Effect of Heparin Loading During Congenital Heart Operation on Thrombin Generation and Blood Loss

doi:10.1016/S0003-4975(96)01215-5

The Annals of Thoracic Surgery

Volume 63, Issue 2, February 1997, Pages 482-488

https://doi.org/10.1016/S0003-4975(96)01215-5 Get rights and content

Abstract

Background. The heparin protocols used during cardiopulmonary bypass (CPB) in children undergoing surgical repair for congenital heart disease are extrapolated from adult data. Studies are needed that assess the optimal heparin dosing in these children, whose heparin clearance is increased compared with that in adults.

Methods. We assessed the effects of two commonly used doses of heparin in the prime solution at the start of CPB operation on plasma heparin levels, on thrombin production (thrombin–antithrombin III complexes, prothrombin fragment 1 + 2, D-dimer, and antithrombin III), and on the risk of hemorrhage. Before CPB, 48 children with congenital heart disease received heparin intravenously in a loading dose of 300 U/kg, followed by either 1 U/mL of heparin in the prime (low-dose group: 22 patients—acyanotic, 9; cyanotic, 13) or 3 U/mL of heparin in the prime (group: high-dose, 26 patients—acyanotic, 15; cyanotic, 11).

Results. In all patients, CPB resulted in the generation of thrombin. The duration of CPB was a significant covariate factor for heparin levels (p = 0.002), thrombin production (p < 0.001), and postoperative blood loss (p < 0.001). In the patients in the high-dose group, the total heparin dose and the plasma heparin levels were higher (p = 0.0005 and 0.005, respectively) and the D-dimer levels tended to be lower (p = 0.06). The postoperative blood loss was higher in the cyanotic patients (p = 0.02; both high-dose and low-dose groups), with 2 cyanotic patients (1 in low-dose group, 1 in high-dose group) requiring reoperation, one of whom subsequently died. The increased heparin dose had no significant effect on the rate or volume of postoperative blood loss.

Conclusions. Increasing the heparin dose in the prime solution from 1 to 3 U/mL increased the plasma heparin levels and showed a trend toward reducing the postoperative laboratory values indicative of fibrinolysis. Thrombin generation during CPB and the incidence of postoperative hemorrhage were not significantly altered. Larger randomized trials are needed to determine the optimal heparin-dosing regimen in patients with congenital heart disease.

(Ann Thorac Surg 1997;63:482–8)

Section snippets

Patients and Methods

Using a protocol approved in April 1992 by the Human Subjects Committee at the Hospital for Sick Children, Toronto, Ontario, we obtained informed consent from parents of all patients before their inclusion in the study. Children under 1 year of age were excluded. Forty-eight consecutive patients with acyanotic or cyanotic CHD, aged 1.1 to 15.7 years (median, 3.6 years; mean, 5 years), were enrolled in the study. However, because of reservations on the part of the attending physicians regarding

Patient Population

The ages and diagnoses in the patients receiving high-dose and low-dose heparin were similar within the acyanotic and cyanotic group of patients with CHD (see Table 1). However, the acyanotic children were older than the cyanotic children, which was a reflection of our current surgical practice (p < 0.05). The median total time on CPB was 45 minutes (14–129 minutes) for the acyanotic group and 132 minutes (95–264 minutes) for the cyanotic group. There was no appreciable difference between the

Comment

This study assessed the effect of two doses of heparin in the CPB prime solution on plasma heparin levels, on indices of thrombin generation, and on the risk of hemorrhage. In our analyses of the data, we used the preoperative IgG level as a covariate factor. By doing so, we corrected for the influence of confounding factors, such as preoperative polycythemia and the degree of hemodilution during CPB. We identified that increasing the heparin concentration in the prime solution resulted in an

Acknowledgements

We gratefully acknowledge the assistance of Ms Mary Lou Schmuck, BA, Research Assistant, McMaster University, in the analysis of the data from this study. The assistance of the technologists at McMaster University Medical Centre is also greatly appreciated.

Supported by grant XG91-003 from the Hospital for Sick Children Foundation.

References (20)

ARC Dobell et al.
Atrial thrombi after the Fontan operation
Ann Thorac Surg
(1986)
D Tamisier et al.
Modified Blalock-Taussig shuntsresults in infants less than 3 months of age
Ann Thorac Surg
(1990)
SO Turner-Gomes et al.
Thrombin regulation in congenital heart disease after cardiopulmonary bypass operations
J Thorac Cardiovasc Surg
(1994)
AN Teien et al.
Assay of heparin in plasma using a chromogenic substrate for activated factor X
Thromb Res
(1976)
F Horkay et al.
Response to heparinization in adults and children undergoing cardiac operations
Ann Thorac Surg
(1992)
JG Coles et al.
Surgical experience with the modified Fontan procedure
Circulation
(1987)
Y Okita et al.
Massive systemic venous thrombosis after Fontan operationreport of a case
Thorac Cardiovasc Surg
(1988)
S Turner-Gomes et al.
Heparin is cleared faster in children with congenital heart disease than in adults
J Am Coll Cardiol
(1993)
JW Fenton
Regulation of thrombin generation and functions
Semin Thromb Hemost
(1988)
FA Ofosu et al.
Mechanisms of action of heparin
Semin Thromb Hemost
(1988)

There are more references available in the full text version of this article.

Cited by (18)

Thrombin Generation and Antithrombin Activity in Infants Undergoing Cardiopulmonary Bypass—An Exploratory Study
2020, Journal of Cardiothoracic and Vascular Anesthesia
Citation Excerpt :
In adults after prolonged CPB, particularly after deep hypothermic circulatory arrest, a decreased activity of AT was observed.18 Similarly to this study, the decline of AT after CPB also was demonstrated in pediatric cardiac patients.7,19 All the proposed explanations for the decline in thrombin generation also pertain to the etiology of decline in AT activity.
Coagulopathic bleeding is a major complication of pediatric cardiac surgery. Investigating perioperative dynamics of thrombin generation and antithrombin (AT) activity might provide more insight into the underlying mechanisms of coagulopathy. This can help develop a targeted hemostatic approach in the future. The authors hypothesized that there is a decline in both thrombin generation and AT activity in infants undergoing cardiopulmonary bypass (CPB).
Prospective observational study.
Single academic medical center.
Infants <10 kg of weight undergoing cardiac surgery with CPB.
Blood specimen collection and testing.
The authors performed assays of thrombin generation and AT activity on the samples of platelet-poor plasma of 25 infants, repeating them at 3 points: before CPB and heparinization, after separation from CPB and protamine administration, and after chest closure. The authors observed a statistically significant decline in thrombin generation shortly after separation from CPB compared with baseline. The geometric mean for lag time was prolonged (4.0 v 5.5 minutes, p = 0.013), and peak thrombin and the net amount of generated thrombin declined almost 3-fold (80.7 v 25.1 nmol, p < 0.001; 1264 v 476 nmol, p < 0.001, respectively). This was accompanied by a decline in AT activity (59.8 v 50.1, p = 0.001). After platelet and cryoprecipitate transfusion, at the case conclusion AT activity had recovered marginally (59.8 v 55.4, p = 0.042), but thrombin generation remained reduced.
In pediatric patients <10 kg undergoing cardiac surgery with CPB, thrombin generation and AT activity decline and do not recover completely after transfusion of platelets and cryoprecipitate.
Prothrombin Complex Concentrates in Pediatric Cardiac Surgery: The Current State and the Future
2017, Annals of Thoracic Surgery
Citation Excerpt :
A key step in hemostasis is the generation of thrombin. Thrombin cleaves fibrinogen so that a fibrin clot can subsequently form [26, 27]. The prothrombin time and activated partial thromboplastin time are crude methods for monitoring thrombin generation.
After decades of practice of pediatric cardiac surgery, postoperative bleeding due to the immaturity of hemostasis, hemodilution, and hypothermia remains a concern. Recently, a new approach for adult coagulopathy after bypass has emerged. Prothrombin complex concentrates (PCCs), designed to treat bleeding in hemophilia patients, are safely and efficiently used off label for hemorrhage after bypass. However, optimal dosing, indications and contraindications, and laboratory tests to assess the efficacy of PCC use in children have not yet been established. This literature review outlines the challenges of bypass-related coagulopathy, the pharmacology, and the experience in use of PCCs, with a focus on their potential in pediatric cardiac surgery.
After a thorough literature search of MEDLINE, Scopus, and Ovid databases using the term “prothrombin complex concentrate AND pediatric,” 23 relevant articles were selected.
The data supporting successful use of PCCs in acquired coagulopathy after cardiac surgery in adults have been increasing. Although small volume, low immunogenicity, efficiency, and speed in correcting coagulopathy are attractive qualities of PCCs for pediatric practice, current evidence is only anecdotal. The main concerns are unknown dosing regimens, the inability to closely monitor the effects of PCCs in real time, and a possibility of thrombotic complications, which can be particularly devastating in young congenital cardiac patients whose lives frequently depend upon the patency of artificial shunts.
Extensive, high-quality research is warranted to fill in the gaps of knowledge regarding using PCCs in pediatric cardiac practice.
Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery: The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists Clinical Practice Guideline
2007, Annals of Thoracic Surgery
Citation Excerpt :
Because of concerns about harmful effects of heparin, several investigators proposed reduced heparin to maintain an ACT level of approximately 300 s as a safe alternative that limits heparin exposure and protamine reversal [374, 398, 424, 425]. Numerous studies evaluated the impact of reduced heparin dose and heparin-coated circuits on postoperative bleeding and blood transfusion without a clear consensus arising [391, 392, 395–402, 426–436]. Again, the studies are too heterogeneous to lend themselves to meta-analysis, but no clear-cut advantage in blood conservation accrues to low-dose heparin for patients perfused with heparin-coated circuits.
A minority of patients having cardiac procedures (15% to 20%) consume more than 80% of the blood products transfused at operation. Blood must be viewed as a scarce resource that carries risks and benefits. A careful review of available evidence can provide guidelines to allocate this valuable resource and improve patient outcomes.
We reviewed all available published evidence related to blood conservation during cardiac operations, including randomized controlled trials, published observational information, and case reports. Conventional methods identified the level of evidence available for each of the blood conservation interventions. After considering the level of evidence, recommendations were made regarding each intervention using the American Heart Association/American College of Cardiology classification scheme.
Review of published reports identified a high-risk profile associated with increased postoperative blood transfusion. Six variables stand out as important indicators of risk: (1) advanced age, (2) low preoperative red blood cell volume (preoperative anemia or small body size), (3) preoperative antiplatelet or antithrombotic drugs, (4) reoperative or complex procedures, (5) emergency operations, and (6) noncardiac patient comorbidities. Careful review revealed preoperative and perioperative interventions that are likely to reduce bleeding and postoperative blood transfusion. Preoperative interventions that are likely to reduce blood transfusion include identification of high-risk patients who should receive all available preoperative and perioperative blood conservation interventions and limitation of antithrombotic drugs. Perioperative blood conservation interventions include use of antifibrinolytic drugs, selective use of off-pump coronary artery bypass graft surgery, routine use of a cell-saving device, and implementation of appropriate transfusion indications. An important intervention is application of a multimodality blood conservation program that is institution based, accepted by all health care providers, and that involves well thought out transfusion algorithms to guide transfusion decisions.
Based on available evidence, institution-specific protocols should screen for high-risk patients, as blood conservation interventions are likely to be most productive for this high-risk subset. Available evidence-based blood conservation techniques include (1) drugs that increase preoperative blood volume (eg, erythropoietin) or decrease postoperative bleeding (eg, antifibrinolytics), (2) devices that conserve blood (eg, intraoperative blood salvage and blood sparing interventions), (3) interventions that protect the patient's own blood from the stress of operation (eg, autologous predonation and normovolemic hemodilution), (4) consensus, institution-specific blood transfusion algorithms supplemented with point-of-care testing, and most importantly, (5) a multimodality approach to blood conservation combining all of the above.
A comparison of heparin management strategies in infants undergoing cardiopulmonary bypass
2008, Anesthesia and Analgesia
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.
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.
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.
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.
Pediatric cardiopulmonary bypass
2015, Cardiopulmonary Bypass and Mechanical Support: Principles and Practice: Fourth Edition
Challenges and priorities for research a report from the National Heart, Lung, and Blood Institute (NHLBI)/ National Institutes of Health (NIH) working group on thrombosis in pediatric cardiology and congenital heart disease
2014, Circulation

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Original ArticlesEffect of Heparin Loading During Congenital Heart Operation on Thrombin Generation and Blood Loss

Abstract

Section snippets

Patients and Methods

Patient Population

Comment

Acknowledgements

Ann Thorac Surg

Ann Thorac Surg

J Thorac Cardiovasc Surg

Thromb Res

Ann Thorac Surg

Surgical experience with the modified Fontan procedure

Circulation

Massive systemic venous thrombosis after Fontan operationreport of a case

Thorac Cardiovasc Surg

Heparin is cleared faster in children with congenital heart disease than in adults

J Am Coll Cardiol

Regulation of thrombin generation and functions

Semin Thromb Hemost

Mechanisms of action of heparin

Semin Thromb Hemost

Original Articles
Effect of Heparin Loading During Congenital Heart Operation on Thrombin Generation and Blood Loss