Pediatric Pulmonology
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Hasan Kahveci, MD,1* Osman Yilmaz, MD,2 Ummu Zeynep Avsar, MD,3 Murat Ciftel, Omer Kilic, MD,4 Fuat Laloglu, MD,5 and Kezban Ozturk, MD6
2 MD,
Summary. Objective: This study was performed to examine the effectiveness and safety of oral sildenafil and inhaled iloprost in term newborns with persistent pulmonary hypertension of the newborn (PPHN). Patients and Methods: Oral sildenafil and inhaled iloprost were administered to 27 and 20 neonates, respectively, for treatment of persistent pulmonary hypertension. All patients were term infants at 37 gestational weeks or older. In the sildenafil group, 14 patients had meconium aspiration syndrome, 8 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, 1 had transient tachypnea, and 1 had idiopathic PPHN. In the iloprost group, 9 patients had meconium aspiration syndrome, 7 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, and 1 had transient tachypnea. Sildenafil citrate was administered via an oral feeding tube. Iloprost was administered endotracheally to patients on mechanical ventilation using a jet nebulizer. Results: Iloprost appeared to be more effective than sildenafil in the treatment of PPHN with regard to time to adequate clinical response, ventilatory parameters, duration of drug administration, duration of mechanical ventilation, duration of return to normal values of respiratory failure indices, use of MgSO4 as a second vasodilator and requirement for support with inotropic agents. We observed no side effects on blood pressure or homeostasis in any of the patients in the iloprost group. Systemic hypotension was significantly elevated in the sildenafil group. Four and three infants died of PPHN in the sildenafil and iloprost groups, respectively. Pulmonary systolic arterial pressure decreased to normal levels in the remaining 40 patients, and they were discharged from hospital. Conclusion: We suggested that inhaled iloprost may be a safe and effective treatment choice in newborn infants with persistent pulmonary hypertension. In cases where treatment with inhaled iloprost, ECMO or INO is not possible, oral sildenafil can be an alternative therapy option in the ß 2014 Wiley Periodicals, Inc. treatment of PPHN. Pediatr Pulmonol. Key words: iloprost; sildenafil; pulmonary hypertension; newborn.
1
Division of Neonatal Intensive Care Unit, Erzurum District Training and Research Hospital, Erzurum, Turkey.
2
Division of Pediatric Cardiology, Erzurum District Training and Research Hospital, Erzurum, Turkey.
3
Department of Medical Education, Ataturk University Medical Faculty, Erzurum, Turkey.
4
Division of Pediatric Infectious Diseases, Erzurum District Training and Research Hospital, Erzurum, Turkey.
5
Division of Neonatal Intensive Care Unit, Nenehatun Obstetrics and Gynecology Hospital, Erzurum, Turkey.
6
Department of Pediatrics, Erzurum District Training and Research Hospital, Erzurum, Turkey.
Conflict of interest: None.
Correspondence to: Hasan Kahveci, MD, Division of Neonatal Intensive Care Unit, Erzurum District Training and Research Hospital, Erzurum, Turkey. E-mail: [email protected] Received 28 June 2013; Accepted 30 November 2013. DOI 10.1002/ppul.22985 Published online in Wiley Online Library (wileyonlinelibrary.com).
ß 2014 Wiley Periodicals, Inc.
2
Kahveci et al.
INTRODUCTION
Persistent pulmonary hypertension of the newborn (PPHN) is defined as failure of the pulmonary vasculature to relax at birth and consequent failure of normal adaptation of the fetal heart/lung system to extrauterine life.1,2 In the early postnatal period, failure to reduce pulmonary resistance and suprasystemic pressure causes intrapulmonary and extrapulmonary right-to-left shunting of blood through the ductus arteriosus and/or foramen ovale.3 This leads to marked systemic arterial hypoxemia, respiratory acidosis, and marked cyanosis due to the shunting of deoxygenated blood to the systemic circulation. In infants with PPHN, a 10-fold decrease in pulmonary blood flow increases the hypoxemia because of reduced pulmonary perfusion, and affected patients can develop myocardial failure secondary to oxygen depletion due to increased right ventricular overload.1–7 Although studies from developed countries have reported a PPHN incidence rate of 0.46–6.8/1,000 live births with a mortality rate of 10%–20%, the incidence is thought to be much higher in developing countries.1,2,7 Survivors have high morbidity in the form of neurodevelopmental and audiological impairments, cognitive delays, and hearing loss, and experience a high rate of rehospitalization.6 The main pathophysiological event in PPHN is failure of postnatal adaptation of the fetal cardiopulmonary system with failure of pulmonary vascular bed relaxation.1,2 The principal goal of PPHN treatment is to overcome this failure of the pulmonary vascular bed to relax. Therefore, various therapeutic methods have been used to treat PPHN, including ventilation strategies such as high-frequency oscillatory ventilation (HFOV) and extracorporeal membrane oxygenation (ECMO); pulmonary vasodilators such as magnesium sulfate (MgSO4), sildenafil, adenosine, prostacyclin, tolazolin, and L-arginine; specific agents such as inhaled nitric oxide (INO), bosentan, and synthetic prostacyclin analogs such as inhaled iloprost.2,4–8 Although INO and ECMO are the established agents for PPHN therapy, they are expensive therapeutic modalities associated with technical and economic difficulties in developing countries. Therefore, alternative treatments for PPHN have been evaluated over the past two decades.8 The present clinical study compared the effectiveness and safety of oral sildenafil and inhaled iloprost therapy in newborns with persistent pulmonary hypertension in a referral center in a low-income region of Turkey. MATERIALS AND METHODS
This was a retrospective comparative study, and the data were obtained from the PPHN follow-up protocol form present in patients’ files and used in the neonatal intensive care unit (NICU). Written consents were Pediatric Pulmonology
obtained from the families of all the investigated neonates, and the study protocol was approved by the ethics committee of the Erzurum District Training and Research Hospital. Between September 2007 and January 2012, a total of 47 patients diagnosed with PPHN at the NICU of Erzurum Nenehatun Obstetrics and Gynecology State Hospital in Turkey were analyzed. This hospital is one of the largest perinatal referral centers in Eastern Anatolia, with approximately 8,500 births annually. The most severely affected neonatal patients are transferred from 12 provinces, and approximately 2,500 sick infants are accepted at this NICU each year. All patients were full-term. PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital. When we had iloprost available, we gave iloprost only; when we had no iloprost, we gave oral sildenafil. In the sildenafil group, 14 patients had meconium aspiration syndrome, 8 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, 1 had transient tachypnea, and 1 had idiopathic PPHN. In the iloprost group, 9 patients had meconium aspiration syndrome, 7 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, and 1 had transient tachypnea (Table 1). Eligible neonates were term newborns with hypoxemic respiratory failure and echocardiographic evidence of PPHN. The study entry criteria were systolic pulmonary artery pressure (SPAP) 40 mmHg, oxygenation index (OI) 25, and the need for mechanical ventilation. The exclusion criteria were congenital diaphragmatic hernias, lethal congenital anomalies, congenital heart disease, substantial bleeding diathesis, massive intracranial hemorrhage, and/or intraventricular hemorrhage, multiorgan failure before starting the PPHN treatment, premature birth, and pulmonary hemorrhage due to patent ductus arteriosus. The gestational ages of infants were determinated based on the history of the last menstrual period of their mothers, intrauterine ultrasound measurements, and the New Ballard scores of infants. PPHN was diagnosed by a combination of a full medical history, physical examination, laboratory tests, chest X-ray, blood gas analysis, and echocardiography. PPHN was suspected based on a history of asphyxia and meconium aspiration, respiratory distress, central cyanosis, differential cyanosis, lung parenchymal disease diagnosed by chest X-ray, congenital pneumonia, clinical deterioration, and OI 25 despite ventilator support. The OI, alveolar–arterial oxygen difference (A–aDO2), and arterial/alveolar oxygen ratio (a/AO2) were analyzed in all patients. The difference between the partial arterial oxygen pressure of preductal and postductal blood samples was examined and hyperoxia tests were carried out. The diagnosis of PPHN was confirmed by suprasystemic pulmonary arterial pressure and atrial or ductal right-to-left or
Sildenafil and Iloprost in the Treatment of PH
3
TABLE 1— Baseline Characteristics of Infants With PPHN Treated With Oral Sildenafil and Inhaled Iloprost Variables Gender, male/female Mean gestational age SD (weeks) Mean birth weight SD (g) Mode of delivery, n (%) Caesarean section Vaginal Underlying diagnosis, n (%) MAS Asphyxia (HIE grades II and III) Pneumonia Transient tachypnea Idiopathic
Sildenafil group (n ¼ 27)
Iloprost group (n ¼ 20)
P-value
14/13 39.23 0.9 3328.17 643
12/8 39.89 1.1 3311.6 639.5
0.821 0.631 0.911
17 (63) 10 (37)
13 (65) 7 (35)
0.872 0.612
14 (51.9) 8 (29.6) 3 (11.1) 1 (3.7) 1 (3.7)
9 7 3 1
(45) (35) (15) (5) —
0.762 0.32 0.672 0.82 NA
MAS, meconium aspiration syndrome; HIE, hypoxic ischemic encephalopathy; PPHN, persistent pulmonary hypertension of the newborn. 1 Student t-test. 2 Chi-Square test.
bidirectional shunting on color Doppler examination with no structural cardiac anomalies to explain these findings on echocardiography. Pulmonary pressure was determined by echocardiography. The pressure difference between the right ventricle and the right atrium was measured using a tricuspid regurgitation jet, and the estimated right atrial pressure of 5 mmHg was added to obtain the systolic pulmonary artery pressure. Iloprost (Ilomedin1; Schering AG, Berlin, Germany) was administered by inhalation using a jet nebulizer (CX3, NE-V16/EN1; Omron, Hoofddorp, The Netherlands) at doses of 1–2.5 mg/kg with an interval of 2–4 hr between doses for all patients as recommended in the literature.9–11 In intubated patients, the jet nebulizer was adapted to the respiratory circuit with a T-connector so that iloprost could be administered endotracheally. The calculated dose was diluted with 1 ml of isotonic sodium chloride and administered after 10 min. A 25-mg tablet of sildenafil was diluted with 25 ml of sterile water to achieve a final concentration of 1 mg/ml. One dose of the solution (0.5 mg/kg) was given via an orogastric tube every 6 hr.8 If the OI did not improve, the dose could be doubled until a maximum of 2 mg/kg was reached. The dose of sildenafil was tapered by 50% after reaching OI
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Hasan Kahveci, MD,1* Osman Yilmaz, MD,2 Ummu Zeynep Avsar, MD,3 Murat Ciftel, Omer Kilic, MD,4 Fuat Laloglu, MD,5 and Kezban Ozturk, MD6
2 MD,
Summary. Objective: This study was performed to examine the effectiveness and safety of oral sildenafil and inhaled iloprost in term newborns with persistent pulmonary hypertension of the newborn (PPHN). Patients and Methods: Oral sildenafil and inhaled iloprost were administered to 27 and 20 neonates, respectively, for treatment of persistent pulmonary hypertension. All patients were term infants at 37 gestational weeks or older. In the sildenafil group, 14 patients had meconium aspiration syndrome, 8 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, 1 had transient tachypnea, and 1 had idiopathic PPHN. In the iloprost group, 9 patients had meconium aspiration syndrome, 7 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, and 1 had transient tachypnea. Sildenafil citrate was administered via an oral feeding tube. Iloprost was administered endotracheally to patients on mechanical ventilation using a jet nebulizer. Results: Iloprost appeared to be more effective than sildenafil in the treatment of PPHN with regard to time to adequate clinical response, ventilatory parameters, duration of drug administration, duration of mechanical ventilation, duration of return to normal values of respiratory failure indices, use of MgSO4 as a second vasodilator and requirement for support with inotropic agents. We observed no side effects on blood pressure or homeostasis in any of the patients in the iloprost group. Systemic hypotension was significantly elevated in the sildenafil group. Four and three infants died of PPHN in the sildenafil and iloprost groups, respectively. Pulmonary systolic arterial pressure decreased to normal levels in the remaining 40 patients, and they were discharged from hospital. Conclusion: We suggested that inhaled iloprost may be a safe and effective treatment choice in newborn infants with persistent pulmonary hypertension. In cases where treatment with inhaled iloprost, ECMO or INO is not possible, oral sildenafil can be an alternative therapy option in the ß 2014 Wiley Periodicals, Inc. treatment of PPHN. Pediatr Pulmonol. Key words: iloprost; sildenafil; pulmonary hypertension; newborn.
1
Division of Neonatal Intensive Care Unit, Erzurum District Training and Research Hospital, Erzurum, Turkey.
2
Division of Pediatric Cardiology, Erzurum District Training and Research Hospital, Erzurum, Turkey.
3
Department of Medical Education, Ataturk University Medical Faculty, Erzurum, Turkey.
4
Division of Pediatric Infectious Diseases, Erzurum District Training and Research Hospital, Erzurum, Turkey.
5
Division of Neonatal Intensive Care Unit, Nenehatun Obstetrics and Gynecology Hospital, Erzurum, Turkey.
6
Department of Pediatrics, Erzurum District Training and Research Hospital, Erzurum, Turkey.
Conflict of interest: None.
Correspondence to: Hasan Kahveci, MD, Division of Neonatal Intensive Care Unit, Erzurum District Training and Research Hospital, Erzurum, Turkey. E-mail: [email protected] Received 28 June 2013; Accepted 30 November 2013. DOI 10.1002/ppul.22985 Published online in Wiley Online Library (wileyonlinelibrary.com).
ß 2014 Wiley Periodicals, Inc.
2
Kahveci et al.
INTRODUCTION
Persistent pulmonary hypertension of the newborn (PPHN) is defined as failure of the pulmonary vasculature to relax at birth and consequent failure of normal adaptation of the fetal heart/lung system to extrauterine life.1,2 In the early postnatal period, failure to reduce pulmonary resistance and suprasystemic pressure causes intrapulmonary and extrapulmonary right-to-left shunting of blood through the ductus arteriosus and/or foramen ovale.3 This leads to marked systemic arterial hypoxemia, respiratory acidosis, and marked cyanosis due to the shunting of deoxygenated blood to the systemic circulation. In infants with PPHN, a 10-fold decrease in pulmonary blood flow increases the hypoxemia because of reduced pulmonary perfusion, and affected patients can develop myocardial failure secondary to oxygen depletion due to increased right ventricular overload.1–7 Although studies from developed countries have reported a PPHN incidence rate of 0.46–6.8/1,000 live births with a mortality rate of 10%–20%, the incidence is thought to be much higher in developing countries.1,2,7 Survivors have high morbidity in the form of neurodevelopmental and audiological impairments, cognitive delays, and hearing loss, and experience a high rate of rehospitalization.6 The main pathophysiological event in PPHN is failure of postnatal adaptation of the fetal cardiopulmonary system with failure of pulmonary vascular bed relaxation.1,2 The principal goal of PPHN treatment is to overcome this failure of the pulmonary vascular bed to relax. Therefore, various therapeutic methods have been used to treat PPHN, including ventilation strategies such as high-frequency oscillatory ventilation (HFOV) and extracorporeal membrane oxygenation (ECMO); pulmonary vasodilators such as magnesium sulfate (MgSO4), sildenafil, adenosine, prostacyclin, tolazolin, and L-arginine; specific agents such as inhaled nitric oxide (INO), bosentan, and synthetic prostacyclin analogs such as inhaled iloprost.2,4–8 Although INO and ECMO are the established agents for PPHN therapy, they are expensive therapeutic modalities associated with technical and economic difficulties in developing countries. Therefore, alternative treatments for PPHN have been evaluated over the past two decades.8 The present clinical study compared the effectiveness and safety of oral sildenafil and inhaled iloprost therapy in newborns with persistent pulmonary hypertension in a referral center in a low-income region of Turkey. MATERIALS AND METHODS
This was a retrospective comparative study, and the data were obtained from the PPHN follow-up protocol form present in patients’ files and used in the neonatal intensive care unit (NICU). Written consents were Pediatric Pulmonology
obtained from the families of all the investigated neonates, and the study protocol was approved by the ethics committee of the Erzurum District Training and Research Hospital. Between September 2007 and January 2012, a total of 47 patients diagnosed with PPHN at the NICU of Erzurum Nenehatun Obstetrics and Gynecology State Hospital in Turkey were analyzed. This hospital is one of the largest perinatal referral centers in Eastern Anatolia, with approximately 8,500 births annually. The most severely affected neonatal patients are transferred from 12 provinces, and approximately 2,500 sick infants are accepted at this NICU each year. All patients were full-term. PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital. When we had iloprost available, we gave iloprost only; when we had no iloprost, we gave oral sildenafil. In the sildenafil group, 14 patients had meconium aspiration syndrome, 8 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, 1 had transient tachypnea, and 1 had idiopathic PPHN. In the iloprost group, 9 patients had meconium aspiration syndrome, 7 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, and 1 had transient tachypnea (Table 1). Eligible neonates were term newborns with hypoxemic respiratory failure and echocardiographic evidence of PPHN. The study entry criteria were systolic pulmonary artery pressure (SPAP) 40 mmHg, oxygenation index (OI) 25, and the need for mechanical ventilation. The exclusion criteria were congenital diaphragmatic hernias, lethal congenital anomalies, congenital heart disease, substantial bleeding diathesis, massive intracranial hemorrhage, and/or intraventricular hemorrhage, multiorgan failure before starting the PPHN treatment, premature birth, and pulmonary hemorrhage due to patent ductus arteriosus. The gestational ages of infants were determinated based on the history of the last menstrual period of their mothers, intrauterine ultrasound measurements, and the New Ballard scores of infants. PPHN was diagnosed by a combination of a full medical history, physical examination, laboratory tests, chest X-ray, blood gas analysis, and echocardiography. PPHN was suspected based on a history of asphyxia and meconium aspiration, respiratory distress, central cyanosis, differential cyanosis, lung parenchymal disease diagnosed by chest X-ray, congenital pneumonia, clinical deterioration, and OI 25 despite ventilator support. The OI, alveolar–arterial oxygen difference (A–aDO2), and arterial/alveolar oxygen ratio (a/AO2) were analyzed in all patients. The difference between the partial arterial oxygen pressure of preductal and postductal blood samples was examined and hyperoxia tests were carried out. The diagnosis of PPHN was confirmed by suprasystemic pulmonary arterial pressure and atrial or ductal right-to-left or
Sildenafil and Iloprost in the Treatment of PH
3
TABLE 1— Baseline Characteristics of Infants With PPHN Treated With Oral Sildenafil and Inhaled Iloprost Variables Gender, male/female Mean gestational age SD (weeks) Mean birth weight SD (g) Mode of delivery, n (%) Caesarean section Vaginal Underlying diagnosis, n (%) MAS Asphyxia (HIE grades II and III) Pneumonia Transient tachypnea Idiopathic
Sildenafil group (n ¼ 27)
Iloprost group (n ¼ 20)
P-value
14/13 39.23 0.9 3328.17 643
12/8 39.89 1.1 3311.6 639.5
0.821 0.631 0.911
17 (63) 10 (37)
13 (65) 7 (35)
0.872 0.612
14 (51.9) 8 (29.6) 3 (11.1) 1 (3.7) 1 (3.7)
9 7 3 1
(45) (35) (15) (5) —
0.762 0.32 0.672 0.82 NA
MAS, meconium aspiration syndrome; HIE, hypoxic ischemic encephalopathy; PPHN, persistent pulmonary hypertension of the newborn. 1 Student t-test. 2 Chi-Square test.
bidirectional shunting on color Doppler examination with no structural cardiac anomalies to explain these findings on echocardiography. Pulmonary pressure was determined by echocardiography. The pressure difference between the right ventricle and the right atrium was measured using a tricuspid regurgitation jet, and the estimated right atrial pressure of 5 mmHg was added to obtain the systolic pulmonary artery pressure. Iloprost (Ilomedin1; Schering AG, Berlin, Germany) was administered by inhalation using a jet nebulizer (CX3, NE-V16/EN1; Omron, Hoofddorp, The Netherlands) at doses of 1–2.5 mg/kg with an interval of 2–4 hr between doses for all patients as recommended in the literature.9–11 In intubated patients, the jet nebulizer was adapted to the respiratory circuit with a T-connector so that iloprost could be administered endotracheally. The calculated dose was diluted with 1 ml of isotonic sodium chloride and administered after 10 min. A 25-mg tablet of sildenafil was diluted with 25 ml of sterile water to achieve a final concentration of 1 mg/ml. One dose of the solution (0.5 mg/kg) was given via an orogastric tube every 6 hr.8 If the OI did not improve, the dose could be doubled until a maximum of 2 mg/kg was reached. The dose of sildenafil was tapered by 50% after reaching OI
