- Email: [email protected]
Antithrombin replacement in neonates: Is there any indication?
Thrombosis Research (2006) 118, 107 — 111
intl.elsevierhealth.com/journals/thre
Review
Antithrombin replacement in neonates: Is there any indication? Dirk Basslera, Barbara Schmidta,b,* a
Departments of Pediatrics, McMaster University, Hamilton, Ontario, Canada Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
b
Received 5 January 2005; received in revised form 5 January 2005; accepted 18 January 2005 Available online 8 February 2005
KEYWORDS Antithrombin; Infant newborn; Respiratory distress syndrome; Intraventricular hemorrhage; Sepsis
Abstract Introduction: Activation of the coagulation system and severe acquired antithrombin (AT) deficiency are common and prognostically important findings in sick and preterm neonates. It has been hypothesised that treatment of the acquired AT deficiency with AT concentrate may improve the outcome of conditions such as the neonatal respiratory distress syndrome (RDS), intracranial hemorrhage (ICH) and sepsis. Materials and methods: We performed a systematic review of randomised controlled trials (RCTs) of AT replacement therapy in newborn infants. Results: Two full-length trial reports were found. Both were placebo-controlled. The first RCT examined the effects of AT therapy in 122 preterm infants with RDS. Administration of AT prolonged rather than shortened the duration of mechanical ventilation and oxygen therapy. The second RCT determined whether AT replacement decreased the incidence of ICH in 60 preterm infants who were born before 30 weeks of gestation. No beneficial effect on ICH was found. Conclusions: Preterm infants with RDS do not benefit from therapy with AT concentrate and may be harmed. There is also little evidence that the administration of AT reduces the risk of ICH. The role of AT replacement during neonatal sepsis remains uncertain. D 2005 Elsevier Ltd. All rights reserved.
Abbreviations: AT, Antithrombin; ICH, Intracranial hemorrhage; RCT, Randomised controlled trial; RDS, Respiratory distress syndrome. * Corresponding author. Room 3N11 E, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5. Tel.: +1 905 521 2100x73243; fax: +1 905 521 5007. E-mail address: [email protected] (B. Schmidt). 0049-3848/$ - see front matter D 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2005.01.007
108
D. Bassler, B. Schmidt
Contents Introduction . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . AT therapy in neonatal RDS . . . . . . . Evidence from RCTs . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . AT therapy for the prevention of ICH in Evidence from RCTs . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . AT therapy for neonatal sepsis . . . . . Evidence from RCTs . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . Comments. . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . preterm infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Antithrombin (AT) is a potent physiologic inhibitor of the clotting system. AT is a glycoprotein that is synthesised in the liver and released into the plasma where it controls the activity of thrombin and of other serine proteases such as activated factors IX, X, XI and XII [1]. The well-recognised association between inherited AT deficiency and the risk of venous thrombosis in adults points to the important role of AT as a modulator of blood coagulation [2]. Compared with healthy adults, healthy newborn infants have physiologically low plasma concentrations of AT [3—6]. However, activities of AT are even lower in critically ill infants such as those with respiratory distress syndrome (RDS) [7], intracranial hemorrhage (ICH) [8] and sepsis [9]. The effects of this acquired AT deficiency on the regulation of neonatal thrombin formation have been studied extensively during the course of RDS in preterm infants. Schmidt et al. demonstrated a strong relationship between the activation of the clotting system, the depletion of AT activity and the severity of RDS [10]. These observations were later confirmed and extended by Brus et al. [11]. These findings led to the hypothesis that unopposed thrombin activity may contribute to the progression of neonatal diseases that are accompanied by hypercoagulability. The logical subsequent hypothesis was that to regulate thrombin activity, sick newborn infants might benefit from the administration of AT concentrates. Our objective in this systematic review has been to search the biomedical literature for potential indications of AT replacement therapy in neonates with acquired AT deficiency. We focused on strong evidence arising from randomised controlled trials
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
108 108 108 108 109 109 109 109 110 110 110 110 110 110
(RCTs) with clinically meaningful endpoints in human infants.
Materials and methods An electronic literature search in Pubmed was performed using the following search terms: (antithrombin OR antithrombin III OR ATIII OR AT III OR AT-III) and (neonat* OR infant OR newborn), Limits: Randomised controlled trial. The Cochrane Controlled Trial Register (CCTR) was also searched for clinical trials. The Cochrane Database of Systematic Reviews (CDSR) was searched for systematic reviews on AT therapy in neonates. We checked all reports of neonatal RCTs that were identified by the electronic literature search for references to additional trials. In order to be included in this systematic review, study reports had to state clearly that allocation to AT therapy was randomised.
Results AT therapy in neonatal RDS Neonatal RDS is an acute lung injury in preterm infants that is characterized by diffuse atelectasis, high permeability pulmonary oedema, hyaline membrane formation and right to left shunting of pulmonary blood flow. Surfactant deficiency in the immature lung is the primary cause [12] and surfactant replacement has significantly reduced mortality and morbidity from this disease [13]. However, residual lung injury may persist after surfactant therapy. Increased thrombin formation
Antithrombin replacement in neonates: Is there any indication? due to acquired AT deficiency was hypothesised to contribute to the progression and abnormal resolution of neonatal RDS and similarly that AT therapy may improve the outcomes of affected infants [14]. Evidence from RCTs We could find only one full-length publication of an RCT of AT therapy in neonatal RDS [15]. A second trial was published as an abstract only and was not placebo-controlled [16]. Schmidt et al. studied 122 preterm infants with birth weights between 750 and 1900 g who required mechanical ventilation for RDS [15]. Only infants with moderate to severe disease were included, i.e. those with a ratio of arterial to alveolar oxygen pressure (a/A PO2) less than 0.3 after the first dose of exogenous surfactant when the infants were between 2 and 12 h old [15]. AT was given as a loading dose of 2 ml/kg (equivalent to 100 U/kg of AT) intravenously, followed by 1 ml/kg (equivalent to 50 U/kg) every 6 h for 48 h. A 1% human albumin solution was used as placebo. The authors reported 6 clinical efficacy outcomes. They included measures of gas exchange (a/A PO2 at 48 h and 7 days, and the ventilator efficiency index at 48 h and 7 days), as well as the median duration of mechanical ventilation and need for supplemental oxygen. The rates of ICH, clinically apparent bleeding from puncture sides, the umbilicus, nasogastric tubes or endotracheal tubes and deaths before first discharge home were reported as safety outcomes. AT activity was significantly increased in the treatment group, above the normal range for the healthy newborn infant, but sensitive markers of increased thrombin formation were not fully normalised by these fairly large doses of AT concentrate [15]. Table 1 summarizes clinically important endpoints. Infants allocated to the AT group needed mechanical ventilation and oxygen therapy for a significantly longer period of time than infants who were allocated to the placebo group. There was also some evidence to suggest that clinical bleeding and deaths were more common following high-dose AT therapy (Table 1). The ICH rates that were
Table 1 The effect of AT therapy on RDS: data by Schmidt et al. [15] Outcome measure
AT
Placebo
Mechanical ventilation (median number of days) Supplemental oxygen (median number of days) Clinical bleeding no./total no. (%) Deaths no./total no. (%)
7.1
4.8
7.9
5.5
37/61 (61) 7/61 (12)
30/61 (49) 3/61 (5)
Definition of abbreviations: AT=antithrombin.
109
observed in this trial will be reviewed in Section 2 below. Muntean and Rosegger randomised 103 preterm infants to a single low dose of AT concentrate or no therapy. An abstract was published in 1989 [16], but to date, no full-length report of this open RCT has been published. The authors reported no benefits of AT therapy in the abstract [16]. Conclusion One well-designed and sufficiently powered trial has shown conclusively that the administration of AT concentrate during the first 2 days of life does not improve gas exchange in preterm infants with moderate to severe RDS. Moreover, the results of this RCT suggest that AT therapy may be harmful in this patient population. Therefore, neonatal RDS is not an indication for the use of AT concentrate.
AT therapy for the prevention of ICH in preterm infants Severe ICH contributes to death and neurosensory impairment in preterm infant survivors [17]. Although the etiology of ICH is multifactorial, reduced clotting substrate and inhibitors such as AT have been reported in preterm infants with ICH [8]. Beverley et al. reported a significant correlation between the severity of intraventricular hemorrhage and the degree of hemostatic abnormalities both in cord blood and in blood obtained at age 48 h in preterm infants of 34 weeks’ gestation or less [18]. The observed hypocoagulability was speculated to have followed an earlier phase of hypercoagulability, and the possibility was raised that the initial lesion in many of these bleeds may have been a hemorrhagic infarction [19]. Anticoagulant therapy was suggested [19] including replacement of AT [20,21]. Evidence from RCTs Our literature search revealed two randomised controlled trials that compared AT and placebo therapy in preterm infants and measured ICH as an outcome. Fulia et al. studied 60 infants who were born at less than 30 weeks’ gestation and who had an AT activity less than 40% in the first 12 h of life [22]. Only infants without sonographic evidence of ICH were enrolled. AT was given as a loading dose of 2 ml/kg (equivalent to 100 U/kg of AT) intravenously, followed by 1 ml/kg (equivalent to 50 U/ kg) every 8 h for 48 h. A 5% glucose solution was used as placebo. The authors did not comment whether staff in the nursery was able to distin-
110 guish between the crystalloid and colloid study solutions in the two treatment groups. Three infants died during the first week of life, one in the AT group and two in the placebo group. The observed ICH rates in survivors are summarised in Table 2 and compared with those reported by Schmidt et al. [15]. Neither group of investigators found a significant effect of AT therapy on the overall rate of ICH, though Schmidt et al. showed a trend towards a higher combined rate of any intraventricular hemorrhage and periventricular echodensities on day 7, which was still present after adjustment for birth weight and gender stratum as well as the presence or absence of intraventricular and periventricular lesions at baseline: the adjusted odds ratio was 2.30 (95% CI, 0.86 to 6.16; p=0.06) [15]. When comparing ICH and death rates in the two studies one must remember that their entry criteria differed importantly and that the infants who were enrolled in the RCT by Schmidt et al. were sicker than the infants who were eligible for the trial by Fulia et al. Thus, the results of both trials cannot be combined in a meta-analysis. Conclusion Two RCTs examined the effect of AT therapy on the rate of ICH in preterm infants; neither study was able to show a benefit. Therefore, the prevention of ICH in preterm infants is not an indication for the use of AT concentrate.
AT therapy for neonatal sepsis The administration of AT concentrate has been recommended as part of the bmultifacetedQ approach to neonatal septic shock and disseminated intravascular coagulation [23]. The rationale for the use of AT replacement in severe sepsis has included both the anticoagulant and anti-inflammatory properties of AT [1]. A meta-analysis of three small double blind, placebo-controlled trials of AT with a total of 122 septic adult patients demonstrated a 22.9% relative reduction in a 30-day all-cause mortality in patients treated with AT [24]. Because of this promising, but not statistically significant finding, the authors recommended that a sufficiently powered phase III trial be conducted to prove the benefits of AT replacement in patients with severe sepsis [24]. This placebo-controlled, multicentre RCT was performed in 2314 adult patients with severe sepsis. High-dose AT (30 000 IU in total over 4 days) had no effect on 28-day all-cause mortality, but did increase the risk of bleeding [25].
D. Bassler, B. Schmidt Table 2
The effect of AT therapy on ICH
Fulia et al. [22] Any ICH ICH grade 3 ICH grade 4
AT no./total no. (%)
Placebo no./total no. (%)
8/29 (28) 4/29 (14) None
9/28 (32) 6/28 (21) None
Schmidt et al. [15] Any ICHa 27/56 (48) ICH grade 3 5/56 (9) ICH grade 4 7/56 (13)
19/59 (32) 4/59 (7) 6/59 (10)
a Includes bperiventricular echodensitiesQ, a term that is often used synonymously with ICH grade 4.
Evidence from RCTs Our electronic literature search did not retrieve any RCT or systematic review of AT therapy in neonatal sepsis. Conclusion There is no evidence from RCTs to support or discourage AT therapy in neonatal sepsis. AT replacement in septic infants should only be considered in the context of well-designed controlled clinical trials. Because of the potential for harm, anecdotal use of AT replacement should be discouraged.
Comments AT concentrates have been available for more than 20 years, yet the evidence to justify their use in acquired neonatal AT deficiency remains weak. We could find no RCT of this therapy in newborn infants that documented clinically important benefits of neonatal AT therapy. Moreover, there is some suggestion that high-dose AT therapy may be harmful in preterm infants with moderate to severe RDS. We are aware that our literature search may have missed relevant trials although we believe that this is fairly unlikely. Importantly, however, our search was performed at a single point in time, in early 2004. Therefore, and because we were not able to find systematic reviews of neonatal AT therapy nor protocols for future reviews, we recommend that regularly updated systematic reviews of AT replacement in neonates be added to the list of neonatal reviews that are published by the Cochrane Collaboration.
References [1] Roemisch J, Gray E, Hoffmann JN, Wiedermann CJ. Antithrombin: a new look at the actions of a serine protease inhibitor. Blood Coagul Fibrinolysis 2002;13:657 – 70.
Antithrombin replacement in neonates: Is there any indication? [2] Bick RL. Prothrombin G20210A mutation, antithrombin, heparin cofactor II, protein C, and protein S defects. J Pediatr 2003;17:9 – 36. [3] Hathaway WE, Neumann LL, Borden CA, Jacobson LJ. Immunologic studies of antithrombin III heparin cofactor in the newborn. Thromb Haemost 1978;39:624 – 30. [4] Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, et al. Development of the human coagulation system in the full-term infant. Blood 1987;70:165 – 72. [5] Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72:1651 – 7. [6] Peters M, ten Cate JW, Jansen E, Breederveld C. Coagulation and fibrinolytic factors in the first week of life in healthy infants. J Pediatr 1985;106:292 – 5. [7] van den Berg W, Breederveld C, ten Cate JW, Peters M, Borm JJ. Low antithrombin III: accurate predictor of idiopathic respiratory distress syndrome in premature neonates. Eur J Pediatr 1989;148:455 – 8. [8] McDonald MM, Johnson ML, Rumack CM, Koops BL, Guggenheim MA, Babb C, et al. Role of coagulopathy in newborn intracranial hemorrhage. Pediatrics 1984;74:26 – 31. [9] Manco-Johnson MJ. Neonatal antithrombin III deficiency. Am J Med 1989;87:49S – 52S. [10] Schmidt B, Vegh P, Weitz J, Johnston M, Caco C, Roberts R. Thrombin/antithrombin III complex formation in the neonatal respiratory distress syndrome. Am Rev Respir Dis 1992;145:767 – 70. [11] Brus F, Van Oeveren W, Okken A, Oetomo SB. Disease severity is correlated with plasma clotting and fibrinolytic and kinin-kallikrein activity in neonatal respiratory distress syndrome. Pediatr Res 1997;41:120 – 7. [12] Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. AMA J Dis Child 1959;97:517 – 23. [13] Soll RF, McQueen MC. Respiratory distress syndrome. In: Sinclair JC, Bracken MB, editors. Effective care of the newborn infant. Oxford7 Oxford University Press; 1992. p. 325 – 58. [14] Schmidt BK. Antithrombin III deficiency in neonatal respiratory distress syndrome. Blood Coagul Fibrinolysis 1994;5:13 – 7. [15] Schmidt B, Gillie P, Mitchell L, Andrew M, Caco C, Roberts R. A placebo-controlled randomised trial of antithrombin
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
111
therapy in neonatal respiratory distress syndrome. Am J Respir Crit Care Med 1998;158:470 – 6. Muntean W, Rosegger H. Antithrombin III concentrate in preterm infants with IRDS: an open, controlled randomized clinical trial (abstract). Thromb Haemost 1989;62:288. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve MF, Whitfield MF. Trial of indomethacin prophylaxis in preterms (TIPP) investigators. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003 (Mar. 5);289:1124 – 9. Beverley DW, Chance GW, Inwood MJ, Schaus M, O’Keefe B. Intraventricular haemorrhage and haemostasis defects. Arch Dis Child 1984;59:444 – 8. Hathaway WE. Role of hemostasis in neonatal intracranial hemorrhage. In: Suzuki S, Hathaway WE, Bonnar J, Sutor AH, editors. Perinatal thrombosis and hemostasis. Tokyo7 Springer Verlag; 1991. p. 225 – 9. Brangenberg R, Bodensohn M, Bu ¨rger U. Antithrombin-III substitution in preterm infants: effect on intracranial hemorrhage and coagulation parameters. Biol Neonate 1997;72:76 – 83. Ikenoue T, Ibara S, Hirano T, Ninomiya Y. Antithrombin III administration in premature infants with intracranial hemorrhage. In: Suzuki S, Hathaway WE, Bonnar J, Sutor AH, editors. Perinatal thrombosis and hemostasis. Tokyo7 Springer Verlag; 1991. p. 271 – 6. Fulia F, Cordaro S, Meo P, Gitto P, Gitto E, Trimarchi G, et al. Can the administration of antithrombin III decrease the risk of cerebral hemorrhage in premature infants? Biol Neonate 2003;83:1 – 5. Kreuz W, Veldmann A, Fischer D, Schlosser R, Volk WR, Ettingshausen CE. Neonatal sepsis: a challenge in hemostaseology. Semin Thromb Hemost 1999;25:531 – 5. Eisele B, Lamy M, Thijs LG, Keinecke HO, Schuster HP, Matthias FR, et al. Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Intensive Care Med 1998;24:336 – 42. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, et al. High-dose antithrombin III in severe sepsis. A randomized controlled trial. JAMA 2001;286:1869 – 78.
intl.elsevierhealth.com/journals/thre
Review
Antithrombin replacement in neonates: Is there any indication? Dirk Basslera, Barbara Schmidta,b,* a
Departments of Pediatrics, McMaster University, Hamilton, Ontario, Canada Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
b
Received 5 January 2005; received in revised form 5 January 2005; accepted 18 January 2005 Available online 8 February 2005
KEYWORDS Antithrombin; Infant newborn; Respiratory distress syndrome; Intraventricular hemorrhage; Sepsis
Abstract Introduction: Activation of the coagulation system and severe acquired antithrombin (AT) deficiency are common and prognostically important findings in sick and preterm neonates. It has been hypothesised that treatment of the acquired AT deficiency with AT concentrate may improve the outcome of conditions such as the neonatal respiratory distress syndrome (RDS), intracranial hemorrhage (ICH) and sepsis. Materials and methods: We performed a systematic review of randomised controlled trials (RCTs) of AT replacement therapy in newborn infants. Results: Two full-length trial reports were found. Both were placebo-controlled. The first RCT examined the effects of AT therapy in 122 preterm infants with RDS. Administration of AT prolonged rather than shortened the duration of mechanical ventilation and oxygen therapy. The second RCT determined whether AT replacement decreased the incidence of ICH in 60 preterm infants who were born before 30 weeks of gestation. No beneficial effect on ICH was found. Conclusions: Preterm infants with RDS do not benefit from therapy with AT concentrate and may be harmed. There is also little evidence that the administration of AT reduces the risk of ICH. The role of AT replacement during neonatal sepsis remains uncertain. D 2005 Elsevier Ltd. All rights reserved.
Abbreviations: AT, Antithrombin; ICH, Intracranial hemorrhage; RCT, Randomised controlled trial; RDS, Respiratory distress syndrome. * Corresponding author. Room 3N11 E, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5. Tel.: +1 905 521 2100x73243; fax: +1 905 521 5007. E-mail address: [email protected] (B. Schmidt). 0049-3848/$ - see front matter D 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2005.01.007
108
D. Bassler, B. Schmidt
Contents Introduction . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . AT therapy in neonatal RDS . . . . . . . Evidence from RCTs . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . AT therapy for the prevention of ICH in Evidence from RCTs . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . AT therapy for neonatal sepsis . . . . . Evidence from RCTs . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . Comments. . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . preterm infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Antithrombin (AT) is a potent physiologic inhibitor of the clotting system. AT is a glycoprotein that is synthesised in the liver and released into the plasma where it controls the activity of thrombin and of other serine proteases such as activated factors IX, X, XI and XII [1]. The well-recognised association between inherited AT deficiency and the risk of venous thrombosis in adults points to the important role of AT as a modulator of blood coagulation [2]. Compared with healthy adults, healthy newborn infants have physiologically low plasma concentrations of AT [3—6]. However, activities of AT are even lower in critically ill infants such as those with respiratory distress syndrome (RDS) [7], intracranial hemorrhage (ICH) [8] and sepsis [9]. The effects of this acquired AT deficiency on the regulation of neonatal thrombin formation have been studied extensively during the course of RDS in preterm infants. Schmidt et al. demonstrated a strong relationship between the activation of the clotting system, the depletion of AT activity and the severity of RDS [10]. These observations were later confirmed and extended by Brus et al. [11]. These findings led to the hypothesis that unopposed thrombin activity may contribute to the progression of neonatal diseases that are accompanied by hypercoagulability. The logical subsequent hypothesis was that to regulate thrombin activity, sick newborn infants might benefit from the administration of AT concentrates. Our objective in this systematic review has been to search the biomedical literature for potential indications of AT replacement therapy in neonates with acquired AT deficiency. We focused on strong evidence arising from randomised controlled trials
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
. . . . . . . . . . . . . .
108 108 108 108 109 109 109 109 110 110 110 110 110 110
(RCTs) with clinically meaningful endpoints in human infants.
Materials and methods An electronic literature search in Pubmed was performed using the following search terms: (antithrombin OR antithrombin III OR ATIII OR AT III OR AT-III) and (neonat* OR infant OR newborn), Limits: Randomised controlled trial. The Cochrane Controlled Trial Register (CCTR) was also searched for clinical trials. The Cochrane Database of Systematic Reviews (CDSR) was searched for systematic reviews on AT therapy in neonates. We checked all reports of neonatal RCTs that were identified by the electronic literature search for references to additional trials. In order to be included in this systematic review, study reports had to state clearly that allocation to AT therapy was randomised.
Results AT therapy in neonatal RDS Neonatal RDS is an acute lung injury in preterm infants that is characterized by diffuse atelectasis, high permeability pulmonary oedema, hyaline membrane formation and right to left shunting of pulmonary blood flow. Surfactant deficiency in the immature lung is the primary cause [12] and surfactant replacement has significantly reduced mortality and morbidity from this disease [13]. However, residual lung injury may persist after surfactant therapy. Increased thrombin formation
Antithrombin replacement in neonates: Is there any indication? due to acquired AT deficiency was hypothesised to contribute to the progression and abnormal resolution of neonatal RDS and similarly that AT therapy may improve the outcomes of affected infants [14]. Evidence from RCTs We could find only one full-length publication of an RCT of AT therapy in neonatal RDS [15]. A second trial was published as an abstract only and was not placebo-controlled [16]. Schmidt et al. studied 122 preterm infants with birth weights between 750 and 1900 g who required mechanical ventilation for RDS [15]. Only infants with moderate to severe disease were included, i.e. those with a ratio of arterial to alveolar oxygen pressure (a/A PO2) less than 0.3 after the first dose of exogenous surfactant when the infants were between 2 and 12 h old [15]. AT was given as a loading dose of 2 ml/kg (equivalent to 100 U/kg of AT) intravenously, followed by 1 ml/kg (equivalent to 50 U/kg) every 6 h for 48 h. A 1% human albumin solution was used as placebo. The authors reported 6 clinical efficacy outcomes. They included measures of gas exchange (a/A PO2 at 48 h and 7 days, and the ventilator efficiency index at 48 h and 7 days), as well as the median duration of mechanical ventilation and need for supplemental oxygen. The rates of ICH, clinically apparent bleeding from puncture sides, the umbilicus, nasogastric tubes or endotracheal tubes and deaths before first discharge home were reported as safety outcomes. AT activity was significantly increased in the treatment group, above the normal range for the healthy newborn infant, but sensitive markers of increased thrombin formation were not fully normalised by these fairly large doses of AT concentrate [15]. Table 1 summarizes clinically important endpoints. Infants allocated to the AT group needed mechanical ventilation and oxygen therapy for a significantly longer period of time than infants who were allocated to the placebo group. There was also some evidence to suggest that clinical bleeding and deaths were more common following high-dose AT therapy (Table 1). The ICH rates that were
Table 1 The effect of AT therapy on RDS: data by Schmidt et al. [15] Outcome measure
AT
Placebo
Mechanical ventilation (median number of days) Supplemental oxygen (median number of days) Clinical bleeding no./total no. (%) Deaths no./total no. (%)
7.1
4.8
7.9
5.5
37/61 (61) 7/61 (12)
30/61 (49) 3/61 (5)
Definition of abbreviations: AT=antithrombin.
109
observed in this trial will be reviewed in Section 2 below. Muntean and Rosegger randomised 103 preterm infants to a single low dose of AT concentrate or no therapy. An abstract was published in 1989 [16], but to date, no full-length report of this open RCT has been published. The authors reported no benefits of AT therapy in the abstract [16]. Conclusion One well-designed and sufficiently powered trial has shown conclusively that the administration of AT concentrate during the first 2 days of life does not improve gas exchange in preterm infants with moderate to severe RDS. Moreover, the results of this RCT suggest that AT therapy may be harmful in this patient population. Therefore, neonatal RDS is not an indication for the use of AT concentrate.
AT therapy for the prevention of ICH in preterm infants Severe ICH contributes to death and neurosensory impairment in preterm infant survivors [17]. Although the etiology of ICH is multifactorial, reduced clotting substrate and inhibitors such as AT have been reported in preterm infants with ICH [8]. Beverley et al. reported a significant correlation between the severity of intraventricular hemorrhage and the degree of hemostatic abnormalities both in cord blood and in blood obtained at age 48 h in preterm infants of 34 weeks’ gestation or less [18]. The observed hypocoagulability was speculated to have followed an earlier phase of hypercoagulability, and the possibility was raised that the initial lesion in many of these bleeds may have been a hemorrhagic infarction [19]. Anticoagulant therapy was suggested [19] including replacement of AT [20,21]. Evidence from RCTs Our literature search revealed two randomised controlled trials that compared AT and placebo therapy in preterm infants and measured ICH as an outcome. Fulia et al. studied 60 infants who were born at less than 30 weeks’ gestation and who had an AT activity less than 40% in the first 12 h of life [22]. Only infants without sonographic evidence of ICH were enrolled. AT was given as a loading dose of 2 ml/kg (equivalent to 100 U/kg of AT) intravenously, followed by 1 ml/kg (equivalent to 50 U/ kg) every 8 h for 48 h. A 5% glucose solution was used as placebo. The authors did not comment whether staff in the nursery was able to distin-
110 guish between the crystalloid and colloid study solutions in the two treatment groups. Three infants died during the first week of life, one in the AT group and two in the placebo group. The observed ICH rates in survivors are summarised in Table 2 and compared with those reported by Schmidt et al. [15]. Neither group of investigators found a significant effect of AT therapy on the overall rate of ICH, though Schmidt et al. showed a trend towards a higher combined rate of any intraventricular hemorrhage and periventricular echodensities on day 7, which was still present after adjustment for birth weight and gender stratum as well as the presence or absence of intraventricular and periventricular lesions at baseline: the adjusted odds ratio was 2.30 (95% CI, 0.86 to 6.16; p=0.06) [15]. When comparing ICH and death rates in the two studies one must remember that their entry criteria differed importantly and that the infants who were enrolled in the RCT by Schmidt et al. were sicker than the infants who were eligible for the trial by Fulia et al. Thus, the results of both trials cannot be combined in a meta-analysis. Conclusion Two RCTs examined the effect of AT therapy on the rate of ICH in preterm infants; neither study was able to show a benefit. Therefore, the prevention of ICH in preterm infants is not an indication for the use of AT concentrate.
AT therapy for neonatal sepsis The administration of AT concentrate has been recommended as part of the bmultifacetedQ approach to neonatal septic shock and disseminated intravascular coagulation [23]. The rationale for the use of AT replacement in severe sepsis has included both the anticoagulant and anti-inflammatory properties of AT [1]. A meta-analysis of three small double blind, placebo-controlled trials of AT with a total of 122 septic adult patients demonstrated a 22.9% relative reduction in a 30-day all-cause mortality in patients treated with AT [24]. Because of this promising, but not statistically significant finding, the authors recommended that a sufficiently powered phase III trial be conducted to prove the benefits of AT replacement in patients with severe sepsis [24]. This placebo-controlled, multicentre RCT was performed in 2314 adult patients with severe sepsis. High-dose AT (30 000 IU in total over 4 days) had no effect on 28-day all-cause mortality, but did increase the risk of bleeding [25].
D. Bassler, B. Schmidt Table 2
The effect of AT therapy on ICH
Fulia et al. [22] Any ICH ICH grade 3 ICH grade 4
AT no./total no. (%)
Placebo no./total no. (%)
8/29 (28) 4/29 (14) None
9/28 (32) 6/28 (21) None
Schmidt et al. [15] Any ICHa 27/56 (48) ICH grade 3 5/56 (9) ICH grade 4 7/56 (13)
19/59 (32) 4/59 (7) 6/59 (10)
a Includes bperiventricular echodensitiesQ, a term that is often used synonymously with ICH grade 4.
Evidence from RCTs Our electronic literature search did not retrieve any RCT or systematic review of AT therapy in neonatal sepsis. Conclusion There is no evidence from RCTs to support or discourage AT therapy in neonatal sepsis. AT replacement in septic infants should only be considered in the context of well-designed controlled clinical trials. Because of the potential for harm, anecdotal use of AT replacement should be discouraged.
Comments AT concentrates have been available for more than 20 years, yet the evidence to justify their use in acquired neonatal AT deficiency remains weak. We could find no RCT of this therapy in newborn infants that documented clinically important benefits of neonatal AT therapy. Moreover, there is some suggestion that high-dose AT therapy may be harmful in preterm infants with moderate to severe RDS. We are aware that our literature search may have missed relevant trials although we believe that this is fairly unlikely. Importantly, however, our search was performed at a single point in time, in early 2004. Therefore, and because we were not able to find systematic reviews of neonatal AT therapy nor protocols for future reviews, we recommend that regularly updated systematic reviews of AT replacement in neonates be added to the list of neonatal reviews that are published by the Cochrane Collaboration.
References [1] Roemisch J, Gray E, Hoffmann JN, Wiedermann CJ. Antithrombin: a new look at the actions of a serine protease inhibitor. Blood Coagul Fibrinolysis 2002;13:657 – 70.
Antithrombin replacement in neonates: Is there any indication? [2] Bick RL. Prothrombin G20210A mutation, antithrombin, heparin cofactor II, protein C, and protein S defects. J Pediatr 2003;17:9 – 36. [3] Hathaway WE, Neumann LL, Borden CA, Jacobson LJ. Immunologic studies of antithrombin III heparin cofactor in the newborn. Thromb Haemost 1978;39:624 – 30. [4] Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, et al. Development of the human coagulation system in the full-term infant. Blood 1987;70:165 – 72. [5] Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72:1651 – 7. [6] Peters M, ten Cate JW, Jansen E, Breederveld C. Coagulation and fibrinolytic factors in the first week of life in healthy infants. J Pediatr 1985;106:292 – 5. [7] van den Berg W, Breederveld C, ten Cate JW, Peters M, Borm JJ. Low antithrombin III: accurate predictor of idiopathic respiratory distress syndrome in premature neonates. Eur J Pediatr 1989;148:455 – 8. [8] McDonald MM, Johnson ML, Rumack CM, Koops BL, Guggenheim MA, Babb C, et al. Role of coagulopathy in newborn intracranial hemorrhage. Pediatrics 1984;74:26 – 31. [9] Manco-Johnson MJ. Neonatal antithrombin III deficiency. Am J Med 1989;87:49S – 52S. [10] Schmidt B, Vegh P, Weitz J, Johnston M, Caco C, Roberts R. Thrombin/antithrombin III complex formation in the neonatal respiratory distress syndrome. Am Rev Respir Dis 1992;145:767 – 70. [11] Brus F, Van Oeveren W, Okken A, Oetomo SB. Disease severity is correlated with plasma clotting and fibrinolytic and kinin-kallikrein activity in neonatal respiratory distress syndrome. Pediatr Res 1997;41:120 – 7. [12] Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. AMA J Dis Child 1959;97:517 – 23. [13] Soll RF, McQueen MC. Respiratory distress syndrome. In: Sinclair JC, Bracken MB, editors. Effective care of the newborn infant. Oxford7 Oxford University Press; 1992. p. 325 – 58. [14] Schmidt BK. Antithrombin III deficiency in neonatal respiratory distress syndrome. Blood Coagul Fibrinolysis 1994;5:13 – 7. [15] Schmidt B, Gillie P, Mitchell L, Andrew M, Caco C, Roberts R. A placebo-controlled randomised trial of antithrombin
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
111
therapy in neonatal respiratory distress syndrome. Am J Respir Crit Care Med 1998;158:470 – 6. Muntean W, Rosegger H. Antithrombin III concentrate in preterm infants with IRDS: an open, controlled randomized clinical trial (abstract). Thromb Haemost 1989;62:288. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve MF, Whitfield MF. Trial of indomethacin prophylaxis in preterms (TIPP) investigators. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003 (Mar. 5);289:1124 – 9. Beverley DW, Chance GW, Inwood MJ, Schaus M, O’Keefe B. Intraventricular haemorrhage and haemostasis defects. Arch Dis Child 1984;59:444 – 8. Hathaway WE. Role of hemostasis in neonatal intracranial hemorrhage. In: Suzuki S, Hathaway WE, Bonnar J, Sutor AH, editors. Perinatal thrombosis and hemostasis. Tokyo7 Springer Verlag; 1991. p. 225 – 9. Brangenberg R, Bodensohn M, Bu ¨rger U. Antithrombin-III substitution in preterm infants: effect on intracranial hemorrhage and coagulation parameters. Biol Neonate 1997;72:76 – 83. Ikenoue T, Ibara S, Hirano T, Ninomiya Y. Antithrombin III administration in premature infants with intracranial hemorrhage. In: Suzuki S, Hathaway WE, Bonnar J, Sutor AH, editors. Perinatal thrombosis and hemostasis. Tokyo7 Springer Verlag; 1991. p. 271 – 6. Fulia F, Cordaro S, Meo P, Gitto P, Gitto E, Trimarchi G, et al. Can the administration of antithrombin III decrease the risk of cerebral hemorrhage in premature infants? Biol Neonate 2003;83:1 – 5. Kreuz W, Veldmann A, Fischer D, Schlosser R, Volk WR, Ettingshausen CE. Neonatal sepsis: a challenge in hemostaseology. Semin Thromb Hemost 1999;25:531 – 5. Eisele B, Lamy M, Thijs LG, Keinecke HO, Schuster HP, Matthias FR, et al. Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Intensive Care Med 1998;24:336 – 42. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, et al. High-dose antithrombin III in severe sepsis. A randomized controlled trial. JAMA 2001;286:1869 – 78.