**6. Blood lactate levels as a biomarker**

### **6.1 General**

314 Perioperative Considerations in Cardiac Surgery

early postoperative period in patients after cardiac surgery under extracorporeal circulation. Post-cardiac surgery hyperlactatemia is mostly the consequence of excess lactate production, although a reduction of hepatic lactate clearance may contribute to the condition. Early postoperative measurable adverse effects, such as base deficit, maximal anion gap and bicarbonate levels, were significantly different between patients with postoperative hyperlactatemia and patients with low-normal lactatemia in the early postoperative period (i.e., less than 12 hours after admission to the ICU), while postoperative lactate and glucose

Inadequate tissue oxygen delivery because of impaired cardiac output after pediatric cardiac surgery is a relatively common problem which can be expressed in early stages by hyperlactatemia, and one that has been associated with significant morbidity and mortality

Elevated lactate concentrations were associated with metabolic acidosis following cardiac surgery. Moreover, postoperative episodes of hypotension, hyperglycemia, and epinephrine, norepinephrine or dobutamine consumption were more frequent in patients with hyperlactatemia following cardiac surgery compared to patients with non-elevated

Clinical indicators used for diagnosing decreased cardiac output other than hyperlactatemia include a low peripheral temperature/core temperature gradient, long capillary refill time, high pulse and low blood pressure, decreased urine output and base deficit (Bohn, 2011). Most of these indicators do not reflect cardiovascular performance very well (Tibby et al.,

Averaged cerebral and renal rS02 levels of less than 65% as measured by near-infrared spectroscopy (NIRS) predict hyperlactatemia (>3 mmol/L, 27 mg/dL ) in acyanotic children after congenital heart surgery (Chakravarti et al., 2009). The averaged cerebral and renal rS02 was a good predictor of the lactate status, with a value less than or equal to 65%, predicting a lactate level of greater than or equal to 3.0 mmol/L (27 mg per dL), with a sensitivity of 95% and a specificity of 83% in the studied patients. Consequently, monitoring of rS02 could aid in the prompt identification of patients at risk for hyperlactatemia and low-cardiacoutput syndrome (Chakravarti et al., 2009). A combination of cerebral and renal rS02 with an average value less than 65% using the intravenous NIRS device could, therefore, predict hyperlactatemia (>3 mmol/L (>27 mg/dL)) in acyanotic children after congenital heart

Patients with higher blood lactate levels during CPB were also more likely to have myocardial infarction and postoperative neurologic, hemodynamic, pulmonary, digestive,

Moreover, sepsis as postoperative complication, can be the cause for late postoperative

Patients without signs of clinical shock can still be hypoperfused and are at high risk for preperi- and postoperative complications. They tend to develop postoperative hyperlactatemia. Patients undergoing surgery with a RACHS-1 score of IV and higher are not expected to maintain good cardiac output in the postoperative period, emphasizing the importance of combining pre- peri- and postoperative prognosis predictors, especially for the so called

levels were significantly correlated (Abraham et al., 2010; Chiolero et al., 2000).

(Chakravarti et al., 2009).

1997).

surgery.

hyperlactatemia.

**5.3 Summary** 

blood lactate levels (Maillet et al., 2003).

or renal complications (Demers et al., 2000).

"preoperative good prognosis" groups.

Biomarkers that are sensitive and rapidly measurable could allow early intervention and improve patient outcomes. Efforts are aimed at developing novel biomarkers and surrogates for disease severity to indicate conditions associated with organ dysfunction early on and by early intervention lead to improved outcome. Lactate levels are commonly used to stratify risk and to assess adequacy of resuscitation among high risk patients in the ICU (Smith et al., 2001). Lactate may have prognostic value in critically ill patients with either observed or occult tissue hypoperfusion.

Lactate levels higher than 2 mmol/L (18 mg/dL) after 48 hours predicted mortality with a specificity of 86% and poor neurologic outcome with a specificity of 87%. Sensitivity for both end points was 31%. Lactate at 48 hours after cardiac arrest is an independent predictor of mortality and unfavorable neurologic outcome. Persisting hyperlactatemia over 48 hours. predicts a poor prognosis (Kliegel et al., 2004). Sensitivity and specificity of lactate >2 mmol/L (18 mg/dL) to predict ICU mortality was 74.8% and 77.8%, respectively. The odds ratio for dying in patients with hyperlactatemia was 10.39 (95% CI, 6.378-16.925), with a relative risk of 1.538 (95% CI, 1.374-1.721) (Juneja et al., 2011). In one multicenter, open-label randomized controlled study on patients who had hyperlactatemia on general ICU admission, lactate monitoring followed by hyperlactatemia-targeted treatment significantly reduced length of stay in the ICU. In addition, ICU and hospital mortality were reduced when adjusting for predefined risk factors (Jansen et al., 2010). In that study, the time of the first available lactate level immediately after ICU admission was taken as the baseline and patients were randomly allocated to either treatment aimed to decrease lactate levels by at least 20%/2 hours or to standard therapy for the following 8 hours.

Elevated blood lactate levels in the presence of normal vital signs (occult hypoperfusion) are good markers of mortality in surgical patients. It is therefore important to identify the highrisk surgical patients who have had a stable hemodynamic course during surgery and immediately after admission to the ICU. Blood lactate levels are superior to several clinical markers of shock or organ failure, including the heart rate, diuresis and the mean arterial pressure, or indices of metabolic acidosis.

In adults following cardiac surgery, blood lactate levels at admission to the ICU were the best predictors of ICU mortality (AUC, 0.84; 95% CI, 0.73 to 0.95), compared to lactatemia measured during the ICU stay (Maillet et al., 2003). Early postoperative hyperlactatemia is associated with adverse outcome of surgery. When they were compared with patients with a normal lactate profile, patients with late hyperlactatemia showed no increase in hospital mortality (OR 0.57, 95%CI 0.07 to 5.05) (O'Connor & Fraser 2010). However, Nichol et al. (2010) reported that early (at admission) and late (post-admission) hyperlactatemia were both strongly associated with mortality in cardiac/vascular surgical patients of whom a significant number were postoperative cardiac patients).

Boyd et al. (1993) demonstrated a 75% reduction in postoperative mortality in adults when targeted therapy was guided by blood lactate levels as predictors for poor prognosis.

Moreover, Kliegel et al. (2004) claimed that sequential measurements during therapy may be more useful than a single measurement since the rapidity at which lactate is cleared from the blood during resuscitation correlates better with outcome — including mortality or organ failure — than a single measure. They showed that survivors' blood lactate levels decreased significantly with time, while those levels remained stable in the non-survivor group.

Among a cohort of 9107 first admissions with an ICU stay of at least one day, both hyperlactatemia at presentation and its later development were associated with significantly increased fatality rates compared with patients without elevated lactate (20% vs. 5%; P < 0.001 and 27% vs. 4%; P < 0.001, respectively). After controlling for confounding effects in multivariable logistic regression analyses, hyperlactatemia was an independent risk factor for death (Khosravani et al., 2009). When broadly implemented in routine practice, measurement of lactate in patients with infection and possible sepsis can affect assessment of mortality risk. Specifically, an initial lactate level equal to or greater than 4.0 mmol/l (36 mg/dL) substantially increases the probability of acute phase death (Trzeciak et al., 2007).

Blood lactate concentrations greater than 5 mmol/L in patients with severe acidosis (pH less than 7.35 or base deficit greater than 6) carries a mortality of 80% (Stacpoole et al., 1994).

It is well established that hyperlactatemia is also a postoperative prognostic factor. Historically, a rise in blood lactate levels was associated with a decrease in survival rates (Weil & Afifi 1970). These results were recently repeated by a number of investigators. The severity of hyperlactatemia was shown to correlate with oxygen debt and poor survival (Mizock & Falk, 1992), and sustained presence of hyperlactatemia was confirmed as being an important risk factor for poor outcome of critically ill patients (Abubacker et al., 2003; Bakker et al., 1996; Gogos et al., 2003; Kobayashi et al., 2001).

Patients with lactic acidosis were shown to have a higher mortality rate and are at a greater risk of developing multiple organ failure (Bakker et al. 1996). ICU mortality was significantly increased in patients with hyperlactatemia who did not have hypotension (P = .009) (Juneja et al., 2011). Similarly to other changes in blood acid-base balance and electrolytic composition, this metabolic disturbance is a factor that frequently complicates the early postoperative period in patients after cardiac surgery under extracorporeal circulation.

#### **6.2 Post-pediatric congenital heart disease repair**

An elevated lactate level has been associated with an increased risk for morbidity and mortality after pediatric cardiac surgery (Basaran et al., 2006; Charpie et al., 2000; Cheifetz et al., 1997; Duke et al., 1997). Elevated blood lactate levels were associated with a higher mortality rate and postoperative complications in hemodynamically stable surgical patients, and failure of serum lactate levels to reach normal values within a specific time during critical illness could be even more closely related to survival than the initial level (Meregalli et al., 2004). Hyperlactatemia during and after CPB has been linked to increased morbidity and mortality in children undergoing surgical repair of complex CHD (Cheung et al., 2005; Munoz et al., 2000). Several factors contribute to lactic acidosis because of global ischemia occurring during circulatory arrest and the hypocirculatory state during cardiopulmonary resuscitation. Oxygen deficiency leads to anaerobic metabolism and therefore to overproduction of lactate. At the same time, the profound ischemic state may impair liver function, leading to reduced lactate elimination. Basaran et al. (2006) reported that mean lactate levels correlated significantly with inotrope score, intubation time, and duration of intensive care unit stay.

In their prospective cohort study of 90 children post-congenital heart surgery, Duke et al.'s (1997) multivariable logistic regression analysis showed that lactate levels were an independent predictor of major adverse events. These adverse events included death,

Among a cohort of 9107 first admissions with an ICU stay of at least one day, both hyperlactatemia at presentation and its later development were associated with significantly increased fatality rates compared with patients without elevated lactate (20% vs. 5%; P < 0.001 and 27% vs. 4%; P < 0.001, respectively). After controlling for confounding effects in multivariable logistic regression analyses, hyperlactatemia was an independent risk factor for death (Khosravani et al., 2009). When broadly implemented in routine practice, measurement of lactate in patients with infection and possible sepsis can affect assessment of mortality risk. Specifically, an initial lactate level equal to or greater than 4.0 mmol/l (36 mg/dL) substantially increases the probability of acute phase death

Blood lactate concentrations greater than 5 mmol/L in patients with severe acidosis (pH less than 7.35 or base deficit greater than 6) carries a mortality of 80% (Stacpoole et al., 1994). It is well established that hyperlactatemia is also a postoperative prognostic factor. Historically, a rise in blood lactate levels was associated with a decrease in survival rates (Weil & Afifi 1970). These results were recently repeated by a number of investigators. The severity of hyperlactatemia was shown to correlate with oxygen debt and poor survival (Mizock & Falk, 1992), and sustained presence of hyperlactatemia was confirmed as being an important risk factor for poor outcome of critically ill patients (Abubacker et al., 2003;

Patients with lactic acidosis were shown to have a higher mortality rate and are at a greater risk of developing multiple organ failure (Bakker et al. 1996). ICU mortality was significantly increased in patients with hyperlactatemia who did not have hypotension (P = .009) (Juneja et al., 2011). Similarly to other changes in blood acid-base balance and electrolytic composition, this metabolic disturbance is a factor that frequently complicates the early postoperative period in patients after cardiac surgery under extracorporeal

An elevated lactate level has been associated with an increased risk for morbidity and mortality after pediatric cardiac surgery (Basaran et al., 2006; Charpie et al., 2000; Cheifetz et al., 1997; Duke et al., 1997). Elevated blood lactate levels were associated with a higher mortality rate and postoperative complications in hemodynamically stable surgical patients, and failure of serum lactate levels to reach normal values within a specific time during critical illness could be even more closely related to survival than the initial level (Meregalli et al., 2004). Hyperlactatemia during and after CPB has been linked to increased morbidity and mortality in children undergoing surgical repair of complex CHD (Cheung et al., 2005; Munoz et al., 2000). Several factors contribute to lactic acidosis because of global ischemia occurring during circulatory arrest and the hypocirculatory state during cardiopulmonary resuscitation. Oxygen deficiency leads to anaerobic metabolism and therefore to overproduction of lactate. At the same time, the profound ischemic state may impair liver function, leading to reduced lactate elimination. Basaran et al. (2006) reported that mean lactate levels correlated significantly with inotrope score, intubation time, and duration of

In their prospective cohort study of 90 children post-congenital heart surgery, Duke et al.'s (1997) multivariable logistic regression analysis showed that lactate levels were an independent predictor of major adverse events. These adverse events included death,

Bakker et al., 1996; Gogos et al., 2003; Kobayashi et al., 2001).

**6.2 Post-pediatric congenital heart disease repair** 

(Trzeciak et al., 2007).

circulation.

intensive care unit stay.

cardiac arrest, emergency chest reopening, and an increased risk of failure of 3 or more organ systems. The only measurement that those authors found to consistently predict major adverse events was an elevated serum lactate concentration at the time of ICU admission and at 4, 8, 12, and 24 hours postoperatively (Duke et al., 1997). Of the all variables tested by Seear et al. by stepwise discriminant analysis, serum lactate and Scv02 emerged as the only ones with significant predictive power for major adverse events. This predictive effect was present at all measurement time points (3, 6, 9, 12, and 24 hours, postoperatively) (Seear et al., 2008). Initial postoperative lactate levels above 4.2 mmol/L (38 mg/dL), above 4.5 mmol/L (40.5 mg/dL), and above 6 mmol/L (54 mg/dL) were associated with a positive predictive value for mortality of 16.7%, 32% and 100% respectively (Hatherill et al., 2000; Siegel et al., 1996).

Hyperlactatemia during CPB is relatively frequent and is associated with an increased postoperative morbidity. Hyperlactatemia has an independently predictive value for major adverse events post-CHD surgical repair, when measured at ICU admission and at 4 and 8 hours, with an odds ratio of 5.1, 8.3 and 9.3 respectively, and with a specificity of 91%, 94% and 95%, respectively (Duke et al., 1997). Death was predicted at ICU admission only by the patient's blood lactate value (p = 0.03) and not by any of the other physiologic measures. The odds ratio for death was 29.3 (with a confidence interval of 2.7 to 315) when the admission blood lactate level was greater than 4.5 mmol/L (40.5 mg/dL). However, it should be emphasized that the finding of a normal lactate level did not preclude the possibility of a major adverse event. A lactate level greater than 3 mmol/L (27 mg/dL) at the time of admission to the ICU identified only 50% of those who subsequently had a major complication, thus the sensitivity was relatively low but the specificity was very high (Duke et al., 1997).

As noted earlier, hyperlactatemia post-CHD repair is usually due to decreased cardiac output and hypoperfusion (secondary, type A). Basaran et al. (2006) prospectively studied 60 infants undergoing surgery for CHD and showed that mortality was higher in the group with a mean lactate of greater than 4.8 in the early postoperative period. In another group of 46 infants, the mean initial lactate level was significantly higher in patients who had a poor outcome (as defined as death or the need for extracorporeal membrane oxygenation in the first 72 Hours) than in patients with a good outcome (Charpie et al., 2000).

Studies have shown that blood lactate levels are even superior to mixed venous oxygen saturation in predicting outcome (Duke et al., 1997). Our previous work has validated the measurement of lactate levels as a reliable tool for predicting the postoperative survival of children undergoing cardiac surgery (Molina Hazan et al., 2010). The progression of lactate levels with time was significantly different between the patients in different RACHS-1 subgroups (p = 0.029), and the lower the RACHS-1 score at each time point, the lower were the mean lactate levels for each time point (p < 0.001). Moreover, postoperative blood lactate levels differed significantly between survivors and nonsurvivors within the same RACHS-1 subgroup. The lactate level at admission to the PCCU compared with the postoperative lactate level was the most significant parameter for predicting non-survival (odds ratio = 1.038, AUC =0.881, p < 0.001). Lactate levels above 53 mg/dL had the sensitivity for non-survival of 88.9% and specificity of 23.4%: accordingly, a patient admitted to the PCCU with lactate levels higher than 53 mg/dL would have an almost 90% risk of dying. Patients who died or survived with complications had higher admission lactate levels compared with survivors without complications (8.5 vs. 4.6 vs. 2.0 mmol/L) (Munoz et al., 2000).

Serum lactate best predicted major adverse events for values greater than 8 mmol/L (>72 mg/dL) with a low sensitivity (73.7%), a high specificity (96.3%) and a low positive predictive value (63.6%) in high risk cases (Seear et al., 2008). The ratio of central venous oxygen sampling (Scv02, measured in %) per lactate (measured in mmol/L) had a better predictive value for major adverse events than each individual value measured alone (if the value of the ratio fell below 5 at any time after surgery, the positive predictive value for major adverse events was above 90%).

The length of time it took for serum lactate levels to reach normal values was a useful predictor of mortality in children undergoing repair or palliation of CHD under CPB, while initial and peak lactate levels had a poor positive predictive value for mortality in that retrospective study (Kalyanaraman et al., 2008). Hyperlactatemia was described as the only predictor of persistent renal impairment at 48 hours at the time of admission to the intensive care unit was the admission blood lactate level (p = 0.018) (Duke et al., 1997). The odds ratio for renal impairment was 3.2 (with a confidence interval of 1.1 to 9.5) for patients whose admission lactate level was greater than 4 mmol/L (36 mg/dL) (Duke et al., 1997). According to the results of a retrospective review of children aged 0-21 years who had been admitted to a cardiac ICU, the length of time during which the lactate level remained greater than 2 mmol/L (18 mg/dL) was associated with the number of ventilator days and hospital days for the survivors. They all had surgery for CHD and required CPB (DeCampli & Burke, 2009; Kalyanaraman et al., 2008).

The lactate level was also considered as being a risk factor for cerebral damage, which was defined as the development of seizures, movement disorders, developmental disorders, cerebral hemorrhage, infarction, hydrocephalus, or marked cerebral atrophy in children after they had undergone cardiac surgery (Trittenwein et al., 2003).

## **6.3 Summary**

Measurements of blood lactate reflect oxygen delivery to tissues and, therefore, are useful in guiding clinical management. Levels of serum lactate are indirect markers of tissue hypoxia secondary to insufficient peripheral oxygen delivery. They have been used to monitor progress after pediatric heart surgery and to report positive predictive values (Duke et al., 1997; Hatherill et al., 2000; Munoz et al., 2000).

Lactate levels differed significantly between survivors and non-survivors even within the same preoperative prognosis subgroup. As such, a combination of preoperative scores and postoperative serial lactate measurements is needed in order to serve as a useful marker for the postoperative course of cardiac patients, allowing the targeting of appropriately intensive interventions and therapies for the sickest among them, especially for the apparently low risk groups whose poorer perioperative course and worse outcome may not have been predictable from the preoperative scores alone. A cutoff threshold of 3 mmol/L (27 mg/dL) at ICU admission will identify a subpopulation of patients at higher postoperative risk.
