Secondary Logo

Journal Logo

Cardiovascular Anesthesiology

Lactate Elevation During and After Major Cardiac Surgery in Adults: A Review of Etiology, Prognostic Value, and Management

Andersen, Lars W. MD, MPH, PhD*†‡§

Author Information
doi: 10.1213/ANE.0000000000001928

Ever since the first successful use of a heart–lung machine for open cardiac surgery in 1953,1,2 there has been an interest in the metabolic changes seen during cardiac surgery and cardiopulmonary bypass.3,4 The underlying disease processes, the stress of the surgery, and the use of cardiopulmonary bypass all contribute to complex metabolic changes, which may include elevation of lactate.5,6 The exact etiology of lactate elevation after cardiac surgery and in other diseases such as sepsis is complex and remains controversial.7–9 The first aim of this review was to provide an overview of the literature considering potential mechanisms for lactate elevation in cardiac surgery patients.

Although the association between elevated lactate and outcomes were described as early as 1964 in patients with undifferentiated shock,10 the association between elevated lactate and outcomes after cardiac surgery has only been rigorously evaluated within the past 2 decades. The second aim of this review was to provide a brief overview of this literature and critically review the prognostic role of lactate elevation in patients undergoing cardiac surgery.

Finally, although the etiology and prognostic role of lactate have been described in a large number of studies, little is known about the optimal management of postcardiac surgical patients with elevated lactate. The third aim of this review was to evaluate the literature on the management of lactate elevation.

METHODS

This review included studies of adult patients undergoing major cardiac surgery, including but not limited to coronary artery bypass grafting, valve repair/replacement, and heart transplant, that assessed the etiology/production of lactate, the prognostic value of lactate, or the management of lactate elevation. A systematic search of PubMed was performed on February 1, 2016 (see Supplemental Digital Content 1, Methods for details on the search strategy, http://links.lww.com/AA/B677). The search was restricted to human studies published in English. Letters, commentaries, editorials, and case reports were not included; nor were pediatric studies.11 The search retrieved 1253 titles and abstracts, which were reviewed by a single reviewer. Of these, 216 full articles were reviewed. In addition, informal searches were performed related to specific topics, and the reference lists of previous reviews11–14 were studied. All studies related to prediction/prognosis and management of elevated lactate were included. For studies related to the causes of lactate elevation, those that were deemed most relevant to the present review were included. No formal criteria, except as noted above, were applied for inclusion of these studies.

FINDINGS

Lactate Metabolism

Figure.
Figure.:
Simplified graphical representation of pyruvate and lactate metabolism. ATP indicates adenosine triphosphate; CoA, coenzyme A; ECT, electron transport chain; LDH, lactate dehydrogenase; NAD, nicotinamide adenine dinucleotide; PDH, pyruvate dehydrogenase; TCA, tricarboxylic acid.

Detailed description of lactate metabolism has been provided previously.7,15 In brief, lactate is produced from pyruvate through a reversible step catalyzed by the enzyme lactate dehydrogenase (Figure). Given that all tissues have capacity for lactate transport, lactate serves as an important fuel for many tissues, including skeletal muscle, the brain, and the heart, and may serve as a signal for various tissues to coordinate certain metabolic processes.12,15–19

Lactate Production During and After Cardiac Surgery

Table.
Table.:
Potential Causes of Lactate Elevationa

In general, lactate elevation can be caused by increased production or decreased clearance/consumption. Cohen and Woods20,21 divided lactate elevation into 2 categories: “type A,” with lactate elevation resulting from circulatory insufficiency (tissue hypoxia), and “type B,” compromising all other types. With some modification to Cohen and Woods’ classification, the sections below are divided into: oxygen delivery, oxygen utilization, increased metabolism, organ-specific release, lactate clearance, medications and fluids, postoperative complications, and finally, a section on preoperative and intraoperative characteristics associated with elevated lactate. An overview is provided in the Table.

Oxygen Delivery.

The relationship between oxygen delivery and lactate has been evaluated in multiple studies.22–30 In a prospective study of 112 patients, Raper et al25 compared patients with a peak lactate of >5.0 mmol/L (16 patients) within the first 24 hours in the intensive care unit (ICU) with those without. They found no difference in mean arterial pressure, cardiac index, oxygen delivery, or oxygen consumption, and concluded that a type B lactate elevation was most likely.25 Similar findings have been reported by other authors.26,27

In a prospective study of 470 patients from 2006, Ranucci et al29 found that the lowest oxygen delivery value during the surgery was associated with peak lactate levels. A lowest oxygen delivery value below approximately 260 mL/min/m2 was especially associated with higher peak lactates.29 Therefore, these authors concluded that lactate elevation during surgery was type A.29 Trekova et al31 estimated that the critical oxygen delivery rate was 350 mL/min/m2 during surgery and found higher lactate values after the surgery in those with an oxygen delivery lower than this threshold.

In summary, it appears that there might be an oxygen delivery–dependent increase in lactate during cardiopulmonary bypass, but that lactate in the postoperative period is less related to oxygen delivery.14

Intact oxygen delivery to the cells is dependent on the macrocirculation and microcirculation, in addition to adequate oxygen content and carrying capacity in the blood. Inoue et al27 found that low mean arterial pressure during the first 30 minutes of cardiopulmonary bypass was associated with increased maximal lactate levels during and after surgery.27 Similarly, Ranucci et al29 found that the lowest pump flow was associated with increased lactate levels during cardiopulmonary bypass, although this association did not remain in multivariable analysis. A few small studies have assessed the association between the microcirculation and lactate.32,33 Although both studies found some impairment in sublingual microcirculation during the surgery, one found no association with lactate levels,32 whereas the other did.33

Although some observational studies have found that lower hematocrits are associated with higher lactates,34–36 a small randomized controlled trial comparing a hematocrit of 25% with a hematocrit of 20% during surgery found no difference in intraoperative or postoperative lactate levels.37

Oxygen Utilization.

Decreased cellular oxygen utilization, a phenomenon also termed “cytopathic hypoxia,”38 refers to an intrinsic defect in cellular respiration at the level of the mitochondria despite adequate oxygen delivery. This concept has been described in sepsis,9,38 but little has been published on this subject in relation to lactate elevation in cardiac surgery. Inoue et al27 found that patients with lactate elevation (>5.0 mmol/L) had lower oxygen extraction during cardiopulmonary bypass compared with those without elevated lactate. This was reversed 6 hours after the surgery, potentially indicating an oxygen utilization defect during cardiopulmonary bypass with development of a cellular oxygen “debt” in these patients.27 However, whether this decreased extraction was attributable to a microcirculatory or a mitochondrial defect is unknown. Other authors have not found differences in oxygen extraction between those with and without elevated lactate.25,28,39

An elevation in lactate could theoretically be caused by a defect anywhere from the enzyme pyruvate dehydrogenase, which converts pyruvate to acetyl-coenzyme A, to the enzymes in the tricarboxylic acid cycle or defects in the electron transport chain (Figure). In a small study, Andersen et al40 found that pyruvate dehydrogenase activity decreased during cardiac surgery. Thiamine, which is an important cofactor for pyruvate dehydrogenase, has also been found to be depleted during cardiac surgery, with lower postoperative thiamine levels associated with higher lactate levels.40,41 Despite this, 2 randomized controlled trials failed to decrease postoperative lactate levels with intravenous thiamine supplementation.42,43

Previous authors have proposed that the systemic inflammatory response seen after cardiac surgery may have a global inhibitory effect on oxygen utilization, thereby playing an important role in lactate elevation.39,44 Although a systemic inflammatory response has been described extensively after cardiac surgery,5,6,45,46 little is known about the association between this response and oxygen utilization and lactate production. Studies have shown no or only weak correlations between interleukin-10 or tumor necrosis factor-β gene polymorphisms and lactate elevation.47,48 Randomized controlled trials of corticosteroids aimed, at least partly, at the inflammatory response have shown mixed results, with decreased lactate levels in the intervention group in one trial49 and no difference in others.50,51 A large trial of dexamethasone found increased lactate levels in the intervention arm potentially as a consequence of increased catecholamine production and hyperglycemia.52

Increased Metabolism.

A hypermetabolic state with increased levels of endogenous catecholamines has been proposed as a potential cause of lactate elevation in sepsis.9,17,19 The increase in lactate is thought to be mediated through β2-receptor stimulation and increased Na+/K+-ATPase pump activity, glycogenolysis, and aerobic glycolysis.9,17,53 Although a hypermetabolic state is present in patients after cardiac surgery,5,6 little is known about the potential causal relationship between these metabolic changes and lactate elevation in this setting.

Organ-Specific Release.

Organ-specific lactate metabolism in healthy humans is complex and has been described in great detail previously.7,15 Under resting conditions, there is, in general terms, a net release of lactate from skeletal muscle, brain, blood cells, and adipose tissue, whereas there is a net uptake in the heart, kidney, and liver, and no or little net production or consumption in the lungs.7,15 However, this may change substantially under pathophysiological conditions.

The literature on myocardial lactate metabolism during cardiac surgery is vast,54–76 and a detailed description is beyond the scope of this review. In general, the heart utilizes lactate before surgery, with a decrease in utilization or an absolute production during surgery, although with wide variability between studies and between patients within studies.

The splanchnic circulation, including the intestine and the liver, has received a lot of attention in relation to lactate production during cardiac surgery,12,44,77–85 and a well-cited review from 1993 concluded that splanchnic ischemia with subsequent lactate production was a significant problem by the end of surgery.86 More recent studies have shown mixed results, finding that normothermic cardiopulmonary bypass is not associated with a decrease in global intestinal oxygen supply,79 that the splanchnic circulation does not contribute to metabolic acidosis,80 that splanchnic blood flow is negatively correlated with hepatic and arterial lactate levels,81 and that rectal luminal lactate correlates with arterial lactate.84 In a study from 2004, Braun et al82 estimated that approximately 20% of mixed-venous lactate is accounted for by lactate leaving the hepatic vein. Although it remains somewhat unclear how much the splanchnic circulation contributes to elevated lactate under normal intraoperative and postoperative conditions, it is clear that bowel ischemia is often accompanied by lactate elevation.87–93

Using microdialysis, Mandak et al94 assessed lactate metabolism in skeletal muscle during and after cardiac surgery. They found that interstitial lactate increases during surgery and remains stable early in the postoperative period.94 An increase in interstitial skeletal muscle lactate during surgery has been confirmed in a number of subsequent studies.44,95–98 A few studies have assessed the association between skeletal muscle tissue oxygenation using near-infrared spectroscopy and lactate levels, with mixed results.99–101

Lactate metabolism in the lung has been assessed in a few studies indicating that the lung is a producer of lactate during surgery.102,103 Lactate production by the brain has not been well studied in this setting. In a small study, Harris et al104 were not able to detect cerebral lactate using magnetic resonance spectroscopy. Dabrowski et al105 found a small increase in brain lactate production during surgery.

Lactate Clearance.

Two studies have directly assessed lactate clearance in the postoperative period by exogenous infusion of lactate.106,107 Chioléro et al106 compared 7 postcardiac surgery patients with cardiogenic shock and high lactates with a group of 7 healthy volunteers. The authors found no difference in lactate clearance between the 2 groups. Contrary to these findings, Mustafa et al107 found that patients after cardiac surgery with cardiopulmonary bypass had decreased lactate clearance, although this decrease was relatively modest, and the authors concluded that “… lactate production increase is probably responsible for a high lactate concentration after cardiac surgery.”

Medications and Fluids.

A number of various medications may be responsible for elevated lactate. These have been described in more detail previously,8 and only those particularly pertinent to cardiac surgery are described here. Metformin has been implicated in the development of elevated lactate. However, a review from 2010 concluded that metformin does not have an impact of postoperative lactate elevation in patients without relevant comorbidities.108 This was confirmed in 2 subsequent randomized controlled trials.109,110 Although these trials cannot rule out rare events, it is unlikely that metformin plays an important role in lactate elevation after cardiac surgery.

Administration of epinephrine may increase lactate levels. In a small, randomized controlled trial from 1997 comparing epinephrine to norepinephrine infusion, Totaro and Raper111 found that patients in the epinephrine group had higher lactate levels. This was accompanied by an increase in glucose levels, supporting increased glycogenolysis.111

Other medications could theoretically affect lactate levels. Nonselective β-blockers could have opposite effects when compared with epinephrine through blockade of β2-receptors, with decreased glycogenolysis and potentially decreased lactate levels.112 The contrary would be true for β2-agonists.8 Propofol has been implicated in the development of lactate elevation, although only with prolonged high-dose use (ie, the propofol infusion syndrome).8,113

Lactate containing fluids such as Hartmann’s solution or lactated Ringer’s solution could theoretically artificially increase circulating lactate levels. In healthy adults, short-term infusion of lactated Ringer’s solution does not increase circulating lactate values,114 although sampling blood from catheters containing lactated Ringer’s solution may.115 A randomized study by Liskaser et al116 found that lactate levels were elevated within the first 30 minutes after cardiopulmonary bypass, when Hartmann’s solution was used as the pump prime.

Postoperative Complications.

A number of postoperative complications may be responsible for elevated lactate levels, such as shock (distributive, cardiogenic, hypovolemic, or obstructive), sepsis, cardiac arrest, or regional tissue ischemia (eg, mesenteric or limb ischemia). These conditions and their relation to lactate elevation have been reviewed in detail previously.8

Preoperative and Intraoperative Characteristics Associated With Elevated Lactate.

Preoperative and intraoperative characteristics associated with elevated postoperative lactate levels have been assessed in a large number of studies.25–29,35,36,39,117–129 Sizeable studies (>1000 patients) have consistently found the duration of cardiopulmonary bypass to be associated with postoperative lactate elevation.35,36,124,125,128,129 Findings are less consistent regarding other characteristics, although complex, acute, or redo surgery,35,36,124,129 low hemoglobin,35,36 renal impairment,35,124,128 low preoperative ejection fraction,35,36 and diabetes124,125 have been associated with elevated lactate. The results regarding the association between age and elevated lactate have been mixed.124,128,129

Limitations of the Literature.

Although the literature on this topic is plentiful, there are important general limitations to consider. First, cause and effect with regard to biological processes is extraordinarily difficult to study in humans. The majority of included studies simply provide assessments of associations between one physiologic process (such as oxygen delivery) and another (such as lactate). The causal pathway is hard to establish. Second, the majority of studies are small and focus on elective, uncomplicated surgery in low-risk patients (often with normal blood lactate levels) or other specific subgroups. This makes generalizability difficult. As such, individual studies should be interpreted with caution.

Lactate and Outcomes

Overview.

The association between lactate elevation and a number of various outcomes has been assessed in a large number of observational studies.29,35,36,39,87–92,120–169 A brief overview of these studies is provided in Supplemental Digital Content 2, Table 1, http://links.lww.com/AA/B678. The studies included varying sample sizes ranging from <20 to >5000 patients, and all studies but 2159,169 were single-center studies. Most studies included a broad category of cardiac surgery patients, whereas others were restricted to certain subgroups such as those receiving intra-aortic balloon pump support after the surgery,130,138 patients with preexisting liver cirrhosis,150,160 patients receiving heart transplants,144,167 or patients receiving postoperative extracorporeal hemodynamic support.134,135,141,148,152,157,161,163,165 The majority of studies assessed systemic lactate values (either venous or arterial), whereas a few measured lactate values in the coronary sinus,131,139,143 from the lungs,120 or in the myocardium with the use of microdialysis.132 Although these studies vary substantially with regard to outcomes, study population, and timing and type of lactate measurements, lactate elevation appears to be strongly associated with poor outcomes. However, despite the relatively consistent findings across studies, this great heterogeneity in design, methods, and outcomes makes comparison between studies difficult.

Mortality and Length of Stay.

As presented in Supplemental Digital Content 2, Table 1, http://links.lww.com/AA/B678, lactate elevation has been associated with ICU and hospital length of stay as well as in-hospital mortality in a number of studies. In one of the earliest studies, Demers et al36 retrospectively studied 1259 patients and found that patients with a lactate level >4.0 mmol/L during surgery (18% of the cohort) had higher mortality, more postoperative complications, and longer hospital and ICU length of stay. These results were confirmed in 2 large prospective studies by Maillet et al121 and Toraman et al,122 although these studies used different definitions of high lactate (>3.0 mmol/L [21% of the patients] and >2.0 mmol/L [31% of the patients], respectively) and measured lactate levels after the surgery. Largely similar results were found in 2 more contemporary, large, prospective studies.128,151 In a study specifically focusing on hospital length of stay, Andersen et al129 found that both moderate (2–4 mmol/L) and high (≥4 mmol/L) lactate levels were associated with increased hospital length of stay.

Few studies have evaluated mortality extending beyond hospital discharge. Lopez-Delgado et al128 prospectively included 2935 patients and found that a lactate level >4 mmol/L at any time within 24 hours after the surgery was strongly associated with long-term mortality (mean follow-up, 6 years).

Postoperative Complications.

Elevated lactate has been associated with a variety of postoperative complications (Supplemental Digital Content 2, Table 1, http://links.lww.com/AA/B678). Although most studies have assessed a composite of postoperative complications, some have studied specific complications such as gastrointestinal complications,87–91 renal complications (renal replacement therapy137 and acute kidney injury153,164,166,169), atrial fibrillation,139 bleeding,159 cerebral complications,147 and the low cardiac output syndrome.131 In general (see Supplemental Digital Content 2, Table 1, http://links.lww.com/AA/B678 for details), elevated lactate was associated with these complications except for the development of atrial fibrillation, in which the authors found no difference in lactate levels between those developing atrial fibrillation and those not.139

Change in Lactate.

Lactate change has been studied extensively in critically ill patients,170 but few studies exist on cardiac surgery patients.128,149,163 Lindsay et al149 retrospectively studied 1291 patients and used lactate levels obtained within the first 12 hours after surgery to calculate the “predicted lactate clearance time,” defined as the predicted time to reach a lactate of 1.5 mmol/L. This variable was associated with mortality and a composite of complications in both unadjusted and adjusted analyses.149 However, the mean lactate level was a better predictor of outcomes.149 In a retrospective study of 123 patients receiving postsurgical extracorporeal membrane oxygenation, Li et al163 examined lactate change during the first 6 and 12 hours after extracorporeal membrane oxygenation initiation. Both 6- and 12-hour lactate change were associated with mortality in multivariable analysis, with the 12-hour lactate change being a better predictor. In a large, prospective study, Lopez-Delgado et al128 reported no difference in lactate dynamics between survivors and nonsurvivors, but they provided limited description and analysis of these results.

Lactate as a Prognostic Marker.

The test characteristics and prognostic value of lactate depends heavily on the specific patient population, timing of the lactate measurement, the cutoff used, and the outcome of interest. A “normal” lactate level is not clearly defined. Svenmarker et al124 conducted a retrospective, single-center study of 5121 cardiac surgical patients to determine what a normal lactate value is at the time of weaning from cardiopulmonary bypass. The authors defined an abnormal lactate value as one above the 90th percentile, which they found to be a lactate value of 2 mmol/L.124 However, whether this definition truly represents a normal value and whether these results are generalizable to other centers remains unclear. Other studies have used a variety of cutoffs (see Supplemental Digital Content 2, Table 1, http://links.lww.com/AA/B678), including but not limited to >2 mmol/L,122 >3 mmol/L,29,121,128,151 or >4 mmol/L.36,142,159 Others have defined a value between 2 and 4 mmol/L as a moderately elevated value and a value ≥4 mmol/L as a high lactate level.127,129

Choosing a useful cutoff for prognostication and subsequent treatment decisions depends on the preference for sensitivity versus specificity, with increasing specificity but decreasing sensitivity with higher cutoffs. For example, in the study by Svenmarker et al,124 sensitivity was 54%, 44%, and 30%, and specificity was 98%, 99%, and 99% for in-hospital mortality for the cutoffs of 2, 3, and 4 mmol/L, respectively. The preference for sensitivity versus specificity is a function of multiple characteristics, including the downstream consequences and costs of a true/false positive and a true/false negative test. Choosing an optimal cutoff value therefore requires a complete cost-effectiveness analysis, and a simple maximization of the sum of specificity and sensitivity is less useful.171–173 This review did not identify such a study, and the most appropriate cutoff will depend on the clinical or research question at hand.

In general, elevated lactate has relatively high specificity but only moderate sensitivity in predicting outcomes with a corresponding high negative predictive value and a moderate positive predictive value; that is, a normal lactate level is reassuring, whereas an elevated lactate level is only a moderate predictor of poor outcomes. As such, lactate as a single biomarker provides limited prognostic value.11

Finally, lactate has been incorporated into a number of postoperative prediction scores.133,142,154–156,162,169 Although these scores generally perform well, their clinical utility and actual use is not well described.

Management of Postoperative Lactate Elevation

Despite the extensive literature on the association between lactate elevation and poor outcomes, little is known about the optimal management strategy for postoperative patients with lactate elevation.

Studies Evaluating Management of Elevated Lactate.

Pölönen et al174 conducted a single-center, randomized, nonblinded trial in 393 patients after cardiac surgery. Patients were randomized to standard of care or standard of care plus a protocol (including volume expansion and dobutamine) to maintain central venous oxygen saturation >70% and lactate levels ≤2 mmol/L for the first 8 hours of ICU admission. Patients in the interventional group had statistically significant shorter hospital lengths of stay (median, 7 [quartiles: 5, 8] vs 6 [quartiles: 5, 7], P < .05), and fewer patients had organ dysfunction at the time of hospital discharge. There was no difference in ICU length of stay or short-term and long-term mortality. There was furthermore no difference in lactate levels between the 2 groups during the intervention period.174 A before and after observational study found largely similar results, although that study focused primarily on optimization of central venous saturation.175

In a study of a broad group of ICU patients, Jansen et al176 randomized patients with a lactate level ≥3.0 mmol/L to standard of care or standard of care with an additional goal of achieving a decrease in lactate level of ≥20% through a complex protocol. Patients in the interventional group had shorter ICU stays, but similar to the study by Pölönen et al, there was no difference in lactate levels between the groups.176

General Considerations.

As discussed in more detail previously in relation to critically ill patients,8 a strategy solely focusing on optimization of oxygen delivery might not be optimal for patients with elevated lactate. Elevated lactate may be multifactorial and not simply and only related to decreased oxygen delivery, as discussed throughout this manuscript. As such, it appears plausible, although not tested in controlled studies, that a broader approach to postoperative lactate elevation, including but not solely focusing on oxygen delivery, might be beneficial.

CONCLUSIONS

This review provides a brief overview of the complex mechanisms related to lactate elevation during and after cardiac surgery. Although the true contribution of these various mechanisms is unknown, it is likely that lactate elevation is most often multifactorial, and that the relative contributions vary from patient to patient, as well as over time within individual patients. Future studies should acknowledge this complexity and focus on the multifactorial nature of lactate elevation.

Despite the consistent association with poor outcomes, little is known about what truly constitutes an abnormal lactate level in this patient population, and even less is known about the optimal management of postoperative patients with elevated lactate. Future studies should aim to explore and address these important knowledge gaps.

Like most biomarkers, the measurement of lactate has not been directly proven to benefit patients in controlled trials, and this should be the focus of future investigations. However, lactate is an easily available and inexpensive biomarker177 that may provide important information to the clinical team. Although not a strong prognostic biomarker in and of itself, an elevated lactate level may prompt the clinician to reevaluate the patient and assess for potentially reversible causes of lactate elevation (eg, low oxygen delivery), with the important caveat that some causes are currently not directly treatable (eg, low oxygen utilization) or are probably relatively benign (eg, epinephrine-induced lactate elevation). Until specific evidence-based approaches to lactate elevation have been proven beneficial in randomized, multicenter studies, a clinical approach to lactate elevation in postcardiac surgery patients focusing on optimizing oxygen delivery while identifying potential postoperative complications seems reasonable.

ACKNOWLEDGMENTS

The author thanks Jessica Zhu, Mathias Karlsson, and Carol Mita for assistance with article retrieval. The author thanks Mathias J. Holmberg, Else Tønnesen, and Michael W. Donnino for review of the article, and Francesca Montillo for editorial assistance.

DISCLOSURES

Name: Lars W. Andersen, MD, MPH, PhD.

Contribution: This author conceived and designed the study, performed the search, reviewed the articles, and wrote the article.

This manuscript was handled by: W. Scott Beattie, PhD, MD, FRCPC.

REFERENCES

1. Gibbon JH Jr.. Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med. 1954;37:171–185.
2. Zimmer HG. Perfusion of isolated organs and the first heart-lung machine. Can J Cardiol. 2001;17:963–969.
3. Pontius RG, Watkins E, Manheim BS, Allen RG, Sauvage LR, Gross RE. Studies of acid-base derangement during total cardiac bypass. Surg Forum. 1957;8:393–397.
4. Litwin MS, Panico FG, Rubini C, Harken DE, Moore FD. Acidosis and lacticacidemia in extracorporeal circulation: the significance of perfusion flow rate and the relation to preperfusion respiratory alkalosis. Ann Surg. 1959;149:188–199.
5. Jakob SM, Ensinger H, Takala J. Metabolic changes after cardiac surgery. Curr Opin Clin Nutr Metab Care. 2001;4:149–155.
6. Jakob SM, Stanga Z. Perioperative metabolic changes in patients undergoing cardiac surgery. Nutrition. 2010;26:349–353.
7. Adeva-Andany M, Lopez-Ojen M, Funcasta-Calderon R, et al. Comprehensive review on lactate metabolism in human health. Mitochondrion. 2014;17:76–100.
8. Andersen LW, Mackenhauer J, Roberts JC, Berg KM, Cocchi MN, Donnino MW. Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc. 2013;88:1127–1140.
9. Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care. 2014;18:503.
10. Broder G, Weil MH. Excess lactate: an index of reversibility of shock in human patients. Science. 1964;143:1457–1459.
11. Allen M. Lactate and acid base as a hemodynamic monitor and markers of cellular perfusion. Pediatr Crit Care Med. 2011;12:S43–S49.
12. Takala J, Uusaro A, Parviainen I, Ruokonen E. Lactate metabolism and regional lactate exchange after cardiac surgery. New Horiz. 1996;4:483–492.
13. Attanà P, Lazzeri C, Picariello C, Dini CS, Gensini GF, Valente S. Lactate and lactate clearance in acute cardiac care patients. Eur Heart J Acute Cardiovasc Care. 2012;1:115–121.
14. O’Connor E, Fraser JF. The interpretation of perioperative lactate abnormalities in patients undergoing cardiac surgery. Anaesth Intensive Care. 2012;40:598–603.
15. van Hall G. Lactate kinetics in human tissues at rest and during exercise. Acta Physiol (Oxf). 2010;199:499–508.
16. Brooks GA. Cell-cell and intracellular lactate shuttles. J Physiol. 2009;587:5591–5600.
17. Levy B. Lactate and shock state: the metabolic view. Curr Opin Crit Care. 2006;12:315–321.
18. Leverve XM, Mustafa I. Lactate: a key metabolite in the intercellular metabolic interplay. Crit Care. 2002;6:284–285.
19. Gladden LB. Lactate metabolism: a new paradigm for the third millennium. J Physiol. 2004;558:5–30.
20. Cohen RD, Woods HF. Clinical and Biochemical Aspects of Lactic Acidosis. 1976.Oxford: Blackwell Scientific Publications Ltd.
21. Cohen RD, Woods HF. Lactic acidosis revisited. Diabetes. 1983;32:181–191.
22. Harris EA, Seelye ER, Barratt-Boyes BG. On the availability of oxygen to the body during cardiopulmonary bypass in man. Br J Anaesth. 1974;46:425–431.
23. Komatsu T, Shibutani K, Okamoto K, et al. Critical level of oxygen delivery after cardiopulmonary bypass. Crit Care Med. 1987;15:194–197.
24. Fiaccadori E, Vezzani A, Coffrini E, et al. Cell metabolism in patients undergoing major valvular heart surgery: relationship with intra and postoperative hemodynamics, oxygen transport, and oxygen utilization patterns. Crit Care Med. 1989;17:1286–1292.
25. Raper RF, Cameron G, Walker D, Bowey CJ. Type B lactic acidosis following cardiopulmonary bypass. Crit Care Med. 1997;25:46–51.
26. Cartier R, Prieto J, Leclerc Y, Hébert Y, Jean D, Hardy JF. Factors predictive of oxygen consumption during the immediate postoperative period in open heart surgery. Can J Cardiol. 2000;16:467–472.
27. Inoue S, Kuro M, Furuya H. What factors are associated with hyperlactatemia after cardiac surgery characterized by well-maintained oxygen delivery and a normal postoperative course? A retrospective study. Eur J Anaesthesiol. 2001;18:576–584.
28. Ranucci M, Isgrò G, Romitti F, Mele S, Biagioli B, Giomarelli P. Anaerobic metabolism during cardiopulmonary bypass: predictive value of carbon dioxide derived parameters. Ann Thorac Surg. 2006;81:2189–2195.
29. Ranucci M, De Toffol B, Isgrò G, Romitti F, Conti D, Vicentini M. Hyperlactatemia during cardiopulmonary bypass: determinants and impact on postoperative outcome. Crit Care. 2006;10:R167.
30. Ariza M, Gothard JW, Macnaughton P, Hooper J, Morgan CJ, Evans TW. Blood lactate and mixed venous-arterial PCO2 gradient as indices of poor peripheral perfusion following cardiopulmonary bypass surgery. Intensive Care Med. 1991;17:320–324.
31. Trekova NA, Dementyeva II, Dzemeshkevich SL, Asmangulyan YeT. Blood oxygen transport function in cardiopulmonary bypass surgery for acquired heart valvular diseases. Int Surg. 1994;79:60–64.
32. den Uil CA, Lagrand WK, Spronk PE, et al. Impaired sublingual microvascular perfusion during surgery with cardiopulmonary bypass: a pilot study. J Thorac Cardiovasc Surg. 2008;136:129–134.
33. De Backer D, Dubois MJ, Schmartz D, et al. Microcirculatory alterations in cardiac surgery: effects of cardiopulmonary bypass and anesthesia. Ann Thorac Surg. 2009;88:1396–1403.
34. Huybregts RA, de Vroege R, Jansen EK, van Schijndel AW, Christiaans HM, van Oeveren W. The association of hemodilution and transfusion of red blood cells with biochemical markers of splanchnic and renal injury during cardiopulmonary bypass. Anesth Analg. 2009;109:331–339.
35. Ranucci M, Carboni G, Cotza M, Bianchi P, Di Dedda U, Aloisio T; Surgical and Clinical Outcome Research (SCORE) Group. Hemodilution on cardiopulmonary bypass as a determinant of early postoperative hyperlactatemia. PLoS One. 2015;10:e0126939.
36. Demers P, Elkouri S, Martineau R, Couturier A, Cartier R. Outcome with high blood lactate levels during cardiopulmonary bypass in adult cardiac operation. Ann Thorac Surg. 2000;70:2082–2086.
37. von Heymann C, Sander M, Foer A, et al. The impact of an hematocrit of 20% during normothermic cardiopulmonary bypass for elective low risk coronary artery bypass graft surgery on oxygen delivery and clinical outcome—a randomized controlled study [ISRCTN35655335]. Crit Care. 2006;10:R58.
38. Fink MP. Bench-to-bedside review: cytopathic hypoxia. Crit Care. 2002;6:491–499.
39. Dixon B, Santamaria JD, Campbell DJ. Plasminogen activator inhibitor activity is associated with raised lactate levels after cardiac surgery with cardiopulmonary bypass. Crit Care Med. 2003;31:1053–1059.
40. Andersen LW, Liu X, Peng TJ, Giberson TA, Khabbaz KR, Donnino MW. Pyruvate dehydrogenase activity and quantity decreases after coronary artery bypass grafting: a prospective observational study. Shock. 2015;43:250–254.
41. Donnino MW, Cocchi MN, Smithline H, et al. Coronary artery bypass graft surgery depletes plasma thiamine levels. Nutrition. 2010;26:133–136.
42. Luger M, Hiesmayr M, Köppel P, et al. Influence of intravenous thiamine supplementation on blood lactate concentration prior to cardiac surgery: a double-blinded, randomised controlled pilot study. Eur J Anaesthesiol. 2015;32:543–548.
43. Andersen LW, Holmberg MJ, Berg K, et al. Thiamine as an adjunctive therapy in cardiac surgery: a randomized, double-blind, placebo-controlled, phase II trial. Crit Care. 2016;20:92.
44. Solligard E, Wahba A, Skogvoll E, Stenseth R, Gronbech JE, Aadahl P. Rectal lactate levels in endoluminal microdialysate during routine coronary surgery. Anaesthesia. 2007;62:250–258.
45. Suleiman MS, Zacharowski K, Angelini GD. Inflammatory response and cardioprotection during open-heart surgery: the importance of anaesthetics. Br J Pharmacol. 2008;153:21–33.
46. Larmann J, Theilmeier G. Inflammatory response to cardiac surgery: cardiopulmonary bypass versus non-cardiopulmonary bypass surgery. Best Pract Res Clin Anaesthesiol. 2004;18:425–438.
47. Ryan T, Balding J, McGovern EM, et al. Lactic acidosis after cardiac surgery is associated with polymorphisms in tumor necrosis factor and interleukin 10 genes. Ann Thorac Surg. 2002;73:1905–1909; discussion 19101911.
48. Riha H, Hubacek JA, Poledne R, Kellovsky P, Brezina A, Pirk J. IL-10 and TNF-beta gene polymorphisms have no major influence on lactate levels after cardiac surgery. Eur J Cardiothorac Surg. 2006;30:54–58.
49. Kilger E, Weis F, Briegel J, et al. Stress doses of hydrocortisone reduce severe systemic inflammatory response syndrome and improve early outcome in a risk group of patients after cardiac surgery. Crit Care Med. 2003;31:1068–1074.
50. Weis F, Beiras-Fernandez A, Schelling G, et al. Stress doses of hydrocortisone in high-risk patients undergoing cardiac surgery: effects on interleukin-6 to interleukin-10 ratio and early outcome. Crit Care Med. 2009;37:1685–1690.
51. Mayumi H, Zhang QW, Nakashima A, et al. Synergistic immunosuppression caused by high-dose methylprednisolone and cardiopulmonary bypass. Ann Thorac Surg. 1997;63:129–137.
52. Ottens TH, Nijsten MW, Hofland J, et al. Effect of high-dose dexamethasone on perioperative lactate levels and glucose control: a randomized controlled trial. Crit Care. 2015;19:41.
53. Levy B, Gibot S, Franck P, Cravoisy A, Bollaert PE. Relation between muscle Na+K+ ATPase activity and raised lactate concentrations in septic shock: a prospective study. Lancet. 2005;365:871–875.
54. McCord CW, Crampton RS, Nasser MG, Case RB. Myocardial potassium and lactate balance during valve-replacement surgery. Circulation. 1969;39:I234–I238.
55. Goldschlager N, Gerbode F, Osborn JJ, Cohn KE. Patterns of myocardial oxygen and lactate extraction in patients undergoing cardiopulmonary bypass. Am Heart J. 1972;83:167–178.
56. Isom OW, Kutin ND, Falk EA, Spencer FC. Patterns of myocardial metabolism during cardiopulmonary bypass and coronary perfusion. J Thorac Cardiovasc Surg. 1973;66:705–719.
57. Wisheart JD, Archie JP, Kirklin JW, Tracy WG. Myocardial blood flow and oxygen consumption in man early after valve replacement. Circulation. 1974;49:933–942.
58. Hashimoto S, Kawashima Y, Fujita T, et al. Myocardial metabolism during prolonged selective hypothermic coronary perfusion. Recent Adv Stud Cardiac Struct Metab. 1976;12:491–499.
59. Bomfim V, Kaijser L, Bendz R, Sylvén C, Morillo F, Olin C. Myocardial protection during aortic valve replacement. Cardiac metabolism and enzyme release following continuous blood cardioplegia. Scand J Thorac Cardiovasc Surg. 1981;15:141–147.
60. Jalonen J, Irjala J, Vänttinen E, Inberg MV. Reduced lactate washout from the myocardium after combining St. Thomas I type cardioplegia with topical cooling of the heart. Myocardial oxygenation and performance after cardioplegia in coronary artery bypass grafting patients. Scand J Thorac Cardiovasc Surg. 1981;15:67–73.
61. Fremes SE, Weisel RD, Mickle DA, et al. Myocardial metabolism and ventricular function following cold potassium cardioplegia. J Thorac Cardiovasc Surg. 1985;89:531–546.
62. Heikkilä H, Jalonen J, Arola M, Laaksonen V. Haemodynamics and myocardial oxygenation during anaesthesia for coronary artery surgery: comparison between enflurane and high-dose fentanyl anaesthesia. Acta Anaesthesiol Scand. 1985;29:457–464.
63. Hultman J, Ronquist G, Hansson HE, Aberg T, Bertrand-Guy M. Myocardial energy metabolism during mitral valve replacement. Thorac Cardiovasc Surg. 1986;34:351–355.
64. Jalonen J, Heikkilä H, Arola M, Engblom E, Laaksonen V. Myocardial oxygen balance and cardiopulmonary bypass in patients undergoing coronary artery bypass grafting. J Cardiothorac Anesth. 1989;3:311–320.
65. Smolenski RT, Swierczyński J, Narkiewicz M, Zydowo MM. Purines, lactate and phosphate release from child and adult heart during cardioplegic arrest. Clin Chim Acta. 1990;192:155–163.
66. Elia S, Liu P, Hilgenberg A, Skourtis C, Lappas D. Coronary haemodynamics and myocardial metabolism during weaning from mechanical ventilation in cardiac surgical patients. Can J Anaesth. 1991;38:564–571.
67. Ando H, Tanaka J, Hisahara M, Nagano I, Shimizu I. Implication of myocardial lactate metabolism during coronary artery bypass grafting. Cardiovasc Surg. 1997;5:210–215.
68. Koh TW, Carr-White GS, DeSouza AC, et al. Intraoperative cardiac troponin T release and lactate metabolism during coronary artery surgery: comparison of beating heart with conventional coronary artery surgery with cardiopulmonary bypass. Heart. 1999;81:495–500.
69. Raman JS, Bellomo R, Hayhoe M, Tsamitros M, Buxton BF. Metabolic changes and myocardial injury during cardioplegia: a pilot study. Ann Thorac Surg. 2001;72:1566–1571.
70. Kennergren C, Mantovani V, Strindberg L, Berglin E, Hamberger A, Lonnroth P. Myocardial interstitial glucose and lactate before, during, and after cardioplegic heart arrest. Am J Physiol Endocrinol Metab. 2003;284:E788–E794.
71. Bortone F, Mazzoni M, Repossini A, et al. Myocardial lactate metabolism in relation to preoperative regional wall motion and to early functional recovery after coronary revascularization. J Cardiothorac Vasc Anesth. 2003;17:478–485.
72. Bahlmann L, Misfeld M, Klaus S, et al. Myocardial redox state during coronary artery bypass grafting assessed with microdialysis. Intensive Care Med. 2004;30:889–894.
73. Poling J, Rees W, Klaus S, et al. Myocardial metabolic monitoring with the microdialysis technique during and after open heart surgery. Acta Anaesthesiol Scand. 2007;51:341–346.
74. Pöling J, Leptien A, Klaus S, et al. Analysis of the myocardial metabolism by microdialysis during open beating heart surgery. Scand Cardiovasc J. 2007;41:114–119.
75. Turer AT, Stevens RD, Bain JR, et al. Metabolomic profiling reveals distinct patterns of myocardial substrate use in humans with coronary artery disease or left ventricular dysfunction during surgical ischemia/reperfusion. Circulation. 2009;119:1736–1746.
76. Mantovani V, Kennergren C, Bugge M, Sala A, Lönnroth P, Berglin E. Myocardial metabolism assessed by microdialysis: a prospective randomized study in on- and off-pump coronary bypass surgery. Int J Cardiol. 2010;143:302–308.
77. Landow L, Phillips DA, Heard SO, Prevost D, Vandersalm TJ, Fink MP. Gastric tonometry and venous oximetry in cardiac surgery patients. Crit Care Med. 1991;19:1226–1233.
78. Andersen LW, Landow L, Baek L, Jansen E, Baker S. Association between gastric intramucosal pH and splanchnic endotoxin, antibody to endotoxin, and tumor necrosis factor-alpha concentrations in patients undergoing cardiopulmonary bypass. Crit Care Med. 1993;21:210–217.
79. Haisjackl M, Birnbaum J, Redlin M, et al. Splanchnic oxygen transport and lactate metabolism during normothermic cardiopulmonary bypass in humans. Anesth Analg. 1998;86:22–27.
80. Hayhoe M, Bellomo R, Liu G, Kellum JA, McNicol L, Buxton B. Role of the splanchnic circulation in acid-base balance during cardiopulmonary bypass. Crit Care Med. 1999;27:2671–2677.
81. Thorén A, Jakob SM, Pradl R, Elam M, Ricksten SE, Takala J. Jejunal and gastric mucosal perfusion versus splanchnic blood flow and metabolism: an observational study on postcardiac surgical patients. Crit Care Med. 2000;28:3649–3654.
82. Braun JP, Schroeder T, Buehner S, et al. Splanchnic oxygen transport, hepatic function and gastrointestinal barrier after normothermic cardiopulmonary bypass. Acta Anaesthesiol Scand. 2004;48:697–703.
83. Tsunooka N, Hamada Y, Imagawa H, et al. Ischemia of the intestinal mucosa during cardiopulmonary bypass. J Artif Organs. 2003;6:149–151.
84. Perner A, Jorgensen VL, Poulsen TD, Steinbruchel D, Larsen B, Andersen LW. Increased concentrations of L-lactate in the rectal lumen in patients undergoing cardiopulmonary bypass. Br J Anaesth. 2005;95:764–768.
85. Adluri RK, Singh AV, Skoyles J, Baker M, Mitchell IM. Measurement of intraperitoneal metabolites during hypothermic cardiopulmonary bypass using microdialysis. Scand Cardiovasc J. 2011;45:229–235.
86. Landow L. Splanchnic lactate production in cardiac surgery patients. Crit Care Med. 1993;21:S84–S91.
87. Byhahn C, Strouhal U, Martens S, Mierdl S, Kessler P, Westphal K. Incidence of gastrointestinal complications in cardiopulmonary bypass patients. World J Surg. 2001;25:1140–1144.
88. Klotz S, Vestring T, Rötker J, Schmidt C, Scheld HH, Schmid C. Diagnosis and treatment of nonocclusive mesenteric ischemia after open heart surgery. Ann Thorac Surg. 2001;72:1583–1586.
89. Groesdonk HV, Klingele M, Schlempp S, et al. Risk factors for nonocclusive mesenteric ischemia after elective cardiac surgery. J Thorac Cardiovasc Surg. 2013;145:1603–1610.
90. Huwer H, Winning J, Straub U, Isringhaus H, Kalweit G. Clinically diagnosed nonocclusive mesenteric ischemia after cardiopulmonary bypass: retrospective study. Vascular. 2004;12:114–120.
91. Mothes H, Koeppen J, Bayer O, et al. Acute mesenteric ischemia following cardiovascular surgery—a nested case-control study. Int J Surg. 2016;26:79–85.
92. Schütz A, Eichinger W, Breuer M, Gansera B, Kemkes BM. Acute mesenteric ischemia after open heart surgery. Angiology. 1998;49:267–273.
93. Mierdl S, Meininger D, Dogan S, et al. Abdominal complications after cardiac surgery. Ann Acad Med Singapore. 2001;30:245–249.
94. Mand’ak J, Zivny P, Lonsky V, et al. Changes in metabolism and blood flow in peripheral tissue (skeletal muscle) during cardiac surgery with cardiopulmonary bypass: the biochemical microdialysis study. Perfusion. 2004;19:53–63.
95. Pojar M, Mand’ak J, Cibicek N, et al. Peripheral tissue metabolism during off-pump versus on-pump coronary artery bypass graft surgery: the microdialysis study. Eur J Cardiothorac Surg. 2008;33:899–905.
96. Mandak J, Pojar M, Cibicek N, et al. Impact of cardiopulmonary bypass on peripheral tissue metabolism and microvascular blood flow. Perfusion. 2008;23:339–346.
97. Szabó Z, Andersson RG, Arnqvist HJ. Intraoperative muscle and fat metabolism in diabetic patients during coronary artery bypass grafting surgery: a parallel microdialysis and organ balance study. Br J Anaesth. 2009;103:166–172.
98. Cossu AP, Suelzu S, Piu P, et al. Do on- and off-pump coronary bypass surgery differently affect perioperative peripheral tissue metabolism? Minerva Anestesiol. 2012;78:26–33
99. De Blasi RA, Tonelli E, Arcioni R, et al. In vivo effects on human skeletal muscle oxygen delivery and metabolism of cardiopulmonary bypass and perioperative hemodilution. Intensive Care Med. 2012;38:413–421.
100. Tripodaki ES, Tasoulis A, Koliopoulou A, et al. Microcirculation and macrocirculation in cardiac surgical patients. Crit Care Res Pract. 2012;2012:654381.
101. Kopp R, Dommann K, Rossaint R, et al. Tissue oxygen saturation as an early indicator of delayed lactate clearance after cardiac surgery: a prospective observational study. BMC Anesthesiol. 2015;15:158.
102. Bendjelid K, Treggiari MM, Romand JA. Transpulmonary lactate gradient after hypothermic cardiopulmonary bypass. Intensive Care Med. 2004;30:817–821.
103. Gasparovic H, Plestina S, Sutlic Z, et al. Pulmonary lactate release following cardiopulmonary bypass. Eur J Cardiothorac Surg. 2007;32:882–887.
104. Harris DN, Wilson JA, Taylor-Robinson SD, Taylor KM. Magnetic resonance spectroscopy of high-energy phosphates and lactate immediately after coronary artery bypass surgery. Perfusion. 1998;13:328–333.
105. Dabrowski W, Kotlinska E, Rzecki Z, Czajkowski M, Stadnik A, Olszewski K. Raised jugular venous pressure intensifies release of brain injury biomarkers in patients undergoing cardiac surgery. J Cardiothorac Vasc Anesth. 2012;26:999–1006.
106. Chioléro RL, Revelly JP, Leverve X, et al. Effects of cardiogenic shock on lactate and glucose metabolism after heart surgery. Crit Care Med. 2000;28:3784–3791.
107. Mustafa I, Roth H, Hanafiah A, et al. Effect of cardiopulmonary bypass on lactate metabolism. Intensive Care Med. 2003;29:1279–1285.
108. Sirvinskas E, Kinduris S, Kapturauskas J, Samalavičius R. Perioperative use of metformin in cardiac surgery. Medicina (Kaunas). 2010;46:723–729.
109. Baradari AG, Habibi MR, Khezri HD, et al. Does high-dose metformin cause lactic acidosis in type 2 diabetic patients after CABG surgery? A double blind randomized clinical trial. Heart Int. 2011;6:e8.
110. El Messaoudi S, Nederlof R, Zuurbier CJ, et al. Effect of metformin pretreatment on myocardial injury during coronary artery bypass surgery in patients without diabetes (MetCAB): a double-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 2015;3:615–623.
111. Totaro RJ, Raper RF. Epinephrine-induced lactic acidosis following cardiopulmonary bypass. Crit Care Med. 1997;25:1693–1699.
112. Contenti J, Occelli C, Corraze H, Lemoel F, Levraut J. Long-term beta-blocker therapy decreases blood lactate concentration in severely septic patients. Crit Care Med. 2015;43:2616–2622.
113. Krajcova A, Waldauf P, Andel M, Duska F. Propofol infusion syndrome: a structured review of experimental studies and 153 published case reports. Crit Care. 2015;19:398.
114. Didwania A, Miller J, Kassel D, Jackson EV Jr, Chernow B. Effect of intravenous lactated Ringer’s solution infusion on the circulating lactate concentration: Part 3. Results of a prospective, randomized, double-blind, placebo-controlled trial. Crit Care Med. 1997;25:1851–1854.
115. Jackson EV Jr, Wiese J, Sigal B, et al. Effects of crystalloid solutions on circulating lactate concentrations: Part 1. Implications for the proper handling of blood specimens obtained from critically ill patients. Crit Care Med. 1997;25:1840–1846.
116. Liskaser F, Story DA, Hayhoe M, Poustie SJ, Bailey MJ, Bellomo R. Effect of pump prime on acidosis, strong-ion-difference and unmeasured ions during cardiopulmonary bypass. Anaesth Intensive Care. 2009;37:767–772.
117. Dong MF, Ma ZS, Wang JT, Chai SD, Tang PZ, Wang LX. Impact of peripherally established cardiopulmonary bypass on regional and systemic blood lactate levels. Heart Lung Circ. 2012;21:154–158.
118. Shen C, Gu T, Gu L, et al. Change in the perioperative blood glucose and blood lactate levels of non-diabetic patients undergoing coronary bypass surgery. Exp Ther Med. 2013;6:1220–1224.
119. Joudi M, Fathi M, Soltani G, Izanloo A. Factors affecting on serum lactate after cardiac surgery. Anesth Pain Med. 2014;4:e18514.
120. Takami Y, Ina H. Significance of the initial arterial lactate level and transpulmonary arteriovenous lactate difference after open-heart surgery. Surg Today. 2002;32:207–212.
121. Maillet JM, Le Besnerais P, Cantoni M, et al. Frequency, risk factors, and outcome of hyperlactatemia after cardiac surgery. Chest. 2003;123:1361–1366.
122. Toraman F, Evrenkaya S, Yuce M, et al. Lactic acidosis after cardiac surgery is associated with adverse outcome. Heart Surg Forum. 2004;7:E155–E159.
123. Shinde SB, Golam KK, Kumar P, Patil ND. Blood lactate levels during cardiopulmonary bypass for valvular heart surgery. Ann Card Anaesth. 2005;8:39–44.
124. Svenmarker S, Häggmark S, Ostman M. What is a normal lactate level during cardiopulmonary bypass? Scand Cardiovasc J. 2006;40:305–311.
125. Kogan A, Preisman S, Bar A, et al. The impact of hyperlactatemia on postoperative outcome after adult cardiac surgery. J Anesth. 2012;26:174–178.
126. Jabbari A, Banihashem N, Alijanpour E, Vafaey HR, Alereza H, Rabiee SM. Serum lactate as a prognostic factor in coronary artery bypass graft operation by on pump method. Caspian J Intern Med. 2013;4:662–666.
127. Laine GA, Hu BY, Wang S, Thomas Solis R, Reul GJ Jr.. Isolated high lactate or low central venous oxygen saturation after cardiac surgery and association with outcome. J Cardiothorac Vasc Anesth. 2013;27:1271–1276.
128. Lopez-Delgado JC, Esteve F, Javierre C, et al. Evaluation of serial arterial lactate levels as a predictor of hospital and long-term mortality in patients after cardiac surgery. J Cardiothorac Vasc Anesth. 2015;29:1441–1453.
129. Andersen LW, Holmberg MJ, Doherty M, et al. Postoperative lactate levels and hospital length of stay after cardiac surgery. J Cardiothorac Vasc Anesth. 2015;29:1454–1460.
130. Davies AR, Bellomo R, Raman JS, Gutteridge GA, Buxton BF. High lactate predicts the failure of intraaortic balloon pumping after cardiac surgery. Ann Thorac Surg. 2001;71:1415–1420.
131. Rao V, Ivanov J, Weisel RD, Cohen G, Borger MA, Mickle DA. Lactate release during reperfusion predicts low cardiac output syndrome after coronary bypass surgery. Ann Thorac Surg. 2001;71:1925–1930.
132. Heringlake M, Bahlmann L, Misfeld M, et al. High myocardial lactate concentration is associated with poor myocardial function prior to cardiopulmonary bypass. Minerva Anestesiol. 2005;71:775–783.
133. Hekmat K, Kroener A, Stuetzer H, et al. Daily assessment of organ dysfunction and survival in intensive care unit cardiac surgical patients. Ann Thorac Surg 2005;79:1555–1562.
134. Zhang R, Kofidis T, Kamiya H, et al. Creatine kinase isoenzyme MB relative index as predictor of mortality on extracorporeal membrane oxygenation support for postcardiotomy cardiogenic shock in adult patients. Eur J Cardiothorac Surg. 2006;30:617–620.
135. Oshima K, Kunimoto F, Takahashi T, et al. Factors for successful weaning from a percutaneous cardiopulmonary support system (PCPS) in patients with low cardiac output syndrome after cardiovascular surgery. Int Heart J. 2007;48:743–754.
136. Abarbanell GL, Goldberg CS, Devaney EJ, Ohye RG, Bove EL, Charpie JR. Early surgical morbidity and mortality in adults with congenital heart disease: the University of Michigan experience. Congenit Heart Dis. 2008;3:82–89.
137. Hauer D, Kilger E, Kaufmann I, et al. Risk and outcome analysis of renal replacement therapies in patients after cardiac surgery with pre-operatively normal renal function. Anaesthesia. 2009;64:615–619.
138. Boeken U, Feindt P, Litmathe J, Kurt M, Gams E. Intraaortic balloon pumping in patients with right ventricular insufficiency after cardiac surgery: parameters to predict failure of IABP Support. Thorac Cardiovasc Surg. 2009;57:324–328.
139. Gasparovic H, Burcar I, Kopjar T, et al. NT-pro-BNP, but not C-reactive protein, is predictive of atrial fibrillation in patients undergoing coronary artery bypass surgery. Eur J Cardiothorac Surg. 2010;37:100–105.
140. Nogueira PM, Mendonça-Filho HT, Campos LA, et al. Central venous saturation: a prognostic tool in cardiac surgery patients. J Intensive Care Med. 2010;25:111–116.
141. Rastan AJ, Dege A, Mohr M, et al. Early and late outcomes of 517 consecutive adult patients treated with extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock. J Thorac Cardiovasc Surg. 2010;139:302–11, 311.e1.
142. Ranucci M, Ballotta A, Castelvecchio S, Baryshnikova E, Brozzi S, Boncilli A; Surgical and Clinical Outcome Research (SCORE) Group. Intensive care unit admission parameters improve the accuracy of operative mortality predictive models in cardiac surgery. PLoS One. 2010;5:e13551.
143. Kapoor P, Mandal B, Chowdhury U, Singh S, Kiran U. Changes in myocardial lactate, pyruvate and lactate-pyruvate ratio during cardiopulmonary bypass for elective adult cardiac surgery: early indicator of morbidity. J Anaesthesiol Clin Pharmacol. 2011;27:225–232.
144. Noval-Padillo JA, Serra-Gomez C, Gomez-Sosa L, et al. Changes of lactate levels during cardiopulmonary bypass in patients undergoing cardiac transplantation: possible early marker of morbidity and mortality. Transplant Proc. 2011;43:2249–2250.
145. Canadyova J, Zmeko D, Mokracek A. Re-exploration for bleeding or tamponade after cardiac operation. Interact Cardiovasc Thorac Surg. 2012;14:704–707.
146. Hu BY, Laine GA, Wang S, Solis RT. Combined central venous oxygen saturation and lactate as markers of occult hypoperfusion and outcome following cardiac surgery. J Cardiothorac Vasc Anesth. 2012;26:52–57.
147. Nicolini F, Maestri F, Fragnito C, et al. Early neurological injury after cardiac surgery: insights from a single centre prospective study. Acta Biomed. 2013;84:44–52.
148. Slottosch I, Liakopoulos O, Kuhn E, et al. Outcomes after peripheral extracorporeal membrane oxygenation therapy for postcardiotomy cardiogenic shock: a single-center experience. J Surg Res. 2013;181:e47–e55.
149. Lindsay AJ, Xu M, Sessler DI, Blackstone EH, Bashour CA. Lactate clearance time and concentration linked to morbidity and death in cardiac surgical patients. Ann Thorac Surg. 2013;95:486–492.
150. Lopez-Delgado JC, Esteve F, Javierre C, et al. Short-term independent mortality risk factors in patients with cirrhosis undergoing cardiac surgery. Interact Cardiovasc Thorac Surg. 2013;16:332–338.
151. Hajjar LA, Almeida JP, Fukushima JT, et al. High lactate levels are predictors of major complications after cardiac surgery. J Thorac Cardiovasc Surg. 2013;146:455–460.
152. Wang JG, Han J, Jia YX, Zeng W, Hou XT, Meng X. Outcome of veno-arterial extracorporeal membrane oxygenation for patients undergoing valvular surgery. PLoS One. 2013;8:e63924.
153. Lopez-Delgado JC, Esteve F, Torrado H, et al. Influence of acute kidney injury on short- and long-term outcomes in patients undergoing cardiac surgery: risk factors and prognostic value of a modified RIFLE classification. Crit Care. 2013;17:R293.
154. Tamayo E, Fierro I, Bustamante-Munguira J, et al. Development of the Post Cardiac Surgery (POCAS) prognostic score. Crit Care. 2013;17:R209.
155. Tamayo E, Fierro I, Bustamante-Munguira J, et al. Erratum to: development of the post cardiac surgery (POCAS) prognostic score. Crit Care. 2015;19:395.
156. Badreldin AM, Doerr F, Elsobky S, et al. Mortality prediction after cardiac surgery: blood lactate is indispensible. Thorac Cardiovasc Surg. 2013;61:708–717.
157. Park SJ, Kim JB, Jung SH, Choo SJ, Chung CH, Lee JW. Outcomes of extracorporeal life support for low cardiac output syndrome after major cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:283–289.
158. Park SJ, Kim SP, Kim JB, et al. Blood lactate level during extracorporeal life support as a surrogate marker for survival. J Thorac Cardiovasc Surg. 2014;148:714–720.
159. Ranucci M, Baryshnikova E, Simeone F, Ranucci M, Scolletta S. Moderate-degree acidosis is an independent determinant of postoperative bleeding in cardiac surgery. Minerva Anestesiol. 2015;81:885–893.
160. Lopez-Delgado JC, Esteve F, Javierre C, et al. Predictors of long-term mortality in patients with cirrhosis undergoing cardiac surgery. J Cardiovasc Surg. (Torino) 2015;56:647–654.
161. Papadopoulos N, Marinos S, El-Sayed Ahmad A, et al. Risk factors associated with adverse outcome following extracorporeal life support: analysis from 360 consecutive patients. Perfusion. 2015;30:284–290.
162. Rubino AS, Torrisi S, Milazzo I, et al. Designing a new scoring system (QualyP Score) correlating the management of cardiopulmonary bypass to postoperative outcomes. Perfusion. 2015;30:448–456.
163. Li CL, Wang H, Jia M, Ma N, Meng X, Hou XT. The early dynamic behavior of lactate is linked to mortality in postcardiotomy patients with extracorporeal membrane oxygenation support: a retrospective observational study. J Thorac Cardiovasc Surg. 2015;149:1445–1450.
164. Zhang Z, Ni H. Normalized lactate load is associated with development of acute kidney injury in patients who underwent cardiopulmonary bypass surgery. PLoS One. 2015;10:e0120466.
165. Saxena P, Neal J, Joyce LD, et al. Extracorporeal membrane oxygenation support in postcardiotomy elderly patients: the Mayo Clinic experience. Ann Thorac Surg. 2015;99:2053–2060.
166. Zacharias HU, Hochrein J, Vogl FC, et al. Identification of plasma metabolites prognostic of acute kidney injury after cardiac surgery with cardiopulmonary bypass. J Proteome Res. 2015;14:2897–2905.
167. Hsu YC, Hsu CH, Huang GS, et al. Extreme hyperlactatemia after heart transplantation: one center’s experience. Transplant Proc. 2015;47:1945–1948.
168. Youssefi P, Timbrell D, Valencia O, et al. Predictors of failure in fast-track cardiac surgery. J Cardiothorac Vasc Anesth. 2015;29:1466–1471.
169. Jorge-Monjas P, Bustamante-Munguira J, Lorenzo M, et al. Predicting cardiac surgery-associated acute kidney injury: The CRATE score. J Crit Care. 2016;31:130–138.
170. Zhang Z, Xu X. Lactate clearance is a useful biomarker for the prediction of all-cause mortality in critically ill patients: a systematic review and meta-analysis.* Crit Care Med. 2014;42:2118–2125.
    171. Smits N. A note on Youden’s J and its cost ratio. BMC Med Res Methodol. 2010;10:89.
    172. Cantor SB, Sun CC, Tortolero-Luna G, Richards-Kortum R, Follen M. A comparison of C/B ratios from studies using receiver operating characteristic curve analysis. J Clin Epidemiol. 1999;52:885–892
    173. Pauker SG, Kassirer JP. The threshold approach to clinical decision making. N Engl J Med. 1980;302:1109–1117.
    174. Pölönen P, Ruokonen E, Hippelainen M, Poyhonen M, Takala J. A prospective, randomized study of goal-oriented hemodynamic therapy in cardiac surgical patients. Anesth Analg. 2000;90:1052–1059.
    175. Xu R, Laine GA, Hu BY, Solis RT, et al. Outcomes associated with a screening and treatment pathway for occult hypoperfusion following cardiac surgery. World J Cardiovasc Surg. 2013;3:34–41.
    176. Jansen TC, van Bommel J, Schoonderbeek FJ, et al.; LACTATE Study Group. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010;182:752–761.
    177. Jansen TC, van Bommel J, Bakker J. Blood lactate monitoring in critically ill patients: a systematic health technology assessment. Crit Care Med. 2009;37:2827–2839.

    Supplemental Digital Content

    Copyright © 2017 International Anesthesia Research Society