Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03045068 |
| Other study ID # |
HSC-MS-16-1034 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
April 11, 2017 |
| Est. completion date |
November 1, 2018 |
Study information
| Verified date |
March 2023 |
| Source |
The University of Texas Health Science Center, Houston |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Hypothesis:
Dilutional thrombocytopenia after cardiopulmonary bypass (CPB) is universal and
administration of donor apheresis platelets just prior to termination of bypass will assist
in early correction of coagulopathy, early hemostasis and lesser donor exposure of blood
products after cardiac surgery.
Background:
What is the Problem? - Bleeding, Transfusion and Outcomes
1. Excessive bleeding after neonatal cardiac surgery has been independently associated with
increased adverse events, morbidity and mortality.1,2 Bleeding after neonatal open-heart
surgery has multiple etiologies such as immaturity of the building blocks of
coagulation, effects of deep hypothermia, longer CPB times, altered flow states and
dilutional state induced by being on CPB leading to low platelet count, low platelet
function, low fibrinogen levels, altered fibrinogen polymerization, complement
activation, etc.2,3 The strongest predictor of transfusion after cardiopulmonary bypass
in children was deemed to be the CPB circuit volume and the effect of hemodilution.4
2. The dilutional coagulopathy after neonatal CPB requires intense damage control
resuscitation with massive transfusion of platelets, packed red blood cells (PRBC),
cryoprecipitate, fresh frozen plasma (FFP) and supplemental factor concentrates. In a
previous study at this institution (IRB# HSC-MS-13-0647), we have shown that in neonates
undergoing open-heart surgery there was a significant drop in platelet counts after
bypass (71% change, baseline= 268 ± 90, Post CPB= 76 ± 27, 109/L). Associated with this
drop , the average intraoperative transfusion load in neonates undergoing cardiac
surgery with CPB at our institution constitutes of PRBC= 63± 43 ml/kg, FFP=51± 21 ml/kg,
cryoprecipitate =12+6 ml/kg, platelets = 28 +16 ml/kg and cell-saver =27± 10 ml/kg. In
addition 72% of these patients were exposed to a 3-factor prothrombin complex
concentrate (Bebulin®). Although this "throw the kitchen sink" approach is effective in
achieving hemostasis, it comes with significant effects on post CPB hemodynamics,
constantly changing hematocrit, variable blood volume with inability to achieve steady
state inotropic state affecting cardiac output, oxygen delivery and adding to pulmonary
hypertension.
Overall, having higher platelet counts at the time of weaning from cardiopulmonary bypass has
distinct advantages of reducing transfusions and improving outcomes.
Description:
What do we do at our institution? The vast majority of centers including ours continue to
utilize a regimen for neonatal CPB prime that constitutes of PRBCs ( 20-30 ml/kg) added to
achieve a hematocrit > 25 on CPB and FFP (20-30 ml/kg) to assist the lower antithrombin
levels, improve heparin efficiency and improved suppression of the thrombin generation on
CPB. Platelets are not added in the CPB prime at our institution. This regimen of avoiding
donor apheresis platelets transfusion during early CPB is because of the known effects of CPB
on native platelets resulting in decreases in count from hemodilution and mechanical damage.
Donor apheresis platelets administered as an initial constituent of CPB prime also carry the
risk of platelet activation during hypothermia and CPB with potential activation of the
coagulation cascade. Fresh whole blood is also not used secondary to the difficulty and
logistics pertaining to availability fresh whole blood makes this approach unattractive.
What is the advantage of adding platelet apheresis just prior to separation from CPB? We know
that native platelets are significantly reduced in count and function with increasing
duration of CPB and function diminishes independently of platelet count with hypothermia.11
The advantages of adding donor apheresis platelets just prior to separating from CPB are that
the donor platelets don't get spalliated and deformed by the roller pumps for long durations,
they are not subjected to the intense cooling and rewarming process and spared of the early
reperfusion injury/inflammation. Furthermore, addition of 10 ml/kg of platelets would raise
the platelet counts by at least 50% based on a previous study at this institution (IRB#
HSC-MS-13-0647; post-CPB platelet transfusion of 28 ± 16 ml/kg resulted in elevation of
platelet counts from 76 ± 27 to 223 ± 60 (109/L).
Effect of modified ultrafiltration (MUF): MUF is routinely performed immediately on
termination of CPB and prior to protamine administration. During this stage, after successful
weaning from CPB, 10-15% of the cardiac output from the arterial cannula along with residual
volume from the venous reservoir of the CPB pump is pumped through a hemofilter placed under
vacuum to allow rapid hemofiltration with the effluent returned via a single atrial venous
cannula to the patient. This 15-minute rapid hemofiltration allows for removal of excess
water, improvement in hematocrit with improved oxygen delivery, faster achievement of steady
state inotrope levels with improved hemodynamics and removal of inflammatory mediators.12-14
While MUF improves hematocrit, it does not increase platelet count significantly, MUF has no
effect on native platelet function.3 The biggest advantage of transfusion of apheresis
platelets prior to termination of bypass versus standard practice of their transfusion after
protamine is that the transfused fluid load of 10-15 ml/kg of platelets volume that would
have diluted the red cell fraction (hematocrit) and impacted oxygen delivery and pulmonary
dysfunction would now take the full benefit of modified ultrafiltration with excess fluid
removal even prior to protamine administration with overall improved hemodynamics.
Institutional Blood transfusion Management for Neonatal CPB For the CPB prime: PRBCs
(50ml/kg) are added to allow for a hematocrit >30 for the estimated blood volumes. FFP is
added to the pump prime for all patients weighing less than 5 kilograms and in those who
demonstrate heparin resistance on initial heparin dose response assays. Heparin is added in
the CPB prime. Other constituents of the CPB prime are epsilon aminocaproic acid (50 mg/kg),
cefazolin (30 mg/kg) and methylprednisolone.
Post CPB: Current practice in neonates is to administer a combination of cryoprecipitate,
platelet and PRBC in a 1:1:1 ratio till hemostasis is achieved. 3PCC factor administration is
based on diffuse clinical bleeding suggestive of coagulopathy that persists despite one round
of cryoprecipitate and platelet transfusion.
Study Method:
Prospective Randomized trial in neonates comparing platelet apheresis transfusion prior to
termination of CPB versus standard transfusion of platelet apheresis after modified
ultrafiltration and protamine administration. Primary outcomes and secondary outcomes are
detailed below.
Study Group Platelet Transfusion Management
1. Pre-Termination of CPB- Platelet Transfusion 10ml/kg to be administered to the patient
via central venous access when the patient has been rewarmed to 35*C, (the Sano or BT
shunt clip is still on in children with SV physiology)
2. Post CPB- Platelet transfusion 10ml/kg via a central venous line is continued at a rate
of 100 ml/hour till completion.
FFP and Cryoprecipitate:
1. 1 unit of cryoprecipitate administered during MUF and or after MUF as needed
2. FFP transfusion 10ml/kg during MUF and or after MUF as needed
PRBC and cell saver Transfusion:
1. Transfuse for target Hematocrit > 40 in neonates with SV physiology; Transfuse for
Hematocrit> 33 for 2-Ventricle physiology
3- Factor Concentrate (Bebulin):
1. Based on clinical bleeding and achievement of hemostasis
Control Group Platelet Transfusion Management 1. Pre-Termination of CPB- No intervention 2.
Post CPB- Platelet transfusion 20ml/kg via a central venous line is continued at a rate of
100 ml/hour till completion.
1. Initial transfusion to occur proximal to the hemofilter on the MUF circuit for as long
as MUF lasts
2. Subsequent platelet transfusion continued till completion via central venous access to
the patient
FFP and Cryoprecipitate:
1. 1 unit of cryoprecipitate administered during MUF and or after MUF as needed
2. FFP transfusion 10ml/kg during MUF and or after MUF as needed
PRBC and cell saver Transfusion:
1. Transfuse for target Hematocrit > 40 in neonates with SV physiology; Transfuse for
Hematocrit> 33 for 2-Ventricle physiology
3 Factor Concentrate (Bebulin):
1. Based on clinical bleeding and achievement of hemostasis
Objectives
a) Volume of Blood Transfusion (PRBC, FFP, Cryo, Platelets) Number of Donor
Exposures (PRBC, FFP, Cryo, Platelets) from termination of CPB to first 24 hours
post op b) Number of exposures of 4-PCC and Factor 7 c) Time from termination of
CPB to Chest Approximation
1. Chest tube output first 24 hours
2. Inotropic support at time of chest approximation and at 24 hours postop
3. Length of mechanical ventilation
4. 30 day mortality
5. Mediastinal exploration
6. Delayed sternal closure
7. Perioperative cardiac arrest first 72 hours
8. Arrhythmia
Sample size- Based on pilot data we have collected in the standard procedure group,
the mean and standard deviation (SD) of total blood product intake during first 24
hours is 125.3+/- 71.1 (ml/kg). To detect a 1*SD unit reduction on the total blood
intake, we need 17 patients per group with 80% power at 0.05 significance level. To
account for 20% drop out rate, we need 22 patients per group, i.e. 44 patients in
total.
Inclusion Criteria- All neonates and infants less than 3 months of age under 4
kilograms undergoing open heart surgery and cardiopulmonary bypass.
Exclusion Criteria-1) Redo open heart surgery 2) Bleeding Disorders - such as von
Willebrand Disease, Hemophilia
Screening and Recruitment:
The list of newborns to be operated will be obtained daily from the operating room
log.
Care4 records and OR Tracking will be used to screen for patients Initials of
Patients, Date of Brith, Date of Surgery and MRN will be collected. The Research
Team ( PI and Co-PI) will make contact with the family member while obtaining the
surgical and or the anesthesia consent.
Data Collected ( routine Standard operating procedure data)
Patient Demographics:
MRN, Gestational age, Age at operation, weight at birth, weight at operation,
primary Diagnosis, Other diagnosis,
Operative Data:
CPB time, Aortic Cross Clamp time, Deep Hypothermic Circulatory Arrest time,
Antegrade Cerebral perfusion time, Case duration.
Pump Prime Constituents:
Inotrope score: at chest approximation {dopamine + dobutamine + (epinephrine*100) +
(milrinone*10) 15 Procedure performed. Complications All Laboratory values
performed from baseline to 24 hours postoperative
a) Baseline- CBC with Platelets, Fibrinogen, TEG b) Rewarming, prior to termination
at core temperature of 35*C- CBC with platelets, Fibrinogen, TEG c) Arrival to
PICU- CBC with platelets, fibrinogen, TEG d) 24 hours post op- CBC with platelets,
fibrinogen, TEG All Blood products administered with age of the blood product at
time of administration (<5 days, > 5days) Post operative Length of Intubation STS
reportable complications Mortality Cumulative fluid balance first 72 hours.
Outcome Variables:
d) Number of Donor Exposures (PRBC, FFP, Cryo, Platelets) from termination of CPB
to first 24 hours post op e) Number of exposures of 4-PCC and Factor 7 f) Time from
termination of CPB to Chest Approximation i) Chest tube output first 24 hours j)
Inotropic support at time of chest approximation and at 24 hours postop k) Length
of mechanical ventilation l) 30 day mortality m) Mediastinal exploration n) Delayed
sternal closure o) Perioperative cardiac arrest first 72 hours p) Arrhythmia
Study Risks:
There are no perceivable risks from exposure to platelets since the patients will
be exposed to platelet transfusion after protamine administration. Only the timing
of administration is being changed in the study group.
Informed Consent:
A written informed consent will be obtained. If informed consent is not obtainable
or refused, patients will be randomized to control arm.
