Ignite Creation Date:
2024-05-05 @ 5:08 PM
Last Modification Date:
2024-10-26 @ 9:28 AM
Study NCT ID:
NCT00395369
Status:
UNKNOWN
Last Update Posted:
2006-11-03
First Post:
2006-11-01
Brief Title:
Effect of Intraoperative Aprotinin Administration on Post Cardiac Surgery Optic Nerve and Retinal Thickness
Sponsor:
Soroka University Medical Center
Organization:
Soroka University Medical Center
Study Overview
Official Title:
None
Status:
UNKNOWN
Status Verified Date:
2006-11
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 neuroprotectivein 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
Detailed 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 its safety is still controversial Several studies have reported an increase risk for postoperative MI CVA and renal failure after its 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 004 decreased incidence of stroke 31 vs 00 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 42 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 002 to 003 mgkg will be administered to patients two hours before surgery General anesthesia will be induced with fentanyl 15 to 20 µgkg and ketamin Muscle relaxation will be achieved using pancuronium 01 mgkg Before cannulation of the heart heparin at least 300 Ukg 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 320 to 340C Pump prime will be consisted of lactated Ringers solution 2000 mL sodium bicarbonate 84 50 mL and mannitol 20 3 mLkg The pump flow rate will be maintained at 24 Lmin 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 05-1 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 KIUhr-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
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 its safety is still controversial Several studies have reported an increase risk for postoperative MI CVA and renal failure after its 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 004 decreased incidence of stroke 31 vs 00 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 42 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 002 to 003 mgkg will be administered to patients two hours before surgery General anesthesia will be induced with fentanyl 15 to 20 µgkg and ketamin Muscle relaxation will be achieved using pancuronium 01 mgkg Before cannulation of the heart heparin at least 300 Ukg 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 320 to 340C Pump prime will be consisted of lactated Ringers solution 2000 mL sodium bicarbonate 84 50 mL and mannitol 20 3 mLkg The pump flow rate will be maintained at 24 Lmin 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 05-1 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 KIUhr-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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None