Prognostic Cardiac Biomarkers and Tetralogy of Fallot Score: Do they Predict Outcomes in Intracardiac Tetralogy of Fallot Repair?

INTRODUCTION

Tetralogy of Fallot (TOF) is an endemic disease in India. Due to the presence of chronic hypoxia, they are most susceptible to ischemia and infections. With intracardiac repair done for its correction on cardiopulmonary bypass (CPB), systemic inflammatory response syndrome (SIRS) sets in, affecting its hemostatic, hepatic, pulmonary, and renal functions, thus worsening heart failure.^[1] The majority of the time, clinical features and blood gas analysis reports are used as prognostic markers.^[2,3] However, postoperative morbidity and mortality can be predicted earlier by incorporating various biochemical markers in the pre-operative workup, which may help as baseline markers and predict worsening intraoperative and postoperative outcomes of prolonged intensive care unit (ICU) stay and high inotrope use.^[4]

Arterial blood gas parameters such as lactate, partial pressure of oxygen (PO₂), base excess, and biomarkers such as Endothelin, B natriuretic peptide (BNP), and tumor necrosis factor-alpha (TNF-α), during CPB as prognostic markers for major morbidity in TOF undergoing ICR were evaluated in this study. Measuring their levels was the primary objective, and secondary objectives were determining the total ICU length of stay, the incidence of fibrillation on post-CPB, the duration of ventilator use, duration of inotrope, presence of oliguria, and mortality in the ICU.

Inflammatory markers such as Endothelin and TNF-α are proinflammatory cytokines that have been shown to play a major role in SIRS secondary to CPB.^[1-4] It may decrease post CPB according to some in the literature review.^[5-10]

Galasko et al.^[10] also have suggested that studies on BNP in patients with congenital heart disease should be compared with age and gender-specific normal values.

MATERIAL AND METHODS

After the Ethics Committee approval (Trial No-5/4/1-1/08-NCD-II), this ICMR-funded project was carried out on 150 patients in the age groups from 1 month to 20 years of age of TOF patients undergoing an ICR. Patients were divided into two groups using a sealed envelope technique. Group I included patients <15 years of age, and Group II which included patients >15 years of age. Patients with preexisting heart failure, clotting disorders, renal dysfunction (serum creatinine than 2 mg/dL) with oliguria, hepatic or nervous system, and immune compromised patients were excluded from the study.

All routine anesthetic and surgical steps were followed as per institutional protocol for all patients. Patients were pre-medicated with oral midazolam 0.5 mg/kg. Patients were induced with injection ketamine (1–2 mg/kg), injection fentanyl (2–3 mcg/kg), and injection rocuronium (0.8–1 mg/kg) to facilitate tracheal intubation. Anesthesia was maintained with sevoflurane (0.5–2%) in an oxygen-air mixture with intermittent doses of fentanyl, midazolam, and cisatracurium infusion. Monitoring included electrocardiogram, pulse oximetry, invasive blood pressure, central venous pressure (CVP), and urine output. Baseline activated clotting time (ACT) was noted before systemic heparinization with 300–400 units/kg of unfractionated heparin to achieve a target ACT of more than 480 s. After surgery, when ACT was near normal and post sternal closure, the patient was shifted to the ICU. Fast-tracking was done in 6 hours as per institutional protocol.

For each patient, age, height, and weight were documented. As per our standard protocol, routine basal heart rate, invasive blood pressure, and CVP were recorded. Arterial blood gas and all biomarkers levels were done at three different time intervals, first after induction (T1), second after protamine administration (T2), and third following 48 h after surgery in the ICU. Hemodynamic variables recorded in the ICU constitute the primary parameters, whereas the secondary outcome measures included duration of post-operative ventilation, the requirement of inotropes and ICU length of stay, urine output, and the presence of any arrhythmias.

RESULTS

A total of 150 patients of TOF undergoing ICR were included in the study. Demographic data and perioperative parameters of the participants in both groups (75 each) add similar baseline characteristics [Table 1]. However, in Group I (age <15 years), there was a prolongation of the duration of mechanical ventilation, inotrope use, ICU stay, and hospital stay (P < 0.001) when compared with Group II (age more than 15 years). There were 11 in-hospital deaths (overall mortality 7.3%). Although mortality was higher in Group II, it was not statistically significant (P > 0.05) [Table 1]. The results of each individual biomarker are observed as follows:

Endothelin

The average Endothelin levels in Group 1 post-intubation, after the termination of CPB, and 48 hours after surgery were 3.04 ± 2.90, 9.92 ± 7.18, and 6.11 ± 4.63 pg/mL, respectively, and in group 2, they were 2.75 ± 2.25, 8.31 ± 6.20 and 5.70 ± 4.55, respectively. There was a positive correlation between the Endothelin levels at 48 h after bypass and post-operative secondary outcome measures of duration of ICU stay as well.

We observed the Endothelin levels taken at 48 hours postoperatively were higher than 315 pg/mL, and the patients had a high probability of mortality. The following ROC curve in Figure 1 depicts the relationship between Endothelin levels taken 48 hours postoperatively and mortality rate, with a sensitivity of 66.7% and a specificity of 59%. Table 4 displays the average Endothelin levels in both the groups of patients who had died as well as in those who had survived.

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Figure 1:

Receiver operating characteristic (ROC) curve of 4 biomarkers tumor necrosis factor-alpha, Brain natriuretic peptide (BNP) Endothelin, and base excess.

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Table 4: Average Endothelin levels among survivors and non survivors.

group	mean Endothelin levels (pg/ml)
Survivors (n=139)	4.2±0.9
Non-survivors (n=11)	8.9±1.3

Using the model score equation

In Tables 8 and 9, Figure 1, we observed that base excess has maximum contribution toward mortality, and the TNF-α score is next.

Summation of the above equation and from the values of multivariate logistic analysis of regression coefficient, there is a 97% predictability of mortality based (93.8–100%) on these four biomarkers as shown in the ROC curve [Figure 2].

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Figure 2:

Receiver operating characteristic (ROC) curve showing sensitivity and specificity for major four biomarkers used to prognosticate mortality in tetralogy of Fallot.

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DISCUSSION

The study of most cardiac biomarkers in TOF is an enigma. The predictive value after the intracardiac repair of most cardiac biomarkers, such as BNP, has not been estimated extensively, and this indicates worsening postoperative outcomes.^[11]

Endothelin interacts with other vasoactive substances, stimulating the release of Endothelin-derived relaxing factor, prostacyclin, and thromboxane A2 in the lung.^[12]

In agreement with Mair et al.^[13] and Berendes et al.,^[14] the present study showed a trend of increase in most biomarker levels post-CPB due to the ischemia from aortic cross-clamping, which acts as a stimulant for the biomarker release.

Like our study, several studies have validated that high pre-operative BNP levels have been associated with a longer postoperative ICU stay, mechanical ventilation, and inotrope use.^[11]

The increase occurs on early reperfusion after prolonged low-flow ischemia and the CPB might cause endothelial damage and induce the release of Endothelin (ET-1).^[15] A similar rise was seen when the Endothelin levels were noted before and immediately after coming off the bypass in our study in both groups. The levels came down after 48 hours, probably due to the settling down of inflammation and the low flow state.

Mayyas et al.^[16] correlated Endothelin levels to the development of atrial fibrillation. Similarly, in our study, the older age group had a higher incidence of atrial fibrillation.

This could be due to the advanced disease process with resultant ventricular dysfunction seen in the older age group and high Endothelin levels seen in TOF patients with ventricular fibrosis and dysfunction.^[17]

Increased levels of TNF-α in cyanotic heart disease have been shown in many studies. Cyanotic patients had significantly elevated TNF-α levels (33% higher) than the healthy control population in a study done by Sharma et al.^[18-20] Similarly, another study done by Qing et al. demonstrated higher TNF-α in cyanotic than acyanotic heart disease patients.^[19] A wide interindividual variation in TNF-α was observed in our study, which could be attributed to some TOF patients having a genotype that has high TNF-α levels and thus more morbidity and mortality. Our study demonstrated significantly elevated TNF-α levels in the post-CPB period, which peaked post-protamine. Although levels decreased after 48 hours, they were still higher than the pre-operative value. This was in accordance with many previous studies in patients with congenital or acquired heart disease.^[21,22]

Another interesting observation in our study was that the elevated TNF-α level correlated significantly with adverse clinical outcomes in the younger age group but not in Group II. Thus suggesting a similar rise in TNF-α levels might lead to a more severe inflammatory response in younger children. Lequier et al., in their study, showed an aggressive inflammatory response seen in children with cyanotic congenital heart disease (CCHD)^[23,24], which may lead to gut ischemia due to low cardiac output syndrome.

This could be due to age-dependent differences in the inflammatory response, increased susceptibility of immature organ systems, and a larger extracorporeal circuit to patient size ratio resulting in greater susceptibility of younger patients to the damaging effect of CPB.

Oxygen delivery, hematocrit, and cardiac output determinants are all essential for cellular perfusion in TOF patients. Below a certain point, decreased oxygen delivery cannot be compensated for by an increased oxygen extraction, resulting in anaerobic metabolism and lactic acidosis. In comparison between survivors and non-survivors, an interesting observation was that in non-survivors, the PO₂ rise was not sustained after CPB, and PO₂ further decreased in ICU (P < 0.001). In our study, we found that PO₂ in non-survivors was low as compared to the survivors and the cutoff of PO₂ was 66.1, an ROC curve showing an AUC of 67%.^[25] However, PO₂ itself may not always reflect tissue oxygen utilization and may not be an effective marker of occult hypoperfusion in comparison to lactate.

Lactate production results from the cellular metabolism of pyruvate into lactate under anaerobic conditions.^[26,27] In our study, the lactate value increased from its baseline measured at T1 to that after CPB, and then, it started to be cleared from the circulation, as shown by decreasing values measured at T3 in both group 1 and group 2.^[28] Intragroup comparison of lactate value among survivors showed significant changes with time. Increased value was noted after CPB (T2) and decreased in ICU (T3) as lactate was cleared from circulation (P < 0.001). However, in non-survivors, lactate continued to show a significant increasing trend (P < 0.001). In our study, persistently elevated post-operative lactate is associated with increased mortality in both pediatric and adult patients undergoing ICR.

The arterial base deficit level is a calculated value based on the arterial pressure of carbon dioxide, PH, and serum HCO₃ and represents the number of milliequivalents of the additional base that must be added to one liter of blood to normalize the PH.^[29,30] In our study, it was found that base excess is a predictor of mortality in TOF patients with a high sensitivity of 89.9% and specificity of 90.9%. Hypoalbuminemia is a well-documented predictor of general surgical risk and frequently occurs in patients with CCHD. Low pre-operative serum albumin concentrations (<3.3 g/dL) can be used to identify and prognosticate a subset of cyanotic heart disease predisposed to additional surgical risk in TOF patients.^[31] Proper perioperative care is only possible when a correct diagnosis is reached in situations causing a diagnostic dilemma between low oxygen saturation and clinical findings.^[32]

Calculation of AIIMS TOF scoring was done using the regression coefficients for those biomarkers with maximum sensitivity and specificity. Based on scoring, the ROC curve revealed that AUC was 97% (P < 0.001) with (93.8–100) as 95% CI. The cutoff point revealed that if the score is <2.73, then it can differentiate well, with 96.9% as sensitivity and 89.2% as specificity, as shown in Figure 2. This model score classifies 94.7% correctly for depicting mortality in TOF patients.

CONCLUSION

Four biomarkers, namely, Endothelin, TNF-α, BNP, and base excess, were found to be highly sensitive and specific. Using these biomarkers, a score of 2.73 (the AIIMS TOF score) is considered in morbid patients post-ICR in the ICU. The chances of mortality are high, with a sensitivity of 96.9% and a specificity of 89.2%. Predicting morbidity and mortality in ICR patients should be considered using prognostic biomarkers, as cited above.