CASE CONFERENCE

Linda Shore-Lesserson, MD
Mark A. Chaney, MD
Section Editors

CASE 52009
Severe Lactic Acidosis During Cardiac Surgery
Sung (Jason) Chi, MD,* Erica Stein, MD,* Mark A. Chaney, MD,*
Marco Ranucci, MD, and Michael H. Wall, MD, FCCM

ACTIC ACIDOSIS IS A metabolic acidosis that occurs as

a result of elevated serum L-lactate levels. It is classified
according to the presence or absence of associated tissue hypoxia. In type-A lactic acidosis, impaired tissue oxygenation
leads to increased anaerobic metabolism and an excessive
production of pyruvate (which is then converted to lactate).
Shock, hypoxia, heart failure, and/or hypovolemia are common
causes of type-A lactic acidosis. Type-B lactic acidosis is
characterized by an absence of overt tissue hypoxia; causes
include toxin-induced impairment of cellular metabolism (cyanide, metformin, anti-HIV medications), thiamine deficiency,
malignancy, alcoholism, and liver failure.
Patients who undergo cardiac surgery are at risk of developing tissue hypoperfusion. Cardiopulmonary bypass (CPB) is a
highly unphysiologic state that induces a profound systemic
inflammatory response that can impair tissue oxygenation and
extraction and cause both a decrease in lactate clearance and an
increase in lactate production.1 Hypothermia, rewarming, ischemia-reperfusion injury, and gut-derived endotoxemia are all
potential contributors to tissue hypoperfusion. In addition, the
use of vasoconstrictors, somewhat common during the perioperative period, also may contribute to tissue hypoperfusion. For
example, epinephrine has been shown to impair tissue oxygenation in septic shock2-5 and has been associated with lactic
acidosis in cardiac surgery patients after exposure to CPB.5
Furthermore, vasopressin may induce significant reductions in
splanchnic microcirculatory blood flow during septic shock.6
An elevated lactate level during cardiac surgery presents a
unique diagnostic dilemma. Abnormal lactate levels may be
secondary to factors inherent to cardiac surgery (CPB, inflammatory response, and use of vasoconstricting drugs) or pathologic processes (global hypoxia, shock, and hypovolemia).
Distinction between these causes is of great clinical importance
because efforts then can be made to diagnose and treat pathologic processes. A case report of a patient who was found to
have severely elevated lactate levels during the course of a
cardiac surgical procedure is presented.
CASE REPORT*

A 32-year-old man (173 cm and 113 kg) with severe dilated

cardiomyopathy and a biventricular assist device (BiVAD)
presented for orthotopic heart transplantation. The patients
past medical history was significant for severe idiopathic dilated cardiomyopathy (left ventricular ejection fraction 16%),

*S. Chi, E. Stein, and M.A. Chaney

severe mitral regurgitation, severe tricuspid regurgitation, pulmonary hypertension, ventricular fibrillation/cardiac arrest (before BiVAD insertion), hyperlipidemia, gout, and heparin-induced thrombocytopenia (HIT) diagnosed at an outside
hospital. The Thoratec BiVAD (Thoratec Corp, Pleasanton,
CA) was inserted 4 months earlier. The patient also had an
automated implantable cardioverter-defibrillator and previous
inguinal hernia repair. Preoperative medications included warfarin, colchicine, allopurinol, ezetimibe/simvastatin, senna,
and docusate. The patient was alert, oriented, and did not have
any focal neurologic deficits. Preoperative laboratory values
were all within normal range except hemoglobin (8.4 gm/dL),
serum creatinine (1.5 mg/dL), international normalized ratio of
4.5, prothrombin time of 45.5 seconds, and partial thromboplastin time of 102.9 seconds.
The patient was brought into the operating room. Monitors
included electrocardiogram, pulse oximetry, continuous blood
pressure via a right radial arterial catheter, and central venous
pressure and pulmonary artery pressure via a pulmonary artery
catheter. Before the induction of general anesthesia, the heart
rate was 105 beats/min (sinus rhythm), blood pressure was
130/50 mmHg, and the flow rates for the right-ventricular assist
device and left-ventricular assist device were 5.3 L/min and 5.9
L/min, respectively. The patient was premedicated with intravenous (IV) midazolam (1 mg), and general anesthesia was
then induced with etomidate (20 mg IV), fentanyl (250 g IV),
and succinylcholine (100 mg IV) without hemodynamic compromise. Direct laryngoscopy was performed, and the trachea
was intubated without difficulty. General anesthesia was maintained with isoflurane (0.4-0.8 minimum alveolar concentration) and supplemental fentanyl (750 g IV). Before the start of
CPB, aminocaproic acid (loading dose 5 g IV, infusion 1g/h)
and IV alprostadil (0.05 g/kg/min) were started. An initial

From the *Department of Anesthesia and Critical Care, University

of Chicago, Chicago, IL; Department of Anesthesia and Intensive
Care, IRCCS Policlinico S. Donato, Milan, Italy; and Department of
Anesthesiology, Washington University School of Medicine, St
Louis, MO.
Address reprint requests to Mark A. Chaney, MD, Department of
Anesthesia and Critical Care, University of Chicago Medical Center,
5841 South Maryland Avenue, MC 4028, Chicago, IL 60637. E-mail:
mchaney@dacc.uchicago.edu
2009 Elsevier Inc. All rights reserved.
1053-0770/09/2305-0022$36.00/0
doi:10.1053/j.jvca.2009.05.025
Key words: lactic acidosis, cardiac surgery

Journal of Cardiothoracic and Vascular Anesthesia, Vol 23, No 5 (October), 2009: pp 711-719

711

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CHI ET AL

arterial blood gas analysis showed a hemoglobin level of 6.8

g/dL and slightly elevated lactate level (1.89 mmol/L).
A median sternotomy was performed. During surgical exposure, the patient was transfused with 3 units of packed red
blood cells and 2 units of fresh frozen plasma, secondary to
increased bleeding from the sternal edges and generalized coagulopathy from preoperative anticoagulation. Hemodynamics
remained stable (heart rate 80 beats/min, mean arterial
pressure 55-70 mmHg, and BiVAD flows 5.3-5.9 L/min)
with volume administration and initiation/titration of IV norepinephrine infusion (0.03-0.05 g/kg/min). Systemic anticoagulation with activated coagulation time guided heparinization (heparin 30,000 units IV: ACT 642 seconds) was
achieved, CPB was begun, and the right- and left-ventricular
assist devices were weaned.
Upon initiation of CPB, arterial blood gas analysis revealed
a mixed metabolic and respiratory acidosis (pCO2 54
mmHg), and the serum lactate level was 7.64 mmol/L. During
CPB, anesthesia was maintained with inhaled isoflurane and IV
midazolam (10 mg). The mean arterial pressure was maintained
between 60 and 70 mmHg using a norepinephrine infusion
ranging from 0.03 to 0.10 g/kg/min. IV vasopressin (4 units)
also was required within the first hour of CPB followed by a
continuous infusion (20 mU/min) for approximately 30 minutes
to maintain an adequate mean arterial pressure. While on CPB
(approximately 4 hours), arterial blood gas analysis was performed every 30 to 60 minutes, and analysis revealed progressively rising serum lactate levels (Table 1). During this time,
the surgeon noted the abdomen to be soft, with peripheral
perfusion seeming reasonable, with a wide pulse pressure.
Separation from CPB was accomplished with IV dobutamine
(5 g/kg/min) and IV dopamine (1 g/kg/min) in addition to
the IV norepinephrine (0.05-0.10 g/kg/min) infusion, which
had been initiated before CPB (and maintained during CPB).
Protamine (400 mg IV) then was administered. Because of the
patients ongoing clinical coagulopathy, multiple blood products were given including 3 units of packed red blood cells, 4
units of fresh frozen plasma, autologous salvaged cell-saver
blood, and recombinant factor VIIa (3.6 mg IV). Because the
patients urine output had been minimal (97 mL in 10.5 hours),
a femoral Quinton catheter (Covidien, Mansfield, MA) was
inserted in anticipation of postoperative dialysis. Once the
patients sternal wound was closed, he was transferred to the
cardiac surgical intensive care unit (ICU), with IV infusions of
norepinephrine (0.07 g/kg/min), dobutamine (5 g/kg/min),
dopamine (1 g/kg/min), and vasopressin (40 mU/min) to
maintain adequate hemodynamics (heart rate 110-120 beats/
min and mean arterial blood pressure 60-90 mmHg).
In the initial postoperative period, the patient was aggressively fluid resuscitated with blood products and colloid to
maintain hemodynamic stability. It was then noted that the

patient was having high chest tube output and decreasing mean
arterial pressure despite increasing inotropic and vasopressor
infusions (dobutamine, 10 g/kg/min; dopamine, 5 g/kg/min;
norepinephrine, 0.28 g/kg/min; and vasopressin, 40 mU/min)
and the addition of an IV epinephrine (0.05 g/kg/min) infusion. The serum lactate levels continued to rise (initial ICU
arrival, 22.6 mmol/L; 8 hours later, 33.6 mmol/L).
The patient was emergently taken back to the operating room
approximately 12 hours into the postoperative period for exploration of the chest and abdomen to evaluate the severe
bleeding, hemodynamic instability, and significant lactic acidosis. The chest was initially explored, and no significant
pericardial tamponade or specific bleeding source was identified. Because of the increasing serum lactate, an exploratory
laparotomy was performed and the patient was found to have
profound cholecystitis with an acutely perforated gallbladder.
After cholecystectomy and abdominal cavity lavage, there were
dramatic improvements in coagulation and hemodynamic stability. Once the sternum and abdomen were closed, the patient
was transferred to the cardiac surgical ICU on dobutamine (5
g/kg/min), dopamine (1 g/kg/min), norepinephrine (0.33
g/kg/min), and vasopressin (40 mU/min) infusions with improved hemodynamics. Lactate levels subsequently decreased
dramatically (initial ICU arrival, 20.7 mmol/L; postoperative
day 1, 11.6 mmol/L; and postoperative day 5, 2.9 mmol/L).
After surgery, the patient had a prolonged ICU course. He
remained intubated and required hemodynamic support with
dobutamine, dopamine, norepinephrine, vasopressin, and an IV
bicarbonate infusion and hemodialysis. Total parenteral nutrition was initiated, along with immunologic agents (antirejection medications). During the patients ICU course, he was
treated with multiple antibiotics for Citrobacter freundii bacteremia. On postoperative day 13, the patient became hemodynamically unstable, with increased abdominal drainage and was
found to have a perforation of the sigmoid colon. Subsequently,
a sigmoidectomy was performed at the bedside in the ICU.
Three days later, the patient was able to be transported to the
operating room for completion of a total abdominal colectomy
with ileostomy. When the patient was in the operating room, it
was noted that there were multiple skin changes of the abdominal wall and lower extremities. These skin changes worsened
over the next 72 hours, and the patient was taken back to the
operating room for debridement of necrotic tissue. In the operating room, multiple skin and muscle biopsies revealed fungus. At that point, it was evident that if all the affected skin and
muscle were removed, the patient would not be able to survive.
After discussion with the patients family, they agreed not to
proceed, and the patient was taken back to the ICU. Later that
day, the family decided to withdraw support, and the patient
passed away from septic shock and multiorgan failure.

Table 1. Serum Lactate Levels

Time
pH
Lactate (mmol/L)

13:46
7.53
1.89

15:35
7.27
7.64

16:28
7.32
11.4

NOTE. CPB initiation time: 1520; CPB separation time: 1901.

17:26
7.27
12.8

18:21
7.20
16.9

18:52
7.23
17.8

19:13
7.10
19.4

20:20
7.19
20

21:24
7.20
20

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713

DISCUSSION

Lactic acid is produced from pyruvic acid in a reaction

catalyzed by lactate dehydrogenase. Lactic acid is rapidly buffered by extracellular bicarbonate, producing lactate. A normal
individual produces 15 to 20 mmol/kg of lactate daily, mostly
via glycolysis. Lactate is metabolized efficiently by the liver
(with some contribution by the kidneys), and normal serum
lactate levels are less than 2 mmol/L. An increase in serum
lactate can be caused by diminished tissue perfusion and oxygen delivery, impaired oxygen extraction, and/or decreased
lactate clearance.
Lactic acidosis is classified as type A or type B. In type A,
tissue hypoperfusion and hypoxia initiate decreased oxidative
phosphorylation, causing a conversion to anaerobic metabolism
in the form of glycolysis, which produces energy in the form of
NAD and ATP while converting glucose to pyruvate. Pyruvate is then converted to lactate in a reaction catalyzed by
lactate dehydrogenase; concomitantly, NADH is converted to
NAD. Hypoxia also causes an underutilization of NADH,
resulting in increased conversion of pyruvate to lactate. These
processes ultimately result in the production of excess lactate.
Any clinical state in which oxygen supply is insufficient for
oxygen demand can result in anaerobic metabolism and, potentially, lactic acidosis. Examples include intense exercise,
grand mal seizure, shock, heart failure, sepsis, and carbon
monoxide poisoning. Ischemia of an isolated organ also can be
an important cause of lactic acidosis, even in the context of
apparently normal systemic perfusion pressures. Intestinal ischemia is an important example of this phenomenon. Type-B
lactic acidosis is characterized by an absence of tissue hypoxia.
Examples include drug-induced or toxin-mediated cellular impairment (metformin, cyanide, nitroprusside, ethanol, methanol, and antiretroviral medications), malignancy, alcoholism,
and inborn errors of metabolism. In contrast to type-A causes,
the precise pathogenesis of the type-B lactic acidoses is not
entirely clear. Possible etiologic contributors include inactivation of pyruvate dehydrogenase by endotoxins and drug-induced mitochondrial dysfunction.
The liver has a very high intrinsic capacity to metabolize
lactate, making it unlikely that simple overproduction of lactate
is the sole cause of elevated serum lactate levels. Indeed, an
infusion of lactic acid into healthy dogs is associated with
increased hepatic metabolism of lactate.7 Conversely, lactic
acidosis induced by hypoxia is associated with decreased hepatic lactate clearance, a finding that is likely related to both
decreased liver oxygen uptake and decreased hepatocellular
intramucosal pH (pHi).7 In clinical shock states, hepatic hypoperfusion and coexisting acidosis may combine to significantly
decrease lactate metabolism in the liver.
This case describes a patient who was found to have lactic
acidosis while undergoing orthotopic heart transplantation.
Lactic acidosis during cardiac surgery is not uncommon. One
retrospective review of 1,376 patients found elevated lactate
levels during CPB in 18% of patients.8 Patients who had lactate
levels greater than 4.0 mmol/L had significantly longer durations of CPB, lower hemoglobin values during CPB, and an
increased risk of postoperative morbidity and mortality.8 A
study of 112 consecutive patients undergoing CPB and cardiac

surgery found 16 patients who developed significant lactic

acidosis (arterial lactate greater than 5.0 mmol/L).9 These patients had significantly longer durations of CPB and significantly greater levels of intraoperative hypothermia, yet the
lactic acidoses resolved uneventfully in all patients.9 A study of
patients undergoing valvular heart surgery found that elevated
lactate levels were associated with higher New York Heart
Association class, longer duration of CPB, mechanical ventilation, and inotropic support.10
Cardiac surgery has several unique aspects that may put
patients at particular risk for lactic acidosis. CPB seems to be
an important contributor to lactate production, inducing a profound systemic inflammatory response that may contribute to
hypoperfusion and impaired oxygen extraction. Alterations in
microvascular perfusion during CPB result in various pathophysiologic derangements including the production of vasoactive mediators, activation of complement, kinin, cytokine and
inflammatory cascades, changes in endothelial permeability,
neutrophil activation, and oxygen radical production.
The splanchnic circulation may be at particular risk during
the perioperative period. Hypoperfusion of the gut mucosa (as
evaluated by intramucosal acidosis) is common during major
surgery, with an incidence of 24% to 62%.11 In addition, CPB
is an important cause of impaired splanchnic perfusion.8,12
Intestinal ischemia and increased intestinal production of lactate have been found during CPB.11-13 Nonpulsatile CPB causes
the release of large quantities of angiotensin II, which is a
potent selective splanchnic vasoconstrictor.14 CPB also causes
impairment of gut-barrier function and increased permeability
to endotoxin; decreases in gastric pHi are proportional to the
duration of CPB.15 Splanchnic ischemia also can increase gut
permeability to endotoxin, resulting in endotoxemia with consequent mismatch of oxygen supply and demand and oxygen
extraction impairment.15 However, it is not clear whether increased permeability to endotoxin and mucosal acidosis are
causally related or are independent markers of injury to gut
epithelium secondary to hypoperfusion.15 Furthermore, endotoxin can inactivate pyruvate dehydrogenase, causing increases
in lactate unrelated to tissue oxygenation.16 CPB, the inflammatory response, gut-derived endotoxemia, and splanchnic hypoperfusion all contribute to an increased risk of elevated
lactate levels even in the presence of normal oxygenation and
circulation.
If maintenance of hemodynamic stability does not necessarily ensure adequate splanchnic perfusion, how can splanchnic
perfusion be monitored? Gastric pHi has been proposed as a
monitor of tissue perfusion in critically ill patients. However,
Bohrer et al17 found that pHi was not helpful in predicting the
likelihood of survival in post cardiac surgery patients who had
low-output syndrome. Gastric pHi and pCO2 have been studied
as markers of splanchnic perfusion and oxygenation. However,
the correlation between these markers and splanchnic blood
flow and oxygen delivery is not consistent, and there is no
evidence of benefit for the use of these markers in patients with
shock.18,19 Monitoring of the gastric mucosal pHi and pCO2 is
also hampered by various technical shortcomings.19 Further
research is needed in the development of sensitive and specific
markers of splanchnic perfusion.

714

The use of catecholamines is common in the perioperative

period, particularly in the cardiac surgical patient. Epinephrine
can improve cardiac output and systemic oxygen delivery, but
it also can induce anaerobic metabolism, worsen tissue hypoxia, and cause lactic acidosis.2-4 Epinephrine causes an increase in lactate levels in healthy volunteers.20 In a study of 8
patients with sepsis,3 epinephrine in doses equal to dobutamine
and norepinephrine had almost identical effects on global hemodynamics and oxygen transport parameters but different
effects on splanchnic perfusion and oxygenation. Patients in the
epinephrine group showed decreased splanchnic oxygen consumption, decreased gastric pHi, and increased lactate levels.3
This study shows that regional hypoxia may not be detectable
by systemic parameters. In a prospective study that compared
epinephrine with norepinephrine, epinephrine was associated
with reversible lactic acidosis in patients undergoing cardiac
surgery.5 Patients were randomized to receive epinephrine or
norepinephrine for post-CPB hemodynamic support. Six of 19
patients in the epinephrine group developed reversible lactic
acidosis, whereas none of the 17 patients randomized to the
norepinephrine group developed lactic acidosis.5 Other studies
suggest that epinephrine may be more likely to cause lactic
acidosis than norepinephrine.2,3,21 Epinephrine enhances glycogenolysis with a net increase in pyruvate production.22 This
effect is mediated through the following mechanisms: -2
receptor stimulation, inhibition of pyruvate dehydrogenase, and
enhancement of lipolysis, which inhibits pyruvate oxidation.1
Indeed, epinephrine-induced lactic acidosis may be a distinct
clinical phenomenon.23
Vasopressin is another vasoconstrictor that is often used
perioperatively in cardiac surgery. Its potent vasoconstrictive
action makes it a popular and useful agent for hemodynamically unstable patients. However, vasopressin has some unfavorable properties, particularly with respect to the splanchnic
circulation. It can reduce gastrointestinal perfusion,24 cause
ischemic injury to the gastrointestinal tract,25,26 reduce portal
and gut mucosal blood flow, and reduce splanchnic oxygen
delivery.20 Vasopressin has been associated with decreased
superior mesenteric artery flow and microcirculatory blood
flow in a pig model of septic shock6 and decreased ileal
mucosal blood flow in a rat model of septic shock.27 Compromised splanchnic circulation, even in the presence of an apparently adequate systemic circulation, can lead to excessive production of lactate.
This case shows some of the diagnostic difficulties that are
encountered in a patient who has elevated lactate levels during
cardiac surgery. As noted, a certain percentage of patients
undergoing cardiac surgery can be expected to have abnormal
but transient elevations in lactate. The present patient had
markedly elevated lactate levels that continued to increase after
the surgical procedure and termination of CPB. The abnormal
lactate levels led to subsequent abdominal exploration, which
revealed an infected and perforated gallbladder, which was the
definitive etiology of the patients septicemia, hemodynamic
instability, and lactic acidosis.
A possible contributing factor in the pathogenesis of this
patients lactic acidosis was the use of vasoconstricting agents,
specifically epinephrine and vasopressin. Epinephrine and vasopressin have been associated with compromised gut mucosal

CHI ET AL

perfusion and maldistribution of blood flow to the splanchnic

circulation despite improvements in systemic circulation parameters. This patient was started on epinephrine and vasopressin infusions in the postoperative period after the lactate had
already been noted to be substantially elevated. Given this
sequence of events, it seems unlikely that the use of vasoconstricting agents was the inciting event that led to the patients
lactic acidosis, but their adverse effects on splanchnic blood
flow may have had a role in exacerbating any pre-existing
pathology (ie, cholecystitis).
Monitoring of the systemic circulation is routine for all
cardiac surgical procedures, yet routine monitoring of the
splanchnic circulation is uncommon. Modalities such as gastric
mucosal pCO2 and pHi have been studied, yet a lack of consistent correlation with other clinical parameters and technical
difficulties has limited their introduction to clinical practice.
Standard monitoring modalities (eg, arterial blood pressure,
pulse oximetry, and mixed venous saturation) apparently do not
reflect the adequacy of splanchnic circulation and oxygenation.
This situation is unfortunate because the splanchnic circulation
is at particular risk for perfusion abnormalities during cardiac
surgery,8,12,13 and elevated lactate levels during CPB may identify a subgroup of patients at an increased risk of morbidity and
mortality.8 In addition, it is unclear which pharmacologic or
anesthetic strategies can be used to selectively enhance gut
perfusion during the perioperative cardiac surgical period.
These important clinical questions provide ample opportunity
for further clinical research.
Despite these shortcomings, the evaluation of lactic acidosis
in a patient undergoing cardiac surgery should proceed in a
stepwise and sensible fashion. Systemic oxygenation and circulation should be optimized, and major possible causes such
as nitroprusside toxicity, liver failure, and/or sepsis should be
investigated. Potential abdominal pathologies also should be
considered. Transient lactate elevations during CPB are not
uncommon, and the majority of the patients with these elevations have similar outcomes to the rest of the cardiac surgical
population.
COMMENTARY 1

Lactic acidosis is a relatively frequent phenomenon during

and after cardiac operations. In a recent study,28 this condition
was identified in about 6% of the patients during CPB, but other
studies found higher rates in the range of 25%.8 Maillet et al29
found that 21% of the patients after cardiac surgery had hyperlactatemia (HL) immediately on arrival to the ICU, indirectly
confirming that this phenomenon started during the operation.
In the same study, late HL (developing in the ICU) was found
in 17% of the patients. HL during CPB was invariably associated with a worse outcome in these studies.8,28,29 Patients manifesting this condition had prolonged mechanical ventilation
and ICU stay; higher rates of intra-aortic balloon pump use and
major morbidity28; higher rates of pulmonary, cardiac, neurologic, renal, and digestive complications; a higher mortality
rate8; prolonged mechanical ventilation, ICU stay, and hospital
stay; and a higher rate of major morbidity.29 Late HL during the

M. Ranucci

CASE 52009

ICU stay was associated with a lower degree of postoperative

complications.29
HL is a complex condition, which may result from several
mechanisms. Type-A HL is defined as impaired tissue oxygenation leading to increased anaerobic metabolism and an excessive production of pyruvate (which is then converted to lactate).
Under normal resting conditions, oxygen delivery matches
overall metabolic demands of the organs, oxygen consumption
is about 25% of oxygen delivery, and energy is produced
mainly through aerobic mechanisms (oxidative phosphorylation). When oxygen delivery starts decreasing (because of a
decreased cardiac output, extreme hemodilution, or both), oxygen consumption is maintained until a critical level is
reached.30 Below this critical point, oxygen consumption starts
decreasing, becoming dependent on oxygen delivery, and failing aerobic energy production is progressively replaced by
anaerobic ATP production (pyruvate conversion to lactate). As
a result, blood lactate concentration increases, and numerous
studies have established the use of lactate level as a marker of
global tissue hypoxia in circulatory shock.31 Under these circumstances, anaerobic metabolism results in excess proton
production and tissue acidosis; buffering of protons by bicarbonate ions then results in anaerobic carbon dioxide production. In contrast, type-B HL is dependent on a number of
factors not directly related to tissue dysoxia, basically representing the inability of the peripheral tissues to use oxygen.
Lactate concentration depends on the balance between production and elimination (by the liver). However, kinetics of
lactate clearance depends on the production rate because hepatic clearance appears to be preserved even during cardiogenic
shock.32 However, in conditions of severe splanchnic hypoperfusion, hepatic blood flow declines, liver capacity to use lactate
is decreased, and the liver itself may become a producer of
lactate.32 HL is almost invariably associated with hyperglycemia during postoperative cardiogenic shock after cardiac surgery,32 a consequence of increased concentrations of plasma
cortisol and glucagon. Moreover, during severe sepsis and
cardiogenic shock, insulin resistance may develop, which favors glycolysis and glucose-lactate cycling.33 Lactate itself may
be converted to glucose through the Cori cycle.33 Lastly, during
CPB, there is a direct correlation between peak blood glucose
levels and peak blood lactate concentration.28
Endogenous or exogenous catecholamines may induce or
worsen HL, and experimental studies show that epinephrine
may cause an increase in lactate plasma concentration to a
greater extent than norepinephrine. Vasopressin also may induce splanchnic vasoconstriction. In summary, catecholamines
may certainly increase total oxygen delivery by improving
cardiac output but often at the expense of a severe regional
maldistribution of flow.
CPB represents a convenient model for addressing the important issue of oxygen delivery under critical conditions.
Blood flow can be measured accurately, and the presence of
different degrees of hemodilution creates experimental conditions for assessing the effects of low levels of oxygen delivery.
In a recent investigation,28 the authors analyzed the role of
hemodilution and oxygen delivery in determining HL during
CPB. Both the lowest hematocrit on CPB and the lowest
oxygen delivery on CPB, if separately analyzed, were found to

715

be associated with peak levels of lactate. However, in multivariable analysis, only the lowest oxygen delivery was found as
an independent predictor of HL. The critical oxygen delivery
for the onset of HL was identified in this study to be 270 mL/
min/m2. This value was lower than the one identified in critically ill patients (around 320 mL/min/m2); however, this could
be explained by the lower oxygen requirements under conditions of general anesthesia and mild hypothermia. At the usual
range of pump flow during cardiac operations (2.4-3.0
L/min/m2), this critical value is reached at hemoglobin levels
of 6.5 to 8.0 g/dL, depending on pump flow. Below this
level, lactate concentration and blood glucose concentration
increase, showing a pattern attributable to type-A HL. Under
these conditions, anaerobic production of carbon dioxide
increases, and, in a recent study, the authors showed that this
increased carbon dioxide production is a marker for hyperlactatemia during CPB conditions.34
This interesting case deals with a patient receiving an orthotopic heart transplant after being implanted for 1 month with a
biventricular-assist device. Immediately after CPB initiation,
the blood gas analysis showed a mixed respiratory and metabolic acidosis and increased serum lactate concentration. During and after CPB, the patient required the extensive use of
vasoconstrictors to maintain an acceptable blood pressure. Lactate increased throughout CPB, and the patient reached the ICU
with extremely elevated values (22 mmol/L and then 33
mmol/L after 8 hours). The patient underwent surgery after 12
hours, and a perforated gallbladder was found. He subsequently
recovered but suffered from sigmoid colon perforation after 13
days followed by systemic fungal infection, leading to death.
From the case description, it is very likely that the initial
phase of the pathologic chain of events finally leading to death
started during CPB. As the authors correctly point out in their
Discussion, splanchnic organs may be at particular risk for
underperfusion during CPB. This was shown for the kidney,
where an oxygen delivery below 270 mL/min/m2 during CPB
may be associated with acute renal failure35 and gut mucosa
and liver may be at risk as well. One interesting point is that
this patient had a large body surface area (2.3 m2) and arrived
in the operating room with anemia (hemoglobin 6.8 g/dL).
He also suffered from blood loss during the early phases of the
operation and received 3 units of packed red blood cells. Even
accounting for this transfusion, because of the large body
surface area and the blood loss, he certainly entered CPB with
a low hemoglobin value and because of hemodilution probably
experienced a low hemoglobin value during CPB (probably
around 6.0 g/dL; these data are lacking in the article). This
means that even accounting for a very large pump flow (3.0
L/min/m2), the oxygen delivery was certainly below the critical
value of 270 mL/min/m2, at least for some time during CPB.
Moreover, it was a very long pump run (approximately 4 hours)
because of the complexity of the procedure. It has been shown
that CPB duration is one of the determinants of HL.8,28 Finally,
the patient was in need of substantial doses of vasoconstrictors
(norepinephrine and vasopressin) during and after CPB. As
already mentioned, this is another factor possibly leading to
HL. No information is available regarding blood glucose concentration during CPB.

716

This commentators interpretation, in agreement with the

authors, is that this patient probably suffered from splanchnic
hypoperfusion as a result of a low oxygen delivery because of
severe hemodilution during CPB, exacerbated by the use of
vasoconstrictors. This ischemic condition may have initiated
the gallbladder perforation and subsequent sigmoid colon perforation. Gallbladder perforation because of ischemia is a rare
condition, but a pre-existing inflammatory disease of the gallbladder cannot be excluded and may have represented an
additional risk factor. It is even possible that the gut mucosa
may have suffered the same insult. Gut mucosa hypoperfusion
leads to bacterial and endotoxin translocation, which may have
been responsible for the profound vasodilation observed. The
sigmoid colon perforation occurred many days after the operation, and it is difficult to hypothesize a clear relationship
between poor splanchnic perfusion during CPB and this late
event.
An interesting finding was the elevated pCO2 values during
the first arterial blood gas analysis while on CPB. The authors
attributed this to a mixed metabolic and respiratory acidosis.
Actually, it is very unlikely that the pump oxygenator was
unable to clear the normal levels of carbon dioxide produced
under aerobic conditions. This may happen only in cases of
extremely high levels of carbon dioxide production. Tissue
dysoxia and anaerobic metabolism are responsible for increased anaerobic carbon dioxide production as a result of
bicarbonate buffering of lactic acid. Under these conditions, the
venous carbon dioxide tension increases, and it has been shown
that the venoarterial pCO2 difference is a marker of anaerobic
metabolism. During CPB, values of carbon dioxide production
higher than 60 mL/min/m2 are predictive of HL.34 Therefore, it
is likely that the elevated pCO2 values detected might have
been a marker of anaerobic metabolism and tissue dysoxia
rather than respiratory acidosis. All these factors, considered
together, make it very likely that this patient suffered from
inadequate oxygen delivery during CPB, developed splanchnic
hypoperfusion, and manifested this condition with type-A HL.
As the authors point out in their Discussion, this raises the
important issue of splanchnic perfusion adequacy monitoring
during CPB. I agree with the authors that this is lacking during
daily clinical practice and that the measurement of gastric
mucosa pCO2 and/or pHi is far from a reliable monitor.
In conclusion, hyperlactatemia after cardiac surgery may be
relatively benign when it occurs during the ICU period (late
HL). In this type of HL, it is often the result of the rewarming
phase, with reperfusion of peripheral tissues and the release of
lactate formed and trapped in these areas. Conversely, HL
occurring during CPB should never be underestimated. It is
constantly accompanied by different degrees of bad outcomes
and often is a marker of poor perfusion (mainly at the level of
the splanchnic circulation). Although the moderate increase in
lactate (up to 3-4 mmol/L) observed during prolonged CPB,
especially during the rewarming phase, is not usually associated with major postoperative morbidity, the finding of severe
HL (and especially constantly increasing values) should always
be considered as a significant problem. Every attempt should be
made to improve oxygen delivery during CPB, and, in the
presence of severe hemodilution, the pump flow should be
increased to counteract the low oxygen content. Severe he-

CHI ET AL

modilution should always be avoided, and the use of adequate

techniques (reduced priming volume, retro-prime, blood cardioplegia, ultrafiltration) may help, particularly in cases of
preoperative anemia. The use of blood transfusion may be
advocated in severe cases, but this point is still a matter of
concern, considering the deleterious effects that allogeneic
blood products may induce. Despite this, clinicians must be
aware that even in the presence of adequate signs of oxygen
delivery during CPB, regional maldistribution of flow may
occur as the result of peripheral microembolism and of critical
obstructions of the mesenteric vessels. Indeed, peripheral vascular disease has been identified as an independent preoperative
predictor of gastrointestinal events after cardiac surgery in a
recent study.36 Therefore, at this time, many factors determining spanchnic complications are beyond monitoring and treatment possibilities.
COMMENTARY 2

This case is representative of what clinicians are seeing more

commonly every day, incredibly high-risk patients undergoing
high-risk surgery. In fact, using the Euroscore, the predicted
mortality of this patient was 57.5% (euroscore.org). The patient
developed severe lactic acidosis intraoperatively, intra-abdominal sepsis postoperatively, and multiple organ failure, and
eventually care was withdrawn on postoperative day 19. Although there are multiple interesting topics in this case, this
author is going to focus mainly on lactic acidosis and then
briefly on the management of patients with HIT for urgent/
emergent surgeries and the use of factor VIIa in cardiac surgery.
Blood lactate concentration is regarded by many as the
simplest marker of tissue dysoxia in the intensive care unit. The
trouble with simple things, however, is that one must understand them very well. The interpretation of blood lactate . . . is
not a simple task. Lactate is an enigma.37 Under normal
aerobic conditions, glucose is split into 2 pyruvate molecules
forming ATP and reducing NAD to NADH. Pyruvate is then
transferred into the mitochondria and transfers electrons to
oxygen, producing additional ATP. Under hypoxic conditions,
pyruvate cannot be used in the mitochondria, but instead is
reduced by lactate dehydrogenase to lactate and NAD, which
allows glycolysis to continue. Lactic acidosis (pH 7.35 and
lactate 5.0 mmol/L) that is associated with global ischemia
(ie, cardiogenic shock) or focal ischemia (ie, mesenteric or
limb) has been termed type-A lactic acidosis. Type-B lactic
acidosis also may occur without evidence of tissue ischemia.
This type has been further subdivided into type B1 (caused by
an underlying disease process), B2 (caused by a pharmacologic
or toxic process), or B3 (caused by a metabolic disorder).38
Lactate levels represent a balance of lactate production
(from normal skeletal muscle or processes causing a type-A
or type-B lactic acidosis) and lactate removal. Lactate is
normally used for energy production by the skeletal and
cardiac muscle. It also can be used by the brain. The liver is
very efficient at removing lactate, converting it to glycogen
via the Cori cycle.37,38 The numerous mechanisms of lactate

M.H. Wall

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717

production, consumption, and elimination are what makes

interpretation so difficult.
Lactate production during uncomplicated CPB was noted in
1958 by Clowes et al.39 Numerous other authors have noted
lactate levels up to 10 mmol/L during routine CPB. Lactate
levels greater than 4.0 mmol/L have been shown to be associated with increased postoperative mortality, morbidity, and
infectious complications.8 The cause of the elevation remains
controversial. Some studies have implicated occult hypoperfusion (the splanchnic bed is the most commonly implicated) as
a source of increased lactate production; however, other studies
using gastric tonometry and indocyanine green showed no
evidence of splanchnic hypoperfusion.40
Elevated lactate also may be related to the systemic inflammatory response initiated by CPB. Tumor necrosis factor inhibits pyruvate dehydrogenase, resulting in increased lactate
levels.41 Ryan et al41 showed that patients with genetic polymorphisms resulting in increased tumor necrosis factor production (and decreased interleukin 10 production) all developed
elevated lactate levels (up to 9 mmol/L). Elevated lactate levels
(up to 14 mmol/L) also have been reported after heart transplantation.42 In these patients, lactate levels peaked at 6.4 1.4
hours postoperatively and were normal within 24 hours. There
was a correlation found between peak lactate levels and dose of
inotropic drugs used. Lactate clearance is also decreased during
CPB.1 Epinephrine clearly has been shown to increase lactate
levels (up to 7 mmol/L) after CPB.5 These patients had no
evidence of hypoxia, and it is thought that the increased lactate
levels were caused by the effect of epinephrine on anaerobic
glycolytic enzymes, leading to increased lactate production
without hypoxia.
Multiple studies have evaluated lactate levels in trauma
patients. Patients with lactate levels greater than 2.2 mmol/L on
admission to the ICU exhibit greater morbidity and mortality
than patients with normal lactate levels, and, importantly, patients with elevated lactate levels for longer than 24 hours have
even higher morbidity and mortality.43 Patients whose lactate
remains elevated for longer than 12 hours have increased
infectious complications as well. Because of this, many centers
commonly use lactate as 1 measure of an endpoint of resuscitation.
Lactate also has been extensively studied in sepsis. In patients with septic shock requiring vasopressors, increased lactate levels were associated with a lactate/pyruvate ratio greater
than 10, which suggests a hypoxic mechanism and is associated
with development of multiple organ failure and death.44 Conversely, lactate production also can be increased by certain
mediators of inflammation (tumor necrosis factor) without evidence of hypoperfusion.45 The anatomic location of the increased lactate production in sepsis is controversial, but, in a
study of 90 patients in septic shock, splanchnic lactate release
was uncommon and splanchnic hypoxia was not observed.46
Finally, a comment on vasopressin and vasodilatory shock is in
order. Vasopressin is a potent vasoconstrictor that has been

used as a splanchnic vasoconstrictor to control esophageal

variceal bleeding. Because of this, there is concern that vasopressin may lead to splanchnic ischemia. However, studies
have shown that at doses of 0.04 U/min, mesenteric, renal, iliac,
and carotid arterial flows are maintained and there is no evidence of organ ischemia.26 Vasopressin also has complex effects on the corticosteroid axis and the inflammatory response.
A very recent study showed that the combination of steroids
and low-dose vasopressin decreased mortality and multiple
organ failure in patients with septic shock.47
The patient presented in this case had all of these causes for
increased lactate. However, a level greater than 5 that continued to worsen clearly was not a benign type B process because
of CPB, epinephrine, or the inflammatory response. This led to
further investigations, which in this case was a laparotomy, in
which a source of intra-abdominal sepsis was found. This
author believes that persistent lactate elevations for longer than
12 hours after cardiac surgery or levels greater than 4 mmol/L
should be followed serially and hypoperfusion and hypoxia
must be evaluated and ruled out. If global indices of oxygen
delivery and consumption (ie, urine output, cardiac output/
cardiac index, mixed venous oxygen saturation) are all adequate, then focal causes of hypoxia (gut, limb, and lung) need
to be examined. Remember that the benign, self-limiting
type-B acidosis almost never will cause a lactate greater than
10 mmol/L.
HIT is an increasing problem in cardiac surgery, especially
in patients with mechanical assist devices. Because of this
problem, at Washington University heparin is avoided postoperatively in all of the assist-device patients; direct thrombin
inhibitors are used instead. The most recent American College
of Chest Physicians Evidenced-Based Clinical Guidelines on
Treatment and Prevention of HIT is required reading for all
who care for patients undergoing cardiac (and noncardiac)
surgery.48
Karkouti et al49 recently published a very well-referenced
retrospective review of factor VIIa use in cardiac surgery
patients from 18 centers in Canada. They found factor VIIa is
most likely being used after routine interventions (8 units of
packed red blood cells, 10 units of platelets, 8 units of fresh
frozen plasma on average) failed to control bleeding. Although
concerns regarding thrombotic complications and increasing
the inflammatory response remain, after risk adjustment, this
study did not show an increased risk of complications in
patients who received factor VIIa.
In conclusion, the presented case shows the complexity/
severity of patients presenting for cardiac surgery in major
medical centers. It also showed how the presence of increasing lactate levels during the perioperative period should
always lead to a comprehensive search for the cause of the
increasing levels. Although such searches are often fruitless,
they may lead to a definitive cause (global, focal, drug
induced) and subsequent specific treatment, perhaps allowing clinicians to avoid major morbidity/mortality.

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