Author + information
- Received January 7, 2010
- Revision received May 5, 2010
- Accepted June 6, 2010
- Published online November 23, 2010.
- Colleen E. Gruenwald, MHSc, RN, CCP, CPC⁎,‡,⁎ (, )
- Cedric Manlhiot, BSc⁎,
- Anthony K. Chan, MD†,
- Lynn Crawford-Lean, BSc, RRT, CCP, CPC⁎,
- Celeste Foreman, BA, CCP, CPC⁎,
- Helen M. Holtby, MB BS⁎,
- Glen S. Van Arsdell, MD⁎,
- Ross Richards, PhD‡,
- Helen Moriarty, BAppSc, MAppSc‡ and
- Brian W. McCrindle, MD, MPH⁎
- ↵⁎Reprint requests and correspondence:
Mrs. Colleen Gruenwald, The Hospital for Sick Children, 555 University Avenue, Black Wing, Room 2324, Toronto, Ontario M5G 1X8, Canada
Objectives We sought to determine whether infants (younger than 1 year old) had similar clinical benefits with individualized anticoagulation management as older children and adult undergoing cardiopulmonary bypass (CPB).
Background Individualized heparin and protamine management in older children and adults undergoing CPB has been associated with improved clinical outcomes.
Methods Ninety infants younger than 1 year of age undergoing CPB were enrolled in a randomized, controlled trial comparing weight-based anticoagulation management using activated clotting time (ACT) to individualized management with Hemostasis Management System Plus. Manufacturer's guidelines were followed for the first 33 patients. A modified protocol was used for the last 57 patients with adjustments for coagulation system immaturity and hemodilution on CPB.
Results The hemostasis management system (HMS) device consistently underestimated plasma anti-Xa levels, leading to an overestimated required heparin dose. After a blinded interim analysis revealed poor outcomes in the experimental HMS group using manufacturer guidelines, the safety committee suspended the study pending protocol modifications. The use of the HMS device following the modified protocol resulted in more stable anti-Xa levels during CPB with improved post-operative outcomes including reduced need for transfusions (71 ml/kg vs. 80 ml/kg; p = 0.003), ventilation time (33 h vs. 49 h; p = 0.04), intensive care (88 h vs. 99 h; p = 0.003), and hospital length of stay (192 h vs. 216 h; p < 0.001), compared with the weight-based protocol.
Conclusions This study supports the use of the HMS device, with a modified protocol for infants younger than 1 year of age, for anticoagulation management during CPB. Clinical guidelines for the use of the HMS device should be modified for infants younger than 1 year of age.
Infants undergoing cardiopulmonary bypass (CPB) for cardiac surgery experience higher surgical morbidity and mortality compared with older children and adults (1). Increased hemodilution, activation of the coagulation system, stimulation of the inflammatory response, and hemostatic derangements in young children lead to thrombotic complications, bleeding, and more blood transfusions in the perioperative period (1–6). The immaturity of the hemostatic system in infants prevents adequate anticoagulation during CPB due to inherent deficiencies in antithrombin (AT) as well as other coagulation proteins. This results in resistance to anticoagulation with heparin and ineffective suppression of thrombin generation (7–9). Unfractionated heparin is most commonly used for anticoagulation during CPB for cardiac surgery, not only to prevent gross clotting of the bypass circuit but also to prevent more subtle activation and consumption of coagulation system components. Despite the large doses of heparin used during CPB, excessive thrombin and plasmin generation still occurs and is associated with bleeding, thrombosis, and organ dysfunction post-operatively (10–12). Current anticoagulation practices in children have been extrapolated from adult protocols and are generally based on an empirical weight-based heparin and protamine dosing regimen using an automated whole blood activated clotting time (ACT) device to monitor anticoagulation. There has been very little validation of any of these protocols in young children (13–19).
Individualized heparin and protamine management using a whole blood hemostasis management system (HMS) in older children and adults undergoing CPB has been associated with improved clinical outcomes. Studies have shown significant reductions in thrombin generation during CPB resulting in reduced post-operative bleeding and decreased need for blood transfusions (20–24) using this regimen. We sought to determine whether using this method of managing and monitoring anticoagulation during CPB in infants younger than 1 year of age was associated with similar improvements.
This randomized, controlled clinical study was conducted after receiving institutional research ethics board approval at The Hospital for Sick Children, Toronto, Ontario, Canada. Written informed consent was obtained from the legal guardian of each patient before randomization. The study began in August 2006 and was temporarily suspended in June 2007 (HMS I: first study group of 33 patients) by the study's independent data safety committee. A blinded interim analysis revealed poor outcomes in the HMS group and study-related adverse events. The original protocol was revised to limit the heparin dose recommended by the HMS system. The research ethics board granted approval for the amended protocol, and the study resumed in October 2007 (HMS II: second study group of 57 patients). Enrollment was completed in February 2009.
Patients were eligible for inclusion if they were younger than 1 year of age at the time of elective surgery. Exclusion criteria included patients weighing <2.0 kg, prematurity (<36 weeks of age), preoperative use of anticoagulants at a therapeutic dose, known history of bleeding or thrombotic disorders, renal and/or liver failure, and AT replacement therapy before surgery. Randomization was stratified by age (birth to 1 month and 1 month to 12 months); subjects were randomized in random blocks of 2, 4, and 6 using a random-number generator. Surgeons, anesthesiologists, and cardiac critical care unit (CCCU) staff were blinded to each patient's group randomization, whereas the perfusionists were not blinded in order to administer the study intervention. All study outcomes were assessed by trained personal unaware of the patient treatment assignment.
Heparin concentration measurement
The HMS Plus Hemostasis Management System (Medtronic Inc., Minneapolis, Minnesota) is an automated protamine titration method of anticoagulation management. It provides both whole blood heparin concentration measurements and ACT (24–29). The principle of HMS management is based on the heparin dose-response test that measures the in vitro anticoagulation response of the patient's blood to a known concentration of heparin and calculates the estimated heparin dose required to achieve the desired target heparin concentration. This response is used to determine the whole blood heparin concentration necessary to achieve and maintain adequate anticoagulation during CPB. The concentration of circulating heparin is monitored during CPB using the heparin protamine titration test. Each channel of the heparin protamine titration test cartridge contains a known quantity of protamine with a constant amount of thromboplastin for activation of the blood. The channel that most closely neutralizes the heparin in the sample will be the first to clot. In this channel, the protamine-to-heparin ratio is nearest to the neutralization point (29). The heparin concentration is also used to calculate the protamine dose required for neutralization of heparin after CPB.
Heparin and protamine management
All heparin and protamine doses given by anesthesia were drawn up and checked by 2 perfusionists for safety and to maintain blinding. Empirical weight-based heparin and protamine management was used for patients in the control group. The ACT (ACT Plus, Medtronic Inc.) was used to guide heparin requirements before and during bypass. The HMS was used for heparin and protamine management for patients randomized to the treatment group. The decision to administer the total dose (patient + pump) of protamine as calculated by the HMS was supported by literature describing an increase in heparin concentration after modified ultrafiltration (30). The observation of residual laboratory plasma anti-Xa levels after the protocol in the HMS I group prompted a further increase in the calculated protamine dose by a factor of 1.5 subsequently used in the HMS II group. This was required to fully reverse residual heparin after CPB. Specific details regarding these protocols are shown in Table 1.
Blood transfusion protocol
Blood transfusion protocol was standardized throughout the study. Packed red blood cells (PRBCs) were added to the prime to achieve and maintain patient hematocrit at 28% to 30% during CPB. For cyanotic patients, PRBCs were given to increase the hematocrit 33% to 35% before CPB termination. All patients received one-half unit of frozen plasma and one-half unit of platelets in the prime, with the remainder was given before removal of the cross-clamp. After CPB and in the CCCU, patients received 10 ml/kg of platelets if the platelet count decreased to <100,000/mm3or if bleeding was >20 ml/kg/h. Patients were given cryoprecipitate (1 U/10 kg) if fibrinogen was <1.0 g/l. Finally, in the post-operative period, PRBCs were given as necessary to maintain a hematocrit of >28% for noncyanotic patients, 35% to 40% for cyanotic patients or if patients had clinical evidence of low cardiac output including an arterial-mixed venous saturation difference >40, lactic acid >4 mmol/l, or poor ventricular function by echocardiogram (ejection fraction <40%). All patients underwent modified ultrafiltration for 15 to 20 min after CPB.
Arterial blood samples were obtained for all patients immediately after placement of the arterial line, after the pre-CPB heparin loading dose, 10 min after initiation of CPB, every 30 min during and at the termination of CPB, at 5 and 45 min after protamine administration, and on arrival and after 24 h in the CCCU. The heparin dose response was determined on the sample obtained on arterial line insertion. Blood samples were analyzed for biochemistry, heparin protamine titration, complete blood count, and anti-Xa at all time points. Fibrinogen, d-dimers, AT, thrombin–AT (TAT) complexes, and prothrombin fragments 1 and 2 (F1.2) were measured after arterial line insertion, at initiation and termination of CPB, at 5 and 45 min after protamine administration, on arrival and after 24 h in the CCCU. TAT complex and F1.2 measurements were used to quantify thrombin generation throughout CPB. The measurements were performed using Enzygnost TAT complex and F1.2 (monoclonal) (Dade Behring, Marburg, Germany) assays. Total blood loss was estimated by measuring chest tube losses during the first 24 h after CCCU admission. Blood transfusion requirements intraoperatively and for 24 h post-operatively were tabulated by the total volume per patient weight and the type and number of blood product units transfused. Inotropic support score was calculated every 6 h after CCCU arrival up to 24 h after arrival by means of the following formula, using drug doses expressed as μg/kg/min: dopamine + dobutamine + (epinephrine × 100) + (milrinone × 10) (31). Total ventilation hours, CCCU and hospital length of stay, and intravascular thrombosis until hospital discharge were also recorded.
Data are given as frequencies, medians with ranges and means with SDs as appropriate. Baseline characteristics and outcomes between study groups were compared with the Fisher exact test, chi-square test, Wilcoxon nonparametric test, and Student ttest as appropriate. Comparisons of outcomes were performed in multivariable logistic or linear regression models adjusted for age at surgery, surgeon, and surgery Aristotle score. All regression models used maximum likelihood methodology for parameter estimation. Separate linear regression models adjusted as previously described were created for each laboratory test at every time point. Data from both protocols were analyzed separately. The following variables were log-transformed in linear regression models (descriptive statistics throughout this paper remained from the nontransformed distribution): heparin and protamine doses, transfusion volumes, time to chest closure, chest tube volume loss, duration of ventilation and hospitalization, platelet count, TAT complex, and F1.2. All analyses were performed using SAS statistical software version 9.1 (SAS Institute, Inc., Cary, North Carolina).
Enrollment and demographics
A total of 90 patients were enrolled, 33 in the original protocol (HMS I group) and 57 in the modified protocol (HMS II group). In the HMS I protocol, 16 of 33 patients (48%) were randomized to the treatment arm compared with 28 of 57 patients (49%) randomized to the treatment arm with the HMS II protocol. Baseline and surgical patient characteristics are detailed in Table 2and were comparable between the treatment and control groups for both protocols.
Clinical outcomes of the HMS I protocol
The HMS device was found to underestimate actual laboratory plasma anti-Xa levels in infants. This caused an overestimated required dose of heparin (Table 3).The result was significantly poorer clinical outcomes including greater chest tube volume loss (Table 4),transfusion requirement (Table 5),intravascular thrombosis along with greater ventilation time, and longer CCCU and hospital stay (Table 4).
Clinical outcomes of the HMS II protocol
In the HMS II protocol, patients in the treatment arm received significantly more heparin and protamine (all p values <0.001) than control patients during the perioperative period, but much less than those in the HMS I (Table 2). Patients in the treatment group were more likely to receive periodic doses of heparin throughout CPB, which was a rare occurrence in the control group. As a result, the plasma anti-Xa concentrations were more stable throughout CPB (Fig. 1). A statistically significant increase in the ratio of protamine to pre-CPB heparin dose was observed in the treatment group versus the control (Table 3).
Laboratory measurements of coagulation and activation
Treatment patients had significantly higher platelet counts measured at all time points throughout CPB, significantly lower levels of TAT complexes measured on arrival and at 24 h in the CCCU and significantly lower levels of F1.2 consistently measured after protamine on arrival and at 24 h in the CCCU (Fig. 1). There was no significant difference between groups in serial measurements of AT, fibrinogen, d-dimers, hemoglobin, or hematocrit at any time point.
Bleeding and transfusions
There was no significant difference between groups in chest tube loss at both time points (4 and 24 h after CCCU arrival) (Table 4). However, patients in the treatment group received significantly fewer transfusions in the operating room and over the first 24 h after surgery. Furthermore, we observed a clinically important reduction in the number of patients who received >5 U of blood in the operating room, any transfusions in the CCCU, and >7 U of blood overall (Table 5) in the treatment group. This did not, however, reach statistical significance.
Morbidity and hospital stay
Patients in the treatment group had significantly shorter ventilation times and CCCU and hospital lengths of stay compared with the control group. Five control patients (17%) (including 1 patient who received recombinant activating factor VII) had thrombosis during their hospital stay compared with 1 (4%) in the treatment group. There were no significant differences in inotrope requirements or in-hospital mortality between groups (Table 4).
The application of medical knowledge from adult studies to pediatric patients without further evaluation is a potentially dangerous yet all too common occurrence. In this study, we found that a technology shown to have benefits in older children and adults could not be readily applied to infants. The physiology of children younger than 1 year of age is fundamentally different, from both hematological and cardiovascular perspectives. The use of a modified protocol for the HMS device, taking these factors into account, is associated with improved surgical outcomes for patients undergoing cardiac surgery. This study exemplifies the need for medical devices, protocols, and drug dosing to be appropriately validated for use in young children.
Post-operative bleeding and the restoration of hemostasis in infants are the result of interactions between many mechanisms. Disturbances of coagulation arise due to factors such as hemostatic system immaturity, hemodilution, systemic inflammation, prolonged bypass time, and the use of deep hypothermic circulatory arrest as well as age-related differences in responses to heparin (9). Children with congenital heart disease, particularly cyanotic polycythemic children, have further derangements of both platelet function and coagulation proteins (6,32–37). The physiological impact of CPB during infant surgery exceeds that in adults. There are few clinical studies that have investigated strategies for anticoagulation and monitoring in infants or the subsequent effects on hemostasis and clinical outcomes.
There is well documented evidence that the ACT has serious limitations as a monitor of heparin-induced anticoagulation during CPB. ACT measurements are being affected by many variables other than heparin such as hemodilution and hypothermia, as well as decreased platelet function. It is an inadequate monitor of anticoagulation (17,24). The prolongation of the ACT during bypass may lead to misinterpretation that adequate anticoagulation is present even when heparin levels may be inadequate. Most importantly, studies have shown poor correlation between ACT values and plasma heparin concentrations in children undergoing CPB (18,25,26,38). Despite this, anticoagulation management and monitoring during infant CPB continue to be weight based (and derived from adult protocols), and the ACT is commonly used for pediatric patients undergoing cardiac surgery.
Even in adults, empirical protocols for CPB anticoagulation have been shown to be suboptimal in reducing hemostatic activation (10). Individual heparin and protamine management with patient-specific heparin concentrations maintained during CPB is a more favorable method of anticoagulation in adults and leads to improved clinical outcomes (21,23).
Previously published studies in pediatric populations have also demonstrated that individualized heparin concentration–based protocols for anticoagulation and protamine reversal appear superior to empirical weight-based protocols for infants and children (18,20). In 1 study, the use of individualized patient-specific heparin management in children resulted in positive results: less blood loss and fewer blood product transfusions. However, this study focused on older children, not on infants younger than 1 year of age (20). Guzzetta et al (18) studied infants younger than 6 months of age (none younger than 1 month of age) undergoing elective repair of a congenital heart defect and compared weight-based heparin dosing to individualized heparin management. They showed significantly higher total heparin doses in the treatment group compared with controls and greater suppression of thrombin generation. There was, however, an increase in 24-h chest tube drainage, which was not statistically significant, and a higher blood product exposure in the treatment group (18). Our data confirm these findings with a larger cohort of patients younger than 1 year of age including neonatal patients younger than 1 month of age. In addition, we have further elucidated some of the issues that complicate anticoagulation management during CPB in this very unique infant patient population, including the effect of the immaturity of the coagulation system on anticoagulant sensitivity, the influence of hemodilution on anticoagulation monitoring, and the need for higher anticoagulant doses in this population to limit overt inflammation and activation. Our modification of the protocol resulted in lower blood product exposure in the treatment group.
The benefits of using the HMS device for heparin and protamine management have been established in the adult literature. This study has uncovered certain limitations that precondition its use in infants. The protocol described by the manufacturer has been well investigated for use in adults. However, it is clear that the device needs further validation for use in infants younger than 1 year of age based on the results of the HMS I protocol. The device cannot be safely used with the manufacturer's suggested protocol.
Also, the cartridge used for detection of heparin reversal is limited to a gross range of 0 to 0.4 U/ml heparin. We found that 47% of all patients in the treatment groups had therapeutic laboratory plasma anti-Xa levels of ≥0.3 U/ml at 5 min after protamine reversal despite a heparin protamine titration measurement of 0 U/ml. Furthermore, 54% of patients in the control groups also demonstrated therapeutic anti-Xa levels after protamine reversal, indicating that full protamine reversal of the anti-Xa effects of heparin was not achieved in approximately 50% of all patients. Elevated anti-Xa levels were not widely observed on arrival in the CCCU in any group. This may contribute to bleeding in the immediate post-operative period when aggressive blood component therapy is used to achieve hemostasis. Further investigation of these findings is required to elucidate the role of protamine and anti-Xa levels. Others have demonstrated decreased post-operative blood losses when reduced protamine doses are used as well as increased anti-Xa levels from the use of protamine itself (39).
Heparin management in the HMS I protocol was strictly followed according to the heparin concentration recommended by the heparin dose response calculated by the HMS device at induction. As a result, patients received significantly more heparin and protamine in the treatment group that resulted in worse clinical outcomes including increased chest tube volume losses, increased transfusion, longer ventilation time, and longer CCCU and total hospital length of stay. There were important observations made as a result of the HMS I clinical trial. The HMS overestimated the amount of heparin required to achieve adequate anticoagulation during CPB. The HMS may be limited due to the programmed standard algorithms used to calculate blood volume in this unique patient population in which blood and plasma volume is highly variable. The immaturity of the hemostatic system, cyanosis, congestive heart failure, and the need for multiple surgical procedures may limit the accuracy of the calculation of the heparin dose, predicting that higher levels of heparin are required to obtain optimal anticoagulation. Learning from the results in the HMS I protocol, heparin management algorithms were established for anesthesia loading and prime doses and heparin concentration targets to be maintained while on CPB to maintain the equivalent plasma heparin concentration (anti-Xa) of 4.0 U/ml (25,26). This rationale for the HMS II protocol led us to set the whole blood heparin management algorithm for all treatment patients at 3.0 U/ml on the HMS device for the duration of CPB, thereby still allowing for individualized patient management throughout each case. To maintain this heparin concentration throughout CPB, patients in the treatment group received significantly more heparin than patients in the control group both at induction and throughout CPB, which resulted in significantly higher and more stable laboratory anti-Xa levels.
This prospective, randomized, controlled trial highlights the importance of evaluating equipment appropriately for different patient populations. It also affirms the benefit of achieving and maintaining adequate anticoagulation and monitoring in patients younger than 1 year of age during CPB. The use of the HMS device with a modified protocol is a useful component of an anticoagulation strategy. This study demonstrates that both low and very high levels of heparin concentration lead to worse clinical outcomes. Additional clinical studies that refine the appropriate protamine dosing will complement these results.
The authors are grateful for the assistance of many colleagues who participated in conducting this clinical trial. Specifically, the authors would like to thank the cardiac surgical team including the anesthesiologists, nurses, perfusionists, and surgeons, as well as the cardiac critical care team including the intensivists and nurses.
Funded by the Heart and Stroke Foundation of Ontarioand MedtronicCanada. Drs. Gruenwald, Chan, Holtby, Van Arsdell, and McCrindle have received support from HSFO. Dr. Gruenwald has received support from Medtronic. All other authors have reported that they have no relationships to disclose.
- Abbreviations and Acronyms
- activated clotting time
- cardiac critical care unit
- cardiopulmonary bypass
- prothrombin fragments 1 + 2
- hemostasis management system
- packed red blood cells
- Received January 7, 2010.
- Revision received May 5, 2010.
- Accepted June 6, 2010.
- American College of Cardiology Foundation
- Andrew M.,
- Paes B.,
- Milner R.,
- et al.
- Boisclair M.D.,
- Lane D.A.,
- Philippou H.,
- et al.
- Olshove V.F.,
- Langwell J.,
- Burnside J.,
- Bennett D.
- Schriever H.G.,
- Epstein S.E.,
- Mintz M.D.
- Koster A.,
- Huebler S.,
- Merkle F.,
- et al.
- Raymond P.D.,
- Ray M.J.,
- Callen S.N.,
- Marsh N.A.
- Raymond P.D.,
- Ray M.J.,
- Callen S.N.,
- Marsh N.A.
- Harloff M.,
- Taraskiewicz J.,
- Fotouhi C.
- Andrew M.,
- Vegh P.,
- Johnston M.,
- Bowker J.,
- Ofosu F.,
- Mitchell L.
- Shayevitz J.R.,
- O'Kelley S.W.
- Svenmarker S.,
- Appelblad M.,
- Jansson E.,
- Haggmark S.
- Lake C.L.
- Ni Ainle F.,
- Preston R.J.,
- Jenkins P.V.,
- et al.