Discussion:
In the patients with advanced heart failure, LVAD implantation confirmed superiority over optimal medical therapy1. LVAD therapy currently represents standard approach in selected patients before heart transplantation (bridge-to-transplantation) as well as in the patients who are not eligible for heart transplantation (destination/permanent therapy).
Despite ongoing technological progress in device construction, e.g. smaller implantable continuous flow pumps and postoperative care improvements including new antibacterial agents or better vital functions monitoring infection still remains life-threating complication after LVAD implantation2,3. Altogether, the need for early and accurate diagnosis of this complication followed by appropriate therapy is necessary. PCT has been extensively studied not only in general intensive care settings but also after routine cardiac surgery with promising results in distinguishing infectious and non-infectious SIRS6,7,8,9,10,11. On the other hand, our preliminary prospective data suggested limitation of PCT for diagnosis of the infection after LVAD implantation12. In this study we assessed PCT and PSEP (novel inflammatory biomarker) dynamics after LVAD implantation and their relationship to infectious and non-infectious complications.
In our patients both PCT and PSEP levels were significantly higher in first 2 days after surgery compared to preoperative values and then decreased to the baseline level during 30 day follow-up – see figures 1 and 2. While PCT levels were basically normal before LVAD implantation, PSEP levels were already mildly elevated before procedure probably due to non-infectious SIRS. Interestingly, we didn´t find any difference in PCT or PSEP kinetics between our subjects with or without infectious complications (figures 3 and 4). Moreover, current papers describing diagnostic utility of PCT after a routine cardiac surgery (CABG, valve surgery or combined procedures) report threshold values for the presence of the infection in the range of 0.47 to 2.47 µg/L6,7,8,9,10,11. In our study most of the patients (41/50) had at least one PCT value above this range during 30-day post-operative follow-up. And we observed similar situation in PSEP measurements – every patient had at least some PSEP level above upper reference limit 365 ng/L and 42 subjects (84%) reached cut-off value for sepsis (729 ng/L). However, our data showed link between other non-infectious complications, such as acute renal failure or right heart failure with additional RVAD implantation, and the levels of inflammatory biomarkers.
The likely explanation is that excessive activation of inflammatory cascade (non-infectious SIRS) in the setting of advance heart failure causes even new inflammatory biomarkers to lose their ability to distinguish infection. While certain pathophysiological processes are unclear, we assume that there are 3 major ways leading to excessive activation of non-infectious SIRS. First, it is well described effect of CPB during cardiac surgery5. Second, all the patients were in severe condition with organ failure before LVAD implantation. While in papers describing PCT dynamics after routine cardiac surgery mentioned above most of procedures were elective, all LVAD implantations in our study were urgent or even emergent (INTERMACS profiles: 2 - 19/50, 3 - 18/50, 4 - 13/50). Also preoperative characteristics reflect this fact – 98% of patients needed intravenous diuretics, 82% inotropes, 12% vasopressors, 20% sildenafil as specific therapy of pulmonary hypertension. Furthermore, mean left ventricle ejection fraction was 25%, only 3 subjects (6%) had cardiac index above 2,3 L/min.m2, 92% of patients had also right ventricle dysfunction with associated renal insufficiency in 28 subjects (56%). We can see this correlation in PSEP values before LVAD implantation, where 34 patients (68%) had PSEP levels above upper reference limit 365 ng/L. Even current papers describe the association between PCT and organ dysfunction15 or heart failure without any infection16, 17. And finally, there is a contact of immune cells in the blood with non-physiological surface causing the activation of SIRS18. This way is already involved during CPB, but in LVAD pump this process is not short-term and limited only to surgery procedure itself. Moreover, with additional RVAD implanted due to right heart failure and/or ARF treated with continuous renal replacement therapy this non-specific activation is much more important. Accordingly, we observed in our patients higher PTC values when ARF occurred (figure 5) and higher PSEP levels 14 days after LVAD implantation, probably caused by renal replacement therapy itself19.
In accordance with this hypothesis later decrease in PCT and PSEP levels back to baseline can be explained by improved hemodynamics and organ function with possible immune tolerance to the non-physiological surface.
In addition, we analyzed the correlation between 1-year mortality and the levels of PCT and PSEP dynamics during 30-day post-operative period. We observed higher PCT levels in non-survivors but without statistical significance (in relatively small cohort), and no difference in PSEP values – see figures 9 and 10.
Conclusions :
Our data showed limited ability of PCT and PSEP to detect infection in the patients after LVAD implantation. Their levels more likely correlate with severity of post-operative period in general. The explanation could be excessive activation of non-infectious SIRS caused by critical perioperative state including organ dysfunction and contact of blood elements with non-physiological surface in ventricle assist device or during renal replacement therapy. In these circumstances the levels of novel inflammatory biomarkers don’t discriminate between the activation of inflammatory system due to infection or non-infectious causes.