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.