Initial experience of enoxaparine as anticoagulant during mechanical circulatory support in children
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《血管的通路杂志》
a Department of Anesthesiology and Intensive Care, Helsinki University Hospital, Hospital for Children and Adolescents, P.O. BOX 281, 00029 HUS, Helsinki, Finland
b Department of Cardiac Surgery, Helsinki University Hospital, Hospital for Children and Adolescents, Helsinki, Finland
This study was presented as a poster at the 4th World Congress of Pediatric Cardiology and Cardiac Surgery, Buenos Aires, Argentina, 2005.
Abstract
Unfractioned heparin–infusion is traditionally used for anticoagulation during mechanical circulatory support. We evaluated initial experience of subcutaneous enoxaparine during mechanical circulatory support in children. Nine consecutive children treated with Berlin Heart mechanical support were enrolled in this retrospective analysis. Of these, 3/9 were anticoagulated with enoxaparine, 6/9 anticoagulated with unfractioned heparin served as historical controls. Unfractioned heparin-group was divided in two (early/late) according to patients chronological order. All enoxaparine-treated children survived and had no significant bleeding or thromboembolic disorders. Four of the 6 children anticoagulated with unfractioned heparin died. The mean daily substitution of platelets, red blood cells, fresh frozen plasma and anti-thrombin III-concentrate was lower in the enoxaparine group compared to both early and late unfractioned heparin-groups. Enoxaparine as anticoagulant for mechanical circulatory support in children seems promising with significantly less bleeding disorders and blood product consumption.
Key Words: Ventricular assist device (VAD); Pediatric heart failure; Anticoagulation
1. Introduction
Mechanical circulatory support (MCS) with pulsatile assist devices is used also in pediatric patients to alleviate the symptoms of acute myocardial failure [1–4]. Unfractioned heparin (UFH)-infusion is traditionally used for anticoagulation during MCS [2]. The side effects of UFH may complicate treatment with MCS. Low molecular weight heparins (LMWHs) may offer some advantages compared to UFH, but until now, there is little experience with LMWH use with MCS [5,6]. Heparin-induced thrombocytopeny (HIT) may be life threatening with MCS [6]. There is some evidence that HIT is less frequent with LMWH compared to UFH-use [7–9]. However, there are very little data available whether LMWH provides satisfactory anticoagulant effect for MCS.
Berlin Heart Excor (Berlin Heart, Berlin Heart AG, Berlin, Germany) is a pulsatile mechanical device which allows short- and long-term use of MCS for newborns and children. The survival rate with Berlin Heart Excor has improved greatly in recent years and it now offers a good treatment of choice for bridge to transplant, and even for full myocardial recovery, even in small infants [1–4].
This study evaluated the initial experience of s.c. enoxaparine as an anticoagulant during MCS in children.
2. Materials and methods
Nine children treated with Berlin Heart mechanical support in Helsinki University Hospital during the years 2000–2004 were included in this retrospective analysis. Six children (0.9–16 years), anticoagulated with UFH-infusion, served as historical controls. UFH-group was divided in two (early/late) according to patients chronological order to minimize the learning curve-effect. Three children (1.4–15 years) were anticoagulated with s.c. enoxaparine (Table 1).
UFH-infusion was titrated to keep the ACT-level between 150 and 180 s. The initial dose of enoxaparine was 0.5 mg/kg subcutaneously (s.c.). All following doses were adjusted according to 4 h antiFXa-value, which was targeted at 0.5–1 U/ml. In both groups AT III-concentrate was given if measured AT III-level was below 70%. Platelets and RBC were infused in both groups if the measured levels fell below 100x109/l and 100 g/l, respectively.
Heparin analogues were used until hemodynamic stabilization was achieved and patient was extubated. Thereafter, oral anticoagulants, i.e. acetyl salicylic acid (ASA), dipyridamol and warfarin were started. When satisfactory anticoagulation was achieved, heparin was discontinued.
3. Results
Four of the 6 children anticoagulated with UFH-infusion died (Table 1). Two of these deaths were cardiac, one intra-cerebral bleeding and one intra-cerebral infarction. One of the survivors had two sternal re-openings because of bleeding. All enoxaparine-treated children survived and had no significant bleeding or thromboembolic disorders. None of the transplanted patients had any thrombus formation in the cavities of dissected heart. Neither was there need to change the pneumatic chambers of the device because of thrombus formation in any patient.
ASA was given to 5 patients (patients number 3, 6, 7, 8, 9), dipyridamol to 3 patients (patients number 3, 6, 9) and warfarine to 2 patients (patients number 3, 9). One patient in enoxaparine group (patient number 8) received UFH-infusion for 9 days during acute infection with APTT targeted to 80–100 s.
Mean daily substitution of blood products during MCS is depicted in Table 2.
4. Discussion
Enoxaparine as anticoagulant for MCS in children seems promising with significantly less bleeding disorders and blood product consumption compared to the traditional UFH-infusion. Enoxaparine has only anti-factor Xa effect, which seems to give appropriate protection against thrombus formation during MCS. In addition to anti-FXa, UFH has also anti-thrombin effect, which makes it more effective [8,9]. Traditionally UFH-treatment was targeted to ACT level of 140–160 s. However, the ACT-method cannot differentiate exactly between low and therapeutic levels of anticoagulation, with the consequence that the heparin dose is often too high. Recently smaller doses of heparin have been used with MCS, the dose being titrated according to APTT-level of 60–80 s. This is one of the suggested reasons for improved outcome with MCS in children [2]. Also in our UFH-treated patients, this anticoagulation protocol with less heparin might have decreased bleeding.
While enoxaparine is effective and safe for both management and prophylaxis of thromboembolic events in children, there are very little data of enoxaparine with MCS. In two adult patients with MCS, enoxaparine was successfully used in, together with, ASA and fluindione [6]. Enoxaparine was also used together with ASA and clopidrogel on an infant with MCS after cessation of UFH-infusion [5]. In our patient group anticoagulation was satisfactory with enoxaparine as a sole anticoagulant even during the first days on MCS. Also, successful use of enoxaparine only as anticoagulant for cardiopulmonary perfusion has been previously published by Prifti et al. [10].
UFH predisposes to HIT, which is a life-threatening disorder in MCS-patients. The incidence of HIT is reported to be lower with LMWH, but the risk of HIT still exists [7,8]. In our patients no thrombocyte antibodies were measured, so the prevalence of HIT remains unanswered. AT III-level was kept over 70% in all treatment groups. The higher use of AT III-substitution in both UFH-groups might cause a higher anti-thrombin level and thus predispose to more bleeding. Also, the learning curve effect cannot be ruled out. We tried to minimize this phenomenon by dividing the UFH-group in two, i.e. early and late according to patients chronological order. The consumption of blood products is very similar in both of these groups compared to the enoxaparine group. However, a scientific comparison of these three groups is not possible with these very small groups of children, which also differ in age, diagnosis and support period.
Poor venous access influences both the delivery and monitoring of UFH. Also the inconsistent dose response of UFH necessitates frequent monitoring of APTT. The use of enoxaparine is simple, twice per day s.c. administration with predictable pharmacokinetics and minimal monitoring. [7–9]. Long term UFH-use with MCS predisposes the patients also to heparin-induced osteopenia. This effect is not evident with LMWH use [9]. During infection the clotting potential is enhanced and the anticoagulant effect of LMWH might be insufficient [2]. In our study, enoxaparine was changed to UFH-infusion in one patient until recovery from infection. However, LMWH has been successfully used during ongoing infection without any thrombus formation [6].
In conclusion, enoxaparine is a promising alternative as a primary anticoagulant for MCS in children. Although our results are favorable, significant blood loss with prolonged circulating time and slower plasma clearance with enoxaparine and possible cross-reactivity in cases with HIT remain as potential threats with enoxaparine use.
The small sample size and retrospective design of this study limits direct conclusions of the safety of this treatment. Further studies with a larger patient population are needed in order to establish new anticoagulation protocols with MCS.
References
Stiller B, Hetzer R, Weng Y, Hummel M, Hennig E, Nagdyman N, Ewert P, Lehmkuhl H, Lange PE. Heart transplantation in children after mechanical circulatory support with pulsatile pneumatic assist device. J Heart Lung Transplant 2003; 22:1201–1208.
Stiller B, Weng Y, Hubler M, Lemmer J, Nagdyman N, Redlin M, Lange PE, Hetzer R. Pneumatic pulsatile ventricular assist devices in children under 1 year of age. Eur J Cardiothorac Surg 2005; 28:234–239.
Merkle F, Boettcher W, Stiller B, Hetzer R. Pulsatile mechanical cardiac assistance in pediatric patients with the Berlin heart ventricular assist device. J Extra-Corporeal Technology 2003; 35:115–120.
Throckmorton AL, Allaire PE, Gutesell HP, Matherne GP, Olsen DB, Wood HG, Allaire JH, Patel SM. Pediatric circulatory support systems. ASAIO J 2002; 48:216–212.
Camboni D, Schmid C, Rellensmann G, Tjan T. Enoxaparine for long-term anticoagulant with the pediatric EXCOR left ventricular assist device. Interact CardioVasc Thorac Surg 2005; 4:561–562.
Vermes E, Kirsch M, Farrokhi T, Boval B, Melon E, Loisance D, Drouet L. Management of intracranial hemorrhage in patients with mechanical circulatory support: a role for low-molecular-weight heparins ASAIO J 2005; 51:485–486.
Monagle P, Chan A, Chalmers E, Michelson AD. Antithrombotic therapy in children. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:645S–687S.
Cines DB, Bussel JB, McMillan RB, Zehnder JL. Congenital and acquired thrombocytopenia. Hematology (Am Soc Hematol Educ Program) 2004;390–406.
Dix D, Maureen A, Marzinotto V, Charpantier K, Bridge S, Mongale P, deVeber G, Leaker M, Chan A, Massicotte MP. The use of low molecular weight heparin in pediatric patients: a prospective cohort study. J Pediatr 2000; 136:439–445.
Prifti E, Bonacchi M, Leacche M, Miraldi F. Undergoing cardiopulmonary bypass using enoxaparin only during a cardiac transplantation procedure. Eur J Cardiothorac Surg 2000; 17:760–762.(Leena Mildh, Paula Tynkky)
b Department of Cardiac Surgery, Helsinki University Hospital, Hospital for Children and Adolescents, Helsinki, Finland
This study was presented as a poster at the 4th World Congress of Pediatric Cardiology and Cardiac Surgery, Buenos Aires, Argentina, 2005.
Abstract
Unfractioned heparin–infusion is traditionally used for anticoagulation during mechanical circulatory support. We evaluated initial experience of subcutaneous enoxaparine during mechanical circulatory support in children. Nine consecutive children treated with Berlin Heart mechanical support were enrolled in this retrospective analysis. Of these, 3/9 were anticoagulated with enoxaparine, 6/9 anticoagulated with unfractioned heparin served as historical controls. Unfractioned heparin-group was divided in two (early/late) according to patients chronological order. All enoxaparine-treated children survived and had no significant bleeding or thromboembolic disorders. Four of the 6 children anticoagulated with unfractioned heparin died. The mean daily substitution of platelets, red blood cells, fresh frozen plasma and anti-thrombin III-concentrate was lower in the enoxaparine group compared to both early and late unfractioned heparin-groups. Enoxaparine as anticoagulant for mechanical circulatory support in children seems promising with significantly less bleeding disorders and blood product consumption.
Key Words: Ventricular assist device (VAD); Pediatric heart failure; Anticoagulation
1. Introduction
Mechanical circulatory support (MCS) with pulsatile assist devices is used also in pediatric patients to alleviate the symptoms of acute myocardial failure [1–4]. Unfractioned heparin (UFH)-infusion is traditionally used for anticoagulation during MCS [2]. The side effects of UFH may complicate treatment with MCS. Low molecular weight heparins (LMWHs) may offer some advantages compared to UFH, but until now, there is little experience with LMWH use with MCS [5,6]. Heparin-induced thrombocytopeny (HIT) may be life threatening with MCS [6]. There is some evidence that HIT is less frequent with LMWH compared to UFH-use [7–9]. However, there are very little data available whether LMWH provides satisfactory anticoagulant effect for MCS.
Berlin Heart Excor (Berlin Heart, Berlin Heart AG, Berlin, Germany) is a pulsatile mechanical device which allows short- and long-term use of MCS for newborns and children. The survival rate with Berlin Heart Excor has improved greatly in recent years and it now offers a good treatment of choice for bridge to transplant, and even for full myocardial recovery, even in small infants [1–4].
This study evaluated the initial experience of s.c. enoxaparine as an anticoagulant during MCS in children.
2. Materials and methods
Nine children treated with Berlin Heart mechanical support in Helsinki University Hospital during the years 2000–2004 were included in this retrospective analysis. Six children (0.9–16 years), anticoagulated with UFH-infusion, served as historical controls. UFH-group was divided in two (early/late) according to patients chronological order to minimize the learning curve-effect. Three children (1.4–15 years) were anticoagulated with s.c. enoxaparine (Table 1).
UFH-infusion was titrated to keep the ACT-level between 150 and 180 s. The initial dose of enoxaparine was 0.5 mg/kg subcutaneously (s.c.). All following doses were adjusted according to 4 h antiFXa-value, which was targeted at 0.5–1 U/ml. In both groups AT III-concentrate was given if measured AT III-level was below 70%. Platelets and RBC were infused in both groups if the measured levels fell below 100x109/l and 100 g/l, respectively.
Heparin analogues were used until hemodynamic stabilization was achieved and patient was extubated. Thereafter, oral anticoagulants, i.e. acetyl salicylic acid (ASA), dipyridamol and warfarin were started. When satisfactory anticoagulation was achieved, heparin was discontinued.
3. Results
Four of the 6 children anticoagulated with UFH-infusion died (Table 1). Two of these deaths were cardiac, one intra-cerebral bleeding and one intra-cerebral infarction. One of the survivors had two sternal re-openings because of bleeding. All enoxaparine-treated children survived and had no significant bleeding or thromboembolic disorders. None of the transplanted patients had any thrombus formation in the cavities of dissected heart. Neither was there need to change the pneumatic chambers of the device because of thrombus formation in any patient.
ASA was given to 5 patients (patients number 3, 6, 7, 8, 9), dipyridamol to 3 patients (patients number 3, 6, 9) and warfarine to 2 patients (patients number 3, 9). One patient in enoxaparine group (patient number 8) received UFH-infusion for 9 days during acute infection with APTT targeted to 80–100 s.
Mean daily substitution of blood products during MCS is depicted in Table 2.
4. Discussion
Enoxaparine as anticoagulant for MCS in children seems promising with significantly less bleeding disorders and blood product consumption compared to the traditional UFH-infusion. Enoxaparine has only anti-factor Xa effect, which seems to give appropriate protection against thrombus formation during MCS. In addition to anti-FXa, UFH has also anti-thrombin effect, which makes it more effective [8,9]. Traditionally UFH-treatment was targeted to ACT level of 140–160 s. However, the ACT-method cannot differentiate exactly between low and therapeutic levels of anticoagulation, with the consequence that the heparin dose is often too high. Recently smaller doses of heparin have been used with MCS, the dose being titrated according to APTT-level of 60–80 s. This is one of the suggested reasons for improved outcome with MCS in children [2]. Also in our UFH-treated patients, this anticoagulation protocol with less heparin might have decreased bleeding.
While enoxaparine is effective and safe for both management and prophylaxis of thromboembolic events in children, there are very little data of enoxaparine with MCS. In two adult patients with MCS, enoxaparine was successfully used in, together with, ASA and fluindione [6]. Enoxaparine was also used together with ASA and clopidrogel on an infant with MCS after cessation of UFH-infusion [5]. In our patient group anticoagulation was satisfactory with enoxaparine as a sole anticoagulant even during the first days on MCS. Also, successful use of enoxaparine only as anticoagulant for cardiopulmonary perfusion has been previously published by Prifti et al. [10].
UFH predisposes to HIT, which is a life-threatening disorder in MCS-patients. The incidence of HIT is reported to be lower with LMWH, but the risk of HIT still exists [7,8]. In our patients no thrombocyte antibodies were measured, so the prevalence of HIT remains unanswered. AT III-level was kept over 70% in all treatment groups. The higher use of AT III-substitution in both UFH-groups might cause a higher anti-thrombin level and thus predispose to more bleeding. Also, the learning curve effect cannot be ruled out. We tried to minimize this phenomenon by dividing the UFH-group in two, i.e. early and late according to patients chronological order. The consumption of blood products is very similar in both of these groups compared to the enoxaparine group. However, a scientific comparison of these three groups is not possible with these very small groups of children, which also differ in age, diagnosis and support period.
Poor venous access influences both the delivery and monitoring of UFH. Also the inconsistent dose response of UFH necessitates frequent monitoring of APTT. The use of enoxaparine is simple, twice per day s.c. administration with predictable pharmacokinetics and minimal monitoring. [7–9]. Long term UFH-use with MCS predisposes the patients also to heparin-induced osteopenia. This effect is not evident with LMWH use [9]. During infection the clotting potential is enhanced and the anticoagulant effect of LMWH might be insufficient [2]. In our study, enoxaparine was changed to UFH-infusion in one patient until recovery from infection. However, LMWH has been successfully used during ongoing infection without any thrombus formation [6].
In conclusion, enoxaparine is a promising alternative as a primary anticoagulant for MCS in children. Although our results are favorable, significant blood loss with prolonged circulating time and slower plasma clearance with enoxaparine and possible cross-reactivity in cases with HIT remain as potential threats with enoxaparine use.
The small sample size and retrospective design of this study limits direct conclusions of the safety of this treatment. Further studies with a larger patient population are needed in order to establish new anticoagulation protocols with MCS.
References
Stiller B, Hetzer R, Weng Y, Hummel M, Hennig E, Nagdyman N, Ewert P, Lehmkuhl H, Lange PE. Heart transplantation in children after mechanical circulatory support with pulsatile pneumatic assist device. J Heart Lung Transplant 2003; 22:1201–1208.
Stiller B, Weng Y, Hubler M, Lemmer J, Nagdyman N, Redlin M, Lange PE, Hetzer R. Pneumatic pulsatile ventricular assist devices in children under 1 year of age. Eur J Cardiothorac Surg 2005; 28:234–239.
Merkle F, Boettcher W, Stiller B, Hetzer R. Pulsatile mechanical cardiac assistance in pediatric patients with the Berlin heart ventricular assist device. J Extra-Corporeal Technology 2003; 35:115–120.
Throckmorton AL, Allaire PE, Gutesell HP, Matherne GP, Olsen DB, Wood HG, Allaire JH, Patel SM. Pediatric circulatory support systems. ASAIO J 2002; 48:216–212.
Camboni D, Schmid C, Rellensmann G, Tjan T. Enoxaparine for long-term anticoagulant with the pediatric EXCOR left ventricular assist device. Interact CardioVasc Thorac Surg 2005; 4:561–562.
Vermes E, Kirsch M, Farrokhi T, Boval B, Melon E, Loisance D, Drouet L. Management of intracranial hemorrhage in patients with mechanical circulatory support: a role for low-molecular-weight heparins ASAIO J 2005; 51:485–486.
Monagle P, Chan A, Chalmers E, Michelson AD. Antithrombotic therapy in children. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:645S–687S.
Cines DB, Bussel JB, McMillan RB, Zehnder JL. Congenital and acquired thrombocytopenia. Hematology (Am Soc Hematol Educ Program) 2004;390–406.
Dix D, Maureen A, Marzinotto V, Charpantier K, Bridge S, Mongale P, deVeber G, Leaker M, Chan A, Massicotte MP. The use of low molecular weight heparin in pediatric patients: a prospective cohort study. J Pediatr 2000; 136:439–445.
Prifti E, Bonacchi M, Leacche M, Miraldi F. Undergoing cardiopulmonary bypass using enoxaparin only during a cardiac transplantation procedure. Eur J Cardiothorac Surg 2000; 17:760–762.(Leena Mildh, Paula Tynkky)