Antithrombin III Supplementation for Cardiopulmonary Bypass in Neonates
Summary
A prospective, non-randomized, single-armed pilot study is planned. Single ventricle patients with aortic arch hypoplasia undergoing initial Norwood type palliation will receive antithrombin III (ATIII) supplementation in addition to standard anticoagulation with heparin as currently practiced at Children's Hospital of Wisconsin. We plan to enroll the first 20 sequential patients meeting criteria who consent to inclusion. The primary outcomes will be rates of adverse events to monitor safety. Secondary outcomes include volume of postoperative blood loss and packed red blood cell transfusion during the first 24 postoperative hours, and ATIII levels during and after bypass to determine pharmacokinetics. These outcomes will be compared to historical controls.
Description
Hypothesis:
ATIII supplementation prior to initiation of cardiopulmonary bypass (CPB) to neonates undergoing initial Norwood type palliation of single ventricle heart disease with aortic arch hypoplasia will be safe and result in less postoperative bleeding and transfusion of packed red blood cells (pRBC) as compared to historical controls.
Specific Aims:
1. To determine the safety and feasibility of ATIII supplementation prior to initiation of CPB in neonates undergoing initial Norwood type palliation.
2. To determine the pharmacokinetics of ATIII supplementation prior to initiation of CPB in neonates undergoing initial Norwood type palliation
3. To compare the postoperative blood loss and pRBC transfusion requirements in an experimental group of neonates undergoing initial Norwood type palliation supplemented with ATIII prior to initiation of CPB to that of a historical control group that did not receive ATIII.
Inclusion Criteria:
Historical Control Group: All (~40) sequential neonates (<30 days of age) who underwent initial Norwood type palliation for single ventricle heart disease at CHW from January 2008 through December 2009.
Experimental Group: 20 sequential neonates (< 30 days of age) undergoing initial Norwood type palliation for single ventricle heart disease with aortic arch hypoplasia are eligible to be included in the study.
Exclusion Criteria:
Patients with a prior operation utilizing CPB, weight less than 2 kilograms, prematurity less than 36 weeks estimated gestational age, previously diagnosed pro-thrombotic or hemorrhagic disorder, known intracranial hemorrhage, prior ATIII supplementation, and prior therapeutic anticoagulant use.
All historical controls and the first 20 experimental group patients who meet these criteria and provide informed consent will be enrolled.
Protocol for Experimental Group:
After informed consent, a pre-operative ATIII blood level will be obtained. This level will guide the dosing of ATIII as neonatal congenital heart disease patients have variable baseline ATIII levels. The dose of ATIII will be determined by the following formula in order to obtain ATIII blood levels similar to adults and older children (1.0 U/mL):
ATIII dose given to patient = [(1.0 U/mL - patient's measured ATIII concentration in U/mL) X weight (kg) X 80 mL/kg]
The CHW pharmacy will use the above formula to obtain the appropriate dose of ATIII for each patient. ATIII will be administered after induction of general anesthesia and prior to administration of heparin and initiation of CPB.
Heparin management during CPB will be accomplished according to the current standard practice at CHW. Anticoagulation during bypass will be monitored and titrated by use of the Medtronic Hepcon® HMS Plus Hemostasis Management System. A 3mL sample of the patient's blood is drawn pre-incision and is used by the HMS device to determine the in vitro individual response to heparin. A patient specific heparin dose of between 300 and 800 units/kg of heparin will be administered before initiation of CPB with the appropriate level of anticoagulation maintained at a minimum activated clotting time (ACT) of 480 seconds. The level of anticoagulation will be measured every half hour during the CPB time with additional doses of heparin periodically administered as dictated by the HMS System measurements. At the completion of CPB, the heparin will be reversed with a patient specific protamine dose as calculated by the HMS System.
ATIII levels will be measured within 30 minutes after administration (prior to start of CPB), within 30 minutes of start of CPB, just prior to discontinuation of CPB, and upon admission to the ICU.
Intraoperative blood loss while on the CPB machine will be collected and placed back in the CPB circuit as per standard practice at CHW. Blood loss (mL/kg) will be determined intraoperatively from 10 minutes after protamine administration until admission to the intensive care unit (ICU). Chest tube output will then be recorded as a measure of blood loss for the first 24 hours after admission to the ICU.
After admission to the ICU, a transfusion protocol will then be used to ensure common indications for blood product replacement. Patients will be transfused with pRBC (10-15 mL/kg) if their hematocrit is less than 42% (higher target for evidence of inadequate oxygen delivery such as low SvO2, decreased cerebral NIRS, rising lactate, etc.). This protocol is consistent with our current standard practice at CHW.
If the bedside clinician decides a transfusion is/is not indicated outside of these guidelines, it will be recorded as a protocol variation and will be analyzed inclusively and separately. Volume of whole blood transfused will be multiplied by 0.5, as the concentration of red blood cells in whole blood is about 0.5 times the concentration present in packed red blood cells.
Data Collection, Analysis, and Power Calculation:
Data Management: Data will be recorded on a standardized data collection forms and stored in a RedCap data base which allows for menu driven options, inbuilt checks and generation of reports.
Safety (Aim 1): We hypothesize that measurements of safety will be same or less than historical controls over the last two years from CHW. We will record the mortality rate, incidence of ECMO support within 24 hours postoperatively, incidence of mediastinal exploration for bleeding and other indications within 24 hours postoperatively, incidence of thrombotic disease at discharge (ultrasound or other radiographic evidence if obtained for routine patient care), incidence of intracranial hemorrhage (ultrasound or computed tomography if obtained for routine patient care), days to delayed sternal closure, days to cessation of mechanical ventilation, and days to hospital discharge in the experimental and control groups. We will compare these data using a chi-square for categorical data, a t-test for continuous data and Kaplan Meir curves with a Wilcoxon rank sum test for censored data.
Feasibility (Aim 1): We hypothesize that recruitment will be at a rate of 3-4 per month.
During the course of this project, a summary of the numbers of subjects approached for consent, those consented and difficulties in measurement (including unobtainable measures) will be summarized overall and by demographics. Associations will be investigated with scatter plots, Loess smooth curves, and Pearson correlation coefficients
ATIII Pharmacokinetics (Aim 2): ATIII levels drawn preoperatively, within 30 minutes after administration (prior to start of CPB), within 30 minutes of start of CPB, just prior to discontinuation of CPB, and upon admission to the ICU will be assessed to determine if the single dose of ATIII sustained normal ATIII levels in the experimental group throughout these time periods.
Postoperative Blood Loss and pRBC Transfusion Volume (Aim 3): Our primary efficacy hypothesis for this study is that blood loss and pRBC transfusion volumes will be less than historic controls collected in the last two years from CHW. Blood loss will be volumes (mL/kg) of blood loss and chest tube output from 10 minutes after protamine administration to 24 hours after ICU admission. If a patient requires re-exploration of the chest in the first 24 hours postoperatively, the volume of chest tube output for the duration of exploration will be recorded as a time-weighted average equal to the chest tube loss for the 2 hours prior to and 2 hours after the exploration. Volumes (mL/kg) of packed red blood cells and 0.5 X volume (mL/kg) of whole blood transfused from 10 minutes after protamine administration to 24 hours after ICU admission will be recorded. Patients who require ECMO within the first 24 hours postoperatively will be analyzed separately as this is a known risk factor of increased bleeding and transfusion support. We will compare the blood loss and pRBC transfusion volumes in the two groups using a t-test or a Mann Whitney test. Further we will allow for demographics such as sex and race, using a regression model with blood loss or pRBC volume as the outcome and group, and demographics as the independent variables.
Power analysis: Since there are two primary outcomes of blood loss volume and pRBC transfusion volume, we will use a Bonferroni adjustment and an alpha of 0.05/2= 0.025. It is possible that 20 will not consent. Therefore we provide a calculation also for 25% refusal. With 20 (15) patients in the experimental group and approximately 40 historical controls, we will have at least 80% power to detect a difference of 0.9 (1.0) standard deviations.
Study Design
Allocation: Non-Randomized, Control: Historical Control, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
Conditions
Postoperative Hemorrhage
Intervention
Antithrombin (Recombinant)
Location
Children's Hospital of Wisconsin
Milwaukee
Wisconsin
United States
53226
Status
Not yet recruiting
Source
Medical College of Wisconsin
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT01158729
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Antithrombin Proteins
An endogenous family of proteins belonging to the serpin superfamily that neutralizes the action of thrombin. Six naturally occurring antithrombins have been identified and are designated by Roman numerals I to VI. Of these, Antithrombin I (see FIBRIN) and ANTITHROMBIN III appear to be of major importance.
Postoperative Hemorrhage
Hemorrhage following any surgical procedure. It may be immediate or delayed and is not restricted to the surgical wound.
Antithrombin Iii Deficiency
An absence or reduced level of Antithrombin III leading to an increased risk for thrombosis.
Antithrombin Iii
A plasma alpha 2 glycoprotein that accounts for the major antithrombin activity of normal plasma and also inhibits several other enzymes. It is a member of the serpin superfamily.
Antithrombins
An endogenous family of proteins belonging to the serpin superfamily that neutralizes the action of thrombin. Six naturally occurring antithrombins have been identified and are designated by Roman numerals I to VI. Of these, Antithrombin I (see FIBRIN) and ANTITHROMBIN III appear to be of major importance.
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