Original Article 211
Intravenous Sildenafil i. v. as Rescue Treatment for Refractory Pulmonary Hypertension in Extremely Preterm Infants
Authors
M. Steiner1, U. Salzer1, S. Baumgartner1, T. Waldhoer2, K. Klebermass-Schrehof1, M. Wald1, M. Langgartner1, A. Berger1
Affiliations
1
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Vienna, Austria 2 Department of Epidemiology, Medical University of Vienna, Center of Public Health, Vienna, Austria
Key words ▶ preterm ● ▶ pulmonary hypertension ● ▶ sildenafil ● ▶ echocardiography ●
Abstract
Zusammenfassung
Background: Intravenous sildenafil treatment has recently shown promising results and good tolerability in the treatment of refractory pulmonary hypertension (PH) in term and near-term neonates, while comparable data in preterm infants are still lacking. However, for critically ill preterm infants suffering from PH refractory to conventional treatment, sildenafil may represent a last treatment resort. Patients and methods: We reviewed the records of 6 critically ill extremely preterm infants who had suffered from PH refractory to conventional treatment and had obtained intravenous sildenafil after careful consideration as ultima ratio treatment. Aim: To describe the responses to sildenafil in terms of hemodynamic and respiratory changes during treatment and outcome. Results: 4/6 patients showed resolution of severe PH with full reversal of ductal shunt direction into pure left-to-right shunt within 82 ± 35 h after sildenafil start. Remarkably, 2/6 patients developed pulmonary hemorrhage at a time point when significant improvement of PH had already taken place, both of them survived. Overall 4/6 patients died, two deaths were related to treatment-refractory PH. Conclusion: Intravenous sildenafil treatment seems effective in improving severe PH and hemodynamic instability in extremely preterm infants with refractory PH. Pulmonary hemorrhage may represent a distinct adverse effect of sildenafil treatment in these patients, presumably due to sudden reversal of ductal shunt. Accordingly, sildenafil should be restricted to most severe and refractory cases in this population.
Hintergrund: Die intravenöse Sildenafiltherapie hat bei reifen Neugeborenen mit schwerer pulmonaler Hypertension (PHT) vielversprechende Ergebnisse gezeigt. Bei Frühgeborenen hingegen fehlen diesbezügliche klinische Daten weitgehend. Dennoch stellt Sildenafil bei kritisch kranken Frühgeborenen mit therapierefraktärer PHT in Ermangelung anderer Therapiemöglichkeiten eine letzte Therapieoption dar. Patienten und Methoden: Echokardiografische und klinische Daten von 6 Frühgeborenen wurden ausgewertet, die aufgrund einer schweren pulmonalen Hypertension ohne Ansprechen auf konventionelle Therapie (d. h. Beatmungsoptimierung, Milrinon ± inhalatives NO) additiv i. v. Sildenafil als ultima ratio erhalten hatten. Studienziel: Erfassung des Ansprechens auf Sildenafil anhand hämodynamischer und respiratorischer Veränderungen unter Therapie und des Outcomes. Ergebnisse: 4/6 Patienten zeigten ein Ansprechen im Sinne einer kompletten Shuntumkehr über einen offenen Ductus arteriosus in einen reinen Links-Rechts-Shunt innerhalb von 82 ± 35 Stunden nach Beginn der Sildenafiltherapie. Auffallend war, dass 2 Patienten eine Lungenblutung zu einem Zeitpunkt entwickelten, wo bereits eine deutliche Verbesserung der Lungendurchblutung im Rahmen der PHT stattgefunden hatte, beide überlebten. Insgesamt verstarben 4/6 Patienten, 2 Todesfälle waren auf eine refraktäre PHT zurückzuführen. Schlussfolgerung: Bei Frühgeborenen mit schwerer therapierefraktärer PHT scheint i. v. Sildenafil die PHT und die damit einhergehende kardiopulmonale Instabilität verbessern zu können. Lungenblutungen könnten allerdings eine mögliche schwere Nebenwirkung in dieser Altersgruppe darstellen. Entsprechend sollte diese Therapieoption auf schwerste, refraktäre Verläufe beschränkt bleiben.
Schlüsselwörter ▶ Frühgeborene ● ▶ pulmonale Hypertension ● ▶ Sildenafil ● ▶ Echokardiografie ●
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1375697 Klin Padiatr 2014; 226: 211–215 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0300-8630 Correspondence Dr. Manuel Steiner Department of Pediatrics and Adolescent Medicine Medical University of Vienna Division of Neonatology Pediatric Intensive Care and Neuropediatrics Währinger Gürtel 18–20 Vienna Austria 1090 Tel.: + 43/1/40400 29300 Fax: + 43/1/40400 29290 manuel.steiner@meduniwien. ac.at
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Intravenöses Sildenafil als letzte Therapieoption bei refraktärer pulmonaler Hypertension bei extrem unreifen Frühgeborenen
Introduction
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Management of hypoxic respiratory failure accompanied by severe pulmonary hypertension (PH) represents a particular challenge in extremely preterm infants, as treatment options are limited. Inhaled nitric oxide, the gold standard of treatment of hypoxic respiratory failure in term and near-term infants, has not shown comparable benefits in preterm infants up to date, and its risks and benefits in the context of PH in preterm infants at best remain uncertain according to current evidence [3]. Additionally, increasing percentages of non-responders to iNO have been reported with declining gestational age in preterm infants with PH [8]. Furthermore, extracorporal membrane oxygenation as ultima ratio treatment is not feasible in preterm infants. Also, with the advent of improved neonatal care more preterm infants at the lower limit of viability initially survive, which in turn leads to an increase of problems such as PH neonatologists have to face. In this context, particularly PH evolving in the setting of oligohydramnios-lung hypoplasia sequence constitutes an unresolved problem in preterm infants, with no larger controlled studies currently available. In the last years, sildenafil has been recognized as valuable contribution to the armamentarium of drugs for PH of the newborn. As an inhibitor of phosphodiesterase-5 it exerts potent and selective vasodilating effects on the pulmonary vascular bed [5]. For the neonatal population, sildenafil has shown promising results in several trials and case series [1, 9, 12, 15]. A recent multicenter trial assessed the use of intravenous sildenafil in term and near-term neonates with PH and found significant and sustained improvement of oxygenation accompanied by good tolerability [12]. An intravenous sildenafil formulation seems particularly suitable for critically ill patients in whom an inconsistent enteral absorption remains of concern. Still, most present trials and reports on sildenafil treatment for PH are limited to term and near-term infants and their results cannot be extrapolated to the preterm population. Greater cardiovascular and pulmonary immaturity may result in different responses and hemodynamic effects of sildenafil in this age group. However, in view of the limited treatment possibilities for refractory PH in preterm infants and the proven efficacy and safety of sildenafil in term newborns, this drug eventually represents a last treatment resort in selected cases of critically ill preterm infants. We reviewed the records of 6 critically ill extremely preterm infants admitted in the year 2012 who suffered from PH refractory to conventional treatment and had obtained intravenous sildenafil after careful consideration as ultima ratio treatment. We describe the responses to sildenafil in terms of hemodynamic and respiratory changes during treatment and outcome.
Methods
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This retrospective analysis was approved by the local Research and Ethics Committee (EK Nr. 1135/2013). Critically ill extremely preterm infants born below 28 weeks of gestational age (GA) and admitted in the year 2012 who had received intravenous sildenafil as ultima ratio treatment for refractory PH unresponsive to first-line treatment were included. In our institution, first-line treatment of PH in extremely preterm infants consists of optimization of mechanical ventilation and hemodynamic support by targeting pCO2 levels of 40 mmHg, pO2 levels of 70–80 mmHg,
preductal oxygen saturation ≥ 92 % and arterial pH > 7.3. Hemodynamic support further includes continuous infusion of milrinone (0.6 mcg/kg/min) and inotropic support with norepinephrine targeting mean arterial blood pressure (BP) values > 30 mmHg. iNO treatment before commencement of sildenafil is not mandatory in our unit, with regard to the lack of evidence of benefit as rescue treatment in hypoxic respiratory failure and the questionable relation of iNO treatment with increased bleeding complications in the context of extreme prematurity [2, 14]. Intravenous sildenafil represented a last treatment resort for refractory PH in critically ill patients and was administered as loading dose of 0.1 mg/kg over 45 min, followed by a continuous infusion of 0.5 to 1.2 mg/kg/day. Since no dosage recommendations exist for intravenous sildenafil for preterm infants, a marginally modified dosing regimen from the published data for term newborns of Steinhorn et al. was chosen [12]. In anticipation of a lower hepatic drug clearance owing to greater immaturity, both loading dose and continuous infusion dose were reduced compared to the Steinhorn regimen. Prior to sildenafil start, parents were informed of the off label use of sildenafil as ultima ratio approach to refractory PH. All therapeutic decisions, including the initiation of iNO and the commencement and dosage of sildenafil, were at the discretion of the attending neonatologist. PH was diagnosed as being severe by echocardiography if there was evidence of either a pure right-to-left or bidirectional shunt pattern through a patent ductus arteriosus (PDA), systemic or suprasystemic right ventricular systolic pressure as estimated by Doppler interrogation of a tricuspid regurgitation jet as previously described [11] and a left-sided flattening or bowing of the interventricular septum. Direction of ductal shunting through an unrestrictive PDA is driven by the pressure gradients between aorta and pulmonary artery. Accordingly, ductal flow pattern allows an estimation of pulmonary to aortic systolic pressure ratio and thereby offers a sensitive and consistent interpretation of pulmonary pressure and its changes over time. Bidirectional PDA shunting has been related to a pulmonary to aortic systolic pressure ratio of 0.8:1–1.3:1 and pure right-to-left shunting with a ratio > 1.0:1 [10]. Conversely, PDA shunt reversal into pure left-to-right shunt provides evidence for resolution of severe PH. A retrospective review of routinely collected patient data during sildenafil treatment was performed, including findings of serial echocardiograms, blood pressure, blood gases and oxygenation index (OI). Routine functional echocardiograms were performed before sildenafil start, after the loading dose and then every 12–36 h during continuous infusion. All echocardiograms were conducted by one of the authors trained in neonatal echocardiography and analyzed together with a pediatric cardiologist. The following variables were obtained as per routine assessment and therefore available for review: shortening fraction, shunt directions (PDA and foramen ovale), left ventricular output (LVO), mean left pulmonary artery blood flow velocity (LPA Vmean) and tricuspid regurgitation Doppler if present. Wilcoxon signed rank test was used for comparing acute changes of LVO, LPA Vmean, OI and mean BP before and after initiation of sildenafil treatment in SAS 9.3 (SAS Institute Inc., Cary, NC, USA, 2012). Time trend analysis of echocardiographic parameters and OI was done by random effect models using proc mixed in SAS 9.3 (SAS Institute Inc., Cary, NC, USA, 2012) with patients as random effects. Significance level was set to p < 0.05. Data are presented as mean ± standard deviation if not stated otherwise.
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212 Original Article
23 + 2
26 + 4
5/M
6/F
Six extremely preterm infants (mean birth weight 667 ± 201 g, range 440–1 046 g) with refractory PH comprised the study pop▶ Table 1). Primary postnatal stabilization comprised ulation (● surfactant application via a small nasogastric tube positioned in the trachea during spontaneous breathing and nasal continuous positive airway pressure in all patients [7]. All patients developed respiratory failure within the first 6 postnatal days and were intubated. Specific underlying pathologies involved in the ▶ Table 1. Basically lung hypoevolution of PH are depicted in ● plasia in the context of preterm premature rupture of membranes and postnatal infection were the leading pathologies associated with emergence of PH. PH was diagnosed by echocardiography as described. Owing to an insufficient response to first-line treatment for PH, intravenous sildenafil was started after mean of 25 ± 16 h for milrinone and 17 ± 11 h for iNO. Mean duration of sildenafil treatment was 140 ± 93 h (range 37–310 h). No increase in the level of iNO and milrinone support was undertaken 5 h prior to and after sildenafil initiation. Full reversal of patent ductus arteriosus (PDA) shunt direction into pure left-to-right shunt was seen in four patients (67 %) within 82 ± 35 h (range 44–120 h) after sildenafil start (pts. 1, 3, ▶ Table 1). No change of ductal shunt pattern was observed 5, 6) (● in 2 patients, as shunting direction remained bidirectional (pt. 2) and right-to-left (pt. 4), respectively. A prompt, continuous and sustained increase of left ventricular output and pulmonary blood flow as estimated by left pulmonary artery mean blood flow velocity (LPA Vmean) was observed and was statistically significant 24–48 h after sildenafil treatment start (p = 0.007 for ▶ Fig. 1). One hour after sildenafil start, LVO and LPA both) (● Vmean increases displayed a statistical trend (p = 0.060 for both). Shortening fraction remained within normal ranges throughout the study period in all patients. As tricuspid regurgitation was present only in 3 patients data are not shown for lack of comparability. Mean arterial BP tended to decrease and inversely, catecholamine support marginally increased when compared 1 h before and 1 h after start of sildenafil loading dose administration (inotropes: 0.18 mcg/kg/min (range 0–0.44) vs. 0.23 mcg/ kg/min (range 0–0.62), p = 0.500; mean BP 32 ± 8 vs. 28 ± 7, ▶ Table 1 p = 0.187; diastolic BP 26 ± 6 vs 23 ± 6, p = 0.240) (● ▶ Fig. 2). OI decreased significantly within 72 h after sildeand ● ▶ Fig. 3). nafil commencement (21 ± 10 vs. 9 ± 6, p = 0.040) (● Overall 4 patients died at 2, 10, 23 and 147 days of postnatal life. While the 2 early deaths were related to treatment-refractory PH (pt. 2, 4), the 2 later deaths were not PH-related (pt. 3, 6). 2 patients developed pulmonary hemorrhage 19 (pt 1) and 66 (pt 5) hours after sildenafil start, both patients survived. Both survivors showed adequate neurological development up to date, none developed periventricular leukomalacia, and none required additional oxygen at the time of discharge.
Discussion
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In severe PH, elevated pulmonary vascular resistance leads to decreased pulmonary blood flow, followed by reduced pulmonary venous return with reduced left ventricular filling and output. After initiation of sildenafil, we saw a prompt and sustained increase in LVO and LPA Vmean, gradual decrease of OI and resolution of PH in 4/6 patients. Overall, the high rate of deaths observed in this study reflects the particular severity of illness in
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pPROM = preterm premature rupture of membranes, R/L = right-to-left, wk = week
24 + 3 4/M
HOL = hour of life, IUGR = intrauterine growth retardation, IVH = intraventricular hemorrhage, LH = lung hypoplasia, L/R = left-to-right, MOV = multiorgan failure, Nor = norepinephrine, PFO = persistent formane ovale, PH = pulmonary hypertension,
25 + 6 3/M
# number in brackets shows time to reversal into pure left-right shunt of PDA in hours from sildenafil start
23 + 5 2/M
*cause of death
27 + 3
BPD = bronchopulmonary dysplasia, bidirect. = bidirectional shunt, BW = birth weight (in grams), DOL = day of life, Epi = epinephrine, GA = gestational age (in weeks), HELLP = hemolysis, elevated liver enzymes, low platelet count,
bidirect. bidirect. (120) 100 0,7 52 Nor: 0.19→0.19 milrinone (38), iNO (28) 2/24 Early-onset sepsis, perinatal asphyxia
143/145
13/17
▼
605
bidirect. bidirect. (44) 310 0,5 169 Nor: 0.21→0.21
R/L R/L shunt 37 0,5 18 Nor: 0.24→0.36
L/R bidirect. (100) 151 0,7 19
milrinone (10), iNO (12) milrinone (4), iNO (4) milrinone (22), iNO (22) 2/17
Nor & Epi: 0.44→0.62
L/R bidirect. 97 0,7 153 – milrinone (47) 66/100
death)
Results
pulm. hemor- home rhage (100) resp. failure*, expired refractory PH (10) bilat. IVH III expired (55), MOV* (23) refractory expired (2) PH* pulm. hemor- home rhage (235), IVH II BPD* expired (147) L/R bidirect. (63) 144 1,2 81 – milrinone (28) 50/52
HELLP syndrome, early-onset sepsis 633 pPROM wk 22, oligohydramnios 1 046 pPROM wk 22, early-onset sepsis 440 IUGR, sepsis, LH, oligohydramnios 495 pPROM wk 22, postnatal infection
(DOL of
1/M
780
fil start fil start (#) (hours) sion (mg/kg/d) sildenafil start (μg/kg/min) start (HOL) diagnosis (HOL) pathologies
sildenafil)
ComplicaPFO shunt PDA flow pat-
tern at sildena- at sildena- tions (HOL) sildenafil
Duration of Dosage of
sildenafil infusildenafil
Time of
time of PH echo and underlying
Initial PH thera- Inotropes one hour Time of intubation/ Prenatal history
(g) (wk) Sex
BW GA Pt/
Table 1 Demographic data and clinical characteristics
py (hours before before→one hour after
Out-come
Original Article 213
214 Original Article
a
Fig. 1 Changes in left ventricular output (LVO) a given in ml/kg/min and left pulmonary artery blood flow velocity (LPA Vmean) b given in m/sec over the whole study period from 0–5 h prior to sildenafil treatment start until 60–120 h after sildenafil initiation. Significant increase was seen at 24–48 h after initiation of sildenafil as compared to pre-sildenafil values for both parameters (p = 0.007, respectively).
b
350
1
325
0.9 0.8
300
0.7
275
0.6
250
0.5
225
0.4
200
0.2
150
0.1 0
125 pre (0–5 h) 1 h post
12–23 h post
24–48 h 60–120 h post post
Pt 1
Pt 2
Pt 3
Pt 5
Pt 6
Mean
pre (0–5 h) 1h post
Pt 4
12–23 h post
24–48 h post
Pt 1
Pt 2
Pt 3
Pt 5
Pt 6
Mean
41
Pt 4
30.0 25.0 Oxygenation index
36
mmHg
60–120 h post
31
26
20.0 15.0 10.0 5.0
21 0.0 0
16 –3
–2
–1
0
mean BP
1
2
3
4
diastolic BP
12 24 Time (Hours)
48
72
Fig. 3 Oxygenation index (OI) over time from the 6 study patients, given as mean ± 2 × standard error of mean. Time point 0 represents the baseline directly prior to sildenafil start. Significant decrease of OI was seen at 72 h as compared to baseline (21 ± 10 vs. 9 ± 6; p = 0.040). OI was calculated as: OI = (FiO2 × MAP × 100)/paO2 (FiO2: fraction of inspired oxygen, MAP: mean airway pressure, paO2: arterial oxygen tension).
Fig. 2 Time course of mean values with standard deviation of mean and diastolic arterial blood pressure of the 6 patients, beginning 3 h before to 4 h after sildenafil initiation.
these patients. Severe PH in the extremely preterm infant seems to result from a complex interplay of infection, immaturity and different underlying diseases, ultimately causing failure of normal cardiopulmonary transition with high pulmonary vascular resistance and pressure and thus may be considered to be comparable to the entity of persistent pulmonary hypertension of the term newborn. This fact also highlights that sildenafil was used in a highly selected and fortunately rare patient population. For comparison, overall survival at our institution from 2009 to 2011 was 75.8 % for infants born before 28 weeks GA [7]. Interestingly, 5/6 patients exhibiting severe PH were male, which may at least partly reflect recent findings of sexual dimorphism in neonatal lung development favoring structural and functional lung maturation in the female gender [6]. Generally, improvement of hemodynamic parameters (LVO, LPA Vmean) preceded improvement of respiratory parameters (OI) in our population. However, neither LVO nor LPA Vmean increases can be solely attributed to better cardiac function and lower pulmonary vascular resistance, as an increasing proportion of left-to-right shunt through a PDA holds substantial con-
2
tribution to the rise of both parameters. Particularly LPA Vmean has been shown to sensitively reflect ductal influence on pulmonary blood flow and values beyond 0.42 m/s have been associated with significant ductal left-to-right shunt [4]. A remarkable finding was the occurrence of pulmonary hemorrhage 19 and 66 h after initiation of sildenafil in 2 patients (pt 1, 5). Their platelet counts, albeit being moderately low, did not differ from those measured in the other patients. In both patients, serial echocardiography indicated substantial improvement of pulmonary blood flow before the emergence of hemorrhage. Also, these 2 patients revealed the fastest reversal of PDA shunting direction into pure left-to-right shunt. The occurrence of pulmonary hemorrhage and especially its time point within the observed hemodynamic changes suggests that the combination of rapidly increasing pulmonary blood flow in response to sildenafil-induced pulmonary vasodilation and an immature and vulnerable pulmonary vasculature of extremely preterm infants might promote reperfusion injury and bleeding in this patient population. The presence of a PDA with increasing left-to-right shunt as pulmonary pressure drops
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0.3
175
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bilities, with close longitudinal echocardiographic monitoring and rapid tapering of sildenafil in case of hemodynamic improvement. The case series presented herein may provide ground for further controlled clinical studies on this demanding condition in neonatal intensive care.
Conflict of interest: The authors have no conflict of interest to disclose. References 1 Baquero H, Soliz A, Neira F et al. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006; 117: 1077–1083 2 Barrington KJ, Finer N. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev 2010: CD000509 3 Cole FS, Alleyne C, Barks JD et al. NIH Consensus development conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics 2011; 127: 363–369 4 El Hajjar M, Vaksmann G, Rakza T et al. Severity of the ductal shunt: a comparison of different markers. Arch Dis Child Fetal Neonatal Ed 2005; 90: F419–F422 5 Farrow KN, Steinhorn RH. Phosphodiesterases: emerging therapeutic targets for neonatal pulmonary hypertension. Handb Exp Pharmacol 2011; 251–277 6 Gortner L, Shen J, Tutdibi E. Sexual dimorphism of neonatal lung development. Klin Padiatr 2013; 225: 64–69 7 Klebermass-Schrehof K, Wald M, Schwindt J et al. Less invasive surfactant application in extremely preterm infants: impact on mortality and morbidity. Neonatology 2013; 103: 252–258 8 Kumar VH, Hutchison AA, Lakshminrusimha S et al. Characteristics of pulmonary hypertension in preterm neonates. J Perinatol 2007; 27: 214–219 9 Noori S, Friedlich P, Wong P et al. Cardiovascular effects of sildenafil in neonates and infants with congenital diaphragmatic hernia and pulmonary hypertension. Neonatology 2007; 91: 92–100 10 Skinner JR, Alverson D, Hunter S. Echocardiography for the neonatologist. Edinburgh: Churchill Livingstone, 2000; pp 138–141 11 Skinner JR, Boys RJ, Hunter S et al. Non-invasive assessment of pulmonary arterial pressure in healthy neonates. Arch Dis Child 1991; 66: 386–390 12 Steinhorn RH, Kinsella JP, Pierce C et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr 2009; 155: 841–847 e841 13 Stichtenoth G, Demmert M, Bohnhorst B et al. Major contributors to hospital mortality in very-low-birth-weight infants: data of the birth year 2010 cohort of the German Neonatal Network. Klin Padiatr 2012; 224: 276–281 14 Van Meurs KP, Wright LL, Ehrenkranz RA et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med 2005; 353: 13–22 15 Vargas-Origel A, Gomez-Rodriguez G, Aldana-Valenzuela C et al. The use of sildenafil in persistent pulmonary hypertension of the newborn. Am J Perinatol 2010; 27: 225–230
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additionally augments pulmonary blood flow, pulmonary venous return and left ventricular preload. The interaction of these hemodynamic changes might result in an intermittent volume overload of the left heart, with an increase in left atrial pressure leading to congestion into the pulmonary venous system and consecutive pulmonary hemorrhage. Another possible contribution to a rapidly increasing pulmonary blood flow might be seen in the concurrent use of milrinone and sildenafil, which could result in additive effects, since both drugs induce pulmonary vasorelaxation via amplification of cGMP (sildenafil) and cAMP levels (milrinone) [5]. The clinical significance of pulmonary hemorrhage is underscored by a large prospective cohort study that depicted pulmonary hemorrhage as one of the major potentially preventable contributors of mortality in very-lowbirth-weight infants [13]. The use of intravenous sildenafil in preterm infants warrants careful investigation within the context of a randomized controlled trial. Sildenafil use in preterm infants should therefore be highly restricted until such validated results are available. In rare and desperate cases such as presented herein, however, sildenafil may represent a last and potentially life-saving treatment for refractory pulmonary hypertension in most critically ill preterm infants. Moreover, primary PH refractory to conventional treatment in extremely preterm infants is a relatively rare event, which additionally might impede a fast data acquisition within a randomized study in this very selected population. To our knowledge this is the first case series reporting on hemodynamic and respiratory effects of intravenous sildenafil for refractory PH in extremely preterm infants. With regard to the small sample size and the retrospective observational character, interpretation of our results remains hypothetical. However, we think that our observations point towards possible efficacy and caveats in the use of sildenafil in extremely preterm infants and provide clinically relevant and new information. Intravenous sildenafil treatment seemed effective in improving pulmonary vascular resistance and hemodynamic instability in extremely preterm infants with refractory PH. Importantly, pulmonary hemorrhage may represent a distinct adverse effect of sildenafil treatment in these patients, presumably due to sudden reversal of PDA shunt. Until more data are available, it seems reasonable to restrict intravenous sildenafil use for extremely preterm infants to most severe cases of refractory PH (with OI levels repeatedly beyond 15) after having assiduously adopted the full potential of ventilatory and hemodynamic optimization possi-
Intravenous Sildenafil i. v. as Rescue Treatment for Refractory Pulmonary Hypertension in Extremely Preterm Infants
Authors
M. Steiner1, U. Salzer1, S. Baumgartner1, T. Waldhoer2, K. Klebermass-Schrehof1, M. Wald1, M. Langgartner1, A. Berger1
Affiliations
1
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Vienna, Austria 2 Department of Epidemiology, Medical University of Vienna, Center of Public Health, Vienna, Austria
Key words ▶ preterm ● ▶ pulmonary hypertension ● ▶ sildenafil ● ▶ echocardiography ●
Abstract
Zusammenfassung
Background: Intravenous sildenafil treatment has recently shown promising results and good tolerability in the treatment of refractory pulmonary hypertension (PH) in term and near-term neonates, while comparable data in preterm infants are still lacking. However, for critically ill preterm infants suffering from PH refractory to conventional treatment, sildenafil may represent a last treatment resort. Patients and methods: We reviewed the records of 6 critically ill extremely preterm infants who had suffered from PH refractory to conventional treatment and had obtained intravenous sildenafil after careful consideration as ultima ratio treatment. Aim: To describe the responses to sildenafil in terms of hemodynamic and respiratory changes during treatment and outcome. Results: 4/6 patients showed resolution of severe PH with full reversal of ductal shunt direction into pure left-to-right shunt within 82 ± 35 h after sildenafil start. Remarkably, 2/6 patients developed pulmonary hemorrhage at a time point when significant improvement of PH had already taken place, both of them survived. Overall 4/6 patients died, two deaths were related to treatment-refractory PH. Conclusion: Intravenous sildenafil treatment seems effective in improving severe PH and hemodynamic instability in extremely preterm infants with refractory PH. Pulmonary hemorrhage may represent a distinct adverse effect of sildenafil treatment in these patients, presumably due to sudden reversal of ductal shunt. Accordingly, sildenafil should be restricted to most severe and refractory cases in this population.
Hintergrund: Die intravenöse Sildenafiltherapie hat bei reifen Neugeborenen mit schwerer pulmonaler Hypertension (PHT) vielversprechende Ergebnisse gezeigt. Bei Frühgeborenen hingegen fehlen diesbezügliche klinische Daten weitgehend. Dennoch stellt Sildenafil bei kritisch kranken Frühgeborenen mit therapierefraktärer PHT in Ermangelung anderer Therapiemöglichkeiten eine letzte Therapieoption dar. Patienten und Methoden: Echokardiografische und klinische Daten von 6 Frühgeborenen wurden ausgewertet, die aufgrund einer schweren pulmonalen Hypertension ohne Ansprechen auf konventionelle Therapie (d. h. Beatmungsoptimierung, Milrinon ± inhalatives NO) additiv i. v. Sildenafil als ultima ratio erhalten hatten. Studienziel: Erfassung des Ansprechens auf Sildenafil anhand hämodynamischer und respiratorischer Veränderungen unter Therapie und des Outcomes. Ergebnisse: 4/6 Patienten zeigten ein Ansprechen im Sinne einer kompletten Shuntumkehr über einen offenen Ductus arteriosus in einen reinen Links-Rechts-Shunt innerhalb von 82 ± 35 Stunden nach Beginn der Sildenafiltherapie. Auffallend war, dass 2 Patienten eine Lungenblutung zu einem Zeitpunkt entwickelten, wo bereits eine deutliche Verbesserung der Lungendurchblutung im Rahmen der PHT stattgefunden hatte, beide überlebten. Insgesamt verstarben 4/6 Patienten, 2 Todesfälle waren auf eine refraktäre PHT zurückzuführen. Schlussfolgerung: Bei Frühgeborenen mit schwerer therapierefraktärer PHT scheint i. v. Sildenafil die PHT und die damit einhergehende kardiopulmonale Instabilität verbessern zu können. Lungenblutungen könnten allerdings eine mögliche schwere Nebenwirkung in dieser Altersgruppe darstellen. Entsprechend sollte diese Therapieoption auf schwerste, refraktäre Verläufe beschränkt bleiben.
Schlüsselwörter ▶ Frühgeborene ● ▶ pulmonale Hypertension ● ▶ Sildenafil ● ▶ Echokardiografie ●
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1375697 Klin Padiatr 2014; 226: 211–215 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0300-8630 Correspondence Dr. Manuel Steiner Department of Pediatrics and Adolescent Medicine Medical University of Vienna Division of Neonatology Pediatric Intensive Care and Neuropediatrics Währinger Gürtel 18–20 Vienna Austria 1090 Tel.: + 43/1/40400 29300 Fax: + 43/1/40400 29290 manuel.steiner@meduniwien. ac.at
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Steiner M et al. Intravenous Sildenafil i. v. as Rescue … Klin Padiatr 2014; 226: 211–215
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Intravenöses Sildenafil als letzte Therapieoption bei refraktärer pulmonaler Hypertension bei extrem unreifen Frühgeborenen
Introduction
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Management of hypoxic respiratory failure accompanied by severe pulmonary hypertension (PH) represents a particular challenge in extremely preterm infants, as treatment options are limited. Inhaled nitric oxide, the gold standard of treatment of hypoxic respiratory failure in term and near-term infants, has not shown comparable benefits in preterm infants up to date, and its risks and benefits in the context of PH in preterm infants at best remain uncertain according to current evidence [3]. Additionally, increasing percentages of non-responders to iNO have been reported with declining gestational age in preterm infants with PH [8]. Furthermore, extracorporal membrane oxygenation as ultima ratio treatment is not feasible in preterm infants. Also, with the advent of improved neonatal care more preterm infants at the lower limit of viability initially survive, which in turn leads to an increase of problems such as PH neonatologists have to face. In this context, particularly PH evolving in the setting of oligohydramnios-lung hypoplasia sequence constitutes an unresolved problem in preterm infants, with no larger controlled studies currently available. In the last years, sildenafil has been recognized as valuable contribution to the armamentarium of drugs for PH of the newborn. As an inhibitor of phosphodiesterase-5 it exerts potent and selective vasodilating effects on the pulmonary vascular bed [5]. For the neonatal population, sildenafil has shown promising results in several trials and case series [1, 9, 12, 15]. A recent multicenter trial assessed the use of intravenous sildenafil in term and near-term neonates with PH and found significant and sustained improvement of oxygenation accompanied by good tolerability [12]. An intravenous sildenafil formulation seems particularly suitable for critically ill patients in whom an inconsistent enteral absorption remains of concern. Still, most present trials and reports on sildenafil treatment for PH are limited to term and near-term infants and their results cannot be extrapolated to the preterm population. Greater cardiovascular and pulmonary immaturity may result in different responses and hemodynamic effects of sildenafil in this age group. However, in view of the limited treatment possibilities for refractory PH in preterm infants and the proven efficacy and safety of sildenafil in term newborns, this drug eventually represents a last treatment resort in selected cases of critically ill preterm infants. We reviewed the records of 6 critically ill extremely preterm infants admitted in the year 2012 who suffered from PH refractory to conventional treatment and had obtained intravenous sildenafil after careful consideration as ultima ratio treatment. We describe the responses to sildenafil in terms of hemodynamic and respiratory changes during treatment and outcome.
Methods
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This retrospective analysis was approved by the local Research and Ethics Committee (EK Nr. 1135/2013). Critically ill extremely preterm infants born below 28 weeks of gestational age (GA) and admitted in the year 2012 who had received intravenous sildenafil as ultima ratio treatment for refractory PH unresponsive to first-line treatment were included. In our institution, first-line treatment of PH in extremely preterm infants consists of optimization of mechanical ventilation and hemodynamic support by targeting pCO2 levels of 40 mmHg, pO2 levels of 70–80 mmHg,
preductal oxygen saturation ≥ 92 % and arterial pH > 7.3. Hemodynamic support further includes continuous infusion of milrinone (0.6 mcg/kg/min) and inotropic support with norepinephrine targeting mean arterial blood pressure (BP) values > 30 mmHg. iNO treatment before commencement of sildenafil is not mandatory in our unit, with regard to the lack of evidence of benefit as rescue treatment in hypoxic respiratory failure and the questionable relation of iNO treatment with increased bleeding complications in the context of extreme prematurity [2, 14]. Intravenous sildenafil represented a last treatment resort for refractory PH in critically ill patients and was administered as loading dose of 0.1 mg/kg over 45 min, followed by a continuous infusion of 0.5 to 1.2 mg/kg/day. Since no dosage recommendations exist for intravenous sildenafil for preterm infants, a marginally modified dosing regimen from the published data for term newborns of Steinhorn et al. was chosen [12]. In anticipation of a lower hepatic drug clearance owing to greater immaturity, both loading dose and continuous infusion dose were reduced compared to the Steinhorn regimen. Prior to sildenafil start, parents were informed of the off label use of sildenafil as ultima ratio approach to refractory PH. All therapeutic decisions, including the initiation of iNO and the commencement and dosage of sildenafil, were at the discretion of the attending neonatologist. PH was diagnosed as being severe by echocardiography if there was evidence of either a pure right-to-left or bidirectional shunt pattern through a patent ductus arteriosus (PDA), systemic or suprasystemic right ventricular systolic pressure as estimated by Doppler interrogation of a tricuspid regurgitation jet as previously described [11] and a left-sided flattening or bowing of the interventricular septum. Direction of ductal shunting through an unrestrictive PDA is driven by the pressure gradients between aorta and pulmonary artery. Accordingly, ductal flow pattern allows an estimation of pulmonary to aortic systolic pressure ratio and thereby offers a sensitive and consistent interpretation of pulmonary pressure and its changes over time. Bidirectional PDA shunting has been related to a pulmonary to aortic systolic pressure ratio of 0.8:1–1.3:1 and pure right-to-left shunting with a ratio > 1.0:1 [10]. Conversely, PDA shunt reversal into pure left-to-right shunt provides evidence for resolution of severe PH. A retrospective review of routinely collected patient data during sildenafil treatment was performed, including findings of serial echocardiograms, blood pressure, blood gases and oxygenation index (OI). Routine functional echocardiograms were performed before sildenafil start, after the loading dose and then every 12–36 h during continuous infusion. All echocardiograms were conducted by one of the authors trained in neonatal echocardiography and analyzed together with a pediatric cardiologist. The following variables were obtained as per routine assessment and therefore available for review: shortening fraction, shunt directions (PDA and foramen ovale), left ventricular output (LVO), mean left pulmonary artery blood flow velocity (LPA Vmean) and tricuspid regurgitation Doppler if present. Wilcoxon signed rank test was used for comparing acute changes of LVO, LPA Vmean, OI and mean BP before and after initiation of sildenafil treatment in SAS 9.3 (SAS Institute Inc., Cary, NC, USA, 2012). Time trend analysis of echocardiographic parameters and OI was done by random effect models using proc mixed in SAS 9.3 (SAS Institute Inc., Cary, NC, USA, 2012) with patients as random effects. Significance level was set to p < 0.05. Data are presented as mean ± standard deviation if not stated otherwise.
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212 Original Article
23 + 2
26 + 4
5/M
6/F
Six extremely preterm infants (mean birth weight 667 ± 201 g, range 440–1 046 g) with refractory PH comprised the study pop▶ Table 1). Primary postnatal stabilization comprised ulation (● surfactant application via a small nasogastric tube positioned in the trachea during spontaneous breathing and nasal continuous positive airway pressure in all patients [7]. All patients developed respiratory failure within the first 6 postnatal days and were intubated. Specific underlying pathologies involved in the ▶ Table 1. Basically lung hypoevolution of PH are depicted in ● plasia in the context of preterm premature rupture of membranes and postnatal infection were the leading pathologies associated with emergence of PH. PH was diagnosed by echocardiography as described. Owing to an insufficient response to first-line treatment for PH, intravenous sildenafil was started after mean of 25 ± 16 h for milrinone and 17 ± 11 h for iNO. Mean duration of sildenafil treatment was 140 ± 93 h (range 37–310 h). No increase in the level of iNO and milrinone support was undertaken 5 h prior to and after sildenafil initiation. Full reversal of patent ductus arteriosus (PDA) shunt direction into pure left-to-right shunt was seen in four patients (67 %) within 82 ± 35 h (range 44–120 h) after sildenafil start (pts. 1, 3, ▶ Table 1). No change of ductal shunt pattern was observed 5, 6) (● in 2 patients, as shunting direction remained bidirectional (pt. 2) and right-to-left (pt. 4), respectively. A prompt, continuous and sustained increase of left ventricular output and pulmonary blood flow as estimated by left pulmonary artery mean blood flow velocity (LPA Vmean) was observed and was statistically significant 24–48 h after sildenafil treatment start (p = 0.007 for ▶ Fig. 1). One hour after sildenafil start, LVO and LPA both) (● Vmean increases displayed a statistical trend (p = 0.060 for both). Shortening fraction remained within normal ranges throughout the study period in all patients. As tricuspid regurgitation was present only in 3 patients data are not shown for lack of comparability. Mean arterial BP tended to decrease and inversely, catecholamine support marginally increased when compared 1 h before and 1 h after start of sildenafil loading dose administration (inotropes: 0.18 mcg/kg/min (range 0–0.44) vs. 0.23 mcg/ kg/min (range 0–0.62), p = 0.500; mean BP 32 ± 8 vs. 28 ± 7, ▶ Table 1 p = 0.187; diastolic BP 26 ± 6 vs 23 ± 6, p = 0.240) (● ▶ Fig. 2). OI decreased significantly within 72 h after sildeand ● ▶ Fig. 3). nafil commencement (21 ± 10 vs. 9 ± 6, p = 0.040) (● Overall 4 patients died at 2, 10, 23 and 147 days of postnatal life. While the 2 early deaths were related to treatment-refractory PH (pt. 2, 4), the 2 later deaths were not PH-related (pt. 3, 6). 2 patients developed pulmonary hemorrhage 19 (pt 1) and 66 (pt 5) hours after sildenafil start, both patients survived. Both survivors showed adequate neurological development up to date, none developed periventricular leukomalacia, and none required additional oxygen at the time of discharge.
Discussion
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In severe PH, elevated pulmonary vascular resistance leads to decreased pulmonary blood flow, followed by reduced pulmonary venous return with reduced left ventricular filling and output. After initiation of sildenafil, we saw a prompt and sustained increase in LVO and LPA Vmean, gradual decrease of OI and resolution of PH in 4/6 patients. Overall, the high rate of deaths observed in this study reflects the particular severity of illness in
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pPROM = preterm premature rupture of membranes, R/L = right-to-left, wk = week
24 + 3 4/M
HOL = hour of life, IUGR = intrauterine growth retardation, IVH = intraventricular hemorrhage, LH = lung hypoplasia, L/R = left-to-right, MOV = multiorgan failure, Nor = norepinephrine, PFO = persistent formane ovale, PH = pulmonary hypertension,
25 + 6 3/M
# number in brackets shows time to reversal into pure left-right shunt of PDA in hours from sildenafil start
23 + 5 2/M
*cause of death
27 + 3
BPD = bronchopulmonary dysplasia, bidirect. = bidirectional shunt, BW = birth weight (in grams), DOL = day of life, Epi = epinephrine, GA = gestational age (in weeks), HELLP = hemolysis, elevated liver enzymes, low platelet count,
bidirect. bidirect. (120) 100 0,7 52 Nor: 0.19→0.19 milrinone (38), iNO (28) 2/24 Early-onset sepsis, perinatal asphyxia
143/145
13/17
▼
605
bidirect. bidirect. (44) 310 0,5 169 Nor: 0.21→0.21
R/L R/L shunt 37 0,5 18 Nor: 0.24→0.36
L/R bidirect. (100) 151 0,7 19
milrinone (10), iNO (12) milrinone (4), iNO (4) milrinone (22), iNO (22) 2/17
Nor & Epi: 0.44→0.62
L/R bidirect. 97 0,7 153 – milrinone (47) 66/100
death)
Results
pulm. hemor- home rhage (100) resp. failure*, expired refractory PH (10) bilat. IVH III expired (55), MOV* (23) refractory expired (2) PH* pulm. hemor- home rhage (235), IVH II BPD* expired (147) L/R bidirect. (63) 144 1,2 81 – milrinone (28) 50/52
HELLP syndrome, early-onset sepsis 633 pPROM wk 22, oligohydramnios 1 046 pPROM wk 22, early-onset sepsis 440 IUGR, sepsis, LH, oligohydramnios 495 pPROM wk 22, postnatal infection
(DOL of
1/M
780
fil start fil start (#) (hours) sion (mg/kg/d) sildenafil start (μg/kg/min) start (HOL) diagnosis (HOL) pathologies
sildenafil)
ComplicaPFO shunt PDA flow pat-
tern at sildena- at sildena- tions (HOL) sildenafil
Duration of Dosage of
sildenafil infusildenafil
Time of
time of PH echo and underlying
Initial PH thera- Inotropes one hour Time of intubation/ Prenatal history
(g) (wk) Sex
BW GA Pt/
Table 1 Demographic data and clinical characteristics
py (hours before before→one hour after
Out-come
Original Article 213
214 Original Article
a
Fig. 1 Changes in left ventricular output (LVO) a given in ml/kg/min and left pulmonary artery blood flow velocity (LPA Vmean) b given in m/sec over the whole study period from 0–5 h prior to sildenafil treatment start until 60–120 h after sildenafil initiation. Significant increase was seen at 24–48 h after initiation of sildenafil as compared to pre-sildenafil values for both parameters (p = 0.007, respectively).
b
350
1
325
0.9 0.8
300
0.7
275
0.6
250
0.5
225
0.4
200
0.2
150
0.1 0
125 pre (0–5 h) 1 h post
12–23 h post
24–48 h 60–120 h post post
Pt 1
Pt 2
Pt 3
Pt 5
Pt 6
Mean
pre (0–5 h) 1h post
Pt 4
12–23 h post
24–48 h post
Pt 1
Pt 2
Pt 3
Pt 5
Pt 6
Mean
41
Pt 4
30.0 25.0 Oxygenation index
36
mmHg
60–120 h post
31
26
20.0 15.0 10.0 5.0
21 0.0 0
16 –3
–2
–1
0
mean BP
1
2
3
4
diastolic BP
12 24 Time (Hours)
48
72
Fig. 3 Oxygenation index (OI) over time from the 6 study patients, given as mean ± 2 × standard error of mean. Time point 0 represents the baseline directly prior to sildenafil start. Significant decrease of OI was seen at 72 h as compared to baseline (21 ± 10 vs. 9 ± 6; p = 0.040). OI was calculated as: OI = (FiO2 × MAP × 100)/paO2 (FiO2: fraction of inspired oxygen, MAP: mean airway pressure, paO2: arterial oxygen tension).
Fig. 2 Time course of mean values with standard deviation of mean and diastolic arterial blood pressure of the 6 patients, beginning 3 h before to 4 h after sildenafil initiation.
these patients. Severe PH in the extremely preterm infant seems to result from a complex interplay of infection, immaturity and different underlying diseases, ultimately causing failure of normal cardiopulmonary transition with high pulmonary vascular resistance and pressure and thus may be considered to be comparable to the entity of persistent pulmonary hypertension of the term newborn. This fact also highlights that sildenafil was used in a highly selected and fortunately rare patient population. For comparison, overall survival at our institution from 2009 to 2011 was 75.8 % for infants born before 28 weeks GA [7]. Interestingly, 5/6 patients exhibiting severe PH were male, which may at least partly reflect recent findings of sexual dimorphism in neonatal lung development favoring structural and functional lung maturation in the female gender [6]. Generally, improvement of hemodynamic parameters (LVO, LPA Vmean) preceded improvement of respiratory parameters (OI) in our population. However, neither LVO nor LPA Vmean increases can be solely attributed to better cardiac function and lower pulmonary vascular resistance, as an increasing proportion of left-to-right shunt through a PDA holds substantial con-
2
tribution to the rise of both parameters. Particularly LPA Vmean has been shown to sensitively reflect ductal influence on pulmonary blood flow and values beyond 0.42 m/s have been associated with significant ductal left-to-right shunt [4]. A remarkable finding was the occurrence of pulmonary hemorrhage 19 and 66 h after initiation of sildenafil in 2 patients (pt 1, 5). Their platelet counts, albeit being moderately low, did not differ from those measured in the other patients. In both patients, serial echocardiography indicated substantial improvement of pulmonary blood flow before the emergence of hemorrhage. Also, these 2 patients revealed the fastest reversal of PDA shunting direction into pure left-to-right shunt. The occurrence of pulmonary hemorrhage and especially its time point within the observed hemodynamic changes suggests that the combination of rapidly increasing pulmonary blood flow in response to sildenafil-induced pulmonary vasodilation and an immature and vulnerable pulmonary vasculature of extremely preterm infants might promote reperfusion injury and bleeding in this patient population. The presence of a PDA with increasing left-to-right shunt as pulmonary pressure drops
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0.3
175
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bilities, with close longitudinal echocardiographic monitoring and rapid tapering of sildenafil in case of hemodynamic improvement. The case series presented herein may provide ground for further controlled clinical studies on this demanding condition in neonatal intensive care.
Conflict of interest: The authors have no conflict of interest to disclose. References 1 Baquero H, Soliz A, Neira F et al. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006; 117: 1077–1083 2 Barrington KJ, Finer N. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev 2010: CD000509 3 Cole FS, Alleyne C, Barks JD et al. NIH Consensus development conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics 2011; 127: 363–369 4 El Hajjar M, Vaksmann G, Rakza T et al. Severity of the ductal shunt: a comparison of different markers. Arch Dis Child Fetal Neonatal Ed 2005; 90: F419–F422 5 Farrow KN, Steinhorn RH. Phosphodiesterases: emerging therapeutic targets for neonatal pulmonary hypertension. Handb Exp Pharmacol 2011; 251–277 6 Gortner L, Shen J, Tutdibi E. Sexual dimorphism of neonatal lung development. Klin Padiatr 2013; 225: 64–69 7 Klebermass-Schrehof K, Wald M, Schwindt J et al. Less invasive surfactant application in extremely preterm infants: impact on mortality and morbidity. Neonatology 2013; 103: 252–258 8 Kumar VH, Hutchison AA, Lakshminrusimha S et al. Characteristics of pulmonary hypertension in preterm neonates. J Perinatol 2007; 27: 214–219 9 Noori S, Friedlich P, Wong P et al. Cardiovascular effects of sildenafil in neonates and infants with congenital diaphragmatic hernia and pulmonary hypertension. Neonatology 2007; 91: 92–100 10 Skinner JR, Alverson D, Hunter S. Echocardiography for the neonatologist. Edinburgh: Churchill Livingstone, 2000; pp 138–141 11 Skinner JR, Boys RJ, Hunter S et al. Non-invasive assessment of pulmonary arterial pressure in healthy neonates. Arch Dis Child 1991; 66: 386–390 12 Steinhorn RH, Kinsella JP, Pierce C et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr 2009; 155: 841–847 e841 13 Stichtenoth G, Demmert M, Bohnhorst B et al. Major contributors to hospital mortality in very-low-birth-weight infants: data of the birth year 2010 cohort of the German Neonatal Network. Klin Padiatr 2012; 224: 276–281 14 Van Meurs KP, Wright LL, Ehrenkranz RA et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med 2005; 353: 13–22 15 Vargas-Origel A, Gomez-Rodriguez G, Aldana-Valenzuela C et al. The use of sildenafil in persistent pulmonary hypertension of the newborn. Am J Perinatol 2010; 27: 225–230
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additionally augments pulmonary blood flow, pulmonary venous return and left ventricular preload. The interaction of these hemodynamic changes might result in an intermittent volume overload of the left heart, with an increase in left atrial pressure leading to congestion into the pulmonary venous system and consecutive pulmonary hemorrhage. Another possible contribution to a rapidly increasing pulmonary blood flow might be seen in the concurrent use of milrinone and sildenafil, which could result in additive effects, since both drugs induce pulmonary vasorelaxation via amplification of cGMP (sildenafil) and cAMP levels (milrinone) [5]. The clinical significance of pulmonary hemorrhage is underscored by a large prospective cohort study that depicted pulmonary hemorrhage as one of the major potentially preventable contributors of mortality in very-lowbirth-weight infants [13]. The use of intravenous sildenafil in preterm infants warrants careful investigation within the context of a randomized controlled trial. Sildenafil use in preterm infants should therefore be highly restricted until such validated results are available. In rare and desperate cases such as presented herein, however, sildenafil may represent a last and potentially life-saving treatment for refractory pulmonary hypertension in most critically ill preterm infants. Moreover, primary PH refractory to conventional treatment in extremely preterm infants is a relatively rare event, which additionally might impede a fast data acquisition within a randomized study in this very selected population. To our knowledge this is the first case series reporting on hemodynamic and respiratory effects of intravenous sildenafil for refractory PH in extremely preterm infants. With regard to the small sample size and the retrospective observational character, interpretation of our results remains hypothetical. However, we think that our observations point towards possible efficacy and caveats in the use of sildenafil in extremely preterm infants and provide clinically relevant and new information. Intravenous sildenafil treatment seemed effective in improving pulmonary vascular resistance and hemodynamic instability in extremely preterm infants with refractory PH. Importantly, pulmonary hemorrhage may represent a distinct adverse effect of sildenafil treatment in these patients, presumably due to sudden reversal of PDA shunt. Until more data are available, it seems reasonable to restrict intravenous sildenafil use for extremely preterm infants to most severe cases of refractory PH (with OI levels repeatedly beyond 15) after having assiduously adopted the full potential of ventilatory and hemodynamic optimization possi-
