INTRODUCTION

Since the successful use of cardiopulmonary bypass (CPB) in 1953, several advances in cardiac surgery have made it a less morbid procedure, with a significantly less mortality. There is an increasing interest in the metabolic consequences of CPB, the effects of tissue hypoperfusion, inflammatory responses, use of inotropes, and their association with circulating biomarkers as surrogates of patient morbidity and mortality. Risk stratification using scoring systems such as the European System for Cardiac Operative Risk Evaluation (or EuroSCORE) II or the Society of Thoracic Surgeons (or STS) risk stratification score have been acceptable till date, but being risk assessment tools, they don’t address patient outcome parameters following surgery^[1,2]. Postoperative levels of circulating biomarkers can also serve as prognostic indices of patient outcome in cardiac surgery. Among the various circulating markers, lactate has been studied extensively as a marker of tissue perfusion^[3]. Arterial lactate level is an important marker for monitoring shock in a wide range of patients and considered a part of the diagnostic criteria for septic shock^[4-6]. Hyperlactatemia is generally considered a serum lactate level > 2 millimoles per litre (mmol/l)^[7]. The development of hyperlactatemia in patients undergoing surgery on CPB is multifactorial and has been attributed to the time-dependant deleterious effects of CPB on the normal circulatory physiology and cellular function^[8]. Postoperative lactate levels are being actively researched as markers for adverse outcome and predicting mortality.

This study aims to determine the association between lactate and lactate clearance with early mortality and to determine their significance in postoperative morbidity including duration of vasopressor use, intensive care unit (ICU) stay, and hospital stay.

METHODS

This is a prospective cohort study carried out in the Department of Cardiovascular and Thoracic Surgery, King George’s Medical University (Lucknow, India), from January 2020 to December 2022. After obtaining ethical clearance from the institute’s ethics committee (103^rd ECM II B-Thesis/P14), patients in the age group 18-75 years undergoing open heart surgery on CPB were recruited for the study after taking written informed consent. All procedures were in accordance with the ethical standards of the institutional ethics committee and with the Declaration of Helsinki (1975) and its later amendments or comparable ethical standards. Patients who did not consent for participation and those of age groups < 18 or > 75 years were excluded. Patients undergoing off-pump cardiac procedures, aortic surgery (for dissection/aneurysm), and complex congenital cardiac surgery (including cyanotic congenital heart surgery) and emergency cases were excluded. Patients with uncontrolled diabetes (glycated haemoglobin [HbA1C] > 7), unoptimized thyroid function, chronic kidney disease, chronic liver disease, chronic obstructive pulmonary disease, and those with active Coronavirus disease 2019 infection were also not included in the study.

RESULTS

As depicted in Figure 1, 300 patients who fulfilled the inclusion criteria were initially recruited. Thirty patients were lost to follow-up and were further excluded from the study. Therefore, a total of 270 patients were included in this study. The demographic and clinical laboratory findings are detailed in Table 1. The mean age was 38.1 ± 14.2 years, with most patients belonging to < 50-year age group, and there was roughly equal gender distribution. Of the patients, 7.4% were smokers, and 4.8% were diabetic; 83% presented with New York Heart Association (NYHA) class III, and the median preoperative ejection fraction was 58% [54-62]; 74.8% cases had valvular pathology, while the rest had coronary artery disease, congenital heart disease, and tumours. The median bypass time in the study group was 71 [55-103.5] minutes; and median cross-clamping time was 34 [25-62] minutes. Of all the cases, 7.4% needed intraoperative defibrillation, while 2.6% required IABP support. The median duration of mechanical ventilatory support in the postoperative period was 6.5 hours^[6-9], while a median of 1 unit of packed red cell (PRC) was transfused in the patients^[1-2]. The average length of ICU stay was 3.08 ± 0.86 days, while the average postoperative hospital stay was 5.25 ± 1.98 days. The median lactate levels showed a steady rise till the end of the first postoperative day and resolved by 48 hours following surgery. We observed early mortality in 17 cases (6.3%). While low cardiac output syndrome and right ventricular failure were the leading causes, infection resulting in ventilator-associated pneumonia and sepsis were also notable.

Table 1 - Patients’ demographic profile and clinical, procedural, and laboratory parameters.

Fig. 1 - Research methodology - patient selection process.

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Fig. 1 - Research methodology - patient selection process.

Univariate analysis (Table 2) demonstrated a significantly higher early mortality in patients with diabetes, intraoperative use of defibrillation, and IABP use. The early mortality group had a prolonged duration of ventilation and inotrope use, whereas postoperative ICU and hospital stay were shorter. Serial lactate levels significantly raised from the preoperative period to 24 hours following surgery in the mortality group, however, lactate clearance was not significantly different (Table 3).

Table 2 - Association of demographic profile and clinical parameters and lactate with mortality.

Table 3 - Association of lactate values with early mortality.

Duration of mechanical ventilatory support and vasopressor duration showed significant correlation with lactate and lactate clearance from to six to 48 hours following surgery. Correlation of ICU stay was significant with lactate in preoperative period, while on-pump, and at 24 and 48 hours following surgery, while lactate clearance correlated significantly with ICU stay from six through 48 hours. Postoperative hospital stay correlated only at preoperative lactate levels and lactate clearance at 48 hours (Table 4).

Table 4 - Correlation of lactate and lactate clearance with duration of inotrope requirement, mechanical ventilatory support, ICU stay, and hospital stay.

Our logistic regression analysis included the variables that had been significant in the univariate analysis, i.e., diabetes, use of IABP, intraoperative defibrillation, vasopressor duration, ventilatory support duration, packed red cells transfused, length of ICU stay, and length of hospital stay, along with lactate values from the preoperative period to 24 hours following surgery. The logistic regression analysis demonstrated lactate levels at preoperative period (adjusted odds ratio [OR] 4.76 [1.67-13.59], P=0.004), at 24 hours after bypass (OR 1.21 [1.00-1.47], P=0.046), and vasopressor duration (OR 1.11 [1.04-1.19], P=0.002) as key independent predictors of mortality (Table 5).

Table 5 - Logistic regression analysis depicting independent predictors of in-hospital mortality.

In the ROC curve analysis (Figure 2), on-pump, off-pump, and at six, 12, and 24 hours following surgery arterial lactate had significant AUC for mortality.

Fig. 2 - Receiver operating characteristic (ROC) curve analysis for lactate at various intervals and mortality. AUC=area under the curve.

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Fig. 2 - Receiver operating characteristic (ROC) curve analysis for lactate at various intervals and mortality. AUC=area under the curve.

Arterial lactate ≥ 7.3 at 24 hours had the highest specificity (98.1%) for predicting mortality, but with a poor sensitivity (57.1%). The highest sensitivity of arterial lactate for mortality was 76.5% for on-pump arterial lactate levels ≥ 3.25 mmol/l (Table 6).

Table 6 - Sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios of lactate at the preoperative period, intraoperatively on-pump, after coming off-pump, and at six, 12, 24, and 48 hours postoperatively.

DISCUSSION

In our cohort of 270 patients, the early mortality group had a prolonged duration of ventilation, inotrope use, and postoperative ICU and hospital stays. We also found that patients with diabetes and intraoperative use of defibrillation had a significantly higher mortality. While our patients had optimised blood sugars and HbA1C was < 8 in all cases, the overall effects of hyperglycaemia and response to surgical stress may be important factors that affect the outcome. Diabetes - especially uncontrolled - can lead to increased morbidity, however, optimum preoperative level of HbA1C is still being debated. Diabetes itself has been linked to increased incidence of prolonged ICU stay, sternal instability and/or dehiscence, respiratory insufficiency, delirium, stroke, renal dysfunction, and postoperative reintubation^[9,10]. The use of defibrillation was higher in the mortality subgroup, corroborating with data from few studies which also found increased in-hospital mortality for patients receiving treatment for perioperative ventricular fibrillation. This can be explained by the fact that while coming off pump, ventricular fibrillation results in subendocardial ischemia that, in turn, results in myocardial dysfunction^[11,12].

We also found that lactate levels were significantly elevated in the mortality group from the preoperative period till 24 hours following surgery, however, lactate clearance did not show significant difference between the two groups. Lactate and lactate clearance both correlated significantly with duration of mechanical ventilatory support and vasopressor duration in the postoperative period. ICU stay and hospital stay also correlated with the lactate and lactate clearance levels. This indicates that elevated lactate levels have a potential impact on patients undergoing on-pump cardiac surgery.

Hyperlactatemia in cardiac surgery has been linked to prolonged CPB time, which is attributed to tissue hypoperfusion that, in turn, is a result of CPB use^[8,13]. However, age, complexity and urgency of surgery, blood transfusion, pH during CPB, status of venous return, use of lactate containing priming solutions, diabetes, use of milrinone, propofol and norepinephrine, and renal function have been noted as significant causes of postoperative hyperlactatemia. A few important outcome parameters affected by this ensuing hyperlactatemia during CPB include prolonged ICU stay, duration of mechanical ventilatory support, hospital stay, risk of developing acute renal failure, respiratory distress, pneumonia, and circulatory disorders. The arterial lactate level itself has also been investigated, suggesting that normal lactate levels during CPB may well exceed the normal limits^[8,14,15].

The question as to how much lactate levels can be considered as significant, when these levels should be evaluated, and how they reflect on the patient outcome is a matter of ongoing research.

Kogan et al.^[16] had demonstrated a significant association between arterial lactate levels > 4.4 mmol/l during the first postoperative 10 hours with prolonged ventilation time, longer ICU stay, and increased mortality. Algarni et al.^[17], in a study on 307 cardiac surgery patients, had found significant association between early hyperlactatemia (lactate > 3 mmol/l, within 24 hours of surgery) and increased CPB time, requirement of postoperative extracorporeal membrane oxygenation support (0% vs. 5.7%, P<0.0001), increased hospital mortality, and prolonged ICU stay.

In a retrospective analysis of 7,447 patients, Duval et al.^[18] found that while the median ∆-lactate of most patients undergoing cardiac surgery was 0.6 (0.3-1) mmol/L (∆-lactate was defined as the difference between the highest intraoperative blood lactate and the baseline lactate level), most of patients (65.9%) exhibited a ∆-lactate between 0.1 and 0.9 mmol/L. There was a concentration-dependent relationship between ∆-lactate and 30-day mortality (as of a 1 mmol/L increase). Haanschoten et al.^[19] had determined that postoperative peak arterial levels can serve as independent predictors for 30-day mortality (OR 1.44 [1.39-1.48], P<0.001) as well as for late mortality (hazard ratio 1.05 [1.01-1.10], P<0.025). Patra et al.^[20] (2019), in their retrospective analysis of 362 open heart surgery patients, had stated that lactate levels at ICU admission and 12-hour blood lactate level were significant predictors of complications. Whereas, 24-hour blood lactate level was significantly associated with prolonged ICU stay and hospital stay.

Matteucci et al.^[21], in their study of 1,099 adult patients undergoing on-pump surgery, noted that 33.8% of patients developed hyperlactatemia (lactate > 2 mmol/l) postoperatively. Emergency procedure, CPB duration, and aortic cross-clamping time were independently associated with hyperlactatemia. These patients had significantly prolonged ventilation time, hospital stay, vasopressor requirement, IABP support, and 30-day mortality. Kaplan-Meier curve showed worse long-term survival (mean follow-up: 4.02 ± 1.58 years) in these patients.

Naik et al.^[8], in their retrospective analysis of 370 patients undergoing cardiac surgery on CPB, found that there was a significant correlation between aortic cross-clamping time and CPB time with peak intraoperative blood lactate levels. Patients with hyperlactatemia had significantly higher rate of postoperative morbidity like prolonged requirement of inotropes, atrial fibrillation (AF), and prolonged ICU and hospital stays.

To further understand the utility of both lactate and lactate clearance as predictors of mortality, we used multivariate logistic regression analysis, which suggested that preoperative lactate, lactate at 24 hours, and vasopressor duration were independent predictors of early mortality in this cohort. Furthermore, the adjusted odds for mortality were highest for preoperative lactate levels (OR 4.76 [1.67-13.59], P=0.004). Given the abovementioned findings, we can conclude that despite being correlated with duration of ventilatory and vasopressor supports, lactate clearance does not have much significant impact on predicting mortality.

In the ROC curve analysis, we found that on-pump lactate levels > 3.25 mmol/l had the highest sensitivity (76.5%), with a likelihood ratio of 1.98 in predicting mortality. Lactate levels > 7.3 at 24 hours following CPB had maximum specificity (98.1%). We can infer that although very specific at 24 hours, lactate levels don’t provide high sensitivity for use in predictive models for risk stratification.

Kim et al.^[22] (2020), in a study involving 207 adult congenital heart surgery patients, had found that lactate was elevated > 5 mmol/L in 42% of the cases. They could not find any significant difference among different lactate level groups in hospital stay, ICU stay, ventilation requirement, acute kidney injury (AKI), need for redo surgery, or rates of hospital or ICU readmission. In multivariable analysis, lactate levels were not a significant predictor of either hospital length of stay or AKI.

Considering the complexity of biochemical responses and alteration in physiology, perhaps using lactate as a stand-alone marker for predicting mortality may not yield better results. In a study including 1,058 patients and comparing base excess (BE) and lactate for determining ICU mortality after cardiac surgery, Zante et al.^[23] found that lactate levels > 3.9 mmol/l at ICU admission had 61.9% sensitivity and 87.5% specificity for predicting mortality. Their subgroup analyses revealed a combination of lactate ≤ 3.9 mmol/l and BE ≥ -6.7 had stronger impact on mortality than a combination of lactate of > 3.9 mmol/l and BE > -6.7 (hazard ratio 2.56, 95% confidence interval 0.18-37.17). This can indicate that BE might be superior to lactate in predicting ICU mortality after cardiac surgery.

The level of lactate in patients undergoing surgery on CPB is also a matter of debate and despite authors recommending higher than normal lactate values as cutoffs, our findings suggest that on-pump lactate of > 3.25 mmol/l is most sensitive. Svenmarker et al.^[14] had also deduced an on-pump lactate of > 2 mmol/l as a significant predictor for mortality. Therefore, it can benefit the patients if on-pump lactates are kept within range to avoid postoperative complications.

CONCLUSION

We can conclude that arterial lactate and lactate clearance show good correlation with duration of mechanical ventilation, vasopressor support, ICU stay, and hospital stay, and can serve as a good indicator to guide therapeutic decisions in the postoperative period, however, it failed to serve as a sensitive marker (maximum sensitivity on-pump of 76.5% for arterial lactate > 3.25 mmol/l) to predict mortality. Therefore, further attention needs to be focussed on other markers such as BE, lactate clearance, and ∆-lactate to assess their utility in predicting mortality.