Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT00395369 |
| Other study ID # |
SOR439106CTIL |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
November 1, 2006 |
| Last updated |
November 2, 2006 |
| Start date |
December 2007 |
Study information
| Verified date |
November 2006 |
| Source |
Soroka University Medical Center |
| Contact |
Dan Abramov, MD |
| Phone |
97286400962 |
| Email |
danab3[@]clalit.org.il |
| Is FDA regulated |
No |
| Health authority |
Israel: Ministry of Health |
| Study type |
Interventional
|
Clinical Trial Summary
Cognitive and neurological dysfunction after coronary artery bypass surgery (CABG) is common
and multi-factorial in origin. Several previous studies have shown that intraoperative
aprotinin administration may be neuroprotective.in the current prospective randomized study,
the effect of intraoperative aprotinin administration on the integrity of the optic nerve
and retinal nerve fiber layer will be examined. Optical coherance tomography will be used to
examin the optic nerve and retinal nerve fiber layer.
Description:
Cognitive and neurological dysfunction after coronary artery bypass surgery (CABG) is common
and multi-factorial in origin. Causative factors include cerebral Embolization (1), cerebral
ischemia reperfusion (2), cerebral hyperthermia after discontinuation of cardiopulmonary
bypass (CPB) (3), and the systemic inflammatory response to CPB (4). Cognitive dysfunction
is reported in 53% of patients at discharge from the hospital, 36% at six weeks and 42% at
five years (5). Cognitive function at discharge from hospital is a predictor of long-term
cognitive outcome (5). Adverse neurological outcome has been classified as: type I (focal
neurological injury, stupor or coma) and type II (deterioration in intellectual function,
memory deficit or seizures). Patients with adverse cerebral outcomes have greater
in-hospital mortality, longer hospitalization and a greater rate of discharge to facilities
for intermediate or long-term care (6). Adverse neurological outcome after otherwise
successful surgery is devastating for the patient, their family and society.
Neurocognitive testing is the most established method to assess post cardiac surgery
cognitive outcome. Despite the extensive use of neurocognitive testing procedures in the
research literature, there is uncertainty regarding the precise interpretation of findings
in any given study. Thus, new tools to evaluate cognitive outcome are now being
investigated.
Aprotinin is a naturally occurring serine protease inhibitor that is being used with
increasing frequency in cardiac surgery to reduce blood loss and the need for perioperative
blood transfusion. Through inhibition of serine proteases such as plasmin, aprotinin
significantly reduces fibrinolysis, thereby aiding hemostasis during surgical procedures.
These proven benefits are supplemented by the anti-inflammatory properties of aprotinin,
which may help curb some of the deleterious effects of cardiopulmonary bypass. Two aprotinin
dosing regimens are used for prophylactic reduction of perioperative blood loss and the need
for blood transfusion in patients undergoing cardiopulmonary bypass (CPB). Serum
concentrations achieved with the full-dose regimen inhibit both kallikrein and plasmin
activity resulting in attenuation of the systemic inflammatory response to bypass, whereas
serum concentrations achieved with the half-dose regimen only inhibit plasmin activity.
In-spite of the fact that aprotinin has been administered for more than a decade to cardiac
surgery patients, it's safety is still controversial. Several studies have reported an
increase risk for postoperative MI, CVA and renal failure after it's usage. Thus, its usage
is not a standard of care, and depends on the surgeon decision (13).
Evidence supporting the neuroprotective effects of aprotinin given during surgery was
obtained in several studies.
In a post hoc analysis of 816 CABG patients from a multicenter study (7), aprotinin
administration was associated with a significantly (P = 0.04) decreased incidence of stroke
(3.1% vs. 0.0%). A meta-analysis (8) of placebo-controlled, randomized, double-blind studies
of CABG patients receiving high-dose aprotinin or placebo has supported the hypothesis and
reported stroke incidence of 4.2% vs. 0%. A number of prospective studies have shown
reduction in post cardiac surgery cognitive deficits when aprotinin was administered during
CPB (9-10).
Although, the mechanism by which aprotinin may confer neuroprotection is not known, an
anti-inflammatory effect can be postulated. Another possible neuroprotective mechanism is
improved recovery of cerebral metabolism after ischemia (11). Its main site of action may be
the microcirculation, where it decreases ischemic injury by decreasing bradykinin generation
(12) and provides a better microcirculatory environment during early reperfusion.
Processes inflicting Cerebrovascular ischemia and inflammatory damage may also affect the
optic nerve. Thus, pathophysiological findings discovered by optic nerve imaging can reflect
cerebrovascular status.
Ischemic damage to the optic nerve or ischemic optic neuropathy (ION) is a known
complication of CABG. ION describes a defect of the optic nerve leading to irreversible loss
of vision in most cases. Influenced by a variety of factors, pathophysiological
microvascular changes are believed to provoke anterior ischemic neuropathy with sudden
painless loss of vision. Since therapeutic trials have failed, there is no reliable and
effective treatment of anterior ischemic optic neuropathy and prevention of possible causes
is the only way to avoid this rare but severe complication of cardiac surgery. The following
risk factors were determined for ION following CABG: History of glaucoma or other
ophthalmological problems, prolonged cardiopulmonary bypass-time, myocardial ischemia,
general edema during cardiopulmonary bypass, excessive hemodilution with low hemoglobin and
hematocrit, hypo- or hypertension, systemic hypothermia, need for vasoactive medication,
diabetes and anemia.
RNFL thickness as measured by optical coherence tomography OCT has been shown to correlate
very well with optic nerve atrophy and visual function in optic neuritis14, 15. Using OCT
measurements of optic nerve and retinal nerve fiber layer (RNFL) thickness and visual field
testing as the primary outcome, we hypothesize that high-dose aprotinin administration would
decrease the incidence and severity of optic nerve and retinal injury following CABG with
CPB.
Materials and Methods:
Patients scheduled for primary CABG will be studied.
Exclusion criteria:
Preoperative:
1. Patients requiring concomitant noncoronary procedures.
2. Urgent operation.
3. Intra aortic balloon pump
4. Presence of allergy to aprotinin or bleeding diathesis.
5. Previous CVA.
6. Previous eye operation.
7. Glaucoma.
8. Retinopathy.
Postoperative:
1. Postoperative CVA.
2. Postoperative critical condition precluding safe performance of OCT examination.
Anesthesia, surgery and postoperative management Oral lorazepam 0.02 to 0.03 mg/kg will be
administered to patients two hours before surgery. General anesthesia will be induced with
fentanyl 15 to 20 µg/kg and ketamin. Muscle relaxation will be achieved using pancuronium
0.1 mg/kg. Before cannulation of the heart, heparin (at least 300 U/kg iv) will be
administered to each patient. Additional heparin will be administered to achieve and
maintain a cephalin kaolin time > 480 sec. CPB will be instituted using a hollow fibre
oxygenator (--) and a 40-µm screen arterial filter ( ) with crystalloid priming and a
non-pulsatile flow at 32.0 to 34.0°C. Pump prime will be consisted of lactated Ringer’s
solution 2000 mL, sodium bicarbonate 8.4% 50 mL and mannitol 20% 3 mL/kg. The pump flow rate
will be maintained at 2.4 L/min x m–2 during aortic cross clamping. During CPB, pump flows
will be adjusted to maintain mean arterial pressure at 65 to 80 mmHg and hematocrit will be
maintained at 20 to 25%. Intermittent use of cardiotomy suction () (0.5–1 L flows) from
pericardiotomy to closure of pericardium will be used. A cell saver device will not be used.
Myocardial protection will be by intermittent antegrade and retrograde blood cardioplegia
administered via the aortic root and the coronary sinus respectively. A single aortic
cross-clamp will be used to complete distal and proximal anastamosis. Aortic venting will be
used in all patients. At the end of surgery, patients will be transferred to the intensive
care unit, where mechanical ventilation will be continued until local criteria for weaning
and tracheal extubation will be met.
Administration of study drug:
Patients will be randomized to a treatment group or placebo. In the treatment group,
aprotinin will be administered, consisting of 2 x 106 KIU as a loading dose after induction
of anesthesia, 2 x 106 KIU added to the CPB circuit prime, and a continuous infusion of 5 x
105 KIU•hr–1 during surgery. The infusion will be discontinued at the end of surgery.
Patients and the ophthalmologist will be unaware of the study group to which each patient
belong.
OCT and Visual Field measurements:
OCT measurements and visual fields examination will be performed in all patients prior to, 7
days and one month after surgery.
