Cardiac Clinical Trial
Official title:
Evaluation of High-dose Corticosteroids on Microcirculation Alterations in Cardiac Surgery, by FMD (Flow Mediated vasoDilation), Near Infrared Spectrophotometry (NIRS) and Biological Analysis (Syndecan-1)
Cardiac surgery is sometimes associated with organ dysfunction of variable severity (renal
insufficiency, cognitive decline, arrhythmias, ARDS). The phenomenon responsible is an
intense inflammatory reaction induced by cardiopulmonary bypass, leading to microcirculation
alterations, specially in endothelial cell and its protective layer - glycocalyx. Endothelial
dysfunction then reduces the reactivity of peripheral tissues to hypoxia, and is associated
with bad prognosis.
High - dose corticoids administration at anesthesia induction in cardiac surgery could
attenuate the intensity of this inflammatory reaction, and represents the current practice in
our hospital. Nevertheless, this attitude is abandoned in numerous cardiac surgery centres.
Introduction Cardiac surgery is associated with variable severity organ dysfunction, which
further leads to an increase of ICU length of stay (ICU LOS) or even higher mortality.
Various mecanisms enter into account, from global through regional hemodynamics until
microcirculation alterations.
These are due to an intense inflammatory reaction triggered by the contact of blood with
cardiopulmonary bypass surfaces, the contact blood - air from cardiotomy aspiration, heparin
and heparin - protamin complexes, ischemia - reperfusion mediators, and toxins from the
digestive tube.
These alterations are observed in both the beating heart surgery and surgery with
cardiopulmonary bypass (CBP). The inflammatory response is probably less important in off -
pump surgery though this is hypothesis often questionned and some publications show that the
changes associated with CBP could only be transient.
Inflammatory response is possibly reduced by high - dose corticoid administration at
anesthesia induction - by preserving cell membrane integrity, leucocyte adhesion and cellular
immunity attenuation, and finally by complement and cytokine release reduction.
Numerous metaanalyses show benefits of this strategy with an acceptable security profile:
- Atrial fibrillation reduction
- Possible ICU LOS reduction
- Same incidence of wound infection
Within the risks can be observed:
- Higher incidence of hyperglycemia
- No impact on overall mortality However, two recent big RCTs did not find any benefit as
in terms of morbidity-mortality, incidence of wound infection and possibly an increase
in number of reinterventions for tamponnade.
Providing the low level of evidence on real benefits and some of the secondary effects, the
systematic use of corticoids (as applied in our centre) was abandonned by a some of cardiac
surgery centres.
Nevertheless, corticoids could be beneficial in specific subgroups. In order to identify
these patients, it is important to understand the mecanism of microcirculation alterations in
the setting of cardiac surgery with CBP and the effect of corticoids on CBP induced
inflammatory processes.
The alterations of endothelial function under CBP may be observed at three levels :
1. endothelial reactivity (vasodilation et vasoconstriction)
2. blood flow (acceleration et deceleration)
3. glycocalyx (endothelial protective layer) These three components of microcirculation are
tightly linked. De Backer study on sublingual microcirculation shows its alterations
specific for this type of surgery (more pronounced in cardiac surgery with CBP than
off-pump) and not found in minor surgery (thyroidectomy). He also found a positive
correlation with lactate level. Cardiac surgery can be considered as an interesting
microcirculation and endothelial function study model.
The hypothesis of investigators is that microcirculation modifications along with those of
endothelial function in cardiac surgery with CBP are due to endothelial cell impairement and
impairement of its protective layer - glycocalyx, condition which deregulates the peripheral
tissue reactivity to hypoxia, and that corticoids could reduce these alterations.
The investigators will study the endothelial function by three methods :
A/ FMD (Flow Mediated vasoDilation) which is a non invasive technique considered as the gold
standard for endothelial reactivity evaluation since the end of 1990s. It is based on
echographic measurement of brachial artery diameter variation and the Doppler flow
evaluation, during an episode of transient ischemia induced by pneumatic cuff inflation
(vascular occlusion test).
Three studies showed a reversible alteration of endothelial function mainly after cardiac
surgery using CBP with continuous blood flow (FMD variation of about 11%). Expecting a
reduction of endothelial dysfunction with corticoids by 5%, the investigators will analyze a
group of 60 patients (30 in the corticoids group and 30 in the placebo group). In previous
studies, variation is already significative when FMD varies from 1,5 - 2%.
B/ NIRS (near infrared spectroscopy) - it's a non invasive technique which measures
peripheral tissue oxygen saturation and allows to assess oxygen consumption and
microcirculation reactivity during an arterial occlusion test distally to compressive cuff.
Alterations of the variables derived from delta StO2 (peripheral tissue oxygen saturation)
after an ischemic - reperfusion event, rather than absolute value of StO2 are predictive of
bad prognosis in a septic patient or in severe head injury. These variables are delta StO2,
HbT (total tissue hemoglobin) and THI (muscular hemoglobin index). From these elements can be
calculated others: RdecStO2 (StO2 decrease rate during ischemic event reflecting the tissue
oxygen consumption) and RincStO2 (increase rate of StO2 during the reperfusion phase,
corresponding to relative hyperemia). Both are expressed in %/s. The intensity of reperfusion
can be quantified by delta THI.
A recent study in cardiac surgery did not show StO2 modifications under CBP but providing a
small population sample and the type of monitoring used, this study might include some
methodologic biais.
Finally, very recently a correlation between FMD and the variation of NIRS during a vascular
occlusion test has been found in a young healthy subject, which only confirms the influence
of endothelial function onto microcirculation.
C/ Syndecan - 1 concentration assessment: This molecule is closely linked to glycocalyx and
is considered as the most predictive marker of its integrity.
Many factors might cause lesions of this structure (inflammation, hyperglycemia, CBP, etc).
Its destruction causes further an impairement of endothelial function (vasoconstriction et
vasodilation), mediated principally by endothelial factors.
Corticoids can be considered as the most effective molecule for glycocalyx protection.
Yet the investigators will analyze syndecan - 1 as a glycocalyx marker.
Material and methods :
After ethics commitee approbation and signed informed consent obtention, the investigators
will enroll 60 patients scheduled for cardiac surgery with CBP (aorto - coronary bypass graft
or valve replacement).
Patients randomized in the Corticoids group will receive 500mg of methylprednisolone in 100ml
of NaCl 0,9% at anesthesia induction, Placebo group will receive 100ml of NaCl 0,9% - both
solutions are prepared at the hospital pharmacy and only the pharmacist knows the preparation
content (double blinding).
Exclusion criteria are age under 18, extreme emergency surgery if the testing would slow down
the surgical treatment. The investigators also exclude the patients where the placement of
pneumatic cuff would be impossible (amputation, AV fistula)
Anesthesia procedure:
All the patients receive the same anesthesia technique, based on propofol and remifentanil at
objective of concentration. Relaxation is achieved by cisatracurium in continuous infusion.
This type of anesthesia is the current practice in Erasme hospital. All the patients are
equipped with radial artery catheter and central venous catheter, the use of pulmonary artery
catheter is left to anesthetist's discretion.
Before starting the CBP, all patients receive heparin with target ACT (activated clotting
time) above 480seconds. The priming of CBP consists on 500ml of gelatin (Geloplasma,
Fresenius), with 500ml of cristaloids (Plasmalyte, Baxter) and 200ml of mannitol (Mannitol
15%, Baxter). Cardioplegy is achieved by blood infusion (T 36°) with potassium chloride. The
CBP flow is continuous of 2.4L/m2 and mean arterial pressure is maintened between 60 and 90
mm Hg. Glycemia is controlled strictly from the moment of anesthesia induction by short
acting insulin administrered continuously.
All patients are transferred to ICU after the surgery, sedated with propofol and remifentanyl
until hemodynamic stability and absence of bleeding is achieved. Sedation is then stopped and
patient is extubated.
Vascular occlusion test:
Arterial diameter variation and Doppler flow are measured at brachial artery above medial
epicondyl, proximally to the pneumatic cuff placed at forearm. For echography analysis, a
linear probe of 12 MHz will be used, held by a metallic support to allow more precision and
better reproducibility. After initial diameter measurement, pneumatic cuff 50 mmHg will be
inflated above the arterial pressure of the patient during 5minutes, in order to induce
ischemia. Diameter variations in brachial artery are measured continuously from 30 secondes
before releasing of the cuff until 3 minutes afterwards. FMD is evaluated by following
parameters : baseline diameter and maximal FMD variation in pourcents. In numerous studies,
FMD is calculated using the formula: FMD (%) = ([diametre of maximal dilation after cuff
release - baseline diametre]/ baseline diametre) x 100. In order to reduce variability of the
measrure, diameter variation will be adjusted to baseline diameter and to initiating stimulus
assessed by Doppler flow. Data will be stocked and analyzed by Quipu FMD.
StO2 is measured by tissular spectrometer (Invos, Covidien) consisting of a photodetector,
processor and a 15 mm optic probe. This proble is placed over thenar eminence of the arm
without any IV line. StO2 is enregistered every 2 secondes.
Practically, after performing the initial echographic measurements, and after 3 minutes of
stabilisation of StO2 (baseline), an ischemic event of 5 minutes is created by a fast
pneumatic cuff inflation to a value of 50mmHg above patients systemic blood pressure. This
will stop arterial and venous blood flow in the forearm, leading to a decrease of HbO2 (=
rate of decrease StO2 (%/s)).
After 5 minutes the cuff will be rapidly deflated (<1seconds) inducing arterial diameter and
flow increase - the variation is assessed by echography and Doppler. At the same time, StO2
increases (= StO2 increase rate (%/s)) and achieves higher values than baseline (= reactive
hyperemia = delta diametre, flow velocity and StO2). The NIRS device measures also THi
(tissular hemoglobin index) at baseline and 1 minute, its minimum et maximum.
The increase rate of arterial diameter reflects endothelial reactivity while StO2 increase
rate is considered as a tissue = hemoglobin flow marker. Reactive hyperemia can be
interpreted as a test of microcirculation reactivity. Rate of StO2 decrease/THi is considered
as oxygen consumption marker.
Syndecan-1 analysis is performed on frozen plasma by ELISA technique, using specific
antibodies (ELISA kit from Ray Biotech, Inc), this method has already been used in previous
studies.
Timing of measurements:
Measures are performed on the day before surgery, at the ICU admission, at 24h and at the day
7 of hospital stay.
Glycocalyx function assessment:
The first analysis will be performed on the day before surgery, then after anesthesia
induction, at ICU admission, at 24h and 48h.
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