Original Article
171
Intravenous Sildenafil in the Management of Pulmonary Hypertension Associated with Congenital Diaphragmatic Hernia Anja Bialkowski1
Florian Moenkemeyer1
Neil Patel1
1 Newborn Intensive Care, Royal Children’s Hospital, Melbourne,
Victoria, Australia
Address for correspondence Neil Patel, MD, Newborn Intensive Care, Royal Children’s Hospital, Flemington Road, Melbourne, Victoria 3141, Australia (e-mail: [email protected]).
Abstract
Keywords
► congenital diaphragmatic hernia ► pulmonary hypertension ► intravenous sildenafil ► phosphodiesterase 5 inhibitor ► newborn infant
Background Pulmonary artery hypertension (PAH) is a significant cause of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). The phosphodiesterase-5 inhibitor sildenafil may be beneficial as a pulmonary vasodilator in CDH. Use of oral preparations of sildenafil may be restricted by feeding delays and intolerance. This study assessed the cardiorespiratory effects of a newly available intravenous (IV) preparation of sildenafil in CDH. Objectives The objective of the article is to assess the acute effects of IV sildenafil infusion on myocardial function, pulmonary artery pressure (PAP), and oxygenation in infants with CDH. Methods Retrospective case review of infants with CDH who received continuous IV sildenafil. Physiological and echocardiographic data were reviewed to obtain oxygenation index (OI), PAP, patent ductus arteriosus (PDA) flow, myocardial tissue Doppler velocities, and right ventricular output (RVO) at 48 hours presildenafil, and at 24 to 48 hours and 72 to 96 hours after commencing IV sildenafil. Results A total of nine infants received IV sildenafil at a dose of 100 to 290 μg/kg/h after CDH repair but before enteral feeding. Pre-IV sildenafil PAP was systemic blood pressure in all infants, systolic and diastolic right ventricular myocardial velocities were impaired. After 72 to 96 hours of IV sildenafil, OI and FIO2 were significantly reduced. Ratio of right-to-left to left-to-right PDA flow was > 1 pre-IV sildenafil and < 1 post-IV sildenafil. Conclusions IV sildenafil infusion was associated with improved oxygenation. Prospective trials of IV sildenafil are required to determine effects on longer term outcome.
Introduction Pulmonary artery hypertension (PAH) is a significant determinant of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH).1,2 Abnormal pulmonary vascular development leads to raised pulmonary vascular resistance (PVR) and hemodynamic derangement characterized by rightto-left shunting (across the atrial septum or patent ductus
received July 5, 2013 accepted after revision August 29, 2013 published online October 25, 2013
arteriosus [PDA]), impaired left ventricular filling and output, and right ventricular dilatation and dysfunction because of increased afterload. In severe cases, the result is biventricular failure, impaired systemic perfusion, hypoxia, and acidosis demanding high levels of cardiorespiratory support. Pulmonary vasodilator therapies are the logical choice in this setting and inhaled nitric oxide (iNO) is the commonest first line agent. However, the response to iNO may be variable,
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0033-1357757. ISSN 0939-7248.
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Eur J Pediatr Surg 2015;25:171–176.
IV Sildenafil in the Management of PAH Associated with CDH no benefit in long-term outcomes has been demonstrated in CDH and the financial costs are significant.3–5 In the search for additional effective pulmonary vasodilators in CDH interest has focused on phosphodiesterase (PDE) inhibition, including the PDE-5 inhibitor sildenafil.6 Oral sildenafil has been demonstrated in randomized controlled trials to improve oxygenation and reduce mortality in infants with persistent pulmonary hypertension of the newborn (PPHN) in the absence of iNO.7,8 The same benefits in oxygenation have been observed in a cohort of infants with PPHN receiving sildenafil in its intravenous (IV) formulation, both with and without concurrent iNO.9 In CDH, no randomized trials of sildenafil have been performed, yet use of oral sildenafil has increased in the past decade.10 Evidence to support sildenafil use in CDH as an adjunct to iNO and to allow iNO weaning is limited to a small number of cases, in which hemodynamic improvement was observed.11,12 The need to administer sildenafil orally is a further complicating factor in CDH. Delayed feeding and feed intolerance are common problems and may affect tolerance, absorption, and bioavailability of the oral formulation. This study followed the introduction of a newly available IV preparation of sildenafil and investigated the effects on cardiac function, pulmonary artery pressure (PAP), and oxygenation.
Aim The aim of the study is to assess the acute effects of IV sildenafil on myocardial function, PAP, and oxygenation in infants with CDH.
Methods Study Design This retrospective cohort study was conducted at the Newborn Intensive Care Unit of the Royal Children’s Hospital, Melbourne, Australia.
Bialkowski et al.
velocity–time integral of flow across the PDA in each cardiac cycle.14 A PDARl:Lr of more than 1 implies net right-to-left flow and suprasystemic PAP. RVO was assessed as previously described.15 Myocardial function was assessed using pulse wave tissue Doppler imaging (TDI). This modality measures regional systolic and diastolic myocardial velocities, has been validated against gold standard catheter measurements, and normative data previously published.16,17 As previously described longitudinal myocardial velocities were obtained from the basal RV during systolic ejection (S′) and early diastolic relaxation (E′), as measures of systolic and diastolic function.18 All data were averaged over five consecutive cardiac cycles.
Demographic, Physiological, and Treatment Data At each echocardiogram, the most recent PaO2, respiratory support (ventilation mode, mean airway pressure [MAP]), FIO2, and all current cardiovascular therapies (cardiotropes, systemic vasodilators and vasoconstrictors, pulmonary vasodilators) were recorded. Daily mean blood pressure was calculated from hourly recordings. Oxygenation index (OI) ([FIO2 MAP 100]: PaO2). Decisions regarding all therapies, including pulmonary vasodilators, were made by the attending neonatologist. Inhaled nitric oxide (iNO) use was guided by a departmental guideline which proposed iNO, at a starting dose of 20 ppm (ppm), for infants requiring FIO2 > 0.75, preductal SaO2 < 90%, preductal and postductal SaO2difference > 20%, and/or echocardiographic evidence of severe PAH with cardiac dysfunction.
Statistical Analysis Summary statistics were calculated for group data. Repeated measures analysis was used to compare changes in variables between presildenafil, 24 to 48 hours, and 72 to 96 hours time points. Any significant differences were subject to posttest comparison to the presildenafil time point. This study was approved by the Research and Ethics Committee of the Royal Children’s Hospital, Melbourne, Australia.
Subjects Infants with CDH were identified who had received IV sildenafil and had echocardiograms performed within three specified time periods: within 48 hours of commencing IV sildenafil (presildenafil), 24 to 48 hours of sildenafil therapy, and 72 to 96 hours of sildenafil therapy. The decision to start, continue, and dose-adjust sildenafil had been made by the attending neonatologist based on clinical and echocardiographic findings.
Echocardiographic Data Echocardiograms performed by a neonatal echocardiographer (NP or FM) were reviewed to assess PAP and myocardial function. PAP was assessed by two methods. The maximal velocity of tricuspid regurgitant jet was used to estimate RV peak systolic pressure (RVSPest), as previously described and assuming a right atrial pressure of 5 mm Hg.13 PAP was also assessed by calculation of the ratio of right-to-left: left-toright flow in the PDA (PDARl:Lr), by measurement of the European Journal of Pediatric Surgery
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Results Nine infants with CDH, two right-sided and seven left-sided, were identified, in whom IV sildenafil was commenced for treatment of PAH with cardiac dysfunction. Demographic and IV sildenafil dosing data are provided in ►Table 1. Six infants had CDH diagnosed prenatally, three infants were postnatally diagnosed (cases 2, 5, and 6). Median (range) gestation was 38.4 (range, 35.5–39.3 weeks) weeks, birth weight 2.97 (range, 2.69–3.57 kg) kg, and age at time of surgical repair of CDH was 5 (range, 2–15 days) days. Four patients required patch repair. All patients received IV sildenafil after surgical repair. Three (33%) patients received venoarterial extracorporeal membrane oxygenation (ECMO) therapy; two patients before and one patient after starting IV sildenafil. All three patients were successfully decannulated from ECMO, and two patients subsequently survived to discharge.
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Median (range) age at commencing IV sildenafil was 15 (range, 7–33 days) days. No infant received a loading dose and all were on continuous infusion. IV sildenafil dose was 100 to 290 μg/kg/h. Six infants survived to discharge at 81 (range, 38–113 days) days. Three infants died, two infants from respiratory failure and chronic PAH at 160 and 72 days (no ECMO), and one infant from severe air leak at 28 days (received ECMO). Enteral feeds were commenced in seven infants at a median 15 (range, 9–40 days) days. Five infants achieved full feeds at 46 (range, 22–77 days) days. No infant was receiving feeds at the time of commencing IV sildenafil. Concurrent therapies at the commencement of IV sildenafil are provided in ►Table 2. Four infants were receiving highfrequency oscillation ventilation and five infants were receiving high-frequency jet ventilation with a median MAP of 11.5 (range, 7–12 cm H2O) cm H2O and FIO2 of 0.4 (range, 0.3–1.0). Six infants were already receiving a cardiotrope (dobutamine or milrinone), five infants were already receiving iNO at 20 (range, 10–30 ppm) ppm before commencement of IV sildenafil. All infants had a widely PDA of whom three infants were receiving prostaglandin E1 (PGE1). During the study period, seven infants had no change to cardiovascular therapies or ventilation mode except for commencement of IV sildenafil. Of the remaining two infants, one (case 4) infant commenced noradrenaline, milrinone, iNO, and PGE1 within 24 hours of IV sildenafil commencement for acute severe postoperative PAH. Another infant (case 7) commenced milrinone 72 hours after commencing IV sildenafil. After commencement of IV sildenafil OI was significantly lower at both 24 to 48 hours and 72 to 96 hours compared with pre-IV sildenafil OI (►Table 3). OI was reduced in surviving and nonsurviving cases. FIO2 was significantly lower at 72 to 96 hours, but not 24 to 48 hours, mean arterial BP did not change significantly at any time point after commencement of IV sildenafil. Echocardiographic data are provided in ►Table 3. Right S′ and E′ velocities were lower than previously reported normal reference values at all time points.16,17 Neither RV S′ nor RV E′ changed significantly within 96 hours of commencing IV sildenafil. RVO was only measureable in four infants because of incomplete data. Mean RVO increased from 265 (47) mL/ kg/min pre-IV sildenafil to 310 (68) mL/kg/min at 72 to 96 hours, but this was not statistically significant. Pre-IV sildenafil all infants had bidirectional shunting in the PDA with a mean (SD) PDARl:Lr of 2.1 (1.1). After commencement of IV sildenafil PDARl:Lr reduced to 0.9 (0.4) at 72 to 96 hours, (not significant). The change in PDARl:Lr post-IV sildenafil to < 1.0 indicated a change from predominantly right-toleft shunting to left-to-right shunting through the PDA. Maximal tricuspid regurgitation velocity could only be consistently obtained in four infants, in whom mean RVSPest decreased from 6818 pre-IV sildenafil to 5412 after 72 to 96 hours, though again this did not reach statistical significance.
Discussion This series described the use of continuous IV sildenafil infusion in infants with severe PAH after CDH repair. IV European Journal of Pediatric Surgery
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Abbreviations: CDH, congenital diaphragmatic hernia; ECMO, extracorporeal membrane oxygenation.
NS at 160 d
NS at 72 d No feeds
30/77 200
150 15
8 No/No
No/No 5
4
2.862 37 þ 3
Left
2.794 38 þ 2
F 9
8
F
Left
45 11/– 290 31 Yes/No 4 3.108 39 þ 3 7
M
Left
113
88 22/47
15/45 100
100 33
19 Yes/No
No/Yes 15
8
2.690 38 þ 4
Right
2.972 35 þ 5
M 6
5
M
Right
73 10/37 100 9 Yes/Yes 7 3.109 38 þ 4 4
F
Left
38
NS at 28 d No feeds
9/22 100
200 20
7 No/No
Yes/Yes 15
2
38 þ 6
Left
3.245
3.570
38 þ 6
M 3
2
F
Left
90 40/64 200 11 No/No 2 Left 2.720 35 þ 6 1
F
Side of CDH Birth weight (kg) Gest. (wks) Sex Case
Table 1 Demographic data, sildenafil dosing and feeding
Age at repair (d)
Patch repair /ECMO
Age at starting IV sildenafil (d)
Max. IV sildenafil dose (μg/kg/h)
Age at start feeds/full feeds (d)
Age at discharge (days) or nonsurvival (NS)
IV Sildenafil in the Management of PAH Associated with CDH
HFOV
HFOV
HFJV
HFOV
HFJV
HFJV
HFJV
HFJV
HFOV
1
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3
No. 2/2015
4
5
6
7
8
9
12
9
12
7
12
11
9
12
11
Mean airway pressure (mm H2O)
0.4
0.5
1.0
0.3
0.4
0.8
0.7
0.4
0.3
FIO2
Milrinone 0.5b
–
iNO 20
Milrinone 0.5
Milrinone 0.5
Milrinone 0.5
–
iNO 20
10
–
iNO 20
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10
10
5
5a
Noradrenaline 0.5a Milrinone 0.3a
iNO 10a
10
Milrinone 0.7
10
10
PGE1, ng/kg/min
iNO 30
Dobutamine 10
Milrinone 0.7
– iNO 20
Cardiotropes and vasoactive drugs, μg/kg/min
Pulmonary vasodilators iNO, ppm
Fentanyl 2 Midazolam 1.5
Fentanyl 2 Midazolam 1
Fentanyl 2 Midazolam 1
Morphine 30 Midazolam 1.5
Fentanyl 1.5 Midazolam 1
Fentanyl 2 Midazolam 1
Fentanyl 4 Midazolam 1
Morphine 20 Midazolam 1
Morphine 20 Midazolam 1
Sedation, (μg/kg/h)
Y
N
Y
N
N
Y
Y
N
N
Muscle relaxation
IV Sildenafil in the Management of PAH Associated with CDH
Abbreviations: HFJV, high-frequency jet ventilation; HFOV, high-frequency oscillation ventilation; PGE1, prostaglandin E1. a Commenced at same time as IV sildenafil for acute severe pulmonary hypertension. b Commenced 72 hours after sildenafil.
Ventilation mode
Case
Table 2 Cardiorespiratory therapies at time of commencing intravenous sildenafil
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Table 3 Effects of IV sildenafil on physiological and echocardiographic parameters Cardiorespiratory parameters mean (SD) FIO2 Oxygenation index
p value
Pre
24–48 h post
72–96 h post
0.53 (0.20)
0.57 (0.25)
0.46 (0.20)a
12.9 (5.9)
12.5 (9.4)
a
8.8 (5.4)
a,b
Reference values 18
0.006
–
0.002
–
51 (3)
53 (6)
52 (6)
0.97
–
S′ (systolic)
7.4 (1.7)
7.8 (2.0)
7.8 (1.6)
0.58
9.2 (1.9)
E′ (diastolic)
4.4 (3.8)
4.3 (4.1)
3.5 (4.1)
0.95
8.6 (20)
Mean arterial BP (mm Hg) RV TDI myocardial velocities (cm/s)
Sildenafil therapy
RVO (mL/kg/min)
265 (47)
282 (53)
310 (68)
0.1
–
PDA Rl:Lr
2.1 (1.1)
1.4 (1.1)
0.9 (0.4)
0.1
–
RVSPest (mm Hg)
68 (18)
57 (7)
54 (12)
0.16
–
sildenafil was administered before commencement of enteral feeds and was associated with an improvement in oxygenation over the subsequent 72 hours. Previous randomized-controlled trials of oral sildenafil in PPHN demonstrated reduced mortality.8 Extrapolating these findings from PPHN, oral sildenafil has crept into widespread use in CDH.10 However, evidence to support sildenafil in this population is limited. Two case reports19,20 and a series of seven infants12 have reported use of oral sildenafil in CDH. A randomized-controlled trial of oral sildenafil for PAH in CDH is in progress.21 Prior reported use of IV sildenafil in CDH is limited to two recent cases in whom intermittent IV sildenafil was associated with improved oxygenation and clinical status postsurgical repair.22 Our data now potentially provides additional evidence of a beneficial effect of sildenafil in CDH. We observed a reduction in OI within 48 hours, which was sustained at 72 to 96 hours, consistent with reports in PPHN.9 The improvement in OI was accompanied by change in mean PDARl:Lr from > 1 to < 1, indicating a change from predominantly right-to-left shunting to predominantly left-to-right shunting, and consistent with a reduction in PAP. However, the reduction in PDARl:Lr did not reach statistical significance on repeated measures analysis. The absence of a significant reduction in PDARl:Lr could have two possible explanations. First, sildenafil’s action on the pulmonary vasculature may have reduced alveolar intrapulmonary shunting (and improved OI), without significantly altering net PAP. An alternative second explanation is that any reduction in PVR and PAP was accompanied by systemic vasodilatation, which minimized the change in ductal pressure gradient and ductal flow. If the latter were true we might have expected a reduction in systemic BP after sildenafil administration, but none was observed. The trend of increasing RVO during sildenafil therapy was not statistically significant, possibly because of the small number of infants in whom it was measureable. Noori et al previously observed an increase in RVO in response to oral sildenafil in CDH, which was considered to indicate pulmonary vasodilatation.12
In this study, we additionally employed TDI to assess myocardial function directly. TDI measures of RV systolic and diastolic function (RV S′ and E′ velocities) presildenafil were reduced compared with normal reference values,16,17 suggesting impaired systolic, and diastolic function because of PAH, and consistent with previous reports in CDH.18 RV S’ and RV E’ were unchanged after IV sildenafil administration. In contrast, we have previously observed that milrinone (a PDE-3 inhibitor) use in CDH is associated with improved oxygenation (OI) and a significant improvement in RV diastolic function (increase in RV E’).23 Taken together with this study, these findings support the hypothesis that sildenafil is acting predominantly at the level of the pulmonary vasculature, while milrinone has an additional direct lusitropic action on the myocardium.6 This study additionally highlighted the benefits of IV preparations over oral sildenafil in CDH. Delay in feeding infants with CDH (because of surgery, prolonged opiate sedation, and muscle relaxation) were evident in our cohort. Although sildenafil may be administered enterally without feeds, bioavailability may be altered. The IV preparation meanwhile may be administered before commencement of feeds and earlier in the disease course. Early use may produce potential benefits to the patient of stabilizing cardiorespiratory status and shortening intensive care, and a cost benefit if other therapies, notably iNO, can be minimized. Of note, three infants in our cohort were not receiving iNO during IV sildenafil, suggesting that the treating team perhaps chose to trial IV sildenafil before or instead of iNO. The infants in our cohort were receiving a varied number of pulmonary vasodilating and cardiotropic agents. This highlights the complex hemodynamic pathology in CDH, the incomplete response to any single agent and the absence of structured rationale therapeutic guidelines. Understanding the actions, interactions and potential benefits to outcome and cost of these agents, including IV sildenafil, now requires further study including collaborative, multicenter randomized controlled trials. European Journal of Pediatric Surgery
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Note: RV TDI velocities (S′, systolic ejection velocity; E′, early diastolic relaxation velocity); RVO, right ventricular output, n ¼ 4; PDARl:Lr, ratio of rightto-left: left-to-right flow in the PDA; RVSPest, RV peak systolic pressure estimated from peak TR jet velocity, n ¼ 4. a p < 0.05 for repeated measures analysis (ANOVA). b p < 0.05 on posttest comparison to presildenafil values.
IV Sildenafil in the Management of PAH Associated with CDH
8 Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in
Limitations The principle limitation of this small, retrospective cohort is that any changes in intercurrent therapies (e.g., cardiotropes, pulmonary vasodilators, and sedation) or clinical condition (e.g., postoperative recovery, sepsis) during IV sildenafil therapy may have affected the findings. However, in the majority of the cohort (seven infants) no changes in any medications occurred during 96-hour study period, other than commencement of IV sildenafil, and none of the cohort developed evidence of sepsis. It was therefore considered that changes in cardiovascular parameters could be most likely attributed to IV sildenafil. There was no control group. The small number of cases may explain the failure of trends in PDARl:Lr and RVSP to achieve statistical significance. Because of the retrospective nature of the study there was incomplete RVO data in five infants. We did not conduct pharmacokinetic studies, however, the doses of IV sildenafil were selected by the treating neonatal team based on current prescribing guidelines. Doses in this range have been previously demonstrated to produce target blood levels in infants.9 All echocardiographic measures are prone to error. We were unable to reliably obtain maximal tricuspid regurgitation jet velocities in five infants, highlighting the limitations of this technique to estimate PAP.
Conflict of Interest None.
9
10
11
12
13
14
15
16
17
18
References 1 Dillon PW, Cilley RE, Mauger D, Zachary C, Meier A. The relation-
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ship of pulmonary artery pressure and survival in congenital diaphragmatic hernia. J Pediatr Surg 2004;39(3):307–312, discussion 307–312 Wynn J, Krishnan U, Aspelund G, et al. Outcomes of congenital diaphragmatic hernia in the modern era of management. J Pediatr 2013;163(1):114–, e110.1016/j.jpeds.2012.12.036 Shah N, Jacob T, Exler R, et al. Inhaled nitric oxide in congenital diaphragmatic hernia. J Pediatr Surg 1994;29(8):1010–1014, discussion 1014–1015 The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997;99(6):838–845 Everest N, Armstrong R, Hunt R. Neonatal outcomes following the introduction of a time-metered nitric oxide delivery system. J Paediatr Child Health 2012;48(S1):A089 Lakshminrusimha S, Steinhorn RH. Inodilators in nitric oxide resistant persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med 2013;14(1):107–109 Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev 2011;(8):CD005494
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infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006;117(4): 1077–1083 Steinhorn RH, Kinsella JP, Pierce C, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr 2009;155(6):841–847, e1 Hunter L, Richens T, Davis C, Walker G, Simpson JH. Sildenafil use in congenital diaphragmatic hernia. Arch Dis Child Fetal Neonatal Ed 2009;94(6):F467 Keller RL, Hamrick SE, Kitterman JA, Fineman JR, Hawgood S. Treatment of rebound and chronic pulmonary hypertension with oral sildenafil in an infant with congenital diaphragmatic hernia. Pediatr Crit Care Med 2004;5(2):184–187 Noori S, Friedlich P, Wong P, Garingo A, Seri I. Cardiovascular effects of sildenafil in neonates and infants with congenital diaphragmatic hernia and pulmonary hypertension. Neonatology 2007;91(2): 92–100 Skinner JR, Stuart AG, O’Sullivan J, Heads A, Boys RJ, Hunter S. Right heart pressure determination by Doppler in infants with tricuspid regurgitation. Arch Dis Child 1993;69(2):216–220 Phillipos EZ, Robertson MA, Byrne PJ. Serial assessment of ductus arteriosus hemodynamics in hyaline membrane disease. Pediatrics 1996;98(6 Pt 1):1149–1153 Tsai-Goodman B, Martin RP, Marlow N, Skinner JR. The repeatability of echocardiographic determination of right ventricular output in the newborn. Cardiol Young 2001;11(2):188–194 Mori K, Nakagawa R, Nii M, et al. Pulsed wave Doppler tissue echocardiography assessment of the long axis function of the right and left ventricles during the early neonatal period. Heart 2004; 90(2):175–180 Negrine RJ, Chikermane A, Wright JG, Ewer AK. Assessment of myocardial function in neonates using tissue Doppler imaging. Arch Dis Child Fetal Neonatal Ed 2012;97(4):F304–F306 Patel N, Mills JF, Cheung MM. Assessment of right ventricular function using tissue Doppler imaging in infants with pulmonary hypertension. Neonatology 2009;96(3):193–199, discussion 200– 202 De Luca D, Zecca E, Vento G, De Carolis MP, Romagnoli C. Transient effect of epoprostenol and sildenafil combined with iNO for pulmonary hypertension in congenital diaphragmatic hernia. Paediatr Anaesth 2006;16(5):597–598 Filan PM, McDougall PN, Shekerdemian LS. Combination pharmacotherapy for severe neonatal pulmonary hypertension. J Paediatr Child Health 2006;42(4):219–220 Children’s Hospital Los Angeles. Ann & Robert H Lurie Children’s Hospital of Chicago, University of California, San Francisco. Chronic Sildenafil for Severe Diaphragmatic Hernia. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2013 Aug 29]. Available from: http://clinicaltrials. gov/show/NCT00133679 NLM Identifier: NCT00133679 Stultz JS, Puthoff T, Backes C Jr, Nahata MC. Intermittent intravenous sildenafil for pulmonary hypertension management in neonates and infants. Am J Health Syst Pharm 2013;70(5):407–413 Patel N. Use of milrinone to treat cardiac dysfunction in infants with pulmonary hypertension secondary to congenital diaphragmatic hernia: a review of six patients. Neonatology 2012;102(2): 130–136
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Intravenous Sildenafil in the Management of Pulmonary Hypertension Associated with Congenital Diaphragmatic Hernia Anja Bialkowski1
Florian Moenkemeyer1
Neil Patel1
1 Newborn Intensive Care, Royal Children’s Hospital, Melbourne,
Victoria, Australia
Address for correspondence Neil Patel, MD, Newborn Intensive Care, Royal Children’s Hospital, Flemington Road, Melbourne, Victoria 3141, Australia (e-mail: [email protected]).
Abstract
Keywords
► congenital diaphragmatic hernia ► pulmonary hypertension ► intravenous sildenafil ► phosphodiesterase 5 inhibitor ► newborn infant
Background Pulmonary artery hypertension (PAH) is a significant cause of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). The phosphodiesterase-5 inhibitor sildenafil may be beneficial as a pulmonary vasodilator in CDH. Use of oral preparations of sildenafil may be restricted by feeding delays and intolerance. This study assessed the cardiorespiratory effects of a newly available intravenous (IV) preparation of sildenafil in CDH. Objectives The objective of the article is to assess the acute effects of IV sildenafil infusion on myocardial function, pulmonary artery pressure (PAP), and oxygenation in infants with CDH. Methods Retrospective case review of infants with CDH who received continuous IV sildenafil. Physiological and echocardiographic data were reviewed to obtain oxygenation index (OI), PAP, patent ductus arteriosus (PDA) flow, myocardial tissue Doppler velocities, and right ventricular output (RVO) at 48 hours presildenafil, and at 24 to 48 hours and 72 to 96 hours after commencing IV sildenafil. Results A total of nine infants received IV sildenafil at a dose of 100 to 290 μg/kg/h after CDH repair but before enteral feeding. Pre-IV sildenafil PAP was systemic blood pressure in all infants, systolic and diastolic right ventricular myocardial velocities were impaired. After 72 to 96 hours of IV sildenafil, OI and FIO2 were significantly reduced. Ratio of right-to-left to left-to-right PDA flow was > 1 pre-IV sildenafil and < 1 post-IV sildenafil. Conclusions IV sildenafil infusion was associated with improved oxygenation. Prospective trials of IV sildenafil are required to determine effects on longer term outcome.
Introduction Pulmonary artery hypertension (PAH) is a significant determinant of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH).1,2 Abnormal pulmonary vascular development leads to raised pulmonary vascular resistance (PVR) and hemodynamic derangement characterized by rightto-left shunting (across the atrial septum or patent ductus
received July 5, 2013 accepted after revision August 29, 2013 published online October 25, 2013
arteriosus [PDA]), impaired left ventricular filling and output, and right ventricular dilatation and dysfunction because of increased afterload. In severe cases, the result is biventricular failure, impaired systemic perfusion, hypoxia, and acidosis demanding high levels of cardiorespiratory support. Pulmonary vasodilator therapies are the logical choice in this setting and inhaled nitric oxide (iNO) is the commonest first line agent. However, the response to iNO may be variable,
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0033-1357757. ISSN 0939-7248.
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IV Sildenafil in the Management of PAH Associated with CDH no benefit in long-term outcomes has been demonstrated in CDH and the financial costs are significant.3–5 In the search for additional effective pulmonary vasodilators in CDH interest has focused on phosphodiesterase (PDE) inhibition, including the PDE-5 inhibitor sildenafil.6 Oral sildenafil has been demonstrated in randomized controlled trials to improve oxygenation and reduce mortality in infants with persistent pulmonary hypertension of the newborn (PPHN) in the absence of iNO.7,8 The same benefits in oxygenation have been observed in a cohort of infants with PPHN receiving sildenafil in its intravenous (IV) formulation, both with and without concurrent iNO.9 In CDH, no randomized trials of sildenafil have been performed, yet use of oral sildenafil has increased in the past decade.10 Evidence to support sildenafil use in CDH as an adjunct to iNO and to allow iNO weaning is limited to a small number of cases, in which hemodynamic improvement was observed.11,12 The need to administer sildenafil orally is a further complicating factor in CDH. Delayed feeding and feed intolerance are common problems and may affect tolerance, absorption, and bioavailability of the oral formulation. This study followed the introduction of a newly available IV preparation of sildenafil and investigated the effects on cardiac function, pulmonary artery pressure (PAP), and oxygenation.
Aim The aim of the study is to assess the acute effects of IV sildenafil on myocardial function, PAP, and oxygenation in infants with CDH.
Methods Study Design This retrospective cohort study was conducted at the Newborn Intensive Care Unit of the Royal Children’s Hospital, Melbourne, Australia.
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velocity–time integral of flow across the PDA in each cardiac cycle.14 A PDARl:Lr of more than 1 implies net right-to-left flow and suprasystemic PAP. RVO was assessed as previously described.15 Myocardial function was assessed using pulse wave tissue Doppler imaging (TDI). This modality measures regional systolic and diastolic myocardial velocities, has been validated against gold standard catheter measurements, and normative data previously published.16,17 As previously described longitudinal myocardial velocities were obtained from the basal RV during systolic ejection (S′) and early diastolic relaxation (E′), as measures of systolic and diastolic function.18 All data were averaged over five consecutive cardiac cycles.
Demographic, Physiological, and Treatment Data At each echocardiogram, the most recent PaO2, respiratory support (ventilation mode, mean airway pressure [MAP]), FIO2, and all current cardiovascular therapies (cardiotropes, systemic vasodilators and vasoconstrictors, pulmonary vasodilators) were recorded. Daily mean blood pressure was calculated from hourly recordings. Oxygenation index (OI) ([FIO2 MAP 100]: PaO2). Decisions regarding all therapies, including pulmonary vasodilators, were made by the attending neonatologist. Inhaled nitric oxide (iNO) use was guided by a departmental guideline which proposed iNO, at a starting dose of 20 ppm (ppm), for infants requiring FIO2 > 0.75, preductal SaO2 < 90%, preductal and postductal SaO2difference > 20%, and/or echocardiographic evidence of severe PAH with cardiac dysfunction.
Statistical Analysis Summary statistics were calculated for group data. Repeated measures analysis was used to compare changes in variables between presildenafil, 24 to 48 hours, and 72 to 96 hours time points. Any significant differences were subject to posttest comparison to the presildenafil time point. This study was approved by the Research and Ethics Committee of the Royal Children’s Hospital, Melbourne, Australia.
Subjects Infants with CDH were identified who had received IV sildenafil and had echocardiograms performed within three specified time periods: within 48 hours of commencing IV sildenafil (presildenafil), 24 to 48 hours of sildenafil therapy, and 72 to 96 hours of sildenafil therapy. The decision to start, continue, and dose-adjust sildenafil had been made by the attending neonatologist based on clinical and echocardiographic findings.
Echocardiographic Data Echocardiograms performed by a neonatal echocardiographer (NP or FM) were reviewed to assess PAP and myocardial function. PAP was assessed by two methods. The maximal velocity of tricuspid regurgitant jet was used to estimate RV peak systolic pressure (RVSPest), as previously described and assuming a right atrial pressure of 5 mm Hg.13 PAP was also assessed by calculation of the ratio of right-to-left: left-toright flow in the PDA (PDARl:Lr), by measurement of the European Journal of Pediatric Surgery
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Results Nine infants with CDH, two right-sided and seven left-sided, were identified, in whom IV sildenafil was commenced for treatment of PAH with cardiac dysfunction. Demographic and IV sildenafil dosing data are provided in ►Table 1. Six infants had CDH diagnosed prenatally, three infants were postnatally diagnosed (cases 2, 5, and 6). Median (range) gestation was 38.4 (range, 35.5–39.3 weeks) weeks, birth weight 2.97 (range, 2.69–3.57 kg) kg, and age at time of surgical repair of CDH was 5 (range, 2–15 days) days. Four patients required patch repair. All patients received IV sildenafil after surgical repair. Three (33%) patients received venoarterial extracorporeal membrane oxygenation (ECMO) therapy; two patients before and one patient after starting IV sildenafil. All three patients were successfully decannulated from ECMO, and two patients subsequently survived to discharge.
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Median (range) age at commencing IV sildenafil was 15 (range, 7–33 days) days. No infant received a loading dose and all were on continuous infusion. IV sildenafil dose was 100 to 290 μg/kg/h. Six infants survived to discharge at 81 (range, 38–113 days) days. Three infants died, two infants from respiratory failure and chronic PAH at 160 and 72 days (no ECMO), and one infant from severe air leak at 28 days (received ECMO). Enteral feeds were commenced in seven infants at a median 15 (range, 9–40 days) days. Five infants achieved full feeds at 46 (range, 22–77 days) days. No infant was receiving feeds at the time of commencing IV sildenafil. Concurrent therapies at the commencement of IV sildenafil are provided in ►Table 2. Four infants were receiving highfrequency oscillation ventilation and five infants were receiving high-frequency jet ventilation with a median MAP of 11.5 (range, 7–12 cm H2O) cm H2O and FIO2 of 0.4 (range, 0.3–1.0). Six infants were already receiving a cardiotrope (dobutamine or milrinone), five infants were already receiving iNO at 20 (range, 10–30 ppm) ppm before commencement of IV sildenafil. All infants had a widely PDA of whom three infants were receiving prostaglandin E1 (PGE1). During the study period, seven infants had no change to cardiovascular therapies or ventilation mode except for commencement of IV sildenafil. Of the remaining two infants, one (case 4) infant commenced noradrenaline, milrinone, iNO, and PGE1 within 24 hours of IV sildenafil commencement for acute severe postoperative PAH. Another infant (case 7) commenced milrinone 72 hours after commencing IV sildenafil. After commencement of IV sildenafil OI was significantly lower at both 24 to 48 hours and 72 to 96 hours compared with pre-IV sildenafil OI (►Table 3). OI was reduced in surviving and nonsurviving cases. FIO2 was significantly lower at 72 to 96 hours, but not 24 to 48 hours, mean arterial BP did not change significantly at any time point after commencement of IV sildenafil. Echocardiographic data are provided in ►Table 3. Right S′ and E′ velocities were lower than previously reported normal reference values at all time points.16,17 Neither RV S′ nor RV E′ changed significantly within 96 hours of commencing IV sildenafil. RVO was only measureable in four infants because of incomplete data. Mean RVO increased from 265 (47) mL/ kg/min pre-IV sildenafil to 310 (68) mL/kg/min at 72 to 96 hours, but this was not statistically significant. Pre-IV sildenafil all infants had bidirectional shunting in the PDA with a mean (SD) PDARl:Lr of 2.1 (1.1). After commencement of IV sildenafil PDARl:Lr reduced to 0.9 (0.4) at 72 to 96 hours, (not significant). The change in PDARl:Lr post-IV sildenafil to < 1.0 indicated a change from predominantly right-toleft shunting to left-to-right shunting through the PDA. Maximal tricuspid regurgitation velocity could only be consistently obtained in four infants, in whom mean RVSPest decreased from 6818 pre-IV sildenafil to 5412 after 72 to 96 hours, though again this did not reach statistical significance.
Discussion This series described the use of continuous IV sildenafil infusion in infants with severe PAH after CDH repair. IV European Journal of Pediatric Surgery
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Abbreviations: CDH, congenital diaphragmatic hernia; ECMO, extracorporeal membrane oxygenation.
NS at 160 d
NS at 72 d No feeds
30/77 200
150 15
8 No/No
No/No 5
4
2.862 37 þ 3
Left
2.794 38 þ 2
F 9
8
F
Left
45 11/– 290 31 Yes/No 4 3.108 39 þ 3 7
M
Left
113
88 22/47
15/45 100
100 33
19 Yes/No
No/Yes 15
8
2.690 38 þ 4
Right
2.972 35 þ 5
M 6
5
M
Right
73 10/37 100 9 Yes/Yes 7 3.109 38 þ 4 4
F
Left
38
NS at 28 d No feeds
9/22 100
200 20
7 No/No
Yes/Yes 15
2
38 þ 6
Left
3.245
3.570
38 þ 6
M 3
2
F
Left
90 40/64 200 11 No/No 2 Left 2.720 35 þ 6 1
F
Side of CDH Birth weight (kg) Gest. (wks) Sex Case
Table 1 Demographic data, sildenafil dosing and feeding
Age at repair (d)
Patch repair /ECMO
Age at starting IV sildenafil (d)
Max. IV sildenafil dose (μg/kg/h)
Age at start feeds/full feeds (d)
Age at discharge (days) or nonsurvival (NS)
IV Sildenafil in the Management of PAH Associated with CDH
HFOV
HFOV
HFJV
HFOV
HFJV
HFJV
HFJV
HFJV
HFOV
1
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3
No. 2/2015
4
5
6
7
8
9
12
9
12
7
12
11
9
12
11
Mean airway pressure (mm H2O)
0.4
0.5
1.0
0.3
0.4
0.8
0.7
0.4
0.3
FIO2
Milrinone 0.5b
–
iNO 20
Milrinone 0.5
Milrinone 0.5
Milrinone 0.5
–
iNO 20
10
–
iNO 20
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10
10
5
5a
Noradrenaline 0.5a Milrinone 0.3a
iNO 10a
10
Milrinone 0.7
10
10
PGE1, ng/kg/min
iNO 30
Dobutamine 10
Milrinone 0.7
– iNO 20
Cardiotropes and vasoactive drugs, μg/kg/min
Pulmonary vasodilators iNO, ppm
Fentanyl 2 Midazolam 1.5
Fentanyl 2 Midazolam 1
Fentanyl 2 Midazolam 1
Morphine 30 Midazolam 1.5
Fentanyl 1.5 Midazolam 1
Fentanyl 2 Midazolam 1
Fentanyl 4 Midazolam 1
Morphine 20 Midazolam 1
Morphine 20 Midazolam 1
Sedation, (μg/kg/h)
Y
N
Y
N
N
Y
Y
N
N
Muscle relaxation
IV Sildenafil in the Management of PAH Associated with CDH
Abbreviations: HFJV, high-frequency jet ventilation; HFOV, high-frequency oscillation ventilation; PGE1, prostaglandin E1. a Commenced at same time as IV sildenafil for acute severe pulmonary hypertension. b Commenced 72 hours after sildenafil.
Ventilation mode
Case
Table 2 Cardiorespiratory therapies at time of commencing intravenous sildenafil
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Table 3 Effects of IV sildenafil on physiological and echocardiographic parameters Cardiorespiratory parameters mean (SD) FIO2 Oxygenation index
p value
Pre
24–48 h post
72–96 h post
0.53 (0.20)
0.57 (0.25)
0.46 (0.20)a
12.9 (5.9)
12.5 (9.4)
a
8.8 (5.4)
a,b
Reference values 18
0.006
–
0.002
–
51 (3)
53 (6)
52 (6)
0.97
–
S′ (systolic)
7.4 (1.7)
7.8 (2.0)
7.8 (1.6)
0.58
9.2 (1.9)
E′ (diastolic)
4.4 (3.8)
4.3 (4.1)
3.5 (4.1)
0.95
8.6 (20)
Mean arterial BP (mm Hg) RV TDI myocardial velocities (cm/s)
Sildenafil therapy
RVO (mL/kg/min)
265 (47)
282 (53)
310 (68)
0.1
–
PDA Rl:Lr
2.1 (1.1)
1.4 (1.1)
0.9 (0.4)
0.1
–
RVSPest (mm Hg)
68 (18)
57 (7)
54 (12)
0.16
–
sildenafil was administered before commencement of enteral feeds and was associated with an improvement in oxygenation over the subsequent 72 hours. Previous randomized-controlled trials of oral sildenafil in PPHN demonstrated reduced mortality.8 Extrapolating these findings from PPHN, oral sildenafil has crept into widespread use in CDH.10 However, evidence to support sildenafil in this population is limited. Two case reports19,20 and a series of seven infants12 have reported use of oral sildenafil in CDH. A randomized-controlled trial of oral sildenafil for PAH in CDH is in progress.21 Prior reported use of IV sildenafil in CDH is limited to two recent cases in whom intermittent IV sildenafil was associated with improved oxygenation and clinical status postsurgical repair.22 Our data now potentially provides additional evidence of a beneficial effect of sildenafil in CDH. We observed a reduction in OI within 48 hours, which was sustained at 72 to 96 hours, consistent with reports in PPHN.9 The improvement in OI was accompanied by change in mean PDARl:Lr from > 1 to < 1, indicating a change from predominantly right-to-left shunting to predominantly left-to-right shunting, and consistent with a reduction in PAP. However, the reduction in PDARl:Lr did not reach statistical significance on repeated measures analysis. The absence of a significant reduction in PDARl:Lr could have two possible explanations. First, sildenafil’s action on the pulmonary vasculature may have reduced alveolar intrapulmonary shunting (and improved OI), without significantly altering net PAP. An alternative second explanation is that any reduction in PVR and PAP was accompanied by systemic vasodilatation, which minimized the change in ductal pressure gradient and ductal flow. If the latter were true we might have expected a reduction in systemic BP after sildenafil administration, but none was observed. The trend of increasing RVO during sildenafil therapy was not statistically significant, possibly because of the small number of infants in whom it was measureable. Noori et al previously observed an increase in RVO in response to oral sildenafil in CDH, which was considered to indicate pulmonary vasodilatation.12
In this study, we additionally employed TDI to assess myocardial function directly. TDI measures of RV systolic and diastolic function (RV S′ and E′ velocities) presildenafil were reduced compared with normal reference values,16,17 suggesting impaired systolic, and diastolic function because of PAH, and consistent with previous reports in CDH.18 RV S’ and RV E’ were unchanged after IV sildenafil administration. In contrast, we have previously observed that milrinone (a PDE-3 inhibitor) use in CDH is associated with improved oxygenation (OI) and a significant improvement in RV diastolic function (increase in RV E’).23 Taken together with this study, these findings support the hypothesis that sildenafil is acting predominantly at the level of the pulmonary vasculature, while milrinone has an additional direct lusitropic action on the myocardium.6 This study additionally highlighted the benefits of IV preparations over oral sildenafil in CDH. Delay in feeding infants with CDH (because of surgery, prolonged opiate sedation, and muscle relaxation) were evident in our cohort. Although sildenafil may be administered enterally without feeds, bioavailability may be altered. The IV preparation meanwhile may be administered before commencement of feeds and earlier in the disease course. Early use may produce potential benefits to the patient of stabilizing cardiorespiratory status and shortening intensive care, and a cost benefit if other therapies, notably iNO, can be minimized. Of note, three infants in our cohort were not receiving iNO during IV sildenafil, suggesting that the treating team perhaps chose to trial IV sildenafil before or instead of iNO. The infants in our cohort were receiving a varied number of pulmonary vasodilating and cardiotropic agents. This highlights the complex hemodynamic pathology in CDH, the incomplete response to any single agent and the absence of structured rationale therapeutic guidelines. Understanding the actions, interactions and potential benefits to outcome and cost of these agents, including IV sildenafil, now requires further study including collaborative, multicenter randomized controlled trials. European Journal of Pediatric Surgery
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Note: RV TDI velocities (S′, systolic ejection velocity; E′, early diastolic relaxation velocity); RVO, right ventricular output, n ¼ 4; PDARl:Lr, ratio of rightto-left: left-to-right flow in the PDA; RVSPest, RV peak systolic pressure estimated from peak TR jet velocity, n ¼ 4. a p < 0.05 for repeated measures analysis (ANOVA). b p < 0.05 on posttest comparison to presildenafil values.
IV Sildenafil in the Management of PAH Associated with CDH
8 Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in
Limitations The principle limitation of this small, retrospective cohort is that any changes in intercurrent therapies (e.g., cardiotropes, pulmonary vasodilators, and sedation) or clinical condition (e.g., postoperative recovery, sepsis) during IV sildenafil therapy may have affected the findings. However, in the majority of the cohort (seven infants) no changes in any medications occurred during 96-hour study period, other than commencement of IV sildenafil, and none of the cohort developed evidence of sepsis. It was therefore considered that changes in cardiovascular parameters could be most likely attributed to IV sildenafil. There was no control group. The small number of cases may explain the failure of trends in PDARl:Lr and RVSP to achieve statistical significance. Because of the retrospective nature of the study there was incomplete RVO data in five infants. We did not conduct pharmacokinetic studies, however, the doses of IV sildenafil were selected by the treating neonatal team based on current prescribing guidelines. Doses in this range have been previously demonstrated to produce target blood levels in infants.9 All echocardiographic measures are prone to error. We were unable to reliably obtain maximal tricuspid regurgitation jet velocities in five infants, highlighting the limitations of this technique to estimate PAP.
Conflict of Interest None.
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10
11
12
13
14
15
16
17
18
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