Eur J Pediatr DOI 10.1007/s00431-014-2325-3

SHORT COMMUNICATION

The effect of inhaled nitric oxide therapy on thromboelastogram in newborns with persistent pulmonary hypertension Sema Tanriverdi & Ozge Altun Koroglu & Ozgun Uygur & Can Balkan & Mehmet Yalaz & Nilgun Kultursay

Received: 2 February 2014 / Revised: 16 April 2014 / Accepted: 17 April 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Studies about the effects of inhaled nitric oxide (iNO) on bleeding time and platelet aggregation in newborns are limited in number and have inconclusive results. Thromboelastogram (TEG) shows the combined effects of coagulation factors and platelet functions. In this preliminary study, we aimed to evaluate the effects of iNO on coagulation using TEG in newborns with persistent pulmonary hypertension (PPH). TEG assays were performed in 10 term infants receiving iNO treatment for PPH and 32 healthy term infants. Samples of the iNO group were collected before and during iNO. Clot reaction time (R), clot kinetics (K), maximum amplitude (MA), and alpha angle were obtained from the TEG tracing. TEG-R values were statistically higher during iNO treatment (7.75±3.34) when compared to the values before iNO (4.83±1.38) and the healthy controls (3.75± 0.98). The alpha angle was lower in iNO treated infants at both periods (before iNO, 55.33±8.58; during iNO, 42.90± Communicated by Patrick Van Reempts S. Tanriverdi : O. A. Koroglu : O. Uygur : M. Yalaz (*) : N. Kultursay Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Ege University, Bornova 35100, Izmir, Turkey e-mail: [email protected] S. Tanriverdi e-mail: [email protected]

18.34) compared to the control group (64.95±6.88). MA values before iNO treatment were the lowest (44.43±14.09) and improved with the iNO treatment (48.40±9.49) despite still being lower compared to the controls (53.67±5.56). Conclusion: Both PPH and iNO may negatively effect in vitro coagulation tests. Therefore, newborns with PPH requiring iNO treatment should be closely monitored for coagulation problems. Keywords Nitric oxide . Newborn . Thromboelastogram . Coagulation . Pulmonary hypertension Abbreviations APTT TEG-α angle TEG-K GP iNO MA NO PPH PT TEG-R TEG

Activated partial thromboplastin time Alpha angle Clot kinetics Glycoprotein Inhaled nitric oxide Maximum amplitude Nitric oxide Persistent pulmonary hypertension Prothrombin time Reaction time Thromboelastogram

O. A. Koroglu e-mail: [email protected] O. Uygur e-mail: [email protected]

Introduction

N. Kultursay e-mail: [email protected]

Inhaled nitric oxide (iNO), a selective pulmonary vasodilator, has been used to treat neonatal hypoxemic respiratory failure and pulmonary hypertension. Regulatory approval was granted for its use in infants ≥34 weeks gestation in the USA in 1999 and in Europe in 2001. However, in recent years, iNO use has been increased in both term and preterm

C. Balkan Division of Pediatric Hematology, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey e-mail: [email protected]

Eur J Pediatr

infants with severe hypoxemic respiratory failure with various underlying etiologies [4]. Physiological platelet aggregation requires the activation of the fibrinogen-specific receptor molecule glycoprotein (GP) IIb/IIIa. This GP IIb/IIIa activation has been reported to be reduced and even reversed by exposure to nitric oxide (NO) donors in vitro [10]. Platelet adhesion and aggregation have been shown to be inhibited by NO, whereas disaggregation of platelet aggregates is stimulated [2]. Clinical studies have demonstrated prolonged bleeding time and impaired platelet aggregation during iNO treatment in healthy and critically ill adults [6, 7]. In newborns, Keh et al. [10] stated that total GPIIb/IIIa activation was less, and the inhibiting effect of NO in neonatal platelets results in a less GPIIb/IIIa activation. Also, transient age-dependent platelet hyporeactivity, due to an intrinsic defect in receptor expression in newborns resulting in prolonged bleeding time during iNO treatment, causes an additional risk [6]. The effects of iNO on platelet functions and coagulation cascade in newborns are not clearly stated in the current literature and warrant further research. As the first-line tests for evaluation of coagulation, prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen levels are commonly used in NICUs. Thromboelastogram (TEG), first described by Hartert [8], gives information about the whole coagulation cascade showing the combined effects of coagulation factors and platelet functions and informs about the fibrinolytic activity. It evaluates the efficiency of the clot formation besides the clot’s viscoelastic properties [14]. TEG defines a curve comprised by the measurement of the viscoelastic changes related with fibrine polymerization, and this test draws a graphic showing the clot formation [11]. In the last decade, the application of TEG among adults has been well described, but its practice in the pediatric population, especially in neonates, is limited. TEG seems reliable in detecting neonatal sepsis besides showing the effects of hypothermia and adult platelet transfusion in neonates [12]. The aim of this study is to investigate cumulative effects of iNO treatment on coagulation system and platelet functions in newborns with persistent pulmonary hypertension (PPH).

Materials and methods Blood samples were collected from 10 term infants who were hospitalized at the Ege University Children’s Hospital neonatal intensive care unit and received iNO treatment for PPH and from 32 healthy term infants. Ethics committee approved the study (May 17, 2012, 12-4.1/5), and informed consent was granted from the parents of study infants. According to unit policy, iNO therapy is started to PPH patients with relevant clinical symptomatology, when

pulmonary artery pressure measured by echocardiography exceeds 45 mmHg and oxygenation index is higher than 25. The starting dose of iNO is 20 ppm which is gradually weaned to 5 ppm as the patient improves. Plasma samples were collected into a polyethylene tube containing sodium citrate as an anticoagulant from the iNO groups before the iNO treatment and at the end of the first hour of the treatment after lowering iNO dose to 5 ppm. TEG analyses were performed with an automatic device (Haemoscope®, IL, USA), and the parameters from the TEG tracing include four fundamental variables: clot reaction time (R) (minute), clot kinetics (K, time from clot formation to time amplitude reaches 20 mm) (minute), maximum amplitude (MA, amplitude measured at the widest point of TEG tracing) (millimeter), and alpha angle (α, is formed by the slope from the R value to the K value representing the acceleration of fibrin build-up and cross-linking (degree) [12]. PT, APTT, international normalized ratio (INR), and fibrinogen levels were also measured. Samples for PT, PTT, INR, and fibrinogen were anticoagulated with sodium citrate.

Statistical analysis Data were analyzed by Statistical Package for the Social Sciences (SPSS) for Windows 19.0. Values were reported as mean and SD. Mann-Whitney U test and chi-square tests were used, and p values of

The effect of inhaled nitric oxide therapy on thromboelastogram in newborns with persistent pulmonary hypertension.

Studies about the effects of inhaled nitric oxide (iNO) on bleeding time and platelet aggregation in newborns are limited in number and have inconclus...
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