eNeonatal Review Newsletter


		September 2009: VOLUME 6, NUMBER 12 [Editor's Note: If you registered for eNeo LIVE prior to 8/29/09 you will be prompted to register again before returning to the site. A programming error prevented your registration from being saved. We apologize for this inconvenience. This link will take you directly to eNeo LIVE.] *Phosphodiesterase Inhibitors in the Management of Persistent Pulmonary Hypertension of the Newborn (PPHN)* In this Issue... Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that occurs when the pulmonary vascular resistance fails to decrease at birth. Traditional management of PPHN includes ventilation with high concentrations of oxygen and inhaled nitric oxide (iNO). Vasodilators such as nitric oxide (NO) and prostacyclin relax vascular smooth muscle by increasing intracellular concentrations of the second messengers cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). However, nearly 30% to 40% of all patients with PPHN do not demonstrate a sustained improvement in oxygenation with such management. As iNO is not universally effective, there has been considerable interest in understanding and targeting other biochemical pathways that regulate pulmonary vasoconstriction in PPHN. Inhibition of the cGMP degrading phosphodiesterase-5 (PDE5) with sildenafil and inhibition of the cAMP degrading phosphodiesterase-3 (PDE3) with milrinone offer additional ways in which to achieve pulmonary vasodilation in patients with PPHN. In this issue, we review recent data evaluating the rationale behind the use of PDE inhibitors, and discuss the pharmacokinetics and practical aspects of such therapy for the management of PPHN.

LEARNING OBJECTIVES

At the conclusion of this activity, participants should be better able to:

		Describe the limitations of currently approved therapies for persistent pulmonary hypertension of the newborn (PPHN)

		Discuss the rationale behind inhibition of phosphodiesterase enzymes in PPHN

		Identify the benefits and adverse effects associated with the use of sildenafil and milrinone in PPHN

IMPORTANT CME/CNE INFORMATION

Program Begins Below


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THIS ISSUE

		IN THIS ISSUE

		COMMENTARY from our Guest Authors

		HYPEROXIA INCREASES PDE5 EXPRESSION AND ACTIVITY IN FETAL PULMONARY ARTERIES

		ORAL SILDENAFIL IMPROVES OXYGENATION AND REDUCES MORTALITY IN SEVERE PPHN

		PHARMACOKINETICS AND SAFETY OF INTRAVENOUS SILDENAFIL IN PPHN

		INTRAVENOUS MILRINONE IMPROVES OXYGENATION IN PPHN REFRACTORY TO INO

Program Directors

Edward E. Lawson, MD
Professor of Pediatrics
Johns Hopkins University
School of Medicine
Chief, Division of Neonatology
Vice Chair, Department of Pediatrics
Johns Hopkins Children's Center

Christoph U. Lehmann, MD
Associate Professor
Department of Pediatrics
Division of Neonatology
The Johns Hopkins University
School of Medicine

Lawrence M. Nogee, MD
Professor
Department of Pediatrics
Division of Neonatology
The Johns Hopkins University
School of Medicine

Mary Terhaar, DNSc, RN
Assistant Professor
Undergraduate Instruction
The Johns Hopkins University
School of Nursing

Anthony Bilenki, MA, RRT
Technical Director
Respiratory Care Services
Division of Anesthesiology and Critical Care Medicine
The Johns Hopkins Hospital
Baltimore, Maryland

GUEST AUTHORS OF THE MONTH

		Commentary & Reviews
		Satyan Lakshminrusimha, MD Associate Professor of Pediatrics Department of Pediatrics University at Buffalo School of Medicine and Biomedical Sciences Buffalo, New York

		Commentary
		Robin H. Steinhorn, MD Raymond and Hazel Speck Berry Professor of Neonatology Professor of Pediatrics Feinberg School of Medicine Northwestern University Head, Neonatology Children's Memorial Hospital Chicago, Illinois

Guest Faculty Disclosure

Dr. Lakshminrusimha has no relevant financial relationships to disclose

Dr. Steinhorn has no relevant financial relationships to disclose

Unlabeled/Unapproved Uses

The authors have indicated that they will reference the unlabeled/unapproved uses of sildenafil and milrinone in this publication.

Program Directors' Disclosures

	Program Information CE Info Accreditation Credit Designations Intended Audience Learning Objectives Internet CME/CNE Policy Faculty Disclosure Disclaimer Statement Length of Activity 1.0 hour Physicians 1 contact hour Nurses Release Date September 17, 2009 Expiration Date September 16, 2011 Next Issue October 15, 2009


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In this podcast, Dr. Lakshminrusimha discusses the experimental uses of sildenafil and milrinone for treating PPHN.

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COMMENTARY

The primary goal of persistent pulmonary hypertension of the newborn (PPHN) therapy is selective pulmonary vasodilation. Nitric oxide (NO) mediates vasodilation by stimulating soluble guanylate cyclase (sGC) and increasing cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells. Similarly, agents such as prostacyclin stimulate adenylate cyclase and increase intracellular cAMP levels. Both cGMP and cyclic adenosine monophosphate (cAMP) serve as central second messengers that modulate vascular tone in the pulmonary circulation by reducing the cytosolic concentration of ionic calcium (see Figure 1, below). Therapeutic strategies that increase cGMP and cAMP could restore normal vascular reactivity and improve oxygenation in infants with PPHN.

The 5’-phosphodiesterase enzyme (PDE5) is the predominant isoform in the lung that metabolizes cGMP. Inhibition of PDE5 activity would be expected to increase intracellular cGMP in pulmonary vascular smooth muscle cells, increase the efficacy of endogenous and exogenous NO, and result in pulmonary vasodilation. PDE3 is an important enzyme metabolizing cAMP in the vasculature and cardiac myocytes. Inhibition of PDE3 activity increases cAMP in cardiac muscle and vascular smooth muscle, resulting in inotropic vasodilation.

Ventilation with high levels of supplemental oxygen to avoid hypoxia and promote pulmonary vasodilation has traditionally been the mainstay of therapy in PPHN. Infants with PPHN are often ventilated with ~100% oxygen in the acute phase of PPHN. Recently, the rationale behind the use of high concentrations of inspired oxygen has been questioned,¹ with a growing appreciation for the effects of reactive oxygen species on the newborn lung and pulmonary arteries.^2,3 Brief resuscitation with 100% oxygen increased the contractile responses of pulmonary arteries in lambs³ and resulted in prolonged oxidative stress in human infants.⁴ Farrow and colleagues (reviewed in this issue) recently reported that exposure of fetal pulmonary artery smooth muscle cells (FPASMCs) to hyperoxia increased PDE5 protein expression and activity, resulting in reduced accumulation of intracellular cGMP in response to exogenous NO. Inhibition of PDE5 with sildenafil partially rescued cGMP responsiveness to exogenous NO. Ventilation of normal newborn lambs with 100% oxygen for 24 hours resulted in increased PDE5 expression and activity in the resistance pulmonary arteries. Hyperoxic ventilation increases PDE5 protein expression and activity, potentially limiting cGMP response to exogenous and endogenous NO. Inhibition of PDE5 is potentially an ideal target in patients failing to respond to ventilation with high levels of inspired oxygen and iNO.

The NO-sGC pathway is not the only source of cGMP in pulmonary vascular smooth muscle cells. Natriuretic peptides, such as the B-type natriuretic peptide (BNP), stimulate membrane-bound particulate guanylate cyclase (pGC) and increase cGMP in vascular smooth muscle cells (see figure). Although endogenous NO levels are decreased in various animal models of PPHN, circulating BNP levels are significantly elevated in neonates with PPHN.⁵ The natriuretic peptide-pGC system may be an additional source of cGMP in the pulmonary circulation of infants with PPHN and may potentially contribute to the increased effectiveness of PDE5 inhibitors in such patients.

In 1998, the U.S. Food and Drug Administration (FDA) approved sildenafil (Viagra^®; Pfizer Inc; New York, NY), a selective and potent PDE5 inhibitor for the treatment of erectile dysfunction. Following this approval, multiple studies demonstrated the efficacy of sildenafil in animal models and human adults with pulmonary hypertension. In 2005, the FDA approved the use of sildenafil under a different brand name (Revatio^®; Pfizer Inc; New York, NY) for use in adults with pulmonary arterial hypertension. Sildenafil was noted to be effective in attenuating rebound pulmonary hypertension following withdrawal of iNO in cardiac surgery patients.⁶ Studies in animal models⁷ and anecdotal case reports confirmed the efficacy of sildenafil in acute neonatal pulmonary hypertension. A 2006 small, randomized, blinded study conducted by Baquero and associates (reviewed in this issue) evaluated the effect of enteral sildenafil in PPHN. The investigators treated 13 patients with severe PPHN in a neonatal intensive care unit in Colombia — a country with no access to iNO or extracorporeal membrane oxygenation (ECMO) — with either sildenafil or placebo. Improved oxygenation and lower mortality were associated with the use of oral sildenafil. Similar improvements were reported by Herrea and coworkers in a randomized trial of 24 term neonates with PPHN.⁸ As discussed in this issue, Mukherjee and associates and Steinhorn and colleagues recently reported the results of an open-label pharmacokinetic trial of intravenous (IV) sildenafil in 36 infants with PPHN. Sildenafil was effective in improving oxygenation in patients with PPHN with and without prior exposure to iNO. Systemic hypotension was the most common adverse effect reported. Administration of a loading dose slowly over 3 hours, followed by a maintenance dose of sildenafil, reduced the risk for systemic hypotension. These data suggest a beneficial effect with oral as well as IV sildenafil in PPHN.

Milrinone, the prototype PDE3 inhibitor, is commonly used in adult and pediatric intensive care settings as an inotropic vasodilator. Agents that increase cAMP levels in pulmonary artery smooth muscle cells (PASMCs), such as milrinone and prostacyclin, provide an alternate pathway of pulmonary vascular relaxation and potentially result in improved oxygenation in patients with poor response to iNO.⁹ Unpublished data from our laboratory show a marked increase in PDE3 activity and reduced cAMP in pulmonary arteries following ventilation of lambs with iNO. Milrinone can be effective in PPHN by inhibiting PDE3 and increasing cAMP, causing direct pulmonary vasodilation¹⁰ and a synergistic effect with iNO. Milrinone may also improve cardiac function by positive inotropy (improved contraction), lusitropy (improved relaxation), and reduced ventricular afterload. Bassler and associates and McNamara and coworkers (reviewed in this issue) describe 13 patients with PPHN refractory to iNO from Ontario, Canada, who were treated effectively with milrinone.

To summarize, current management strategies for PPHN, including high levels of inspired oxygen and iNO, are not effective in approximately 30% of patients. These therapies can result in increased expression of PDE5 and PDE3 enzymes in pulmonary arteries, thus reducing the intracellular concentrations of cGMP and cAMP in pulmonary arterial smooth muscle cells. The rationale for the use of sildenafil and milrinone in PPHN includes (1) enhancement of the vasodilator effect of iNO; (2) prevention of rebound pulmonary hypertension; (3) limiting the dose and toxicity of iNO; and (4) pulmonary vasodilation in clinical situations in which iNO and ECMO are not available or are contraindicated. By virtue of its being an inotropic vasodilator, milrinone may be effective in infants with left ventricular dysfunction with associated pulmonary venous hypertension — a situation in which iNO is contraindicated.

In conclusion, sildenafil and milrinone are promising therapies for patients with PPHN resistant to iNO. The studies reviewed below and several additional case reports justify the need for large, randomized, controlled studies to establish the efficacy of these agents in critically ill infants with PPHN.^11,12 Unexpected complications, such as intracranial hemorrhage reported by Bassler and colleagues following the use of milrinone in patients with PPHN, underscore the need for such studies.¹³

To print or download full page figure, View here

Commentary References

1.	Aschner JL, Fike CD. New developments in the pathogenesis and management of neonatal pulmonary hypertension. In: Bancalari E, Polin RA, eds. The Newborn Lung—Neonatology Questions and Controversies. Philadelphia, PA: Saunders Elsevier; 2008: 241-299.

2.	Farrow KN, Lakshminrusimha S, Reda WJ, Wedgwood S, Czech L, Gugino SF, et al. Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2008;295(6):L979-L987.

3.	Lakshminrusimha S, Russell JA, Steinhorn RH, et al. Pulmonary arterial contractility in neonatal lambs increases with 100% oxygen resuscitation. Pediatr Res. 2006;59(1):137-141.

4.	Vento M, Asensi M, Sastre J, Lloret A, García-Sala F, Viña J. Oxidative stress in asphyxiated term infants resuscitated with 100% oxygen. J Pediatr. 2003;142(3):240-246.

5.	Reynolds EW, Ellington JG, Vranicar M, Bada HS. Brain-type natriuretic peptide in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatrics. 2004;114(5):1297-1304.

6.	Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology. 1999;91(1):307-310.

7.	Shekerdemian LS, Ravn HB, Penny DJ. Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension. Am J Respir Crit Care Med. 2002;165(8):1098-1102.

8.	Herrea J, Castillo R, Concha E, Soliz A. Oral sildenafil treatment as an alternative to inhaled NO therapy for persistent pulmonary hypertension of the newborn. Abstract presented at: 2006 Pediatric Academic Societies (PAS) Annual Meeting. April 29-May 2, 2006; San Francisco, CA. Abstract 3724.3.

9.	Kelly LK, Porta NF, Goodman DM, Carroll CL, Steinhorn RH. Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide. J Pediatr. 2002;141(6):830-832.

10.	Lakshminrusimha S, Porta NF, Farrow KN, Chen B, Gugino SF, Kumar VH, et al. Milrinone enhances relaxation to prostacyclin and iloprost in pulmonary arteries isolated from lambs with persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med. 2009;10(1):106-112.

11.	Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev. 2007;(3):CD005494.

12.	Kissoon N. Treatment of persistent pulmonary hypertension of the newborn (PPHN) is in its infancy. J Crit Care. 2006;21(2):223.

13.	Bassler D, Choong K, McNamara P, Kirpalani H. Neonatal persistent pulmonary hypertension treated with milrinone: four case reports. Biol Neonate. 2006;89(1):1-5.

HYPEROXIA INCREASES PDE5 EXPRESSION AND ACTIVITY IN FETAL PULMONARY ARTERIES

Farrow KN, Groh BS, Schumacker PT, Lakshminrusimha S, Czech L, Gugino SF, et al. Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells. Circ Res. 2008;102(2):226-233.

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		View Journal Abstract				View Full Article

PDE5 activity is a key factor determining the intracellular levels of cGMP and pulmonary vascular tone. This study evaluated the effect of high oxygen on cGMP content, and PDE5 expression and activity, in the pulmonary arteries. Pulmonary arteries were studied using 2 protocols: (1) FPASMCs were obtained from near-term gestation fetal lambs and incubated in 21%, 50%, or 95% oxygen. Some cells were also exposed to an NO donor—sildenafil or hydrogen peroxide. Levels of cGMP, and PDE5 protein and activity, were determined. (2) Near-term gestation lambs were ventilated for 24 hours and pulmonary arterial tissue was harvested. PDE5 protein and activity were determined in the pulmonary arteries.

Treatment of FPASMCs incubated in 21% oxygen with an NO donor resulted in a significant increase in cGMP levels. However, incubation of FPASMCs in 50% or 95% oxygen significantly blunted the increase in cGMP levels in response to the NO donor. Incubation in 50% or 95% oxygen increased PDE5 protein expression and activity in a dose-dependent manner. Similarly, treatment of FPASMCs with an exogenous oxidant (hydrogen peroxide) significantly increased PDE5 protein expression and activity. Treatment of FPASMCs with the PDE5 inhibitor sildenafil partially rescued cGMP responsiveness to the NO donor. Interestingly, sildenafil decreased PDE5 activity and protein expression in FPASMCs exposed to 100% oxygen. To verify that the effects of hyperoxia on PDE5 were not confined to isolated FPASMCs, the authors mechanically ventilated newborn lambs with 100% oxygen for 24 hours and harvested resistance pulmonary arteries. Nonventilated fetal lambs and 1-day- old spontaneously air-breathing lambs were used for comparison. There was a trend toward decreased PDE5 protein expression in 1-day- old lambs compared with fetal lambs. However, ventilation with 100% oxygen significantly increased PDE5 protein expression and activity. More recently, the authors reported that ventilation of PPHN lambs for 24 hours with 100% oxygen, or with 100% oxygen plus 20 parts per million (ppm) iNO, increased the lung PDE5 activity to 132% and 165% of fetal levels, respectively.¹

This study demonstrates that exposure of pulmonary arterial smooth muscle cells to high concentrations of oxygen (50% and 100%) results in decreased cGMP responsiveness to exogenous NO, which is an important therapeutic vasodilator for infants with pulmonary hypertension. The blunted response to NO is attributed partly to increased PDE5 protein expression and activity. Reactive oxygen species, in general and hydrogen peroxide in particular, induced long-lasting changes in PDE5 expression and activity. As expected, treatment with sildenafil inhibited PDE5 activity and increased cGMP levels in FPASMCs exposed to 100% oxygen. However, sildenafil also decreased PDE5 protein expression in these cells, suggesting that the agent may induce more profound and long-lasting changes that result in increased cGMP levels and prolonged pulmonary vasodilation. These findings represent the first description of redox regulation of PDE5. This study demonstrates that commonly used therapies for PPHN may increase PDE5 expression and activity, and reduce cGMP levels, thus establishing the rationale for PDE5 inhibition in PPHN.

A recent review by Konduri and Kim² pointed out that the incidence of failure to respond to iNO increases with increasing oxygenation index (OI; defined as mean airway pressure x FiO₂ x 100 ÷ postductal PaO₂ [partial pressure of oxygen in arterial blood]) at study entry in the 6 large, randomized, control trials evaluating iNO in PPHN. One of the probable mechanisms of poor response to iNO may be increased PDE5 activity following prolonged hyperoxic ventilation.

References

1.	Farrow KN, Czech L, Lakshminrusimha S, Gugino SF, Russell JA, Steinhorn RH. Effects of hyperoxia and nitric oxide on PDE5 expression and activity in persistent pulmonary hypertension (PPHN).. Abstract presented at: 2006 Pediatric Academic Societies (PAS) Annual Meeting. April 29-May 2, 2006; San Francisco, CA. Abstract 3875.4.

2.	Konduri GG, Kim UO. Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn.. Pediatr Clin North Am. 2009;56(3):579-600. [AUTHOR: Please verify accuracy of citation added here]

ORAL SILDENAFIL IMPROVES OXYGENATION AND REDUCES MORTALITY IN SEVERE PPHN

Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics. 2006;117(4):1077-1083.

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		View Journal Abstract				View Full Article

This was a randomized, masked, proof-of-concept pilot study conducted in Colombia in a unit without iNO, high-frequency ventilation, or ECMO. The objective of the study was to systematically obtain preliminary information regarding the feasibility of oral sildenafil administration and its effect on oxygenation in infants with severe PPHN.

A total of 13 term and near-term infants with hypoxemic respiratory failure, an oxygen index (OI) ≥40, and echocardiographic evidence of pulmonary hypertension were randomized to receive oral sildenafil (n=7) or placebo (n=6). A 50-mg tablet of sildenafil was diluted in Orabase^® (Colgate-Palmolive Company; New York) to 25 mL to provide a final concentration of 2 mg/mL (this preparation is stable for 1 month if refrigerated). The study drug was administered at an initial dose of 1 mg/kg every 6 hours. The dose could be doubled (ie, 2 mg/kg) if the OI did not improve and the infant’s mean systemic blood pressure was stable. A maximum of 8 doses were administered. Treatment was discontinued if the OI was <20. The total cumulative dose in the sildenafil group ranged from 6 to 12 mg/kg (median, 7 mg/kg).

All of the infants were critically ill, with a mean OI of 56 in the treatment group and 46 in the placebo group prior to initiation of the study drug. The etiology of PPHN was parenchymal lung disease (either meconium aspiration or respiratory distress syndrome). In the treatment group, oxygenation improved in all 7 infants some time between 6 and 30 hours after initiation of treatment. One infant in the treatment group died at 72 hours of age because of a pneumopericardium. The remaining infants in the treatment group survived without experiencing any significant adverse effects. Of the 6 infants in the placebo group, 5 died between 36 to 139 hours of age. No evidence of rebound hypoxemia was detected in any of the infants in whom sildenafil was discontinued because of improvement in OI.

In summary, this pilot study shows that oral administration of sildenafil is feasible, and improves oxygenation and survival in critically ill infants with PPHN secondary to parenchymal lung disease in centers without access to high-frequency ventilation, iNO, or ECMO. The authors concluded that larger clinical studies to evaluate the pharmacokinetics, optimal dosing, adverse effects, and long-term outcomes with oral sildenafil are warranted before the agent can be prescribed off-label for the treatment of neonatal hypoxemic respiratory failure.

PHARMACOKINETICS AND SAFETY OF INTRAVENOUS SILDENAFIL IN PPHN

Mukherjee A, Dombi T, Wittke B, Lalonde R. Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period. Clin Pharmacol Ther. 2009;85(1):56-63.

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		View Journal Abstract				View Full Article

Steinhorn RH, Kinsella JP, Butrous G, Dilleen M, Oakes M, Wessel DL. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension of the newborn. J Pediatr. In press.

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No abstract available at this time.

These 2 articles report the results of a pilot study that evaluated the pharmacokinetics, safety, and tolerability of IV sildenafil. Neonates (>34 weeks’ gestation) with PPHN and hypoxemic respiratory failure were included in this trial. All infants had an OI ≥15 on 2 separate occasions, at least 30 minutes apart, prior to infusion of sildenafil. Infants with congenital anomalies (including diaphragmatic hernia) or in immediate need of ECMO were excluded from the study. Administration of iNO was allowed at any time prior to or during the study. IV sildenafil was administered by 8 different sequential “step-up” dosing groups, based on pharmacokinetic profile. These dose protocols differed with respect to loading dose and duration, and maintenance dose. All infants except for those in 1 protocol received a loading dose, followed by a maintenance infusion of variable duration. The loading doses ranged from 0.07 to 1.51 mg, administered over a period of 5 minutes to 3 hours.

A total of 36 infants received IV sildenafil. All infants were treated with inotropic medications for systemic blood pressure support. Overall, 29 infants were already receiving iNO at the time of sildenafil initiation. One infant was withdrawn from the study because the sildenafil infusion had to be stopped after 2 minutes because of hypotension. Another infant developed moderate hypotension 3 hours after sildenafil infusion. Sildenafil was discontinued in this infant, who subsequently required cannulation for ECMO 4 hours later. For the remaining infants, OI values improved significantly during the course of sildenafil infusion, with no significant changes in blood pressure and heart rate. There was no improvement in oxygenation in the treatment groups with low plasma sildenafil levels (3.7 ± 4.6 ng/mL) following the loading dose. Treatment groups with high initial sildenafil levels (58.4 ± 44.8 ng/mL) showed a significant improvement in oxygenation (OI decreased from 28.7 ± 5.6 to 19.3 ± 6.4 at 4 hours after infusion).

A total of 7 infants were enrolled without prior use of iNO, with all experiencing a significant improvement in oxygenation following sildenafil administration. OI improved from 24.6 ± 4.6 (baseline) to 16.1 ± 9.9 at 1 hour after sildenafil infusion and to 14.7 ± 6.4 at 4 hours after beginning sildenafil infusion. Only 1 infant (in a protocol resulting in a low plasma level of sildenafil) required iNO. The 6 remaining infants improved and survived to hospital discharge without the need for iNO or ECMO.

The most common sildenafil-related adverse event was low or labile systemic blood pressure. A rapid loading dose (over 5 minutes) was more likely to cause hypotension. A total of 10 infants receiving milrinone (a PDE3 inhibitor) and sildenafil did not develop hypotension. One baby with meconium aspiration, birth asphyxia, and bilateral tension pneumothoraces died due to complications unrelated to sildenafil treatment.

Additional data from recent literature regarding sildenafil pharmacokinetics are clinically relevant. In healthy adults, sildenafil is absorbed well from the gastrointestinal tract (~ 41%), with a mean half-life between 3 hours and 5 hours.¹ In children with pulmonary hypertension, plasma levels achieved following oral administration of sildenafil are similar to those of adults.² Sildenafil undergoes almost complete hepatic metabolism to N-desmethyl sildenafil (with 50% bioactivity of the parent compound) by the cytochrome P450 3A4 (CYP3A4; 79%) and CYP2C9 (20%) enzyme systems, and a small quantity (<1%) is excreted unchanged in the urine. Studies using in vitro analysis of postmortem samples report a rapid increase in expression of CYP3A4 and CYP2C9 immediately after birth, from substantially low levels in the fetal liver.³ Sildenafil clearance is approximately one-third of adult values 24 hours after birth and increases rapidly by 3-fold from day 1 to day 7. Hence, postnatal age at the time of sildenafil initiation has a significant impact on drug clearance. Significant increases in sildenafil concentrations may occur when the agent is used concomitantly with CYP3A4 inhibitors, such as cimetidine and erythromycin.⁴

These studies report the largest clinical experience with sildenafil in critically ill newborn infants with PPHN, and provide valuable data regarding the safety, efficacy, and pharmacokinetics of the agent. Sildenafil is effective in improving oxygenation both as an independent pulmonary vasodilator and as an adjunct to iNO. The incidence of major adverse effects, need for ECMO, and death were low in this series of critically ill patients.

Previous reports in animal models and infants following cardiac surgery have suggested that the combination of iNO and sildenafil may be associated with significant systemic hypotension and reduced oxygenation. In contrast, in this series, the combination of sildenafil and iNO did not result in significant hypotension, and was associated with improvement in oxygenation. The authors speculate that exposure to high concentrations of inspired oxygen may have increased the activity of PDE5 in the lung (as described in the review by Farrow and colleagues elsewhere in this issue), rendering sildenafil more selective to the pulmonary circulation.

These studies also provide important information on dosing and duration of administration. Groups receiving higher loading and maintenance infusion doses of sildenafil had greater short-term improvements in oxygenation than did groups receiving lower doses. Initiation of sildenafil as a maintenance dose only, without a loading dose, resulted in a delay of at least 24 hours in achieving target plasma levels. Sildenafil-related hypotension was more common with rapid administration of a loading dose (over ≤30 minutes). In contrast, administration of a loading dose over 3 hours was well tolerated. The authors suggested a dosing regimen of 0.4 mg/kg load over 3 hours, followed by a maintenance infusion of 1.6 mg/kg/day for future studies evaluating the use of sildenafil in PPHN. Interestingly, this dose (2 mg/kg on the first day) is approximately equivalent to 5 mg/kg/day of enteral sildenafil (similar to the dose effectively used by Baquero and associates in the study reviewed earlier). The authors concluded their discussion by emphasizing the need for a large, randomized clinical trial to determine the therapeutic role of sildenafil in PPHN.

References

1.	Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol. 2002;53(suppl 1):5S-12S.

2.	Karatza AA, Bush A, Magee AG. Safety and efficacy of Sildenafil therapy in children with pulmonary hypertension. Int J Cardiol. 2005;100(2):267-273.

3.	Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T. Expression of CYP3A in the human liver–evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem. 1997;247(2):625-634.

4.	Young TE, Magnum B. Neofax. 21st ed. Montvale, NJ: Thomson Reuters; 2008.

INTRAVENOUS MILRINONE IMPROVES OXYGENATION IN PPHN REFRACTORY TO INO

Bassler D, Choong K, McNamara P, Kirpalani H. Neonatal persistent pulmonary hypertension treated with milrinone: four case reports. Biol Neonate. 2006;89(1):1-5.

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McNamara PJ, Laique F, Muang-In S, Whyte HE. Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. J Crit Care. 2006;21(2):217-222.

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These 2 retrospective case reports from 2 different hospitals in Ontario, Canada, examined 13 critically ill late preterm or term infants (except 1 infant at 26 weeks’ gestational age) with hypoxemic respiratory failure or PPHN unresponsive to iNO.

Bassler and coworkers reported on 4 infants. Some of the infants were “primed” with normal saline (15 mL/kg) and received a loading dose of 50 µg/kg/min over 30 minutes, followed by 0.33 µg/kg/min. None of the infants developed systemic hypotension and all of them showed consistent improvement in oxygenation. One of the infants, at 26 weeks’ gestational age, developed bilateral intraventricular hemorrhage (IVH) with moderate dilation of all ventricles. Another term infant developed an IVH. A third infant (gestational age, 39 weeks) developed a small left subependymal hemorrhage.

McNamara and associates reported on 9 term infants with PPHN and poor response to inhaled NO, who received IV milrinone. Infants with congenital diaphragmatic hernia and other lung anomalies were excluded from the study. Pharmacokinetic studies in preterm neonates recommend administration of a loading dose to rapidly achieve therapeutic levels. Because of the potential risk for systemic hypotension, a loading dose was avoided in these patients with PPHN. The infusion was started at 0.33 µg/kg/min and increased in increments of 0.33, based on clinical response, to a maximum of 0.99 µg/kg/min. There was a significant improvement in oxygenation after commencement of milrinone, particularly in the first 24 hours of infusion. Tachycardia improved and there was no hypotension. No additional inotropic support was required. The authors noted a trend toward improved blood pressure.

Milrinone is an agent commonly used in intensive care settings and may provide a new strategy for neonates who respond suboptimally to iNO. These authors found that the addition of IV milrinone improved oxygenation without compromising systemic blood pressure. It is of concern that 2 of the 4 cases in the study by Bassler and coworkers reported significant IVH. Although IVH could be the result of multiple factors unrelated to milrinone use, including extreme prematurity in 1 infant, this finding does suggest that the combination of iNO and milrinone may not be entirely benign. McNamara and colleagues suggest that the clinical improvement observed in these patients could be due to a direct effect of milrinone on the pulmonary vascular bed or secondary to improved myocardial performance. As mentioned in the accompanying editorial, neither of these studies addressed the use of milrinone as a single agent for the treatment of PPHN. Additional large, randomized studies evaluating the role of milrinone alone and in combination with iNO in PPHN are warranted.



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