| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
| ||||||||||||||
| ||||||||||||||
|
|
|
|
||||||||||||
|
||||||||||||||
From the *Department of Anesthesiology, Emory University School of Medicine, and Cardiac Research Department, Children’s Healthcare of Atlanta at Egleston Atlanta, Georgia.
Address correspondence to Nina A. Guzzetta, MD, Department of Anesthesiology, Children’s Healthcare of Atlanta at Egleston, 1405 Clifton Road, NE, Atlanta, GA 30322. Address e-mail to nina.guzzetta{at}emoryhealthcare.org.
Abstract
BACKGROUND: Recent investigations in adult patients have suggested that a heparin concentration-based anticoagulation protocol for heparin administration during cardiopulmonary bypass (CPB) significantly reduced hemostatic activation when compared with standard weight-based heparin doses. Reductions in hemostatic activation during CPB could be particularly beneficial in pediatric patients in whom CPB-related coagulation issues are complex and influenced by many variables. However, information regarding heparin levels during CPB and their correlation to hemostatic activation is lacking in children. In this investigation, we compared a patient-specific heparin concentration-based heparin management protocol with a standard weight-based protocol in infants <6-mo-of-age. The efficacy of these two protocols was assessed by comparisons of heparin concentration, levels of biochemical markers of hemostatic activation, and clinical outcome.
METHODS: Twenty-five infants <6-mo-old scheduled for primary, elective repair of a congenital heart defect were enrolled in this study. Patients were randomized to receive either 400 U/kg of heparin (control group) or a patient-specific heparin dose calculated by the Hepcon Hemostasis Management System Plus (Hepcon HMS; Medtronic, Minneapolis, MN; intervention group). Heparin concentrations were compared between the two groups at predetermined intervals. Blood samples for biochemical markers of hemostatic activation were collected before and after CPB, and measurements of clinical outcome were recorded.
RESULTS: Infants in the intervention group received a larger total heparin dose than infants in the control group. Heparin concentrations after the initial heparin dose and 30 min into CPB were similar between groups; however, at the start of rewarming and at the termination of CPB, infants in the intervention group had significantly higher heparin concentrations than infants in the control group. Infants in the intervention group also generated less F1.2 and consumed less factor VIII than infants in the control group. Clinically, however, infants in the intervention group received one more donor exposure from the administration of blood products post-CPB.
CONCLUSION: A heparin concentration-based heparin management protocol in infants <6-mo-old resulted in higher, more constant heparin concentrations during CPB than a standard weight-based protocol. Furthermore, higher heparin concentrations were associated with greater suppression of hemostatic activation, as measured by less generation of thrombin and less consumption of factor VIII. Our findings demonstrate that use of a patient-specific heparin concentration-based protocol for heparin administration during CPB in infants may attenuate hemostatic activation. However, further research is needed to determine if this protocol has clinically beneficial hemostatic effects.
The monitoring of heparin-induced anticoagulation for cardiopulmonary bypass (CPB) is of critical importance. Inadequate anticoagulation during CPB may lead to ineffective suppression of thrombin formation and may result in disorders of hemostasis and thrombosis in the postbypass period, whereas excessive anticoagulation may place patients at risk for postoperative bleeding complications.
The primary monitor of heparin-induced anticoagulation during CPB is the activated clotting time (ACT), a measure of whole blood coagulation status. However, ACT values are often affected by variables other than heparin. Several studies have shown a poor correlation between ACT values and plasma heparin concentrations in adults and children undergoing CPB.1–6 The hypothermia, hemodilution, and decreased platelet function that accompany CPB all contribute to prolongation of the ACT to values deemed "acceptable," even if heparin levels are inadequate.7 Since these variables are especially exaggerated for pediatric cardiac patients, monitoring heparin therapy in children during CPB by ACT values alone may lead to less than optimal heparin-induced anticoagulation. In addition, heparin dosing protocols for pediatric patients are traditionally derived from weight-based dosing protocols used in adults, even though children have higher metabolic rates and larger blood volume to body weight ratios than adults.8 Therefore, it is not unexpected that heparin levels during CPB in children are lower than those found in adults.6,9,10 Despite these concerns, heparin dosing continues to be extrapolated from weight-based adult protocols, and ACT monitoring continues to guide heparin management decisions for most pediatric patients undergoing CPB.
Although weight-based protocols are usually successful in preventing grossly visible clot formation during CPB, this does not ensure successful inhibition of the hemostatic system on a molecular level.11 Small amounts of thrombin bound to fibrin or other surfaces, such as an injured vessel wall or CPB circuit, are protected from inhibition by the antithrombin (AT)III-heparin complex.12 This thrombin remains enzymatically active, and thus may lead to fibrin formation, activation of platelets, depletion of coagulation factors, and fibrinolysis.12 In adults, investigations have shown that maintenance of patient-specific heparin concentrations during CPB may more effectively inhibit clot-bound and surface-bound thrombin as well as facilitate heparin’s ATIII-independent mechanisms of action.13,14 Tailoring heparin dosing for individual patients may prove to be the most effective method of inhibiting thrombin generation during CPB. Patient-specific heparin concentrations, i.e., the amount of heparin required by a specific individual to reach a desired ACT, can be calculated in the operating room by the Hepcon Hemostasis Plus Management System (Hepcon HMS; Medtronic, Minneapolis, MN).
In this investigation, we sought to determine whether a patient-specific heparin concentration-based heparin management protocol, monitored by Hepcon HMS-calculated heparin concentrations, would better inhibit activation of the hemostatic system on a molecular and clinical basis than would a standard weight-based heparin management protocol, monitored solely by ACT values, in infants <6-mo-old undergoing CPB. Comparisons of the two protocols were assessed through biochemical markers of hemostatic activation and by measures of clinical outcome.
METHODS
Patient Population
With IRB approval and written informed parental consent, 25 children younger than 6-mo-old undergoing elective cardiac surgery requiring CPB were enrolled in this prospective, observational study. Infants treated with preoperative anticoagulants or intraoperative antifibrinolytic drugs were excluded from the investigation. Infants were randomly assigned to either a control group (n = 12) or an intervention group (n = 13). One infant in the intervention group required a return to CPB for mitral stenosis and therefore was not included in the clinical outcome measurements.
CPB and Anticoagulation Management
Nonpulsatile hypothermic CPB with a nonheparin-coated system, a Terumo RX-05 hollow-fiber membrane oxygenator (Terumo Cardiovascular Systems, Ann Arbor, MI) and a COBE SMArt neonatal circuit tubing (Sorin Group USA, Inc., Arvada, CO) with a 300-mL priming volume were used for all cardiac surgical repairs. Packed red blood cells were added to the circuit as needed to achieve and maintain a hemocrit of 30% throughout the duration of CPB. Baseline ATIII levels were obtained before surgical incision. ACT measurements during the study were obtained simultaneously by both the Hemochron Response (Hemochron, International Technidyne Corporation, Edison, NJ) and the Hepcon HMS (Medtronic, Minneapolis, MN) instruments using kaolin activation. ACT measurements were performed for all patients in both groups before the institution of CPB and at 30-min intervals during the CPB period. The Hepcon HMS was also used to measure on-site whole blood heparin concentration in all patients at the following intervals: after the initial heparin dose, 30 min after the initiation of CPB, at the start of rewarming, and immediately after the termination of CPB. To compare Hepcon HMS-calculated heparin concentrations with laboratory-measured heparin concentrations, blood samples were obtained at two of the above time intervals: after the initial heparin dose and immediately after the termination of CPB. Laboratory-measured plasma heparin concentrations were quantified by anti-factor Xa activity using a chromogenic substrate assay (Stachrom Heparin, Diagnostica Stago, Parsippany, NJ).
In the control group, infants received our standard weight-based heparin bolus of 400 U/kg before the institution of CPB. One-thousand units of heparin were added to the CPB prime. An ACT of 480 s was targeted and additional heparin boluses of 100 U/kg were administered as necessary to maintain this value. After the termination of CPB, heparin was neutralized by 4 mg/kg of protamine.
In infants assigned to the intervention group, a heparin dose-response assay was performed by the Hepcon HMS before surgical incision. This assay is a patient-specific assay based on body surface area that calculates the heparin concentration required by that patient to achieve an ACT of 480 s. The heparin dose-response assay determined the initial dose of heparin to be given to the patient and the amount of heparin to be added to the CPB prime. Subsequent heparin doses, as calculated by the Hepcon HMS system, were administered if the patient’s Hepcon HMS-calculated heparin concentration decreased to less than the projected reference concentration or if the Hemochron ACT decreased to <480 s. The Hepcon HMS also calculated the protamine dose to be administered after the termination of CPB.
Hematologic Assays
Blood samples for biochemical markers of hemostatic activation were collected from all patients after the administration of the initial heparin dose but before the institution of CPB and again after the conclusion of CPB but before protamine infusion. The following biochemical markers of hemostatic activation were measured: prothrombin fragment 1.2 (F1.2), a measure of thrombin production; fibrinopeptide A (FPA), a measure of fibrinogen activation of which thrombin is the primary initiator; β-thromboglobulin (β-TG), a measure of platelet activation; free tissue factor pathway inhibitor (TFPI), a measure of inhibition of tissue-factor activated coagulation; factor V (FV) and factor VIII (FVIII). All blood samples were obtained from an indwelling arterial catheter after aspirating 5 mL of blood to ensure that no heparin from the flush solution was present in the collection sample. Blood was placed into the appropriate prechilled tubes and immediately centrifuged for 30 min. The resultant plasma was pipetted into microtubes for storage at –70°C until assayed in batches. Enzyme-linked immunosorbent assays were used to measure F1.2 (Enzygnost F1 + 2 micro, Dade Behring Inc., Deerfield, IL), FPA (Zymutest FPA, Diapharma Group, Inc., West Chester, OH), β-TG and free TFPI (Asserachrom β-TG and free TFPI, Diagnostica Stago, Parsipany, NJ). Plasma levels of FV and FVIII were measured using a clotting time partial thromboplastin time test (Diagnostica Stago). All hematologic assays were performed in accordance with their respective manufacturer’s instructions.
Clinical Outcomes
The following measures of clinical outcome were recorded: time between the administration of protamine and leaving the operating room, number of donor exposures after protamine administration, 24-h chest tube drainage, time to tracheal extubation, and duration of intensive care unit stay.
Statistical Analysis
Two-sample, two-sided Student’s t-test assuming unequal variance were used to compare the means of demographic and CPB data, heparin dosing and heparin concentration between the two groups. Pre- and post-CPB biomarker levels were assessed for normal Gaussian distribution by the Anderson-Darling normality test (Minitab statistical software, Minitab, Inc., State College, PA). Paired t-tests were used to compare the pre- and post-CPB means of biomarkers if normal distribution was confirmed. A Wilcoxon’s ranked sum test was used when the normality test presented evidence of nonparametric distribution of the data. Means of the clinical outcome measurements were compared using two-sample, two-sided Student’s t-test assuming unequal variance. For all calculations, a P value <0.05 was considered significant.
RESULTS
Demographic and CPB data are presented in Table 1. As noted in this table, infants in the intervention group were older than those in the control group despite computer randomization of the two groups. In addition, infants in the intervention group had more complex surgeries, as defined by extracardiac suture lines (i.e., tetralogy of Fallot repair), than did infants in the control group.
|
The mean heparin doses administered to infants in each group are presented in Table 2. Infants in the intervention group received more heparin in the circuit prime, and more supplemental heparin during CPB, than infants in the control group. This resulted in a statistically significantly larger mean total heparin dose in the intervention group than in the control group. On-site whole blood heparin concentrations measured by the Hepcon HMS at the predetermined time intervals are depicted in Figure 1. After the initial heparin bolus and 30 min into CPB, heparin concentrations were similar for all infants; however, at the start of rewarming and immediately post-CPB, infants in the intervention group had statistically significantly higher mean heparin concentrations than infants in the control group. Mean post-CPB heparin concentrations in the intervention group, whether measured by the Hepcon HMS or by laboratory assessment of anti-Xa activity, were not statistically significantly different from mean pre-CPB concentrations in this group. This is in contrast to the control group where mean post-CPB heparin concentrations were significantly lower than mean pre-CPB concentrations (Fig. 2). Despite the larger total mean heparin dose administered to infants in the intervention group, there was no difference in the mean amount of protamine administered to infants in each group (control = 4.0 ± 0 mg/kg; intervention = 3.9 ± 1.9 mg/kg; P = 0.84).
|
|
|
We compared changes in the levels of hemostatic biomarkers pre- and post-CPB between the two groups (Table 3). F1.2 levels in the control group showed a statistically significant elevation during CPB that was not found in the intervention group. FVIII levels in the control group showed a statistically significant decline during CPB that again was not found in the intervention group. The changes from pre- to post-CPB of all other measured hemostatic biomarkers were the same in the control and intervention groups.
|
The measures of clinical outcome are shown in Table 4. Infants in the intervention group received one more donor exposure secondary to blood product administration after protamine reversal than infants in the control group. There were no other statistically significant differences in outcome between the two groups.
|
DISCUSSION
In this investigation, we demonstrate that a patient-specific heparin concentration-based protocol to guide heparin administration for CPB in infants <6-mo-old dictated a substantially higher total heparin dose than would have been required by a standard weight-based protocol. The additional amount of heparin mandated by the heparin concentration-based protocol was administered as part of the circuit prime and during CPB as small boluses that supplemented the initial heparin dose. Consequently, these infants had a higher mean heparin concentration at the start of rewarming and at the end of CPB. This leads us to conclude that a heparin concentration-based protocol is superior to our standard weight-based protocol at maintaining a more constant heparin concentration throughout the duration of CPB. Additionally, this heparin concentration-based protocol was associated with greater suppression of thrombin generation, as measured by F1.2, and less consumption of FVIII, thus supporting the concept that enhanced intraoperative anticoagulation may result in improved preservation of certain coagulation factors. However, despite these laboratory findings, infants receiving the heparin concentration-based protocol received one more donor exposure from blood product administration than infants in the control group. Otherwise, no differences were found in clinical outcome measurements between the two groups.
Heparin is the anticoagulant most commonly used to prevent thrombus formation during CPB. Although heparin very effectively catalyzes the inhibition of circulating thrombin by ATIII, it is less effective at inhibiting thrombin that is bound to fibrin or other surfaces.12 Maintenance of higher heparin concentrations during CPB may better facilitate the inhibition of clot- and surface-bound thrombin as well as heparin’s ATIII-independent mechanisms of action.12,15 Reports supporting this concept have been published for adult cardiac surgical patients.13,14 However, investigations regarding heparin levels and their correlation to hemostatic activation are lacking for pediatric cardiac patients. Early investigations that increased heparin dose in the circuit prime of pediatric patients reported higher heparin concentrations with the initiation of CPB, but these levels were not maintained throughout the CPB period.16 Indices of thrombin generation and fibrinolysis in these children did trend lower than those in children receiving the standard circuit prime heparin dose but failed to reach statistical significance. In our investigation, the heparin concentration-based protocol used to guide heparin administration during CPB to infants <6-mo-old prescribed a larger amount of heparin for the CPB prime and continued supplemental boluses throughout the CPB period. As a result, infants in the intervention group had a higher mean heparin concentration from the start of rewarming until the termination of CPB. Furthermore, these infants achieved greater suppression of thrombin generation as measured by F1.2 than infants receiving the standard weight-based protocol.
Other markers of hemostatic activation measured in this investigation, aside from FVIII, did not show the same attenuation of activity in the presence of higher heparin concentrations as did F1.2. One would expect a decrease in fibrinogen activation to accompany the thrombin suppression found in the intervention group. We found however that FPA levels decreased during CPB by an equivalent proportion in both groups. In a previous study in neonates, we also demonstrated a decrease in FPA levels during CPB despite an increase in F1.2.10 This decrease in FPA is in contrast to findings in adult patients where FPA increases during CPB and where this increase is attenuated only in the presence of higher heparin concentrations.13 The difference is most likely explained by the extreme hemodilution encountered during extracorporeal circulation in young infants and neonates. Additionally, evidence exists that fibrinogen in children younger than 12-mo may be qualitatively defective17 and activation of this fibrinogen may not be reflected by a subsequent increase in FPA.
Thrombin is a potent activator of platelets causing aggregation, degranulation and the release of β-TG into the circulation.18 Thus, it is again unexpected that the reduced amount of thrombin produced during CPB in the intervention group was not accompanied by a reduction in β-TG. Our results however are congruent with data by Codispoti et al.19 who used the Hepcon HMS to individualize heparin and protamine management during CPB in pediatric patients older than 1 yr. Measures of hemostatic markers in their study were similar to our results in that, F1.2 levels decreased significantly in the Hepcon group, whereas β-TG levels increased significantly in both groups. Perhaps this is secondary to the cardiotomy suction, which markedly increases post-CPB markers of platelet activation.20 In addition, none of our patients received antifibrinolytic therapy, which in some studies has also been associated with a "platelet-sparing" effect.21 Further research is needed to elucidate the etiology of the substantial platelet activation as measured by β-TG that occurs during CPB in pediatric patients.
TFPI is an important in vivo inhibitor of tissue factor-activated coagulation. An IV injection of heparin causes the release of TFPI from the vascular endothelium and greatly enhances its ability to inhibit factor Xa.22 In our study, the first measurement of TFPI was performed after the initial heparin bolus in preparation for CPB. This measurement revealed a dramatically higher level of TFPI than baseline levels previously documented in the literature for infants.23 We deduce that this demonstrates effective participation of the vascular endothelium in the coagulation process in these infants. Our data also showed that, after CPB, infants in the intervention group appeared quantitatively to maintain slightly higher levels of TFPI, although this difference was not statistically significant. It is unclear if this results from depletion of TFPI from the vascular endothelium after the large initial heparin bolus or if it simply reflects the massive hemodilution experienced by infants during CPB.
The depletion of coagulation factors is another consistent feature of CPB. Most circulating clotting factors decrease substantially during CPB, in particular FV, and such reductions may contribute significantly to post-CPB coagulation disorders.24,25 In our study, baseline values of FV and FVIII in both groups were considerably lower than expected based on benchmark data published by Andrew et al.26 Additionally, while levels of FV decreased significantly during CPB in both groups, levels of FVIII showed a less dramatic decrease and, in the intervention group, this decrease was not significantly different from baseline levels. The difference in preservation of these factors during CPB may be accounted for by their different origins: FV from the liver and FVIII, at least in part, from the endothelium.27 Also, FVIII-von Willebrand factor is an acute phase reactant and this too may play a role in the relative stability of FVIII levels during CPB. Nevertheless, the lack of a significant decrease in FVIII levels seen only in the intervention group may indeed represent a FVIII-sparing effect of higher heparin concentrations.
The primary goal of this study was to use hemostatic molecular markers as a means of quantifying differences in thrombin generation and activation between a patient-specific heparin concentration-based heparin management protocol and a weight-based heparin management protocol. Because of budget constraints, we were able to enroll only a small sample of elective surgical patients undergoing standard surgeries. Complication rates were expected to be low, and the majority of the measured outcome data did not reach statistical significance. Postoperative 24-h chest tube drainage did trend higher in the intervention group as compared to the control group, and infants in the intervention group did receive one more donor exposure from blood products administered after protamine reversal when compared with infants in the control group. However, this may have been a result of more infants in the intervention group undergoing tetralogy of Fallot repair, which comparably requires more extracardiac suture lines than repair of a ventricular septal defect or atrioventricular septal defect. Larger prospective, randomized studies are necessary to clarify whether maintenance of higher heparin concentrations during CPB in this patient population is, in truth, associated with greater postoperative bleeding.
In summary, our investigation demonstrates that maintaining higher heparin concentrations in infants <6-mo-old during CPB, by using a patient-specific heparin concentration-based heparin management protocol, leads to more effective suppression of thrombin generation and more effective preservation of FVIII than a weight-based heparin management protocol. According to our data, heparin levels achieved by a standard weight-based protocol, while initially adequate, begin to decrease at the start of rewarming. Small supplemental heparin boluses directed by the Hepcon HMS maintained a more constant heparin concentration throughout the duration of CPB and, consequently, were associated with decreased levels of thrombin generation. Unfortunately, the measurements of clinical outcome examined in this study are difficult to interpret, due to the small number of patients enrolled and, even more importantly, the discrepancy in the complexity of the operations between the two groups. However, because of the complex interplay of the coagulation system with inflammatory and immunologic processes, we postulate that the attenuation of thrombin generation and the preservation of FVIII associated with higher heparin concentrations will prove to be beneficial to infants undergoing cardiac surgery, especially those who are exposed to even more extended periods of CPB.
Footnotes
Accepted for publication September 11, 2007.
Supported by Children’s Healthcare of Atlanta Cardiac Research Committee.
Reprints will not be available from the author.
REFERENCES
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
