DPP3 levels in out of hospital cardiac arrest patients admitted to the intensive care unit: an explorative study

Despite marked advancements in post-resuscitation care, with different
strategies to prevent secondary organ damage, patients admitted to the ICU
department after an out of hospital cardiac arrest (OHCA) still have an
in-hospital mortality as high as 60-70% [1].

More than half of OHCA-patients in whom return of spontaneous circulation
(ROSC) is achieved will develop post cardiac-arrest syndrome (PCAS) [2]. In
PCAS, generalized ischemia-reperfusion after circulatory arrest causes a sepsis
like-inflammatory response, leading to vasodilatory shock, which often requires
high dose vasopressor therapy despite adequate fluid resuscitation [3, 4].
Approximately half of all patients developing PCAS die as a consequence of
multi-organ failure caused by refractory shock [2]. This sequence of events
takes place in the first 3 days after admission, often before any neurological
assessment is possible. The pathogenesis of PCAS is incompletely understood and
treatment is lacking [2].

Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent metallopeptidase capable of
hydrolyzing a broad spectrum of oligopeptides between 3 and 10 amino-acids in
length [5]. DPP3 has been implicated in blood pressure regulation [6],
inflammation [7], and pain regulation [8, 9] through its capability to
hydrolyze and thus inactivate bioactive peptides like angiotensin II,
enkephalins and endorphins. Recently, specific assays for the detection of DPP3
concentration and enzyme activity in plasma have been developed [10]. Whereas
plasma levels of DPP3 are low in healthy volunteers [10], high levels of plasma
DPP3 (also known as circulating (c)DPP3) were predictive for outcome of septic
and cardiogenic shock patients [10-12]. Furthermore, normalization of cDPP3
following the first 24 hours of treatment was associated with reduced 3 0
day-mortality [11].

Based on these negative clinical associations, it was hypothesized that
persistent elevation of cDPP3 despite adequate supportive treatment represents
a state of ongoing cell death (necrosis) compared to patients with normalizing
cDPP3 values [11]. Since OHCA patients are known to exhibit marked ischemia
reperfusion-induced cell damage [13, 14], increased cDPP3 levels are to be
expected and could represent a novel prognostic marker for subsequent
development of PCAS and mortality.
Next to its value as a prognostic marker, therapeutic effects of cDPP3
modulation were recently evaluated in an animal study [12]. In healthy mice,
intravenous DPP3 injections provoked a rapid decrease in left ventricular
function, while in a murine heart-failure model, inhibition of cDPP3 function
rapidly improved left ventricular function [12]. Interestingly, DPP3 inhibitors
are currently developed for clinical use. Therefore, if OHCA patients indeed
exhibit elevated cDPP3 levels, it could represent a therapeutic target to
combat refractory shock caused by PCAS.

In this explorative-study, we aim to investigate the relation between cDPP3
release kinetics and clinical outcome parameters in OHCA patients after ICU
admission. This could lead to the identification of a new predictive marker, a
potential therapeutic target for post cardiac arrest syndrome, and a timeframe
for therapeutic intervention.

Prospective observational study.

Blood will be sampled at time-points:
- Immediately after admission to the Intensive Care department (timepoint T0)
- 12 hours after admission (T12)
- 24 hours after admission (T24)
- 48 hours after admission (T48)
- 72 hours after admission (T72)

When possible, an existent arterial line or intravenous line will be used to
sample blood. A venapuncture will only be performed when necessary. Informed
consent will be asked if a venapuncture is necessary to obtain blood.

The burden of the study will be neglectable in these patients, because blood
can be drawn from the arterial line, central venous line or during standard lab
rounds no vena puncture will be necessary in the majority of cases.

If vena puncture should be necessary, it carries a small risk on development of
a local hematoma. This risk is reduced by applying adequate pressure for a long
enough time after puncture. If a local hematoma develops nonetheless, it
spontaneously resolves within days to weeks after the injury, and is generally
regarded as a mild adverse event.

This study will (partly) be conducted in incapacitated persons, since cardiac
arrest patients are often sedated during the first days following circulatory
arrest. The conduct of the study in this specific group of patients does not
result in additional risks associated with participation in this study.

This research may be considered group-related, since scientific knowledge on
DPP3 release kinetics after out of hospital cardiac arrest can only be obtained
by studying this specific group of patients.