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Heparin Infusion to Prevent Umbilical Venous Catheter Related Thrombosis in Neonates
Thrombosis Research 130 (2012) 725–728
Contents lists available at SciVerse ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Heparin Infusion to Prevent Umbilical Venous Catheter Related Thrombosis in Neonates Sevim Unal a,⁎, Filiz Ekici b, İbrahim İlker Cetin b, Leyla Bilgin a a b
Division of Neonatology, Ankara Child Health, Hematology, Oncology, Research Hospital, Ankara, Turkey Division of Pediatric Cardiology, Ankara Child Health, Hematology, Oncology, Research Hospital, Ankara, Turkey
a r t i c l e
i n f o
Article history: Received 13 March 2012 Received in revised form 21 June 2012 Accepted 17 July 2012 Available online 16 August 2012 Keywords: Heparin Neonate Thrombosis Venous umbilical catheter
a b s t r a c t Objective: To investigate umbilical venous catheter (UVC) related thrombosis by Doppler echocardiographic evaluation of neonates infused with heparin or placebo. Methods: We conducted a prospective study to determine UVC-related thrombosis in term and nearterm neonates. Heparin or placebo (0.5 IU/mL) was infused at a rate of 1 mL/hr to the study and control group. Doppler echocardiography was performed at 1, 3, and 5 days after UVC insertion. Results: Forty-six neonates (63% males) with a mean gestational age of 38.2 ± 1.8 weeks, and a mean birth-weight of 2993 ± 563 grams were included. No UVC-related thrombosis was observed in the study group, which included 19 neonates. Among the 27 neonates in the control group, one neonate developed UVC-related thrombosis. There were no statistical differences between the groups for gestational age, birth weight, postnatal age, UVC duration, mortality, mechanical ventilation, and inotrope requirement, and hemagram or coagulation profile. The complications were as follows, mild pulmonary hemorrhage, 6.5% (3); leak-out, 4.3% (2); peritoneal leakage, 2.2% (1); occlusion, 2.2% (1); gastrointestinal findings, 6.5% (3); sepsis, 10.9% (5); and catheter-related thrombosis, 2.2% (1). Conclusion: This study demonstrated that heparin infusion of 0.5 IU/mL through the UVC had no effect on catheter-related thrombosis in term and near-term neonates. Randomized controlled trials are necessary to conclusively evaluate the effect of heparin on UVC-related thrombosis. Published by Elsevier Ltd.
Introduction Vascular access is a major challenge in the management of neonates in the neonatal intensive care unit (NICU). Peripheral intravenous lines (PIVs), percutaneous central venous catheters, and umbilical venous catheters (UVCs) are most often used to establish venous access in newborns [1–11]. The peripheral veins of a neonate are small and friable, can be difficult to cannulate, and are easily injured by irritating fluids and medications [12]. The dwell time of PIVs can be short [13,14]. Therefore, UVCs can be used to deal with these difficulties. After birth, the umbilical vein provides an ideal, secure, and rapid catheter access. Umbilical vein catheterization within the first hours of life is a relatively easy procedure with a high success rate and the catheter can be left in place for up to 14 days with a low risk of complications. UVCs have been widely used in critically ill neonates for the urgent administration of resuscitation drugs and intravenous infusions [hypertonic dextrose solution, total parenteral nutrition (TPN), inotropes,
⁎ Corresponding author at: Çukurambar Mah, 39. Cadde, 444. sokak, 17/5, Yüzüncüyıl, Ankara, Turkey. Tel.: +90 312 5969730; fax: +90 312 3472330. E-mail address: [email protected] (S. Unal). 0049-3848/$ – see front matter. Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.thromres.2012.07.018
blood products, sodium bicarbonate and various other medications], blood sampling, exchange transfusion and invasive monitoring [1–11]. Despite their value in infant care, UVCs may cause serious mechanical, infectious and thrombotic complications [10,11]. Several factors may play role in neonates with increased risk of thrombosis together with the newborn's decreased ability to inhibit thrombin and relatively deficient fibrinolysis. Congenital risk factors include deficiency of natural anticoagulants (AT III, Proteins C and S), elevated lipoprotein (a) levels, Factor V Leiden mutation, prothrombin gene mutations, and hyperhomocysteinemia. Acquired risk factors include indwelling catheters, dehydration, polycythemia, asphyxia, septicemia, maternal diabetes, maternal preeclampsia, being small for gestational age (SGA), thrombocytosis, and extracorporeal membranous oxygenation. Factors that have been associated with initiation and progression of catheter-related thrombosis include endothelial damage during catheter placement, disrupted blood flow, vascular occlusion, low flow states, turbulent flow, patient and infusate characteristics, catheter composition, underlying medical conditions, duration of catheterization, infusion of substances that damage endothelial cells such as TPN, thrombogenic catheter materials, and placement of an umbilical arterial catheter (UAC) together with a venous catheter [4–8,15,16].
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There is no consensus on heparin infusion or the optimal dose of heparin administered through the UVC to prevent catheter-related thrombosis [1–11]. In this study, we aimed to assess the effects of heparin infusion with a concentration of 0.5 IU/mL at a rate of 1 mL/hr through UVC in term and near-term neonates in a prospective controlled trial. We hypothesized that the frequency of catheter-related thrombosis would be lower in neonates with heparin infusion than that of neonates without heparin. We also investigated the relation between catheter-related thrombosis and coagulation profile.
Methods We conducted a prospective controlled study to investigate asymptomatic thrombosis associated with an indwelling single lumen polyurethane UVC in term and near-term neonates (gestational age ≥ 35 weeks). We also aimed to evaluate the relation between prothrombin time (PT), partial thromboplastin time (PTT), and D-dimer levels and catheter-related thrombosis. The study was performed throughout 2010 in the NICU of our hospital. Term and near-term neonates with inserted UVCs were included in the study. These neonates were divided into two groups; the study group was infused with heparin and the control group was infused with placebo through an UVC. The medical team was blinded to the study group allocation. The neonates in the heparin group were infused with unfractionated heparin of 0.5 IU/mL in saline via an infusion pump at a rate of 1 mL/hr. Neonates in the placebo group received saline at the same rate as the heparin infusion. All neonates were monitored for coagulation profile and hemogram prior to insertion of UVC. The clinical findings and laboratory results of the neonates were recorded. Catheter placement was performed in the NICU by a pediatrician who was blinded to the study groups. The umbilical stump and the surrounding skin were cleaned with a solution containing iodine, and a systemic sedative (midazolam) was infused to the neonate. The catheter (polyurethane, single lumen 5F or 8F diameter, Vygon catheter) was inserted under sterile conditions. The catheter tip was placed at the inferior vena cava-right atrial junction, and the catheter was sutured to the umbilical cord and taped to the abdomen. A plain abdominal radiograph was obtained to determine the positioning of the catheter. The catheter was connected to an infusion pump, and the entire system was changed every 24 hours. In this way, catheter care was standardized. Doppler echocardiographic [Vivid-7 Pro (GE) with using 7F probe] examinations were performed at the bedside by the same pediatric cardiologist at 1, 3, and 5 days after catheter insertion. The neonates were also evaluated after the removal of the catheters. All patients were monitored for catheter occlusion, defined as an inability to infuse fluid; catheter-related sepsis, defined as symptoms and signs suggestive of sepsis with a positive culture obtained from a normally sterile site (blood, urine, or cerebrospinal fluid) and the catheter for the same microorganism; thrombosis, defined as detection of a thrombus at the catheter tip or heart using Doppler echocardiography; arrhythmia; hemorrhage; and heparin-induced thrombocytopenia (HIT), defined as a platelet count b50,000/mm3 after exclusion of other causes. Local ethical committee approval was obtained, and the parents or guardians of all participating subjects signed a consent form indicating their agreement to take part and to allow the results to be published. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS 13.0). A non-parametric test was used to analyze the effects of heparin infusion on catheter-related thrombosis. The Mann–Whitney U test was used to evaluate the interaction between catheter-related thrombosis and risk factors in the groups. Two-tailed P values b 0.05 were considered statistically significant for all analyses.
Results Among 911 hospitalized neonates, UVCs were inserted in 46 term and near-term neonates (5.1%) throughout 2010, and these infants were included in the study. They were followed-up by Doppler echocardiography for catheter-related thrombosis. In addition to UVC, UACs were inserted into two neonates. Demographic characteristics and clinical findings of the infants are summarized in Table 1. Doppler echocardiography was performed at 24, 72, and 120 hours after UVC insertion for 100%, 91.3% (n = 42), and 59.5% (n = 25) of the catheterized patients, respectively. The decrement in the rates was due to the removal of the UVC in some infants, because a central line was no longer needed. All neonates were reevaluated after the removal of the catheters. The diagnoses of the neonates and indications for UVC insertion are shown in Table 2. The results of laboratory analyses of the infants are shown in Table 3. The percentage of UVCs, which resulted in one or more complications, was 15.2%. Complications included mild pulmonary hemorrhage in 6.5% (3), vascular leakage in 4.3% (2), peritoneal leakage in 2.2% (1), mechanical obstruction in 2.2% (1), gastrointestinal findings resembling necrotizing enterocolitis in 6.5% (3), catheter-related sepsis in 10.9% (5), and catheter-related thrombosis in 2.2% (1) of the neonates. One neonate with severe perinatal asphyxia, disseminated intravascular coagulation (DIC) and multiorgan failure developed central nervous system hemorrhage, considered to be secondary to the underlying diseases. One neonate had mild pulmonary hemorrhage that was assumed to be due to heparin infusion. We removed the catheter because of suspected infection in 3 (6.5%) neonates. Arrhythmia was not recorded in any of the patients.
Table 1 Demographic characteristics and outcomes of the neonates in the study. Factor Female/male ratio Postnatal age (days), mean ± SD (range) Gestation (weeks), mean ± SD (range) Birth weight (g), mean ± SD (range) Maternal age (years), mean ± SD (range) Apgar at 5 minutes, mean ± SD (range) Delivery, n (%) Spontaneous vaginal Cesarean section UVC duration (hours), mean ± SD (range) Mechanical ventilation, n (%) Perinatal asphyxia, n (%) Catheter-related thrombosis, n (%) Inotropic therapy requirement, n (%) Single drug Two or more drugs Congenital heart disorders, n (%) Sepsis ± pneumonia, n (%) Pulmonary hypertension, n (%) Mild Severe Mortality, n (%)
Group 1 (Heparin)
Group 2 (Control)
0.46 (6/13) 5.2 ± 5.6 (0.0-19)
0.69 (11/16) 4.3 ± 3.6 (0.3-15)
37.9 ± 1.9 (35–41)
38.5 ± 1.7 (35–41)
3,087 ± 541 (2,270-4,070)
2,927 ± 545 (1,700-4,250)
28.2 ± 6.9 (18–45)
28.4 ± 5.6 (19–37)
7.5 ± 2.3 (2–10)
6 (31.6%) 13 (68.4%) 131.7 ± 67.5 (70–340)
7.8 ± 2 (3–10)
11 (40.7%) 16 (59.3%) 125.1 ± 85.8 (24–288)
13 (68.4%)
17 (63%)
8 (42.1%)
10 (37%)
0 (0%)
8 (42.1%) 4 (21.1%) 5 (26.3%) 9 (47.4%)
1 (5.3%) 2 (10.5%) 5 (26.3%)
* SD: standard deviation, UVC: umbilical venous catheter.
1 (3.8%)
9 (33.3%) 7 (25.9%) 8 (29.6%) 10 (37%)
5 (18.5%) 4 (14.8%) 7 (25.9%)
S. Unal et al. / Thrombosis Research 130 (2012) 725–728 Table 2 The diagnoses of neonates and indications for umbilical venous catheter insertion. Diagnosis (indications for UVC)
n (%)
Indirect hyperbilirubinemia (exchange transfusion) Congenital heart disease (shock, hypoxia) Coarctation or interruption of aorta Pulmonary atresia Perinatal asphyxia, MODS, HIE (respiratory failure) Neonatal pneumonia (respiratory failure) Persistent pulmonary hypertension (respiratory failure) Persistent hypoglycemia±hyperinsulinemia (venous access) Multiple congenital anomalies, syndrome (respiratory failure) Anomalies of respiratory tract (respiratory failure) Down syndrome, transient myeloproliferative disorder (respiratory failure and exchange transfusion) Epidermolysis bullosa (venous access) Total
12 (26.1%) 6 (13%) 2 (4.3%) 6 (13%) 5 (10.9%) 4 (8.7%) 3 (6.5%) 4 (8.7%) 2 (4.3%) 1 (2.2%) 1 (2.2%) 46 (100%)
* UVC: umbilical venous catheter, MODS: multi-organ dysfunction syndrome, HIE: hypoxic ischemic encephalopathy.
There were no differences between the groups regarding the hemoglobin, hematocrit, PT, PTT, international normalized ratio (INR), or D-dimer levels. The platelet counts in the study group were lower than that in the control group (p b 0.05), but none of the infants had platelet counts lower than 100.000 mm 3. Among neonates included in the study, only one neonate developed catheter-related thrombosis in the control group, but no thrombosis was observed in the study group. The mortality rate was 26.1% (n = 12) with similar rates in the groups. Discussion The placement of a UVC was first reported in 1947 for an exchange transfusion in the treatment of severe indirect hyperbilirubinemia in an infant with erythroblastosis fetalis [17]. The use of UVC is now common in the care of premature and term neonates with illness requiring treatment in the NICU (especially in as many as 50% of very low birth weight infants) [1–8]. Catheter placement rates vary from institution to institution and according to patient weight, ranging from 9% in infants over 2,000 g and above 50% in infants under 1,000 g [10]. In our NICU, a UVC placed in 5.1% of term and near-term neonates during 2010. The low UVC placement rate in our NICU compared to that reported in the literature might be due to the absence of a maternity department in our hospital. We used UVC mainly for drawing blood samples and administering fluid in patients with hypoxia and respiratory failure (Table 2). The second most common indication for UVC placement was exchange transfusion (27.3%) to eliminate indirect bilirubin from the circulation. UVC was also used for secure and easy vascular access in neonates with persistent hypoglycemia and epidermolysis bullosa. The prevention of catheter occlusion under continuous infusion of heparin through central catheters and the effect of such heparin infusion on the occurrence of thrombosis has not been fully determined. Soe suggested that heparin use reduces the incidence of catheter occlusion and increases the life span of the catheter [18]. In a systematic review, Barrington documented that heparin infusion was effective in improving Table 3 Results of laboratory investigations. Test
Group 1
Group 2
Hemoglobin (g/dL) Hematocrit (%) Platelet count (×109/L) Prothrombin time (PT) (s) Partial thromboplastin time (PTT) (s) International normalized ratio (INR) D-dimer (nmol/L)
15.6 ± 2.5 45.4 ± 7.5 224.4 ± 133.7 29.9 ± 42.8 46.7 ± 38.7 1.55 ± 0.69 2,267.7 ± 2,026.6
16.8 ± 3.3 49.2 ± 9.7 178.3 ± 121.5 35.1 ± 39.6 84.1 ± 95.2 2.07 ± 1.09 1,582 ± 1913
727
UAC patency in neonates, with no statistically significant evidence of adverse outcomes [19]. Currently, there are no definitive recommendations for thromboprophylaxis in children, infants, and neonates. In a meta-analysis, heparin administration was deemed to be possibly effective and was recommended to prevent UVC-related thrombosis [20]. However, many questions about heparinization remain open. In a systematic review involving subjects of different age groups including neonates, Randolph et al. found that heparin (administered intermittently or as a continuous infusion) was effective in the prevention of peripheral arterial catheter complications but not for venous catheter complications [21]. We used continuous heparin infusion at a concentration of 0.5 IU/ml and a rate of 1 ml/hr through the UVC. This method had no significant effect on catheter-related thrombosis. Currently, only a few clinics use screening protocols for at-risk neonates, and most thrombi are detected only after clinical suspicion or by chance. Thrombi are usually visualized by ultrasonography (with or without Doppler technique) or angiography [5,6,10,11]. Roy et al. suggested that Doppler echocardiography was not adequate in the infants diagnosing asymptomatic UVC-related thrombosis [22]. He showed that the rate of venographically confirmed thrombosis (30%) was higher than that reported in the previously published studies in which the diagnosis was based on echocardiography (1.8–13%). However, Narang et al., in their study investigating the risk factors associated with catheter related thrombosis, used echocardiography to determine thrombosis even in very low birth weight (VLBW) infants [10]. Butler-O'Hara et al. also used echocardiography in their study to diagnose catheter-associated thrombosis in VLBW infants [23]. Currently, echocardiography is considered as the gold standard method to define catheter-related thrombosis in neonates [10]. In the current study, we used serial Doppler echocardiography to screen neonates for thrombosis. Among the 46 term and near-tem neonates, catheter-related thrombosis was determined in only one neonate from the control group. We considered echocardiography to be an easy, non-invasive, and low-cost method to determine umbilical catheter-related thrombosis, compared to angiography. The benefits of using heparin have to be weighed against the risks involved. All possible side effects of heparin (allergic reactions, bleeding, disturbance of coagulation parameters, HIT, influence on bone structure, etc.) have been carefully studied in neonates [24,25]. Besides complications due to dosing errors, the occurrence of HIT, which has been described in 3% of patients exposed to heparin, should be kept in mind [26]. Furthermore, the stability of heparin in mixed solutions is questionable, and precipitation with other molecules in solution may occur, leading to inactivation of the anticoagulant [24,25]. We observed mild pulmonary hemorrhage in three neonates (6.8%), but no other side effect was observed. Potential complications related to UVC placement include malposition, dislodgement, vascular leakage, hemorrhage, thromboembolism, sepsis, air embolism, vasospasm, portal vein thrombosis and portal hypertension. Furthermore, if the UVC tip lies within the cardiac chambers, myocardial perforation, vessel perforation, pericardial effusion, cardiac tamponade, pleural effusion, endocarditis and arrhythmias have also been reported. Gastrointestinal, hepatic, renal, and limb tissue damages, as well as ascites, hydrothorax, and erosion of the atrium or ventricle have also been described in the literature. The main factors influencing the risks due to UVC placement include the procedure for UVC insertion, the location, size, composition, and care of the catheter, the number of manipulations, the types and contents of parenteral solutions, and medications, the dwelling time, and the education and training of health care providers [27–30]. In this study, complications due to UVC were peritoneal leakage (2.3%), catheter occlusion (2.3%), gastrointestinal findings (6.8%), catheter-related sepsis (10.9%), and catheter-related thrombosis (2.3%); and 84.8% of the UVCs were free of complications. Haumont et al. reported umbilical and percutaneous silicone venous catheter complications as thrombosis (1.2%), catheter-related sepsis (3.5%), and mechanical obstruction (5%) [31]. They reported a total
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complication rate of 27% in infants treated with UVCs, and in some infants more than one complication was noted. Peritoneal leakage observed in one neonate in their study was assumed to be secondary to vessel perforation. Umbilical vein perforation and leakage of fluid into the peritoneal cavity has rarely been reported in the literature [32]. We observed peritoneal leakage in one neonate in this present study. Additionally, our rate of infection related to UVC placement (10.9%) was higher compared with published data, ranging from 3% to 16%. Thus, our practice should be reviewed in relation to the tip position, heparin use, and other aspects regarding sterility. D-dimer is a reliable and sensitive index of fibrin deposition and stabilization. As such, its higher levels in plasma should be indicative of thrombus formation. Plasma D-dimer levels have been shown to be sensitive for the diagnosis of deep venous thrombosis and pulmonary embolism in adults [33]. Furthermore, very high D-dimer levels may be observed in conditions such as massive bleeding, cardiopulmonary resuscitation, sepsis with DIC, multiple traumatic injuries, hyperfibrinolysis, and HELLP syndrome [33,34]. There are few data about the relationship between venous thrombosis and D-dimer levels in childhood, especially in the neonatal period [35–37]. We suggested high D-dimer levels would be indicative of UVC-related thrombosis in neonates, but we could not establish a significant relation between D-dimer levels and UVC-associated thrombosis. In conclusion, no significant differences in the incidence of thrombosis, occlusion, sepsis, mortality, and duration of catheter patency were observed with heparin infusion at the dose used in this study. On the basis of our results with small sample size, routine use of heparin to prevent UVC-related thrombosis cannot be recommended. Randomized controlled trials are necessary to conclusively determine the benefits and risks of continuous heparin infusion through UVC in neonates. Conflict of interest statement The authors have no conflict of interest. References [1] Shah PS, Shah VS. Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters. Cochrane Database Syst Rev 2008;16(2):CD002772. [2] Shah PS, Kalyn A, Satodia P, Dunn MS, Parvez B, Daneman A, et al. A randomized controlled trial of heparin versus placebo infusion to prolong the usability of peripherally placed percutaneous central venous catheters (PCVCs) in neonates. The HIP (Heparin Infusion for PCVC) study. Pediatrics 2007;119(1):e284-91. [3] Seth T. Thrombosis in neonates and children. East J Med 2009;14:36-45. [4] Saxena R, Kannan M, Choudhry VP. Neonatal thrombosis. Indian J Pediatr 2003;70(11): 903-7. [5] Veldman A, Nold MF, Michel-Behnke I. Thrombosis in the critically ill neonate: incidence, diagnosis, and management. Vasc Health Risk Manag 2008;4(6):1337-48. [6] van Elteren HA, Veld H. ST, Te Pas AB, Roest AAW, Smiers FJ, Kollen WJ, Sramek A, Walther FJ, Lopriore E. Management and outcome in 32 neonates with thrombotic events. Int. J Pediatr 2011;2011:217564. [7] Manco-Johnson MJ, Nuss R. Neonatal Thrombotic Disorders. NeoReviews 2000;1: e201-5. [8] Saxonhouse MA, Manco-Johnson MJ. The evaluation and management of neonatal coagulation disorders. Semin Perinatol 2009;33(1):52-65. [9] Anderson JD, Leonard D, Braner DAV, Lai S, Tegtmeyer K. Umbilical Vascular Catheterization. N Engl J Med 2008;359:e18.
[10] Narang S, Roy J, Stevens TP, Butler-O'Hara M, Mullen CA, D'Angio CT. Risk factors for umbilical venous catheter-associated thrombosis in very low birth weight infants. Pediatr Blood Cancer 2009;52(1):75-9. [11] Boo NY, Wong NC, Zulkıflı SS, Lye MS. Risk factors associated with umbilical vascular catheter-associated thrombosis in newborn infants. J Paediatr Child Health 1999;35: 460-5. [12] Loisel DB, Smith MM, MacDonald MG, Martin GR. Intravenous access in newborn infants: impact of extended umbilical venous catheter use on requirement for peripheral venous lines. J Perinatol 1996;16(6):461-6. [13] Johnson RV, Donn SM. Life span of intravenous cannulas in a neonatal intensive care unit. Am J Dis Child 1988;142(9):968-71. [14] Sheehan AM, Palange K, Rasor JS, Moran MA. Significantly improved peripheral intravenous catheter performance in neonates: insertion ease, dwell time, complication rate, and costs. J Perinatol 1992;12(4):369-76. [15] Pottecher T, Forrler M, Picardat P, Krause D, Bellocq JP, Otteni JC. Thrombogenicity of central venous catheters: prospective study of polyethylene, silicone and polyurethane catheters with phlebography or post-mortem examination. Eur J Anaesthesiol 1984;1(4):361-5. [16] Krafte-Jacobs B, Sivit CJ, Mejia R, Pollack MM. Catheter-related thrombosis in critically ill children: comparison of catheters with and without heparin bonding. J Pediatr 1995;126(1):50-4. [17] Greenberg M. Erythroblastosis treated with an exchange transfusion. Clin Proc Child Hosp Dist Columbia 1947;3(9):231-6. [18] Soe A. Central venous catherisation in newborn infants: Results of an audit. Infant 2007;3(5):172-5. [19] Barrington KJ. Umbilical artery catheters in the newborn: effects of heparin. Cochrane Database Syst Rev 2000(2):CD000507. [20] Sutor AH, Massicotte P, Leaker M, Andrew M. Heparin therapy in pediatric patients. Semin Thromb Hemost 1997;23:303-19. [21] Randolph AG, Cook DJ, Gonzales CA, Andrew M. Benefit of heparin in peripheral venous and arterial catheters: systematic review and meta-analysis of randomised controlled trials. BMJ 1998;316(7136):969-75. [22] Roy M, Turner-Gomes S, Gill G, Way C, Mernagh J, Schmidt B. Accuracy of Doppler echocardiography for the diagnosis of thrombosis associated with umbilical venous catheters. J Pediatr 2002;140:131. [23] Butler-O'Hara M, Buzzard CJ, Reubens L, McDermott MP, DiGrazio W, D'Angio CT. A randomized trial comparing long-term and short-term use of umbilical venous catheters in premature infants with birth weights of less than 1251 grams. Pediatrics 2006;118:e25. [24] Newall F, Johnston L, Ignjatovic V, Monagle P. Unfractionated heparin therapy in infants and children. Pediatrics 2009;123(3):e510-8. [25] Krishnaswamy A, Lincoff AM, Cannon CP. The use and limitations of unfractionated heparin. Crit Pathw Cardiol 2010;9(1):35-40. [26] Spadone D, Clark F, James E, Laster J, Hoch J, Silver D. Heparin-induced thrombocytopenia in the newborn. J Vasc Surg 1992;15(2):306-11 [discussion 311–312]. [27] Schlesinger AE, Braverman RM, DiPietro MA. Pictorial essay. Neonates and umbilical venous catheters: normal appearance, anomalous positions, complications, and potential aid to diagnosis. AJR 2003;180(4):1147-53. [28] Korver AM, Walther FJ, van der Molen AJ, de Beaufort AJ. Serious complications of umbilical venous catheterisation. Ned Tijdschr Geneeskd 2007;151(40):2219-23. [29] Hermansen MC, Hermansen MG. Intravascular catheter complications in the neonatal intensive care unit. Clin Perinatol 2005;32(1):141-56 [vii]. [30] Bradshaw WT, Furdon SA. A nurse's guide to early detection of umbilical venous catheter complications in infants. Adv Neonatal Care 2006;6(3):127-38. [31] Haumont D, de Beauregard VG, Van Herreweghe I, Delanghe G, Ciardelli R, Haelterman E. A new technique for transumbilical insertion of central venous silicone catheters in newborn infants. Acta Paediatr 2008;97(7):988-90. [32] Been JV, Degraeuwe PL. Pleural effusion due to intra-abdominal extravasation of parenteral nutrition. Pediatr Pulmonol 2008;43(10):1033-5. [33] Tripodi A. D-dimer testing in laboratory practice. Clin Chem 2011;57(9):1256-62. [34] Wada H, Sakuragawa N. Are fibrin-related markers useful for the diagnosis of thrombosis? Semin Thromb Hemost 2008;34(1):33-8. [35] Biss TT, Brandão LR, Kahr WH, Chan AK, Williams S. Clinical probability score and D-dimer estimation lack utility in the diagnosis of childhood pulmonary embolism. J Thromb Haemost 2009;7(10):1633-8. [36] Karagöl BS, Erdeve O, Fítöz S, Uysal Z, Atasay B, Arsan S. Does D-dimer predict cerebral sinovenous thrombosis in the newborn? Pediatr Hematol Oncol 2007;24(5):355-9. [37] Tay SP, Cheong SK, Boo NY. Elevated plasma tissue factor levels in neonates with umbilical arterial catheter-associated thrombosis. Malays J Pathol 2006;28(1): 41-8.
Contents lists available at SciVerse ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Heparin Infusion to Prevent Umbilical Venous Catheter Related Thrombosis in Neonates Sevim Unal a,⁎, Filiz Ekici b, İbrahim İlker Cetin b, Leyla Bilgin a a b
Division of Neonatology, Ankara Child Health, Hematology, Oncology, Research Hospital, Ankara, Turkey Division of Pediatric Cardiology, Ankara Child Health, Hematology, Oncology, Research Hospital, Ankara, Turkey
a r t i c l e
i n f o
Article history: Received 13 March 2012 Received in revised form 21 June 2012 Accepted 17 July 2012 Available online 16 August 2012 Keywords: Heparin Neonate Thrombosis Venous umbilical catheter
a b s t r a c t Objective: To investigate umbilical venous catheter (UVC) related thrombosis by Doppler echocardiographic evaluation of neonates infused with heparin or placebo. Methods: We conducted a prospective study to determine UVC-related thrombosis in term and nearterm neonates. Heparin or placebo (0.5 IU/mL) was infused at a rate of 1 mL/hr to the study and control group. Doppler echocardiography was performed at 1, 3, and 5 days after UVC insertion. Results: Forty-six neonates (63% males) with a mean gestational age of 38.2 ± 1.8 weeks, and a mean birth-weight of 2993 ± 563 grams were included. No UVC-related thrombosis was observed in the study group, which included 19 neonates. Among the 27 neonates in the control group, one neonate developed UVC-related thrombosis. There were no statistical differences between the groups for gestational age, birth weight, postnatal age, UVC duration, mortality, mechanical ventilation, and inotrope requirement, and hemagram or coagulation profile. The complications were as follows, mild pulmonary hemorrhage, 6.5% (3); leak-out, 4.3% (2); peritoneal leakage, 2.2% (1); occlusion, 2.2% (1); gastrointestinal findings, 6.5% (3); sepsis, 10.9% (5); and catheter-related thrombosis, 2.2% (1). Conclusion: This study demonstrated that heparin infusion of 0.5 IU/mL through the UVC had no effect on catheter-related thrombosis in term and near-term neonates. Randomized controlled trials are necessary to conclusively evaluate the effect of heparin on UVC-related thrombosis. Published by Elsevier Ltd.
Introduction Vascular access is a major challenge in the management of neonates in the neonatal intensive care unit (NICU). Peripheral intravenous lines (PIVs), percutaneous central venous catheters, and umbilical venous catheters (UVCs) are most often used to establish venous access in newborns [1–11]. The peripheral veins of a neonate are small and friable, can be difficult to cannulate, and are easily injured by irritating fluids and medications [12]. The dwell time of PIVs can be short [13,14]. Therefore, UVCs can be used to deal with these difficulties. After birth, the umbilical vein provides an ideal, secure, and rapid catheter access. Umbilical vein catheterization within the first hours of life is a relatively easy procedure with a high success rate and the catheter can be left in place for up to 14 days with a low risk of complications. UVCs have been widely used in critically ill neonates for the urgent administration of resuscitation drugs and intravenous infusions [hypertonic dextrose solution, total parenteral nutrition (TPN), inotropes,
⁎ Corresponding author at: Çukurambar Mah, 39. Cadde, 444. sokak, 17/5, Yüzüncüyıl, Ankara, Turkey. Tel.: +90 312 5969730; fax: +90 312 3472330. E-mail address: [email protected] (S. Unal). 0049-3848/$ – see front matter. Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.thromres.2012.07.018
blood products, sodium bicarbonate and various other medications], blood sampling, exchange transfusion and invasive monitoring [1–11]. Despite their value in infant care, UVCs may cause serious mechanical, infectious and thrombotic complications [10,11]. Several factors may play role in neonates with increased risk of thrombosis together with the newborn's decreased ability to inhibit thrombin and relatively deficient fibrinolysis. Congenital risk factors include deficiency of natural anticoagulants (AT III, Proteins C and S), elevated lipoprotein (a) levels, Factor V Leiden mutation, prothrombin gene mutations, and hyperhomocysteinemia. Acquired risk factors include indwelling catheters, dehydration, polycythemia, asphyxia, septicemia, maternal diabetes, maternal preeclampsia, being small for gestational age (SGA), thrombocytosis, and extracorporeal membranous oxygenation. Factors that have been associated with initiation and progression of catheter-related thrombosis include endothelial damage during catheter placement, disrupted blood flow, vascular occlusion, low flow states, turbulent flow, patient and infusate characteristics, catheter composition, underlying medical conditions, duration of catheterization, infusion of substances that damage endothelial cells such as TPN, thrombogenic catheter materials, and placement of an umbilical arterial catheter (UAC) together with a venous catheter [4–8,15,16].
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There is no consensus on heparin infusion or the optimal dose of heparin administered through the UVC to prevent catheter-related thrombosis [1–11]. In this study, we aimed to assess the effects of heparin infusion with a concentration of 0.5 IU/mL at a rate of 1 mL/hr through UVC in term and near-term neonates in a prospective controlled trial. We hypothesized that the frequency of catheter-related thrombosis would be lower in neonates with heparin infusion than that of neonates without heparin. We also investigated the relation between catheter-related thrombosis and coagulation profile.
Methods We conducted a prospective controlled study to investigate asymptomatic thrombosis associated with an indwelling single lumen polyurethane UVC in term and near-term neonates (gestational age ≥ 35 weeks). We also aimed to evaluate the relation between prothrombin time (PT), partial thromboplastin time (PTT), and D-dimer levels and catheter-related thrombosis. The study was performed throughout 2010 in the NICU of our hospital. Term and near-term neonates with inserted UVCs were included in the study. These neonates were divided into two groups; the study group was infused with heparin and the control group was infused with placebo through an UVC. The medical team was blinded to the study group allocation. The neonates in the heparin group were infused with unfractionated heparin of 0.5 IU/mL in saline via an infusion pump at a rate of 1 mL/hr. Neonates in the placebo group received saline at the same rate as the heparin infusion. All neonates were monitored for coagulation profile and hemogram prior to insertion of UVC. The clinical findings and laboratory results of the neonates were recorded. Catheter placement was performed in the NICU by a pediatrician who was blinded to the study groups. The umbilical stump and the surrounding skin were cleaned with a solution containing iodine, and a systemic sedative (midazolam) was infused to the neonate. The catheter (polyurethane, single lumen 5F or 8F diameter, Vygon catheter) was inserted under sterile conditions. The catheter tip was placed at the inferior vena cava-right atrial junction, and the catheter was sutured to the umbilical cord and taped to the abdomen. A plain abdominal radiograph was obtained to determine the positioning of the catheter. The catheter was connected to an infusion pump, and the entire system was changed every 24 hours. In this way, catheter care was standardized. Doppler echocardiographic [Vivid-7 Pro (GE) with using 7F probe] examinations were performed at the bedside by the same pediatric cardiologist at 1, 3, and 5 days after catheter insertion. The neonates were also evaluated after the removal of the catheters. All patients were monitored for catheter occlusion, defined as an inability to infuse fluid; catheter-related sepsis, defined as symptoms and signs suggestive of sepsis with a positive culture obtained from a normally sterile site (blood, urine, or cerebrospinal fluid) and the catheter for the same microorganism; thrombosis, defined as detection of a thrombus at the catheter tip or heart using Doppler echocardiography; arrhythmia; hemorrhage; and heparin-induced thrombocytopenia (HIT), defined as a platelet count b50,000/mm3 after exclusion of other causes. Local ethical committee approval was obtained, and the parents or guardians of all participating subjects signed a consent form indicating their agreement to take part and to allow the results to be published. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS 13.0). A non-parametric test was used to analyze the effects of heparin infusion on catheter-related thrombosis. The Mann–Whitney U test was used to evaluate the interaction between catheter-related thrombosis and risk factors in the groups. Two-tailed P values b 0.05 were considered statistically significant for all analyses.
Results Among 911 hospitalized neonates, UVCs were inserted in 46 term and near-term neonates (5.1%) throughout 2010, and these infants were included in the study. They were followed-up by Doppler echocardiography for catheter-related thrombosis. In addition to UVC, UACs were inserted into two neonates. Demographic characteristics and clinical findings of the infants are summarized in Table 1. Doppler echocardiography was performed at 24, 72, and 120 hours after UVC insertion for 100%, 91.3% (n = 42), and 59.5% (n = 25) of the catheterized patients, respectively. The decrement in the rates was due to the removal of the UVC in some infants, because a central line was no longer needed. All neonates were reevaluated after the removal of the catheters. The diagnoses of the neonates and indications for UVC insertion are shown in Table 2. The results of laboratory analyses of the infants are shown in Table 3. The percentage of UVCs, which resulted in one or more complications, was 15.2%. Complications included mild pulmonary hemorrhage in 6.5% (3), vascular leakage in 4.3% (2), peritoneal leakage in 2.2% (1), mechanical obstruction in 2.2% (1), gastrointestinal findings resembling necrotizing enterocolitis in 6.5% (3), catheter-related sepsis in 10.9% (5), and catheter-related thrombosis in 2.2% (1) of the neonates. One neonate with severe perinatal asphyxia, disseminated intravascular coagulation (DIC) and multiorgan failure developed central nervous system hemorrhage, considered to be secondary to the underlying diseases. One neonate had mild pulmonary hemorrhage that was assumed to be due to heparin infusion. We removed the catheter because of suspected infection in 3 (6.5%) neonates. Arrhythmia was not recorded in any of the patients.
Table 1 Demographic characteristics and outcomes of the neonates in the study. Factor Female/male ratio Postnatal age (days), mean ± SD (range) Gestation (weeks), mean ± SD (range) Birth weight (g), mean ± SD (range) Maternal age (years), mean ± SD (range) Apgar at 5 minutes, mean ± SD (range) Delivery, n (%) Spontaneous vaginal Cesarean section UVC duration (hours), mean ± SD (range) Mechanical ventilation, n (%) Perinatal asphyxia, n (%) Catheter-related thrombosis, n (%) Inotropic therapy requirement, n (%) Single drug Two or more drugs Congenital heart disorders, n (%) Sepsis ± pneumonia, n (%) Pulmonary hypertension, n (%) Mild Severe Mortality, n (%)
Group 1 (Heparin)
Group 2 (Control)
0.46 (6/13) 5.2 ± 5.6 (0.0-19)
0.69 (11/16) 4.3 ± 3.6 (0.3-15)
37.9 ± 1.9 (35–41)
38.5 ± 1.7 (35–41)
3,087 ± 541 (2,270-4,070)
2,927 ± 545 (1,700-4,250)
28.2 ± 6.9 (18–45)
28.4 ± 5.6 (19–37)
7.5 ± 2.3 (2–10)
6 (31.6%) 13 (68.4%) 131.7 ± 67.5 (70–340)
7.8 ± 2 (3–10)
11 (40.7%) 16 (59.3%) 125.1 ± 85.8 (24–288)
13 (68.4%)
17 (63%)
8 (42.1%)
10 (37%)
0 (0%)
8 (42.1%) 4 (21.1%) 5 (26.3%) 9 (47.4%)
1 (5.3%) 2 (10.5%) 5 (26.3%)
* SD: standard deviation, UVC: umbilical venous catheter.
1 (3.8%)
9 (33.3%) 7 (25.9%) 8 (29.6%) 10 (37%)
5 (18.5%) 4 (14.8%) 7 (25.9%)
S. Unal et al. / Thrombosis Research 130 (2012) 725–728 Table 2 The diagnoses of neonates and indications for umbilical venous catheter insertion. Diagnosis (indications for UVC)
n (%)
Indirect hyperbilirubinemia (exchange transfusion) Congenital heart disease (shock, hypoxia) Coarctation or interruption of aorta Pulmonary atresia Perinatal asphyxia, MODS, HIE (respiratory failure) Neonatal pneumonia (respiratory failure) Persistent pulmonary hypertension (respiratory failure) Persistent hypoglycemia±hyperinsulinemia (venous access) Multiple congenital anomalies, syndrome (respiratory failure) Anomalies of respiratory tract (respiratory failure) Down syndrome, transient myeloproliferative disorder (respiratory failure and exchange transfusion) Epidermolysis bullosa (venous access) Total
12 (26.1%) 6 (13%) 2 (4.3%) 6 (13%) 5 (10.9%) 4 (8.7%) 3 (6.5%) 4 (8.7%) 2 (4.3%) 1 (2.2%) 1 (2.2%) 46 (100%)
* UVC: umbilical venous catheter, MODS: multi-organ dysfunction syndrome, HIE: hypoxic ischemic encephalopathy.
There were no differences between the groups regarding the hemoglobin, hematocrit, PT, PTT, international normalized ratio (INR), or D-dimer levels. The platelet counts in the study group were lower than that in the control group (p b 0.05), but none of the infants had platelet counts lower than 100.000 mm 3. Among neonates included in the study, only one neonate developed catheter-related thrombosis in the control group, but no thrombosis was observed in the study group. The mortality rate was 26.1% (n = 12) with similar rates in the groups. Discussion The placement of a UVC was first reported in 1947 for an exchange transfusion in the treatment of severe indirect hyperbilirubinemia in an infant with erythroblastosis fetalis [17]. The use of UVC is now common in the care of premature and term neonates with illness requiring treatment in the NICU (especially in as many as 50% of very low birth weight infants) [1–8]. Catheter placement rates vary from institution to institution and according to patient weight, ranging from 9% in infants over 2,000 g and above 50% in infants under 1,000 g [10]. In our NICU, a UVC placed in 5.1% of term and near-term neonates during 2010. The low UVC placement rate in our NICU compared to that reported in the literature might be due to the absence of a maternity department in our hospital. We used UVC mainly for drawing blood samples and administering fluid in patients with hypoxia and respiratory failure (Table 2). The second most common indication for UVC placement was exchange transfusion (27.3%) to eliminate indirect bilirubin from the circulation. UVC was also used for secure and easy vascular access in neonates with persistent hypoglycemia and epidermolysis bullosa. The prevention of catheter occlusion under continuous infusion of heparin through central catheters and the effect of such heparin infusion on the occurrence of thrombosis has not been fully determined. Soe suggested that heparin use reduces the incidence of catheter occlusion and increases the life span of the catheter [18]. In a systematic review, Barrington documented that heparin infusion was effective in improving Table 3 Results of laboratory investigations. Test
Group 1
Group 2
Hemoglobin (g/dL) Hematocrit (%) Platelet count (×109/L) Prothrombin time (PT) (s) Partial thromboplastin time (PTT) (s) International normalized ratio (INR) D-dimer (nmol/L)
15.6 ± 2.5 45.4 ± 7.5 224.4 ± 133.7 29.9 ± 42.8 46.7 ± 38.7 1.55 ± 0.69 2,267.7 ± 2,026.6
16.8 ± 3.3 49.2 ± 9.7 178.3 ± 121.5 35.1 ± 39.6 84.1 ± 95.2 2.07 ± 1.09 1,582 ± 1913
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UAC patency in neonates, with no statistically significant evidence of adverse outcomes [19]. Currently, there are no definitive recommendations for thromboprophylaxis in children, infants, and neonates. In a meta-analysis, heparin administration was deemed to be possibly effective and was recommended to prevent UVC-related thrombosis [20]. However, many questions about heparinization remain open. In a systematic review involving subjects of different age groups including neonates, Randolph et al. found that heparin (administered intermittently or as a continuous infusion) was effective in the prevention of peripheral arterial catheter complications but not for venous catheter complications [21]. We used continuous heparin infusion at a concentration of 0.5 IU/ml and a rate of 1 ml/hr through the UVC. This method had no significant effect on catheter-related thrombosis. Currently, only a few clinics use screening protocols for at-risk neonates, and most thrombi are detected only after clinical suspicion or by chance. Thrombi are usually visualized by ultrasonography (with or without Doppler technique) or angiography [5,6,10,11]. Roy et al. suggested that Doppler echocardiography was not adequate in the infants diagnosing asymptomatic UVC-related thrombosis [22]. He showed that the rate of venographically confirmed thrombosis (30%) was higher than that reported in the previously published studies in which the diagnosis was based on echocardiography (1.8–13%). However, Narang et al., in their study investigating the risk factors associated with catheter related thrombosis, used echocardiography to determine thrombosis even in very low birth weight (VLBW) infants [10]. Butler-O'Hara et al. also used echocardiography in their study to diagnose catheter-associated thrombosis in VLBW infants [23]. Currently, echocardiography is considered as the gold standard method to define catheter-related thrombosis in neonates [10]. In the current study, we used serial Doppler echocardiography to screen neonates for thrombosis. Among the 46 term and near-tem neonates, catheter-related thrombosis was determined in only one neonate from the control group. We considered echocardiography to be an easy, non-invasive, and low-cost method to determine umbilical catheter-related thrombosis, compared to angiography. The benefits of using heparin have to be weighed against the risks involved. All possible side effects of heparin (allergic reactions, bleeding, disturbance of coagulation parameters, HIT, influence on bone structure, etc.) have been carefully studied in neonates [24,25]. Besides complications due to dosing errors, the occurrence of HIT, which has been described in 3% of patients exposed to heparin, should be kept in mind [26]. Furthermore, the stability of heparin in mixed solutions is questionable, and precipitation with other molecules in solution may occur, leading to inactivation of the anticoagulant [24,25]. We observed mild pulmonary hemorrhage in three neonates (6.8%), but no other side effect was observed. Potential complications related to UVC placement include malposition, dislodgement, vascular leakage, hemorrhage, thromboembolism, sepsis, air embolism, vasospasm, portal vein thrombosis and portal hypertension. Furthermore, if the UVC tip lies within the cardiac chambers, myocardial perforation, vessel perforation, pericardial effusion, cardiac tamponade, pleural effusion, endocarditis and arrhythmias have also been reported. Gastrointestinal, hepatic, renal, and limb tissue damages, as well as ascites, hydrothorax, and erosion of the atrium or ventricle have also been described in the literature. The main factors influencing the risks due to UVC placement include the procedure for UVC insertion, the location, size, composition, and care of the catheter, the number of manipulations, the types and contents of parenteral solutions, and medications, the dwelling time, and the education and training of health care providers [27–30]. In this study, complications due to UVC were peritoneal leakage (2.3%), catheter occlusion (2.3%), gastrointestinal findings (6.8%), catheter-related sepsis (10.9%), and catheter-related thrombosis (2.3%); and 84.8% of the UVCs were free of complications. Haumont et al. reported umbilical and percutaneous silicone venous catheter complications as thrombosis (1.2%), catheter-related sepsis (3.5%), and mechanical obstruction (5%) [31]. They reported a total
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complication rate of 27% in infants treated with UVCs, and in some infants more than one complication was noted. Peritoneal leakage observed in one neonate in their study was assumed to be secondary to vessel perforation. Umbilical vein perforation and leakage of fluid into the peritoneal cavity has rarely been reported in the literature [32]. We observed peritoneal leakage in one neonate in this present study. Additionally, our rate of infection related to UVC placement (10.9%) was higher compared with published data, ranging from 3% to 16%. Thus, our practice should be reviewed in relation to the tip position, heparin use, and other aspects regarding sterility. D-dimer is a reliable and sensitive index of fibrin deposition and stabilization. As such, its higher levels in plasma should be indicative of thrombus formation. Plasma D-dimer levels have been shown to be sensitive for the diagnosis of deep venous thrombosis and pulmonary embolism in adults [33]. Furthermore, very high D-dimer levels may be observed in conditions such as massive bleeding, cardiopulmonary resuscitation, sepsis with DIC, multiple traumatic injuries, hyperfibrinolysis, and HELLP syndrome [33,34]. There are few data about the relationship between venous thrombosis and D-dimer levels in childhood, especially in the neonatal period [35–37]. We suggested high D-dimer levels would be indicative of UVC-related thrombosis in neonates, but we could not establish a significant relation between D-dimer levels and UVC-associated thrombosis. In conclusion, no significant differences in the incidence of thrombosis, occlusion, sepsis, mortality, and duration of catheter patency were observed with heparin infusion at the dose used in this study. On the basis of our results with small sample size, routine use of heparin to prevent UVC-related thrombosis cannot be recommended. Randomized controlled trials are necessary to conclusively determine the benefits and risks of continuous heparin infusion through UVC in neonates. Conflict of interest statement The authors have no conflict of interest. References [1] Shah PS, Shah VS. Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters. Cochrane Database Syst Rev 2008;16(2):CD002772. [2] Shah PS, Kalyn A, Satodia P, Dunn MS, Parvez B, Daneman A, et al. A randomized controlled trial of heparin versus placebo infusion to prolong the usability of peripherally placed percutaneous central venous catheters (PCVCs) in neonates. The HIP (Heparin Infusion for PCVC) study. Pediatrics 2007;119(1):e284-91. [3] Seth T. Thrombosis in neonates and children. East J Med 2009;14:36-45. [4] Saxena R, Kannan M, Choudhry VP. Neonatal thrombosis. Indian J Pediatr 2003;70(11): 903-7. [5] Veldman A, Nold MF, Michel-Behnke I. Thrombosis in the critically ill neonate: incidence, diagnosis, and management. Vasc Health Risk Manag 2008;4(6):1337-48. [6] van Elteren HA, Veld H. ST, Te Pas AB, Roest AAW, Smiers FJ, Kollen WJ, Sramek A, Walther FJ, Lopriore E. Management and outcome in 32 neonates with thrombotic events. Int. J Pediatr 2011;2011:217564. [7] Manco-Johnson MJ, Nuss R. Neonatal Thrombotic Disorders. NeoReviews 2000;1: e201-5. [8] Saxonhouse MA, Manco-Johnson MJ. The evaluation and management of neonatal coagulation disorders. Semin Perinatol 2009;33(1):52-65. [9] Anderson JD, Leonard D, Braner DAV, Lai S, Tegtmeyer K. Umbilical Vascular Catheterization. N Engl J Med 2008;359:e18.
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