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Ann Thorac Surg 2001;71:922-927
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Individualized heparin and protamine management in infants and children undergoing cardiac operations

Massimiliano Codispoti, MDa, Christopher A. Ludlam, PhDb, David Simpson, FRCAa, Pankaj S. Mankad, PhDa

a Department of Cardiac Surgery, Royal Hospital For Sick Children, Edinburgh, Scotland, United Kingdom
b Department of Hematology, Royal Infirmary, Edinburgh, Scotland, United Kingdom

Accepted for publication September 28, 2000.

Address reprint requests to Dr Mankad, Department of Cardiac Surgery, Royal Infirmary, Lauriston Place, Edinburgh, EH3 9YW, Scotland
e-mail: pankaj.mankad{at}ed.ac.uk


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Measurements of activated coagulation time do not correlate with plasma concentration of heparin. This study investigated the effects of a patient-specific method to manage anticoagulation and its reversal in pediatric patients undergoing cardiopulmonary bypass.

Methods. Infants and children were randomly assigned to receive either a standard dose of heparin (300 IU/kg; group C, n = 13) or an individualized dose, calculated by an in vitro heparin dose-response test (group HC, n = 13). Protamine dose was based on a 1 mg/1 mg ratio of total administered heparin for patients in group C and of the residual heparin concentration in group HC.

Results. Administered heparin was significantly higher and total protamine dose was significantly reduced in the HC group (both p <= 0.001). There was less thrombin generation (p = 0.02) and fibrinolysis (p = 0.05) in group HC. Blood loss and requirement for transfusion of blood and fresh frozen plasma were also lower in group HC (all p <= 0.05).

Conclusions. An individualized management of anticoagulation and its reversal results in less activation of the coagulation cascade, less fibrinolysis, and reduced blood loss and need for transfusions. Further studies are warranted to better define the clinical impact of these findings.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Inadequate anticoagulation with heparin in the setting of exposure of blood to foreign surfaces (cardiopulmonary bypass [CPB], dialysis circuits, cardiac catheterization procedures, and such) is known to lead to the generation of thrombin [1]. Measurements of activated coagulation time (ACT), most widely used to monitor anticoagulation during CPB, do not correlate with concentration of circulating heparin [2], especially under conditions of deep hypothermia and hemodilution [3]. As a result, thrombin formation can occur even at "safe" levels of ACT, triggering a consumptive coagulopathy and several proinflammatory reactions [4].

The objective of this study was to investigate the effects of a patient-specific protocol for administration of heparin and protamine, based on the integrated control of heparin concentration and ACT during CPB in infants and children undergoing elective open heart surgical procedures.


   Material and methods
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
After receiving the approval of our regional ethics committee, infants and children participating in this study were randomly assigned to receive either a standard dose of heparin (300 IU/kg; control group C) or an individualized dose sufficient to maintain an ACT of at least 480 seconds (intervention group HC). The surgeon was blinded as to the randomization group. Patients with known hematologic disorders, receiving long-term oral or intravenous anticoagulant, antiplatelet therapy, or intraoperative aprotinin, with suspected preoperative infection, or undergoing emergency operation were excluded from participation in the trial.

Extracorporeal circulation was accomplished with a roller pump (Stockert Instruments, Munich, Germany), flexible venous reservoir, cardiotomy reservoir (Medtronic Inc, Minneapolis, MN), and a membrane oxygenator (Avecor solid silicone membrane type 0400, 0800, or 1500-2A) in all cases. Heparin was added to the pump priming solution to achieve a concentration of 1 IU/mL in the control group and the concentration indicated by the Hepcon system in patients of group HC (see following paragraph). Cardiotomy and vent suction were used to minimize exposure of blood to air and the pericardial cavity. Modified ultrafiltration was performed at the end of bypass for all patients with bypass time exceeding 30 minutes (group C, n = 10; group HC, n = 11).

In all patients a heparin dose-response test was performed using a fully automated and computerized system (Hepcon HMS, Medtronic Inc, Minneapolis, MN) before skin incision. The heparin dose-response test determines the in vitro anticoagulant response of patients’ blood to a known concentration of heparin and uses these data to calculate the amount of heparin that is required to reach the desired ACT. The results of this test dictated the whole blood heparin concentration to be maintained for each patient in the intervention group throughout CPB (target ACT = 480 seconds). The dose of heparin required to achieve the desired concentration at the beginning of CPB was calculated using the Hepcon software. The concentration of circulating heparin was calculated at the point of care using a heparin/protamine titration test. Kaolin ACT and heparin/protamine titration were measured 5 minutes after the administration of heparin, 5 minutes after initiation of CPB, and every 30 minutes thereafter by on-site testing using the Hepcon system. Heparin was administered accordingly, following the indications of the ACT alone in the control group and the combined results of ACT and heparin/protamine titration in group HC. At the same times, blood samples were taken to analyze heparin activity by means of anti-Xa chromogenic substrate assay (Coatest, Chromogenix, Milan, Italy). At the end of CPB, protamine dose was based on a 1 mg/1 mg ratio of the residual heparin concentration for patients in group HC and of total (patient + CPB) administered heparin in group C.

Blood specimens were obtained either from intraarterial catheters or from the CPB arterial catheter. Coagulation studies included full blood count, prothrombin time, activated partial thromboplastin time, and fibrinogen levels. Hematocrit (Hct) values were obtained using a conventional hemocytometer with optical reading, and whole blood (WB) heparin concentration [Hep] measurements were converted into their plasma equivalent (PE) using the following formula:

To investigate the occurrence of fibrinolysis, D-dimer levels were assayed by means of a commercially available enzyme-linked immunosorbent assay (Asserachrom D-dimer, Diagnostica Stago, Asnieres-sur-Seine, France). Prothrombin fragment 1 + 2 was also measured to quantitate thrombin generation, using a specific enzyme immunoassay (Dade Behring, Marburg, Germany), and, as an indicator of platelet activation, we chose to detect plasma levels of ß-thromboglobulin using an enzyme-linked immunosorbent assay (Asserachrom ß-thromboglobulin, Asnieres-sur-Seine, France). All samples were initially processed, then stored and analyzed according to the recommended techniques described by the manufacturers of each test.

After administration of protamine, a clotting screen and complete blood count were performed. The use of blood and blood products was standardized according to the algorithm outlined in Table 1. On arrival in the intensive care unit, a further clotting screen and full blood count was performed, and appropriate action taken following the same criteria.


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  		Table 1. Transfusion Algorithm

 
From data in our previous study on a similar patient population [5], a sample size of 12 patients in each group was selected to give a power of 0.8 to detect as significant at the 5% level a true mean difference of one standard deviation for the primary outcome measures under consideration. Primary end points were hematologic indices of activation of coagulation (prothrombin fragment 1 + 2, D-dimer, Fibrinogen, ß-thromboglobulin), whereas secondary end points were amount of bleeding at 24 hours, homologous transfusions, and length of stay in intensive care unit and in hospital. All parametric data were log-transformed and analyzed by two-tailed Student t test or one-way single-factor analysis of variance, as appropriate. Nonparametric variables were compared using the Wilcoxon rank sum test. A p value less than 0.05 was considered significant. To assess the agreement of results for heparin concentration values obtained with the Hepcon system and with the chromogenic method, we used the Bland and Altman test, setting a sensitivity limit of 0.7 IU/mL for the Hepcon HMS, as previously suggested [6, 7].


   Results
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 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Twenty-six infants and children operated on for repair or palliation of a congenital cardiac defect using CPB were enrolled in this study during a 6-month period (Table 2). One patient in each group was excluded from the analysis because of an obvious source of surgical bleeding found at reexploration. The groups were comparable with regard to age, weight, disease complexity, duration of CPB, preoperative coagulation profile, and a number of other variables (Table 3).


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  		Table 2. Diagnoses and Procedures Performed

 

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  		Table 3. Demographic and Operative Dataa

 
The patients’ response to unfractionated heparin was not normally distributed. In particular, 37.5% of patients (9 of 24) had a heparin requirement higher than the standard dose of 300 IU/kg (470 ± 17 versus 299 ± 7 IU/kg, p < 0.0001). Furthermore, 5 patients had a heparin requirement z value more than 1, whereas in 4 patients the z value was less than -1 (Fig 1). These patients would have received excessively high or insufficiently low doses of heparin to reach the target ACT of 480 seconds.



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  		Fig 1. The bell-shaped line represents a normal distribution curve built using the same mean and variance of the study population. It is evident that the distribution of heparin sensitivities in the study population is not normal (Shapiro-Wilk test of normality = 0.906; p = 0.03). Although the mean sensitivity (296 U/kg) corresponds almost exactly with the empiric dose of heparin commonly administered (300 U/kg), a significant proportion of patients has a lower or higher heparin requirement to achieve a "safe" activated coagulation time. (HDR = heparin dose-response: amount of heparin necessary to achieve activated coagulation time of 480 seconds; Std. Dev = standard deviation.)

 
The ACT never fell below the limit of 480 seconds in either group (Fig 2). As a result, the total dose of administered heparin was significantly higher in the intervention group (p < 0.001; Fig 2). On the contrary, the control group never received additional heparin during CPB, as the ACT values were always more than 480 seconds.



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  		Fig 2. The activated coagulation time (ACT) remained more than 1,500 seconds at all time points after the initial 30 minutes despite falling heparin concentrations in group C, underlying its inability to guide anticoagulation. On the contrary, in group HC, the administration of heparin was targeted to maintain the concentration indicated by the initial heparin dose-response (HDR), regardless of the activated coagulation time reading. This protocol resulted in significantly higher heparin concentrations in group HC as compared to group C at all time points after the initial 30 minutes on cardiopulmonary bypass (CPB). (*p less than 0.001; #p = 0.02; open circles = ACT of group C; open squares = ACT of group HC; filled circles = heparin concentration of group C; filled squares = heparin concentration of group HC.)

 
Despite receiving significantly higher doses of heparin, the total amount of administered protamine was significantly less in the HC group, when compared with the control group (HC, 2.9 ± 0.2 mg/kg; C, 8.6 ± 1.4 mg/kg; p < 0.001). In all HC patients the initial protamine dose achieved complete neutralization of the residual circulating heparin at the end of CPB. In only 1 of 12 patients (8.3%) in the HC group we encountered "heparin rebound" (0.2 IU/mL) at 1 hour after initial reversal of heparin effect.

There were 186 pairs of observations used to calculate agreement of results between the two methods to measure heparin concentration in the whole blood, and in the plasma obtained from the same samples. The values of heparin concentration obtained from the chromogenic test were found to agree with the measurements obtained on whole blood samples. The mean difference, or bias, between the plasma anti-Xa and the corrected whole blood heparin measurements was 0.004 ± 0.48, making the two methods interchangeable.

Plasma levels of prothrombin fragment 1 + 2 were significantly elevated at the end of CPB in both groups (p < 0.001). However, this rise was significantly less pronounced in the HC group (p = 0.02). Fibrinogen was depleted significantly at the end of CPB in the control group, when compared with group HC (p = 0.05; Table 4). D-Dimer levels were significantly elevated at the end of CPB (p < 0.001) in both groups, although the rise was less pronounced in the intervention group (p = 0.05 for between-group comparison; Table 4). ß-Thromboglobulin levels increased significantly in both groups, but there was no significant difference between groups (Table 4).


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  		Table 4. Hematologic Dataa

 
The prothrombin time measured 5 minutes after protamine administration was significantly shorter in the intervention group (group C, 25.1 ± 1.8 seconds; group HC, 19.8 ± 0.8 seconds; p = 0.01). The activated partial thromboplastin time ratio showed slightly higher ratios in the HC group, without reaching statistical significance (group C, 1.77 ± 0.2; group HC, 2.03 ± 0.1; p = 0.51).

During the first 24 postoperative hours, chest drain losses were significantly less in the intervention group, when compared with the control group (group C, 26.4 ± 4.7 mL/kg; group HC, 15.2 ± 3.7 mL/kg; p = 0.05; Fig 3). The need for blood transfusion in the postoperative period was less in the intervention group, when compared with the control group (red cell concentrate, group C, 11.4 ± 3.6 mL/kg; group HC, 3.1 ± 1.3 mL/kg; p = 0.05). Similarly, the need for transfusion of fresh frozen plasma in the HC group was less than in group C (group C, 6.2 ± 2.2 mL/kg; group HC, 1.0 ± 0.3 mL/kg; p = 0.01; Fig 3).



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  		Fig 3. Blood loss during the first 24 postoperative hours was significantly reduced in group HC. In addition, requirements for blood and blood products were also significantly lower in the intervention group. (FFP = fresh frozen plasma; RCC = red cell concentrate.)

 
There were no hospital deaths. The duration of stay in the intensive care unit and in hospital was similar in both groups (intensive care unit stay: group C, 3.9 ± 1.2 days; group HC, 2.5 ± 1.1 days; p = 0.2; hospital stay: group C, 10 ± 2.1 days; group HC, 10 ± 1.8 days; p = 0.9).


   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
This study demonstrates distinct merits associated with the use of an anticoagulation protocol that takes into account individual patients’ characteristics and applies them to the dosing of heparin and protamine during pediatric CPB. The approach adopted in patients belonging to the intervention group resulted in the administration of higher doses of heparin and smaller amounts of protamine. As a result, a lower degree of consumptive coagulopathy was observed in these patients, which in turn translated into diminished blood loss and a lower need for transfusion of blood and blood products.

The consequences of inadequate systemic heparinization, mainly an exacerbated activation of the coagulation cascade resulting in consumption of procoagulant factors and pronounced deficiency of natural coagulation inhibitors, lead to events that may ultimately account for post-CPB morbidity or even mortality [8, 9]. To avoid these undesired occurrences, some authors have recommended individualized heparin and protamine dosing [10, 11]. Such an approach, as observed in this and other studies [11, 12], leads to the administration of more heparin and less protamine. Several studies have demonstrated the many theoretical advantages of similar anticoagulation protocols, including reduced platelet aggregation [13], complement activation [14], and neutrophil adhesion and sequestration [15]. More importantly, the experimental evidence favoring the administration of higher doses of heparin and lower amounts of protamine has been confirmed in a number of clinical trials conducted in adult cardiac patients [11, 12, 16]. These studies have consistently shown a decrease in postoperative blood loss and requirement for homologous transfusions in patients who received higher heparin doses; however, this practice is not yet widely adopted, particularly in pediatric open-heart operations [17]. The effects of a patient-specific protocol for intraoperative systemic anticoagulation and its reversal has not been reported before in this patient population.

Although the ACT has been the mainstay for monitoring anticoagulation during CPB for more than 20 years [10], numerous studies have shown that it is affected by multiple factors, including hemodilution, hypothermia, and the type of reagent and monitoring machine [2, 3, 16]. To avoid the intrinsic shortcomings of ACT and to reduce the risk of exposing patients to insufficient anticoagulation by underdosing of heparin, a number of monitoring devices have been developed [18]. One such system is the Hepcon, which was used in this study to measure levels of circulating heparin and to guide the dosing of both heparin and protamine. There has been some debate on the accuracy of this system [6, 7], but in this prospective study analyzing 186 pairs of observations a good agreement of results between the measurements obtained at the point of care with this device and the standard laboratory measurements could be confirmed.

Although the number of patients in this study is small, its findings emphasize the inadequacy of a fixed-heparin dose protocol and the inappropriateness of resting on the sole ACT results for monitoring of anticoagulation. An individualized and integrated management of anticoagulation and its reversal during moderately hypothermic CPB based on the accurate maintenance of the target heparin concentration and exact neutralization of the residual circulating heparin results in less activation of the coagulation cascade, lower fibrinolysis, and reduced blood loss and need for homologous transfusions.

Further studies, on a larger number of children, are warranted to confirm our observations and better define the clinical impact of using a patient-specific heparin and protamine administration protocol.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
Doctor Codispoti is supported by grants from the British Heart Foundation and the National Heart Research Fund. We wish to thank Mrs Pam Dawson and Mr Ian Abbott for their fine technical assistance with the hematological assays, Dr Orestis Papasouliotis for his expert advice on the statistical methods, and all the staff members of the cardiac team for their valuable support.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
This article has been selected for the open discussion forum on the STS Web site: http://www.sts.org/section/atsdiscussion/


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Brister S.J., Ofosu F.A., Buchanan M.R. Thrombin generation during cardiac surgery: is heparin the ideal anticoagulant?. Thromb Haemost 1993;70:259-262.[Medline]
  2. Culliford A.T., Gitel S.N., Starr N., et al. Lack of correlation between activated clotting time and plasma heparin during cardiopulmonary bypass. Ann Surg 1981;191:105-111.
  3. Martindale S.J., Shayevitz J.R., D’Errico C. The activated coagulation time: suitability for monitoring heparin effect and neutralization during pediatric cardiac surgery. J Cardiothorac Vasc Anesth 1996;10:458-463.[Medline]
  4. Wachtfogel Y.T., Kettner C., Hack C.E., et al. Thrombin and human plasma kallikrein inhibition during simulated extracorporeal circulation block platelet and neutrophil activation. Thromb Haemost 1998;80:686-691.[Medline]
  5. Morgan I.S., Codispoti M., Sanger K., Mankad P.S. Superiority of centrifugal pump over roller pump in paediatric cardiac surgery: prospective randomised trial. Eur J Cardiothorac Surg 1998;13:526-532.[Abstract/Free Full Text]
  6. Despotis G.J., Joist J.H., Goodnough L.T., Santoro S.A., Spitznagel E. Whole blood heparin concentration measurements by automated protamine titration agree with plasma anti-Xa measurements. J Thorac Cardiovasc Surg 1997;113:611-613.[Free Full Text]
  7. Hardy J.F., Belisle S., Robitaille D., Perrault J., Roy M., Gagnon L. Measurement of heparin concentration in whole blood with the Hepcon/HMS device does not agree with laboratory determination of plasma heparin concentration using a chromogenic substrate for activated factor X. J Thorac Cardiovasc Surg 1996;112:154-161.[Abstract/Free Full Text]
  8. Jaggers J.J., Neal M.C., Smith P.K., Ungerleider R.M., Lawson J.H. Infant cardiopulmonary bypass: a procoagulant state. Ann Thorac Surg 1999;68:513-520.[Abstract/Free Full Text]
  9. Cheung A.T., Levin S.K., Weiss S.J., Acker M.A., Stenach N. Intracardiac thrombus: a risk of incomplete anticoagulation for cardiac operations. Ann Thorac Surg 1994;58:541-542.[Abstract]
  10. Bull B.S., Korpman R.A., Huse W.M., Briggs B.D. Heparin therapy during extracorporeal circulation: II. The use of a dose-response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg 1975;69:685-689.[Abstract]
  11. Despotis G.J., Joist J.H., Hogue C.W., Jr, et al. The impact of heparin concentration and activated clotting time monitoring on blood conservation. A prospective randomized evaluation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1995;110:46-54.[Abstract/Free Full Text]
  12. Jobes D.R., Aitken G.L., Shaffer G.W. Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary cardiac operations. J Thorac Cardiovasc Surg 1995;110:36-45.[Abstract/Free Full Text]
  13. Ellison N., Edmunds L.H., Coleman R.W. Platelet aggregation following heparin and protamine administration. Anesthesiology 1978;48:65-68.[Medline]
  14. Kirklin J.K., Chenoweth D.E., Naftel D.C., et al. Effects of protamine administration after cardiopulmonary bypass on complement, blood elements, and the hemodynamic state. Ann Thorac Surg 1986;41:193-199.[Abstract]
  15. Gullinov A.M., Redmond J.M., Winklestein J.A., et al. Complement and neutrophil activation during cardiopulmonary bypass: a study in the complement-deficient dog. Ann Thorac Surg 1994;57:345-352.[Abstract]
  16. Despotis G.J., Summerfield A.L., Joist J.H., et al. Comparison of activated coagulation time and whole blood heparin measurements with laboratory plasma anti-Xa heparin concentration in patients having cardiac operations. J Thorac Cardiovasc Surg 1994;108:1076-1082.[Abstract/Free Full Text]
  17. Codispoti M., Mankad P.S. Management of anticoagulation and its reversal during paediatric cardiopulmonary bypass: a review of current practice in the UK. Perfusion 2000;15:191-201.[Abstract/Free Full Text]
  18. Reich D.L. Monitoring hemostasis in the perioperative period: anticoagulation control. J Cardiothorac Vasc Anesth 1991;5:4-7.[Medline]



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