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Three Part Question

In [a neonate with pulmonary hypertension in whom conventional treatments have failed] is [the use of sildenafil] likely [to improve his/her clinical outcome]?

Clinical Scenario

I report the use of oral sildenafil in a male preterm of 28 weeks gestation, born with congenital hydrops secondary to maternal parvovirus. He received maximal ventilatory and inotropic support. His neonatal course was complicated with pulmonary hypertension refractory to inhaled nitric oxide treatment. Sildenafil was administered via an orogastric tube to the neonate. Forty-eight hours after treatment commenced, echocardiography revealed that the contractility of both ventricles had improved and evidence of tricuspid incompetence had decreased, resulting in a marked reduction in pulmonary arterial pressure. Low dose oral sildenafil was initiated at 250 to 500 micrograms/kg/dose once a day to 3 times a day for 6 to 8 weeks until complete resolution of pulmonary hypertension. This helped the neonate wean from the ventilator and subsequently discharged home on low flow oxygen. There was no major adverse effect noted during the treatment period, except for a small drop in blood pressure post dose administration which was short lived. He had a normal cranial ultrasound.
Had oral sildenafil contributed to the reduction in pulmonary vascular resistance and therefore successful extubation? Should it be considered as a second line treatment for severe pulmonary hypertension?

Search Strategy

Sildenafil. mp AND Pulmonary Hypertension (include all subheadings) AND limit to: all infant (birth to 23 months) Human, English language.
Primary sources:
Medline 1966 to Jan Week 3 2007—using OVID interface
Sildenafil. mp AND Pulmonary Hypertension (include all subheadings) AND limit to: all infant (birth to 23 months) Human, English language.
This gave 28 references; all titles checked—2 included. Case reports, review articles, comment letters, animal studies, congenital diaphragmatic hernia and congenital heart defects were excluded.
Embase 1996 to present: searched with same strategy—no additional papers.
Cinahl 1982 to present: 186 references; all titles checked- 4 considered, nil selected. Animal and adult data excluded
Secondary Sources
BNF for children 2006, indicates sildenafil for use in pulmonary hypertension after cardiac surgery, weaning from nitric oxide, primary pulmonary hypertension and persistent pulmonary hypertension of the newborn
DARE, Clinical Evidence Dec 2005 —0.
Cochrane Library: Systematic Reviews— protocol published (no results), Abstracts of Reviews of Effectiveness—0, Controlled Trials Register—0 (all adult data)

Search Outcome

This gave 28 references; all titles checked—2 included. Case reports, review articles, comment letters, animal studies, congenital diaphragmatic hernia and congenital heart defects were excluded.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Baquero 2006 Colombia	13 infants >35.5 wks to < 3 days with PPHN(OI >25) (6) placebo, and (7) sildenafil (intragastric administration) Median age = 25 hrs Dx by echo, all ventilated & OI >40,rt to left shunt, PA pressure >40mm Hg	Pilot randomized prospective blinded study (level 2b)	Effect on oxygenation index:	Reduction in OI<20 after 36 hrs)6/7 in treatment group vs placebo gp.	1.risk of observer bias 2.small number 3.degree of change in pulmonary artery pressures not measured pre and post treatment dose.
			Effect on saturation:	SpO2 improved in all pts after 4th dose or 36hrs after entry in treatment gp vs. nil in placebo gp
			Effect on blood pressure:	No effect on blood pressure in both groups.
			Survival rates:	In treatment gp, 6/7 (85%) survived vs. 1/6 (17%) in placebo gp.
Namachivayam 2006 Australia	30 vent infants and children, on iNO at doses of 10ppm or more for at least 12hrs, 15 given placebo & 15 given sildenafil before discontinuing NO.1 pt in placebo died before weaning process (N=14 in placebo). Exclusion criteria: Prev failure to wean from NO, the use of IV nitrovasodilators, hepatic failure, Insp Oxy fraction of >0.6 at time of recruitment, CHD with obst pulm or systemic bld flow or no measurable PA or rt vent pressure	RCT, Prospective randomized double blind placebo-controlled trial (level 2b)	Number with rebound Pulm hypertension:	Rebound PHT in 10/14 placebo pts, and 0 /15 in sildenafil pts.	1.small number 2.mean age of pts not mentioned
			Changes in oxygenation:	PA pressure increased by 25% in placebo pts, and by 1% in sildenafil pts.
			Changes in systemic BP:	4 placebo pts could not wean from NO due to severe CVS instability; vs. all sildenafil patients were weaned.
			Duration of mechanical ventilation:	Duration of ventilation after study was 98.0 (47.0–223.5) h for placebo patients and 28.2 (15.7–54.6) h for sildenafil patients
			Duration of ICU stay:	Total ICU stay after study completion was 47.8 (27.6–121.8) h for the sildenafil group, and 189 (77.2–312) h for the placebo group

Comment(s)

Persistent pulmonary hypertension of the newborn (PPHN) is a cyanotic syndrome that occurs primarily in full-term and post mature infants and causes right to left shunts at the atrial or ductal levels or both. Term babies with PPHN show structural changes in pulmonary vascular smooth muscle as a result of chronic prenatal distress. There is an opinion that in preterm babies that PPHN syndrome also exists. In this group of patients the potential pathways to the persistence of high pulmonary vascular resistance are only functional vascular changes precipitated by acute perinatal stress. The cyanosis of PPHN rapidly decreases in preterm infants with clinical resolution occurring promptly if the diagnosis is correct and treatment is started as early as possible.(5)Persistent pulmonary hypertension of the newborn (PPHN) is a complex syndrome with multiple causes, with an incidence of 0.43–6.8/1,000 live births and a mortality of 10–20%.(3)Survivors have high morbidity in the forms of neurodevelopmental and audiological impairment, cognitive delays , hearing loss and a high rate of rehospitalization.(4) Traditional treatments of PPHN encompass the main aims which are to avoid hypoxia, reduce acidosis and maintain perfusion. Treatment with O2, which is a potent pulmonary vasodilator, is begun to maintain PaO2 between 50 and 90 mm Hg to minimize lung injury. Once PaO2 is stabilized, weaning can be attempted by reducing FIO2, then reducing ventilator pressures; changes are gradual, because a large drop in PaO2 can cause recurrent pulmonary artery vasoconstriction. High-frequency oscillatory ventilation (HFOV) expands and ventilates the lungs while minimizing barotrauma and is considered for infants with underlying lung disease in whom atelectasis and ventilation/perfusion (V/Q) mismatch may exacerbate the hypoxemia of PPHN.Inhaled nitric oxide (a selective pulmonary vasodilator) relaxes endothelial smooth muscle thus increasing pulmonary blood flow and rapidly improves oxygenation. Finally, Extracorporeal membrane oxygenation (ECMO) may be used in patients with severe hypoxic respiratory failure defined by an oxygenation index > 35 to 40 despite maximum respiratory support. For newer treatments such as sildenafil, adult data proves that the use of sildenafil has potential beneficial effects to exercise tolerance, cardiac index and quality of life in cases of primary pulmonary hypertension. Few case reports published consider it a promising drug in persistent neonatal pulmonary hypertension. Inhaled Nitric Oxide (NO) produces pulmonary vasodilatation through activation of endothelial guanylyl cyclase, resulting in increased levels of cyclic guanosine monophosphate (cGMP) which relaxes pulmonary vascular smooth muscle. Inhaled NO results in the down-regulation of endogenous NO synthase in the pulmonary vascular endothelium and a reduction in guanylyl cyclase activity, and its cessation results in acute reduction in plasma and lung tissue of cGMP levels. Stopping inhaled NO can therefore be associated with pulmonary vasoconstriction until cGMP levels become naturally replete over subsequent hours. In addition to rebound PHT, the prolonged use of inhaled NO can be associated with methemoglobinemia, the need for continued mechanical ventilation, potentially increased bleeding risk, and significant expense. Effective and successful weaning from inhaled NO, as and when clinically indicated, is clearly pivotal. In theory, if levels of intrinsic cGMP can be pharmacologically maintained during the final stage of weaning inhaled NO, and for up to 4 h after its discontinuation, then rebound PHT might be avoidable. Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE-5) prevents the hydrolytic breakdown of cGMP in the pulmonary vascular smooth muscle. In addition to its pulmonary vasodilator effects there is evidence that it may prevent the recurrence of rebound in infants who have experienced rebound PHT after withdrawal of NO. PDE-5 inhibitors have been used in the treatment of recurrent rebound PHT after previous unsuccessful attempts to wean from inhaled NO in children after surgery for CHD, and in newborn infants with PHT. A potential limitation for its use in patients with acute lung disease has been an observation of arterial hypoxemia secondary to increased intrapulmonary shunt. There have also been concerns about the long term use of sildenafil because of the potential risk of irreversible retinal damage linked to PDE6 inhibition. Marsh et al reports the development of severe ROP with the use of IV sildenafil of unspecified dose for 16 days in a preterm infant of 26 wks, weighing 525gms, this preterm required >6 weeks of mechanical ventilation with oxygen requirements up to 90%, inhaled nitric oxide at high levels (40ppm for 2-3wks) and had evidence of bacterial and fungal sepsis (7). Pierce et al in response to this case report makes a point to reiterate that the preterm had all the risk factors to developing ROP and that NO also has similar vasodilator properties as sildenafil and that to date there are no data on the effect of sildenafil on the developing ocular circulations (8). The study by Baquero et al (1) was prematurely terminated secondary to the 6 deaths in the untreated group due to refractory hypoxemia at various postnatal ages. This study had ethical approval in Columbia, it was conducted in an area where surfactant use was limited in preterm infants with respiratory distress syndrome and there was no iNO, HFV or ECMO available. The improvement in oxygenation index and saturation was statistically significant compared to the placebo group, with the sildenafil dose ranging from 6 to 12 mg/kg .The degree of change in pulmonary artery pressure before and after each dose were not performed and there were issues with bias as clinical response to each infant could not be masked and 'interpretations' by clinicians could not be forbidden. This was a small study however, and the authors did not see an overall survival rate improvement after the study from an average of 20 -35% in their unit to 29% after the drug was initiated, however, details are not given and other alternative treatments were not available. In the study by Namachivayam (2), a single dose of sildenafil has shown to prevent rebound hypertension after withdrawal of NO and reduced the duration of mechanical ventilation. Interestingly also, all patients who failed to wean in the placebo group were electively given sildenafil during a subsequent weaning attempt (more than 24 hrs) and did so successfully with no requirement to reinstitute NO therapy. This study showed that prophylaxis was helpful when considered for weaning patients from inhaled NO. Both studies have also shown that the oral form of sildenafil seemed well tolerated and well absorbed with maximum plasma concentrations reached within 1 hour of its administration. (6).Its elimination half life is between 3 and 4 hours. Being eliminated primarily by a hepatic route, we would suspect that neonates with hepatic dysfunction and those receiving certain antibiotics and antifungal agents may have a reduced clearance of sildenafil. Such adverse effects, however, were not reported in adults. The efficacy of sildenafil as a synergistic agent along with iNO in PPHN may prove useful before ECMO. Ethical issues may arise about randomizing this drug without alternative therapies, however sildenafil's role as a synergistic agent alongside iNO or other treatments when known, would be pivotal. Larger and carefully designed trials are needed to safely qualify its possible therapeutic use and potential toxicity both in the short term and long term in our pediatric population.

Clinical Bottom Line

1) Sildenafil can improve oxygenation, help wean off inhaled NO and reduce the duration of time on the ventilator (Grade C) 2) Oral route of administration seemed tolerable. (Grade C)

References

1. Hernando Baquero, MD, Amed Soliz, MD, Freddy Neira, MD, Maria E. Venegas, MD and Augusto Sola, MD With Persistent Pulmonary Hypertension of the Newborn: A Pilot Randomized Blinded Study Pediatrics Vol. 117 No 4 April 2006, pp. 1077-1083
2. Namachivayam P.Theilen U.Butt WW.Cooper SM.Penny DJ.Shekerdemian LS Sildenafil prevents rebound pulmonary hypertension after withdrawal of nitric oxide in children American Journal of Respiratory & Critical Care Medicine 174(9):1042-7, 2006 Nov