+

is through the conversion of pyruvate to lactate under the
Lactate is produced exclusively from pyruvate that is influence of lactate dehydrogenase:
itself the end product of glycolysis. In the cytoplasm, one
molecule of glucose is metabolized to two molecules of pyru- Pyruvate þ NADH þ Hþ , NADþ þ lactate ð3Þ
vate. In the process, two molecules of high-energy adeno- The reversible production of lactate from pyruvate allows
sine triphosphate (ATP) are produced and two molecules ongoing glycolysis in the absence of oxygen but yields only
of nicotinamide adenine dinucleotide (NAD) are reduced: two molecules of ATP per molecule of glucose (i.e., much
Glucose þ 2NADþ 2ADP þ 2Pi less than by oxidative phosphorylation).
! pyruvate þ 2NADH þ 2ATP þ 2H2 O þ 2Hþ ð1Þ Lactate generated by anaerobic glycolysis in tissues (e.g.,
skeletal muscle during maximal exercise) may be recycled
ATP is formed by the addition of a high-energy phos- back to glucose (gluconeogenesis) in the liver. Each mole-
phate (Pi) group to adenosine diphosphate (ADP). NAD cule of glucose produced from two lactate molecules requires
is a co-enzyme that functions as an electron carrier. It is six molecules of ATP. Collectively, the anaerobic production
involved in many redox reactions in intermediary metab- of lactate in muscle, transfer via blood, and regeneration
olism, being reversibly oxidized and reduced: of glucose in the liver is known as the Cori cycle. The Cori
cycle serves an important function in working muscle, as it
NADþ ðoxidized formÞ þ Hþ þ 2e
decouples ATP utilization (muscle) from production (liver),
, NADHðreduced formÞ ð2Þ
allowing ongoing muscular activity despite inadequate
For continued glycolysis, it is necessary to regenerate oxygen delivery for full aerobic respiration. However, the
NAD+. Regeneration of NAD+ occurs by one of two process is much less efficient in terms of ATP production
processes: oxidative phosphorylation and the conversion than oxidative phosphorylation.
of pyruvate to lactate.

LACTATE AS AN AEROBIC FUEL

THE CITRIC ACID CYCLE AND
OXIDATIVE PHOSPHORYLATION The traditional view of lactate is as a waste product of
anaerobic metabolism. However, under aerobic conditions,
Under normal circumstances, most of the pyruvate lactate is a precursor for oxidative phosphorylation, through
formed from glycolysis is fully oxidized to carbon dioxide its conversion to pyruvate (Equation 3) and then entry to
and water within mitochondria. Pyruvate combines with the citric acid cycle. Indeed, most lactate produced in the
co-enzyme A and is converted to acetate (acetyl-CoA) body is ultimately oxidized rather than recycled to glucose
under the influence of pyruvate dehydrogenase. The metab- in the Cori cycle (4).
olism of acetate in the citric acid cycle generates further During high-intensity exercise, skeletal muscle releases
NADH (along with other reduced co-enzymes). In the lactate into blood. However, during recovery from intense
presence of oxygen, NADH produced by glycolysis and exercise or during sustained low-intensity exercise, there is
the citric acid cycle is oxidized to NAD+ by the mitochon- a net uptake of lactate into skeletal muscle where it is
drial electron transport chain, and produces a large amount removed by oxidation (3). At rest, cardiac muscle utilizes
of ATP. The complete oxidation of one mole of glucose to glucose and fatty acids as its primary fuels. However, car-
carbon dioxide and water has a net yield of approximately diac muscle can use many energy sources, including lac-
32 molecules of ATP. tate. The uptake of lactate by cardiac muscle and other
The intracellular oxygen tension (PO2) threshold for organs is proportional to the plasma concentration of lac-
oxidative phosphorylation is unknown; however, cellular tate (5), which is normally low (≈1 mmol/L). Conversely,
respiration is clearly inhibited at PO2 values below 1 mmHg during high-intensity exercise, when blood lactate increases
(3). As tissue PO2 falls and oxidative phosphorylation is substantially, glucose utilization by myocytes decreases and
inhibited, there is a progressive increase in the ratios lactate becomes an important fuel for aerobic metabolism
of ADP/ATP and NADH/NAD+, which in turn inhibit (6). Studies using radiolabeled lactate indicate that virtually

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 HYPERLACTATEMIA AND CARDIAC SURGERY 9

all of the lactate taken up by cardiac myocytes during exer- By contrast, if hyperlactatemia is caused by tissue hyp-
cise is fully oxidized (7). There is also evidence that dur- oxia, pyruvate will be preferentially converted to lactate, and
ing exercise, there is uptake and oxidization of lactate by the lactate/pyruvate ratio will be increased. Recall that tissue
the brain (8). hypoxia leads to increased ADP/ATP and NADH/NAD+
Thus, lactate appears to be an important mobile fuel for ratios, inhibiting pyruvate dehydrogenase and blocking entry
aerobic metabolism, particularly during exercise, being able of pyruvate to the citric acid cycle.
to be rapidly exchanged between tissues depending on the Levy and colleagues have investigated the evolution of
local PO2 and workload (3). lactate and L/P ratios in patients with cardiogenic and sep-
tic shock admitted to their intensive care unit (ICU) (18).
Very high L/P ratios (40 ± 6) were identified in patients
LACTATE METABOLISM DURING STRESS with cardiogenic shock, and this was associated with a high
(60%) early mortality. The authors found the situation
During states of metabolic stress, such as sepsis, blood with septic shock to be more complex. Among early non-
lactate concentration increases. The primary source of lac- survivors, similarly high L/P ratios were identified (37 ± 4).
tate in this circumstance is probably skeletal muscle (9). Beyond 24 hours, L/P ratios were higher in patients who
Traditionally, hyperlactatemia during sepsis has been attri- subsequently died (22 ± 1) than in survivors (14 ± 1). By
buted to tissue hypoxia. However, there is clear evidence contrast, L/P ratios in controls (non-septic ICU patients)
that oxygen and ATP levels in skeletal muscle are not were 8 ± 2. In another study, Suistomaa and colleagues
reduced in this circumstance (10–12). Furthermore, dichloro- measured lactate and L/P ratios in 98 consecutive patients
acetate reduces blood lactate concentration in humans with admitted to a medical ICU (19). Median peak lactate levels
septic shock (12,13), which also suggests aerobic respira- on admission were higher in non-survivors (5.3 [inter-
tion is not limited by tissue hypoxia. Dichloroacetate is an quartile range 1.9–7.5]) than survivors vs. (1.9 [1.3–2.9]).
activator of pyruvate dehydrogenase, increasing entry of Furthermore, hyperlactatemia with an elevated L/P ratio
pyruvate into the citric acid cycle but only in the presence (>18) was associated with higher mortality than hyper-
of adequate tissue PO2. lactatemia with normal L/P ratio (<18) (37.5% vs. 12.5%,
Similarly, lactic acidosis can also develop in cardiac respectively, p = .03), and was found mainly in patients
surgical patients following cardiopulmonary bypass (CPB) who had severe circulatory failure rather than sepsis.
in the absence of tissue hypoxia (14–16). The likely explanation for these findings is that in
The likely explanation for the hyperlactatemia that occurs patients with shock (either cardiogenic or septic), a high
in the absence of tissue hypoxia is “accelerated glycolysis,” lactate in association with a high L/P ratio is indicative of
in which stress-induced increased uptake of glucose by peri- circulatory failure and anaerobic glycolysis. Hyperlacta-
pheral tissues leads to enhanced glycolysis and increased temia from this cause is associated with high mortality.
pyruvate production (17). Enhanced pyruvate production However, in patients with “stable” septic shock, elevated
from accelerated glycolysis leads to increased lactate pro- lactate in association with a relatively normal L/P ratio is
duction by a simple mass effect on the lactate–pyruvate indicative of accelerated aerobic metabolism, which is
equilibrium (Equation 3). Furthermore, enhanced pyru- not, of itself, predictive of adverse outcome. Nevertheless,
vate production in sepsis is also associated with greatly higher lactates are typically found in patients with tissue
enhanced oxidation of pyruvate via the citric acid cycle (12). hypoxia and are associated with increased mortality.
Thus, rather than reduced aerobic respiration, the hyper-
lactatemia seen in septic patients is actually associated with
increased aerobic respiration. CATECHOLAMINES AND HYPERLACTATEMIA

A key mechanism for increased lactate during metabolic

LACTATE/PYRUVATE RATIO stress is likely the endogenous release (or exogenous admin-
istration) of epinephrine leading to β2-mediated receptor
One potential way to distinguish aerobic from anaero- uptake of glucose into cells and accelerated glycolysis via
bic lactate production is the lactate/pyruvate (L/P) ratio. a mass effect (20).
Under normal circumstances, the ratio is approximately Of the commonly used catecholamines, only epineph-
10:1; i.e., the equilibrium shown in Equation 3 greatly rine, isoproterenol, and salbutamol exert a potent effect
favors lactate over pyruvate. If the primary mechanism of on peripheral β2-receptors. In one study, 6 of 19 patients
hyperlactatemia is increased pyruvate production (i.e., accel- randomized to receive epinephrine following cardiac sur-
erated aerobic glycolysis), the lactate concentration will gery developed lactic acidosis compared to 0 of 17 patients
increase proportionally to pyruvate, and the L/P ratio will randomized to receive norepinephrine (21). Epinephrine-
remain relatively unchanged. induced lactic acidosis has been demonstrated by several

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10 J. MINTON AND D.A. SIDEBOTHAM

other authors (22–24), and forms part of day-to-day clini-

cal experience. In keeping with the purported mechanism
of accelerated glycolysis, such lactic acidosis is associated
with normal (or increased) oxygen delivery and has a
benign course.
Unsurprisingly, hyperglycemia is a common accompani-
ment to hyperlactatemia associated with accelerated gly-
colysis (14–16,21).

LACTATE CLEARANCE

Approximately 60% of lactate is cleared by the liver with

contributions from the kidneys, heart, and skeletal muscle
(25). Metabolism of lactate involves conversion to pyruvate Figure 1. The SID. The SID is the difference between the strong cations
(Equation 3) and then either oxidation to carbon dioxide and anions in extracellular fluid. The SID is primarily comprised of the
concentration of bicarbonate and the negative charge from dissociated
and water or gluconeogenesis in the liver via the Cori cycle. plasma proteins (ATOT). This display format for the SID, in which the two
In addition to its role as a site of lactate metabolism, in columns are used to demonstrate the cations and anions, is known as a
the presence of hyperlactatemia, renal excretion of lactate gamblegram, after the pediatrician Dr. J.L. Gamble.
becomes clinically important (26).
Although the hyperlactatemia seen in critical illness is
primarily related to increased production, there is also evi- anions are predominantly comprised of HCO−3 and the
dence that reduced hepatic clearance contributes to hyper- negative charge from dissociated plasma proteins, notably
lactatemia in stable septic patients (27). Certainly, in the albumin, termed ATOT.
presence of severe hepatic hypoperfusion or acute liver Changes in SID, pCO2, and ATOT alter pH via their effect
failure, reduced hepatic metabolism almost certainly con- on the dependent variables HCO−3 and H+, which alter their
tributes to acidosis and hyperlactatemia. concentrations to maintain electrical neutrality (29). The
relationship between pH, bicarbonate, and pCO2 is char-
acterized by the Henderson–Hasselbalch equation, which
LACTATE AND ACIDOSIS may be formulated as:
 
As noted earlier, at physiological pH, lactic acid is virtu- HCO 3
pH ∝ log10 ð4Þ
ally completely dissociated. Thus, it is commonly assumed pCO2
that each molecule of lactate leads to the production of
Given the bicarbonate contribution to the anion total
one hydrogen ion, which in turn causes acidosis. This
is SID − ATOT (Figure 1), the Henderson–Hasselbalch
assumption is incorrect. Understanding why requires a
equation may be reformulated as (29):
(brief) review of the Stewart methodology of acid–base  
physiology (28). ðSID  ATOT Þ
pH ∝ log10 ð5Þ
pCO2
THE STEWART FORMULATION OF In simple terms, any condition that reduces the SID
ACID–BASE PHYSIOLOGY results in a metabolic acidosis and any condition that
increases the SID results in a metabolic alkalosis through
The Stewart analysis is based on the principle of electro- alterations in the bicarbonate buffer system.
neutrality, whereby the total number of cations in solution The concept of the SID readily explains the phenome-
must always equal the total number of anions. Only strong non of saline-induced hyperchloremic metabolic acidosis.
ions (i.e., ions fully dissociated at physiological pH), pCO2, When .9% saline is administered to a patient, equal
and weak acids (predominantly plasma proteins such as amounts of sodium and chloride ions are delivered to the
albumin) can change pH directly. This has led to the con- extracellular fluid. However, since the plasma [Cl−] is less
cept of the strong ion difference (SID). The SID is the than [Na+], plasma chloride concentration increases pro-
sum of the strong cations (Na+, K+, Ca2+, Mg2+) minus the portionally more than the plasma sodium concentration,
strong anions (predominantly Cl− but also lactate−). In reducing the SID and therefore causing an acidosis. Simi-
health, the plasma concentration of strong cations exceeds larly, chloride loss in excess of sodium (e.g., the vomiting
the plasma concentration of strong anions, resulting in an of gastric contents) increases the SID and causes a (hypo-
SID of around +40 mEq/L (Figure 1). The remaining chloremic) alkalosis.

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 HYPERLACTATEMIA AND CARDIAC SURGERY 11

LACTATE AS A CAUSE OF ACIDOSIS cant acidosis. It is also worth remembering that shock
states (hypovolemic, cardiogenic, septic) are frequently
As a strong anion, excess lactate production reduces associated with renal failure, which in turn results in the
the SID and causes a metabolic acidosis in a manner sim- buildup of strong anions, notably sulfates. Such anions also
ilar to chloride excess. This is certainly the mechanism by contribute to a reduced SID and metabolic acidosis.
which tissue hypoxia, which is associated with a greatly
increased lactate production, causes a metabolic acidosis.
However, for other conditions, the relationship between RRT, HYPERLACTATEMIA, AND ACIDOSIS
elevated lactate and acidosis is less straightforward.
Lactated Ringer’s solution is a balanced salt solution The effect of RRT on lactate metabolism and acid–base
containing sodium (130 mmol/L), chloride (109 mmol/L), status is complex and incompletely understood (26). In
lactate (28 mmol/L), and small amounts of potassium and patients with lactic acidosis and acute renal failure, RRT
calcium. Lactated Ringer’s has a SID of 28 mEq/L, closer with a bicarbonate-buffered replacement fluid corrects aci-
to the normal value of 40 mEq/L than .9% saline, which dosis and avoids exacerbating hyperlactatemia (32,33). As
has a SID of 0 mEq/L. Rapid administration of large amounts a small, non-protein bound molecule, lactate is cleared by
of lactated Ringers can reduce the SID of plasma, tran- both hemofiltration (convective clearance) and dialysis (dif-
siently causing a metabolic acidosis. However, typically fusive clearance). However, clinically, lactate clearance by
the lactate is rapidly metabolized by the liver, negating RRT represents only a small proportion of total body lactate
this effect. Metabolism of lactate yields a relative excess clearance—less than 3% in one study (34)—and is insuffi-
of sodium that, as a strong cation, increases the SID of cient to treat overproduction.
plasma, exerting an alkalizing effect (30). Similar effects If lactate-buffered replacement fluid is used, moderate
on plasma SID and pH can be expected in patients receiv- hyperlactatemia can occur; however, in the absence of
ing renal replacement therapy (RRT) with lactate-buffered liver failure this is not associated with acidosis (26).
replacement solution.
The situation in patients with accelerated glycolysis
(metabolic stress, endogenous or exogenous catechol-
CLASSIFICATION OF LACTIC ACIDOSIS
amine administration) is incompletely understood. In
general, hyperlactatemia due to metabolic stress is asso-
Lactic acidosis that occurs in the context of impaired tis-
ciated with lower lactate levels (typically in the range of
sue oxygenation is termed Type-A, whereas lactic acidosis
3–6 mmol/L) than that associated with tissue hypoxia.
that occurs in the absence of tissue hypoxia is termed
Modest elevations in plasma lactate are not necessarily asso-
Type-B. Type-A lactic acidosis implies either a global or
ciated with acidosis.
regional impairment of tissue oxygen delivery and is typically
In an attempt to resolve the issue of whether hyper-
associated with an elevated L/P ratio. Causes of regional
lactatemia can occur in the absence of metabolic acidosis, impairment of oxygen delivery include limb, hepatic, and
Morgan and Hall performed an in vitro experiment in which mesenteric ischemia. Accelerated aerobic glycolysis is an
fresh whole blood was diluted in a 3:1 with nine different example of Type-B lactic acidosis, and is typically associ-
crystalloid solutions of varying SID (−5 to 40 mEq/L), cre- ated with a normal L/P ratio. Other causes of Type-B aci-
ated by varying the concentrations of chloride, bicarbonate, dosis include drug toxicity and poisonings (cyanide, methanol,
and lactate (31). All crystalloids had a sodium concentra- salicylates), diabetic ketoacidosis, hepatic dysfunction (reduced
tion of 140 mmol/L. The blood-crystalloid solutions were lactate clearance), and thiamine deficiency (impaired pyruvate
equilibrated with carbon dioxide and air to obtain normo- dehydrogenase function). Depending on the specific etiol-
carbia. The main findings of the simulation were twofold. ogy, the L/P ratio may be normal or elevated.
First, there was a close correlation between SID and pH, It should be clear from the foregoing discussion that there
regardless of whether the strong anion was lactate or chlo- is much overlap between Types A and B lactic acidosis. For
ride. Second, only when the plasma lactate concentration instance, low cardiac output following CPB treated with epi-
exceeded 10 mmol/L did values of base excess and normo- nephrine may be associated with global tissue hypoxia (low
carbic pH fall outside the reference ranges. Although this cardiac output) and accelerated metabolism (epinephrine,
is an in vitro simulation that has not been verified in vivo, systemic inflammatory response syndrome). Other causes of
it seems reasonable to conclude that lactate, like any hyperlactatemia that may occur in such a patient include
strong anion (e.g., chloride, ketoacids, sulfates), exerts an limb ischemia (secondary to an intraaortic balloon pump
acidifying effect due to its effect on the SID. However, [IABP]), hepatic ischemia (which may result in reduced
only high levels of lactate—greater than the levels typically lactate clearance and increased lactate production), and
found with stress-induced aerobic glycolysis—cause signifi- mesenteric ischemia.

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12 J. MINTON AND D.A. SIDEBOTHAM

THE MICROCIRCULATION likelihood of adverse outcome. Clinically, lactate is used to

titrate resuscitation therapy; however, there are no outcome
An important finding in patients with septic shock is that data demonstrating the efficacy of this approach.
while global oxygen delivery may be normal—or in fact,
often supernormal—regional blood flow may be severely
LACTIC ACIDOSIS AND CARDIAC SURGERY
impaired (35,36). Bacterial components and inflammatory
proteins cause a range of effects on the microcirculation
Numerous studies have identified an association between
including vasoconstriction, altered red blood cell deformity,
hyperlactatemia and adverse outcome among cardiac surgical
and activation of platelets and the coagulation cascade.
patients (2,16,38–41). A lactate level of 0–2 mmol/L is consid-
Functional shunting occurs in which oxygenated blood
ered normal but most authors use a cutoff of 3–5 mmol/L to
bypasses capillary beds resulting in tissue ischemia despite
define hyperlactatemia. However, in one study, even lactate
normal (or high) mixed venous oxygen saturation (SVO2).
levels at the higher end of the reference range (0.75–2 mmol/L)
Research has focused on specific organs, notably the kid-
were associated with increased in-hospital mortality (42).
ney, gut, liver, skin, but blood flow is also heterogeneous
The causes of hyperlactatemia following cardiac surgery
within organs. Thus, changes in sublingual (assessed via side-
are varied and include both hypoxic and non-hypoxic causes
stream dark-field imaging) or gastric (assessed via tonome-
(Table 1). Several authors have demonstrated a biphasic dis-
try) perfusion may not be reflective of blood flow in other
tribution of cardiac surgery–associated hyperlactatemia, with
parts of the gastrointestinal tract, notably small and large
important differences in the genesis and outcome from the
bowel mucosa. Although less well established than in septic
two different types (1,14–16).
shock, CPB and cardiac surgery are also associated with
deleterious effects on the microcirculation (37).
A key feature of microcirculatory shock is that normal- EARLY-ONSET HYPERLACTATEMIA
ization or optimization of global indices of oxygen deliv-
ery (cardiac output, SVO2) with fluid and inotrope therapy Early-onset hyperlactatemia is that which occurs from
does not necessarily correlate with restoration of micro- the onset of CPB to arrival in the ICU. Early-onset hyper-
circulatory flow. Bedside tools for assessing microcirculatory lactatemia is associated with a greatly increased likelihood
function (skin mottling, peripheral-to-central temperature of adverse outcome (16,43,44). For instance, Maillet and
gradient, and urine output) are relatively crude, and are colleagues documented a mortality of 14.9% with a lactate
likely to be particularly unhelpful during the post-CPB period. >3 mmol/L at ICU admission compared to 1.5% in patients
Blood lactate is a useful index of both global and regional with a lactate <3 mmol/L (16). Tissue microdialysis studies
tissue perfusion and severe hyperlactatemia portends a high have demonstrated that CPB is associated with increased

Table 1. Potential causes of hyperlactatemia in cardiac surgical patients.

Cause Mechanism(s) Onset

Inadequate oxygen delivery during CPB Tissue hypoxia (Type-A) Early

Low cardiac output Tissue hypoxia (Type-A) Early or late
Severe anemia/hemodilution Tissue hypoxia (Type-A) Early or late
Systemic inflammatory response syndrome Accelerated glycolysis (Type-B) Early
Impaired tissue perfusion due to Early
microcirculatory failure (Type-A)
(e.g., due to prolonged CPB, massive transfusion)
Exogenous catecholamines Accelerated glycolysis (Type-B) Early or late
(epinephrine, salbutamol, isoproterenol)
Hepatic ischemia Tissue hypoxia (Type-A) Early or late
Reduced lactate clearance (Type-B) Early or late
Limb ischemia Tissue hypoxia (Type-A) (e.g., IABP) Early
Mesenteric ischemia Tissue hypoxia (Type-A) (e.g., due to NOMI or Late
arterial embolus)
Septic shock As per systemic inflammatory response syndrome Late
Administration of lactated Ringer’s solution Increased lactate load (sodium lactate) (Type-B) Early or late
Lactate-buffered renal replacement fluid Increased lactate load (sodium lactate) (Type-B) Late
Grand mal seizure Accelerated aerobic glycolysis (Type-B) Late
Renal failure Reduced lactate clearance (Type-B) Late
Tissue hypoxia (Type-A)
Pancreatitis As per systemic inflammatory response syndrome Late
Drug related Propofol syndrome (Type-B) Late
Sodium nitroprusside (Type-A)

NOMI, non-occlusive mesenteric ischemia.

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 HYPERLACTATEMIA AND CARDIAC SURGERY 13

myocardial and peripheral tissue increases in lactate and

L/P ratio (45,46). Although these studies were performed in
“normal” patients, without systemic hyperlactatemia, they
nevertheless indicate that CPB is associated with impaired
tissue oxygenation, and suggest that tissue hypoxia may
be involved in the genesis of early-onset hyperlacta-
temia. Although data are lacking, it makes intuitive sense
that microcirculatory dysfunction, secondary to the pro-
inflammatory effects of CPB, contributes to early-onset
hyperlactatemia. Hyperlactatemia probably also arises from
accelerated aerobic metabolism as a consequence of increased
circulating epinephrine and inflammatory proteins. The
relative contribution of hypoxic and non-hypoxic causes of
hyperlactatemia has not been fully defined in this cir-
cumstance. Irrespective of the etiology, early-onset hyper-
lactatemia should be considered a potent biomarker of
adverse outcome.
Ranucci and colleagues demonstrated that hyperlacta-
temia (>3 mmol/L) during CPB was associated with higher
postoperative IABP usage, longer duration of ICU stay,
and longer postoperative mechanical ventilation (2). Inde-
pendent predictors of developing hyperlactatemia included
longer CPB duration and reduced oxygen delivery (DO2)
during CPB. Peak lactate increased sharply when DO2 fell
below about 250 mL/min/m2, although data were insuffi-
cient to provide a critical cutoff value (Figure 2).
In another study, Ranucci and colleagues demonstrated
that a DO2 < 272 mL/min/m2 and a nadir hematocrit of
26% were predictive of postoperative renal failure in
patients undergoing coronary artery bypass surgery (47).
Various tissues have been implicated as sources of lac-
tate during CPB including the heart, the lungs, the gas-
trointestinal tract, and skeletal muscle (1). In particular,
elevated myocardial lactate levels are strongly associated
with postoperative cardiac dysfunction (48,49). However,
although it is possible to identify increased production of
lactate in specific organs, it is less clear which of these is
primarily responsible for elevated blood lactate levels.

LATE-ONSET HYPERLACTATEMIA

Within the first 6–12 hours of ICU admission, 15–20% of

cardiac surgical patients also develop de novo hyperlacta-
temia. This, so-called, “late-onset hyperlactatemia” is char-
acterized by normal cardiac output and an absence of
impaired tissue oxygen delivery (14,15,21). The condition
typically spontaneously resolves within 24 hours. Tissue
lactate and pyruvate levels increase proportionally to blood
lactate levels resulting in a relatively normal tissue L/P ratio
(15). Importantly, late-onset hyperlactatemia is associated Figure 2. Peak arterial blood lactate values during CPB according to
with a benign postoperative course. In the study by Maillet the CPB duration, the lowest oxygen delivery, and the peak blood glu-
cose. Data are shown as rolling deciles (75% overlapping). Symbols
and colleagues outlined earlier, late-onset hyperlactatemia (open boxes) represent the mean value recorded for each decile (from
was associated with a mortality of 3.6% compared to 14.9% Ranucci et al.,2 Figure 1 with permission).

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14 J. MINTON AND D.A. SIDEBOTHAM

for patients with early-onset hyperlactatemia and 1.5% for warrants a careful search for evidence of mesenteric ische-
patients with a normal lactate (16). A similarly benign course mia or sepsis.
for late-onset hyperlactatemia has been identified by other
investigators (14,41).
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