Our results confirm that cardiac surgery in children induces a systemic release of the pro- and anti-inflammatory cytokines TNF-α, IL-6, IL-10, and IL-12 that persists at least up to POD 5, and that the importance of the inflammatory response is well reflected by the early post-operative PCT levels.
TNF-α is an early pro-inflammatory cytokine that has also a role in the maintenance of homeostasis . It induces among others IL-6 . TNF-α and IL-6 are implicated in the pathophysiology of heart failure and of pulmonary hypertension . IL-6 helps terminating inflammation via the induction of C-reactive protein in the liver and via the induction of the monocyte deactivating cytokine IL-10 . The liver is an important source of IL-10 during cardiac surgery, as we showed previously . IL-10 inhibits the synthesis of all pro-inflammatory cytokines via the activation of the suppressor of cytokine signaling (SOCS) . SOCS in turn is modulated by mechanical stress as it has been shown in human endothelial cells .
IL-12 is a pro-inflammatory cytokine that is produced by antigen presenting cells such as dendritic cells and macrophages. It regulates interferon-γ (INFγ) production by Th1 lymphocytes . In adults and children undergoing cardiac surgery, decreased ex vivo IL-12 production has been demonstrated [21, 22], thus favoring anti-inflammatory balance .
In the present series, upon connection with the ECC circuit, the concentrations of TNF-α and IL-12 fall significantly. This decrease may be the result of the combined effects of dilution and corticosteroids given before the operation . Both pro-inflammatory cytokines showed a similar course with a secondary significant increase of their blood concentrations during ECC and a peak value measured 4 h po, reflecting the pro-inflammatory effect of cardiac surgery . The correlations between TNF-α levels at the end of ECC and the volume of water retention during ECC and the oxygenation index on POD 1, respectively, confirm the harmful impact of inflammation on endothelial- and organ function . The second decrease of TNF-α- and IL-12 concentrations with a nadir on POD 3 reflects the counteracting effect of the anti-inflammatory response . This latter was objectivized in this series by an early and significant increase of IL-10 blood concentrations reaching their peak value at the end of ECC. Interestingly, the importance of the early release of IL-10 was associated with higher mean arterial blood pressure in the early post-operative period, reflecting the clinical relevance of the anti-inflammatory response during cardiac surgery.
IL-6 showed a similar course to IL-10. IL-6 has early pro- and later anti-inflammatory properties as well and its blood levels usually reflect the amount of systemic inflammation . In this series, its early release after connection to ECC was associated with lower CVP, confirming the role of inflammation in the pathophysiology of capillary leakage during cardiac surgery .
The comparison of the time course of TNF-α and IL-12 blood concentrations on the one hand and of IL-6 and IL-10 on the other hand is suggestive for the interplay between pro- and anti-inflammatory signals during and after cardiac surgery . This is supported by the significant correlations between TNF-α and IL-10 concentrations we observed in the early post-operative period.
The TNF-α/IL-10 ratio can be considered a marker of the inflammatory balance . In this series, higher ratio correlated with lower water balance during CPB, confirming again the role of inflammation in capillary leakage during cardiac surgery.
The main objective of this study was to test the hypothesis that patients with UVP circulation would respond differently to cardiac surgery in terms of systemic inflammation than patients undergoing BVR. Our results allow suggesting such a differential response. Indeed, patients after UVP showed significantly lower concentrations of TNF-α and IL-12 with higher IL-6 blood levels and lower TNF-α/IL-10-ratio in the early post-operative period than BVR patients. This is indicative for a shift of the inflammatory balance towards anti-inflammation in patients with UVP.
The systemic inflammatory reaction elicited by cardiac surgery is complex and influenced by numerous patient-dependent or patient-independent variables . With this respect, intra- and post-operative hemodynamics is potentially an important influencing factor . Patients with UVP have as main hemodynamic characteristics high CVP with distension of the systemic venous system and non-pulsatile arterial pulmonary blood flow. Our results showing higher CVP in the early po period in UVP than BVR patients are concordant with this.
Mechanical stretch encountered in arterial and venous vessels under normal or pathological conditions have a direct impact on endothelial cell function throughout the activation of several transcription pathways such as that of NFκB and AP-1 that are common to the inflammation pathways [30, 31].
Thus, high pulsatility flow due to vascular stiffening has been shown to induce significant acute and sustained endothelial inflammation mediated by the activation of NFκB whereas low pulsatility flow was associated with only minor and transient inflammation . Not only flow pulsatility but also the helical flow structure initiates inflammatory signals in endothelial cells via NFκB activation, leading to the downstream synthesis of IL-1β, TNF-α, IL-6, and INFγ .
Helical flow structure has been demonstrated in the right artery after cavo-pulmonary connection  but whether it influences local or the systemic inflammatory pathways has not been investigated yet.
Besides the impact of flow pattern on the endothelial inflammatory signals, mechanical stretch of myocardial cells due to hemodynamic overload of cardiac cavities induces an intra-myocardial expression of pro- and anti-inflammatory cytokines, as we showed previously in children with congenital cardiac defect . These inflammatory mediators are released into the circulation  and may participate to the inflammatory response to cardiac surgery and influence post-operative outcome.
The small patient number that did not allow to test the possible relationship between hemodynamics and markers of inflammation during and after the operation is the main limitation of our study.
It is of note that surgery for the patients described in our study was performed in the years 1995 to 2000. Surgical techniques have been substantially modified and evolved in the meantime. But it was the relatively homogenous group of patients (with pulsatile flow characteristics in the pulmonary circulation preoperatively in all patients) that enabled us to compare the differential cytokine response between patient undergoing UVP or BVR.