Sildenafil, a treatment option for PPHN?

Running head: Sildenafil in the NICU The Use of Sildenafil for patients with Persistent Pulmonary Hypertension in the NICU Jessica Sterr Victoria College RSPT 2147 Abstract Background In the Neonatal Intensive Care Unit, there are term and near term infants who suffer from Persistent Pulmonary Hypertension (PPHN) that require expensive treatment options to control or reverse this condition. Such a treatment being used within the hospital is inhaled Nitric Oxide (iNO). This is an excellent treatment option, but it is expensive and not always effective as a treatment by itself to treat PPHN. In these three studies, Sildenafil is introduced to infants with PPHN. Sildenafil is an effective treatment option by itself to treat PPHN as well as an effective treatment option combined with iNO. Methods In study 1, 13 infants were chosen to be in a randomized study. The patients were infants over the age of 35.5 weeks gestation to under the age of 3 years that had severe PPHN and an oxygen index (OI) over 25. In study 2, 30 ventilated infants and children were randomized to receive 0.4 mg/kg of Sildenafil or placebo before discontinuing 10 ppm of iNO. Pulmonary artery pressures (PA) and arterial blood gases were measured in both groups before and after the study to rule out rebound PPHN. In study 3, 15 ventilated infants were chosen to be in a randomized study. All 15 infants were recovering from recent closure of ventricular or atrioventricular septal defects. Eight infants received 20 ppm of iNO with the addition of intravenous Sildenafil (0.35 mg/kg over 20 min). Seven infants received intravenous Sildenafil (0.35 mg/kg over 20 mins) with the addition of 20 ppm of iNO. Results Study 1 found that Sildenafil improved OI within 6 to 30 hours, and steadily improved pulse oxygen saturation over time with no fluctuations in the patients’ blood pressure. In the treatment group, 6 of 7 patients survived. In the placebo group, 1 of 6 patients survived. Study 2 found that rebound of PPHN was found in 10 of 14 patients in the placebo group with an increase PA pressure of 25% (14-67). Rebound PPHN occurred in 0 of 15 Sildenafil patients with an increase of 1% (-9-5). 4 patients from the placebo group could not be weaned from iNO where as all Sildenafil patients could be weaned off of iNO. Lastly, the duration of mechanical ventilation for the placebo group was 98 hours compared to the duration of the Sildenafil group which was 28.2 hours. Study 3 showed that the group receiving the iNO with the addition of Sildenafil had a decrease of Pulmonary vascular resistance index from 3.45 to 2.45 units. In the group receiving Sildenafil with the addition of iNO, there was a decrease of pulmonary vascular resistance index from 2.84 to 2.15 units. In both groups, Sildenafil reduced systemic blood pressure and systemic vascular resistance, and worsened arterial oxygenation and the alveolar-arterial gradient. Discussion/Conclusion The results of study 1 suggests that Sildenafil as an only treatment option can improve Oxygen Index and steadily improve pulse arterial oxygen saturation without causing any fluctuations in systemic blood pressure. Study 2 suggests that Sildenafil, if used before discontinuing iNO, can completely prevent rebound PPHN, decrease duration of mechanical ventilation and shorten the wean time on iNO. Unexpectedly, Study 3 results showed that Sildenafil can lead to hypotension, lowered systemic vascular resistance, and worsened the patient’s oxygenation. For the exception of study 3 results, Sildenafil is an effective drug in reducing pulmonary vascular resistance, therefore increasing arterial oxygenation as a treatment by itself or in combination with iNO. Introduction Sildenafil is an effective treatment option for patients with Persistent Pulmonary Hypertension. This drug is a vasodilator that decreases pulmonary vascular resistance, therefore increasing systemic arterial oxygenation. This is an excellent treatment option that has been shown to decrease mechanical ventilation time, increase oxygenation, and decrease weaning time of inhaled nitric oxide. Sildenafil is an effective treatment option in itself or combined with inhaled nitric oxide. This paper will discuss more in detail how the intervention of Sildenafil used in patients with PPHN improves patients’ health and decreases hospital stay. Methods and Results Study 1 (Baquero, H., Soliz, A., Neira, F., Venegas, M. E., Sola, A., 2006). This proof-of-concept pilot study was randomized, prospective, and masked and performed between 2003 and 2004 in the NICU of Hospital Nin˜ o Jesu´ s in Barranquilla, Colombia. This is a regional NICU serving a population of _10 000 deliveries per year, which is well equipped with modern technology but in which surfactant used is limited for preterm infants with respiratory distress syndrome, and there is no iNO, HFV, or ECMO available. Eligible infants for the study were term or near-term gestation (_35.5 weeks’ gestation) with severe hypoxemia and pulmonary hypertension confirmed by echocardiogram. Only very sick and critically ill term or nearterm newborn infants with PPHN were considered candidates for the study. The infants had to be on mechanical ventilation with an oxygenation index (OI) _40, show clinical signs of severe refractory hypoxemia, and have a known high risk for mortality at this center. The echocardiogram (Sonosite 180 plus) performed before entry had to show evidence of right-to-left shunt and estimated pulmonary artery pressures _40 mm Hg. Exclusion criteria included congenital abnormalities. Congenital heart disease of any type was excluded, including pulmonic stenosis, atrial septal defect, anomalous pulmonary venous drainage, and ventricular septal defect. Arterial blood gases were monitored from an umbilical arterial catheter, and OI was calculated in every arterial blood gas using the PaO2 from the umbilical arterial catheter and the classic formula to calculate OI: OI _ (fraction of inspired oxygen _ mean airway pressure)/PaO2. For this protocol, we decided a priori to also obtain a blood gas 2 hours after each dose of drug or placebo and analyze and report the OI at this time to ensure consistency and accurate comparisons. Pulse oxygen saturation (SpO2) and mean arterial blood pressure (BP) were monitored continuously. For consistency and to avoid including a large number of data points at many different times, we chose to report the data on SpO2 and BP at these preestablished set points of time, 2 hours after each dose, after the predesigned protocol. Clinical management protocols used in the NICU by attending physicians caring for infants with PPHN were not altered if the infant was a study subject. The clinical approach for all of the infants included: no “hyperventilation” but avoidance of hypercarbia (ie, PacO2: 35–50 mm Hg), manual ventilation when needed (ie, severe episode of hypoxemia or of low pH with high PaCO2), avoidance of significant acidosis, (ie, maintain pH_7.30), no alkalosis (ie, not aiming to keep pH _7.45), inotropes (dopamine), and volume infusion to try to preserve intravascular volume and maintain mean arterial BP _50th percentile, and no nitroprusside or tolazoline were used. Improvement in OI was defined as a decrease in OI of _6 from the previous calculated value. Although this is an arbitrary measure, we agreed a priori on the significance of a reduction _10%. For infants with an initial OI value of 40, a decrease of 6 would be a 15% effect. The preparations and schedule for administration of drug and placebo were as follows. A 50-mg tablet of sildenafil was diluted in Orabase as much as will suffice to 25 mL for a final concentration of 2 mg/mL. (If this compound is refrigerated, it would expire 1 month after preparation.) For placebo, an equal volume of diluents (0.5–1 mL/kg) was used. Both drug and placebo were given by orogastric tube, and the protocol for dosing schedule was (a) first dose of 1 mg/kg (0.5 mL/kg) _30 minutes after randomization, (b) dosing every 6 hours, (c) dose could be doubled (2.0 mg/kg or 1.0 mL/kg) if the OI did not improve and the mean BP remained stable after the previous dose, and (d) discontinuation of treatment decided according to 1 of 2 criteria, whichever is earlier: an OI of _20 or maximum number of doses of 8 (ie, a maximum period of 42 hours after the first dose). Randomization was by simple allocation of presealed numbers. Pharmacy prepared the oral preparations in the same containers for placebo and medication and had the sealed code for identification. The administration of drug or placebo was randomly assigned, masked, and bedside clinicians were unaware of group assignment. At the onset of the study it was elected to enter only very sick and critically ill newborn infants with PPHN (OI _ 40), with a known high mortality rate. The initial sample size calculated to assess feasibility, and OI response was 25 infants in each group. Stopping rules for breaking of the codes and analyzing the data included potential significant adverse effects like hypotension, gastric intolerance or bleeding, renal failure, or death in 6 infants. The main outcome variable was the feasibility of administration, gastric tolerance, and the effect of oral sildenafil on OI values. Other variables analyzed were SpO2, PaO2, BP, and survival. Statistical methods used were analysis of variance for comparison of repeated measurements of OI, BP, and SpO2 and Newman-Keuls for posthoc analyses. Fisher’s test was used to compare baseline characteristics and survival between study groups. Significance was set at P _ .05. The research protocol was reviewed by the institutional review board and approved by the ethics committee at Hospital Nin˜ o Jesu´ s, with the stopping rules mentioned above. Eligible infants were entered only after parental informed consent was obtained. There were 42 infants with significant refractory hypoxemia, and 22 met entry criteria with severe PPHN (OI _ 40). Of the 22 infants, 2 died, for 3 the parents were not approached for consent, and for 4 the parents refused. Thirteen infants with an OI of _40 had been enrolled in the study when the study was stopped at institutional review board request for detailed analysis because of 6 deaths. The median age of the 13 infants at the time of entry was close to 25 hours (range: 3–72 hours). Six of the infants had received placebo, and 7 had received oral sildenafil. Table 1 summarizes the characteristics of the infants enrolled, the ventilator parameters, and the initial blood gases and OI at the time of entry. The gender distribution, gestational age, birth weight, Apgar scores, route of delivery, and condition associated with severe refractory hypoxemia, as well as the ventilatory parameters and blood gases were comparable in both groups (Table 1). The mean OI was 56 in the treatment group and 46 in the placebo group with low PaO2 at entry; 34.2 (_12.5) mm Hg and 42.7 (_11.3) mm Hg, respectively. All of the infants were critically ill, receiving fraction of inspired oxygen 1.0 and dopamine for inotropic support. All had been treated at least once with manual ventilation, sodium bicarbonate, and volume infusion. In the treatment group, oxygenation improved in all of the infants sometime between 6 and 30 hours after initiation of treatment, and all of the infants showed a steady and significant improvement in SpO2 over time, different from the placebo group. Figures 1 and 2 show the changes in oxygenation after placebo and sildenafil. The differences were significant (P _ .05) at different times, as shown in the figures. The first dose induced an improvement in OI compared with baseline and with the placebo group, and the significant differences persisted until the last measurement (Figs 1 and 2). There were also differences in PaO2 between the groups, and this became significant over time after 4 doses or 36 hours after entry. In addition, Table 2 shows the individual OI values for each infant in relation to the dose of sildenafil or placebo. Figure 3 shows that oral sildenafil produced no noticeable effect on BP during the study period with the doses used. All of the infants in both groups received dopamine (dose range: 6–20 _g/kg per minute). There was no difference in pressure support or volume infusions between groups. Furthermore, we were unable to identify any adverse effect that could be associated with the treatment. In the treatment group, 6 (85%) of 7 infants survived; the infant who died did so at 72 hours because of a pneumopericardium. In the placebo group, 1 (17%) of 6 infants survived (P _ .02 versus sildenafil group). The infants who died with refractory hypoxemia in the placebo group did so at various postnatal ages (36, 45, 74, 102, or 139 hours). The intragastric administration of the prepared solution was simple and easily accomplished, and the doses were equally well tolerated in the placebo and treatment groups. The number of doses received per infant varied based on the study protocol as described in the “Methods” section. In the sildenafil group, 2 infants had an OI of _20 after the sixth dose by 36 hours. In 1 of these infants, all of the doses were of 1.0 mg/kg per dose, and in the other infant, the dose was 1.0 mg/kg for the first dose and 2.0 mg/kg per dose for the next 5 doses (Table 2). The other 5 infants in the sildenafil group received 7 doses before the OI was _20 (Table 2). Four of them received all 7 doses at 0.5 mL/kg per dose (1 mg/kg), and 1 received the first 2 doses of 0.5 mL/kg and the other 5 of 1.0 mL/kg (2 mg/kg; Table 2). Therefore, the total amount of sildenafil per kilogram varied between infants from 6 to 12 mg/kg (median: 7 mg/kg). In the placebo group, the 6 infants received 0.5 mL/kg as the first dose. All but 1 of the infants received all of the other doses at 1.0 mL/kg (Table 2). No evidence of rebound hypoxemia was found in any of the infants in whom sildenafil was discontinued because of achievement of the prespecified improvement in OI (ie, OI _ 20). We cannot comment on the degree of change in pulmonary artery pressure, because we did not perform repeated echocardiograms before and after each dose. Study 2 (Namachivayam, P., Theilen, U., Butt,, W. W., Cooper, S. M., Penny, D. J., Shekerdemian, L. S., 2006). The institutional ethics committee at the Royal Children’s Hospital, Melbourne, approved this prospective, randomized, double-blinded, placebo-controlled study. This study was performed between August 2003 and November 2005 in the pediatric ICU at the Royal Children’s Hospital, Melbourne. Identification of potential participants and randomization were performed before any attempt was made to reduce inhaled NO below the therapeutic dose. Parents were given information about the study protocol, and written consent was obtained before randomization. All infants and children who were mechanically ventilated on the pediatric ICU and who had been receiving inhaled NO at a dose of 10 ppm or more for at least 12 h, and who did not have any of the exclusion criteria, were eligible for this study. The exclusion criteria were as follows: previous failure to wean from NO, the use of intravenous nitrovasodilators, hepatic failure, an inspired oxygen fraction of greater than 0.6 at the time of recruitment, CHD with obstructed pulmonary or systemic blood flow, or no measurable PA or right ventricular pressure. Thirty children were recruited for the study between July 2003 and September 2005. All participants were intubated, sedated, and ventilated in the ICU, and receiving inhaled NO at 5 ppm or greater at the time of consent. They all had measurable PA pressures, either by echocardiographic estimation of right ventricular systolic pressure from the Doppler-derived tricuspid regurgitant jet velocity (in 14 patients) or from a direct PA line (in 16 patients). Inhaled NO concentration was measured using a bedside chemiluminescence analyzer. The study protocol commenced when participants were receiving 5 ppm of NO; the weaning of NO until this level was entirely at the discretion of the attending ICU physician. The patient, parents, all clinical staff, and investigators were blinded as to the study drug allocation. The study drug was prepared by the Royal Children’s Hospital pharmacy department, and block randomization was performed so that each group of 10 children contained equal numbers of sildenafil or study drug recipients. Each participant was allocated a “study number,” which corresponded to an envelope containing a range of study drug capsules. The study drug was formulated into 1-mg and 5-mg capsules, and each participant’s dose was calculated at 0.4 mg/kg, and then rounded up or down to the nearest 1 mg. Thus, the final dose range was 0.3 to 0.5 mg/kg. All patients had continuous monitoring of systemic arterial blood pressure and central venous pressure via indwelling catheters, and monitoring of heart rate and oxygen saturation. Patients with an indwelling PA pressure–monitoring catheter also had continuous monitoring of PA pressure. Hemodynamic parameters were recorded at 30-min intervals. In our ICU, it is standard practice to wean inhaled NO by 1 ppm every 30 min, and increase the inspired oxygen fraction by 0.2 (20%) during the final 2 ppm of the NO weaning process. The study drug was given by the bedside nurse, via the nasogastric tube, when the patients were receiving 2 ppm inhaled NO, 1 h before the expected discontinuation of NO. An arterial blood gas and PA pressures were recorded at three time points. These were as follows: just before the study drug being given, 1 h after stopping the NO, and 4 h after stopping NO. In patients without a PA catheter, systolic PA pressure was measured using standard equations: from the peak instantaneous echocardiographic Doppler-derived pressure difference between the right ventricle and right atrium, and the simultaneous central venous pressure. None of these patients had obstruction to the right ventricular outflow tract, or intracardiac shunts, which would influence the accuracy of PA pressure measurement. The primary outcome measure was the development of rebound PHT. Rebound PHT was defined as an increase in PA pressure of greater than 20% after discontinuing NO or the urgent need to recommence NO therapy within 4 h of discontinuing NO. Other outcome measures included changes in oxygenation, systemic blood pressure, and duration of mechanical ventilation and ICU stay. Descriptive data are expressed as mean (SD), if normally distributed, or as median (interquartile range). Within-group and between-group comparisons were made using t tests, Wilcoxon rank sum test, or oneway analysis of variance, as appropriate. Using the primary outcome measure of a change in PA pressure after discontinuation of NO between the sildenafil and placebo groups, the following factors were considered in calculating sample size: first, an increase in PA pressure of 20% was used to define rebound; and second, it was assumed that 90% of untreated (placebo) patients would demonstrate increases in PA pressure of between 10 and 40%. Finally, we considered that a reduction by one-third in the incidence of rebound would be the minimum reduction that is likely to be of clinical importance, and was used as the basis for sample size calculation. With a study power of 83%, assuming a standard two-sided _ level of 0.05, then a total sample size of 40 participants (20 participants per study arm) would be necessary. However, it was agreed that interim analysis would be permitted after the first 30 patients were recruited. Interim analysis was performed after the first 30 patients had been randomized, and the study was then stopped based on the significant findings discussed below. The enrollment flow chart is given in Figure 1. One infant who had been randomized to receive placebo died after randomization, but before the weaning process had started (Figure 1). Patient details and indications for NO therapy are given in Tables 1 and 2. Baseline demographic and cardiopulmonary data were similar for the two groups. There were no adverse events associated with the study drug administration. Study 3 (Stocker, C., et al. 2003). This prospective, clinical randomised trial was approved by the local Ethics in Human Research Committee. All infants at our hospital undergoing surgical repair of ventricular septal defects or atrioventricular septal defects with a large left-to-right shunt, diagnosed on pre-operative echocardiography, were eligible for entry to this study. We initially intended to enrol 30 infants, but the trial was terminated early after interim analysis of the first 15 completed studies (see Results). The parents of 18 infants were approached for participation in the study; written consent was obtained from the parents of 17 infants (median age 132 days, range 48–262 days; mean weight 4.8 kg) and studies were carried out in 15 (see Fig. 1 for trial profile). Nine infants had Down’s syndrome. Studies were commenced between 3.8 and 6.7 h after separation from cardiopulmonary bypass. The infants were sedated and musclerelaxed (vecuronium, midazolam and morphine) and mechanically ventilated during the study. All infants were receiving an inspired oxygen fraction of 0.5 at the start of the study. They were receiving a single inotropic agent, either intravenous dopamine or dobutamine (between 1 and 5 μg/kg per min)during the study and doses were not adjusted during the study period. No patient received alpha-blockers, other phosphodiesterase inhibitors or nitrovasodilators at any time prior to or during the study. Any residual intracardiac shunt or significant atrioventricular valve regurgitation was excluded by intra-operative transoesophageal or epicardial echocardiography and by postoperative transthoracic echocardiography. A 3F catheter (Model 94–011–3F, American Laboratories, CA, USA), which incorporated a thermistor, was placed intra-operatively into the pulmonary artery for monitoring pressure and the measurement of CO by thermodilution [17]. Additional catheters were placed directly in the right and left atria and in a peripheral artery, for injectate, pressure monitoring and for blood gas analysis (Ciba Corning Diagnostic Corp, Massachusetts, USA). Systemic and pulmonary arterial, as well as central venous and left atrial pressures, were directly measured with electromechanical pressure transducers (Abbott, Sligo, Ireland), which were calibrated before each study. Cardiac output was measured in triplicate at each data point by thermodilution. (Baxter-Edwards cardiac output monitor, Irvine, CA, USA). One millimetre of 0.9% NaCl at 0–40C was injected into the right atrial catheter and cardiac output was measured using the change in temperature recorded by the pulmonary arterial thermistor. Where PPA, PLA, PArt and PCV are mean pulmonary arterial, left atrial, systemic arterial and central venous pressures, respectively (mmHg); CI is cardiac index (l/min per m2); PAW is mean airway pressure (cmH2O); FiO2 is the fraction of oxygen in inspired gas; PaO2 is the arterial partial pressure of oxygen (mmHg) and PaCO2 is arterial partial pressure of carbon dioxide. Sixteen infants were randomly assigned to one of two study protocols, and 15 infants entered the clinical study (Fig. 1). Randomisation was done by ‘block allocation’ and, prior to the patient returning from the operating theatre, the envelope containing the patient’s group assignment was opened by one of the investigators. The total study duration was 40 min for all participants. Eight infants were randomised to receive nitric oxide first (20 ppm), with fused over 20 min). The other eight infants were randomised to receive intravenous sildenafil first (dose as above), with the addition of nitric oxide at 20 min. A complete set of haemodynamics and an arterial blood gas were recorded, and cardiac output was measured in triplicate, at 0 min (baseline) and at 20 and 40 min (following each intervention). Intravenous sildenafil was provided by Pfizer Pharmaceuticals, Sandwich, UK and the dose (per kg) was based on a pharmacokinetic study in healthy adults [20]. The results were analysed using Sigmastat for Windows, version 2.03 (SPSS, Chicago, IL). The results are expressed as means +- standard errors of the mean (SEM). Student’s t-test was used to compare between group data at baseline and for changes between baseline and each time point, and paired t-tests to compare withingroup data at different time points. Probability values of less than 0.05 were considered statistically significant. One infant developed early post-operative arrhythmias with significant haemodynamic compromise prior to baseline data collection and was excluded from the study. Data were therefore collected for 15 infants: 7 received iNO first and 8 received intravenous sildenafil first. Demographic variables, baseline systemic and pulmonary haemodynamics, and gas exchange data were similar in the two patient groups (Tables 1 and 2). In patients receiving nitric oxide first, by 20 min, the mean PA pressure had fallen by 1.4+- 0.4 mmHg (by 7.8+-2.1%; p=0.008), while mean systemic arterial, left atrial and central venous pressures and cardiac index were all unchanged. The addition of sildenafil to these patients did not further influence PA pressure. However, systemic blood pressure fell by 8.9+- 2 mmHg (13.4+- 2.7%; p=0.004), while left atrial pressure, central venous pressure and cardiac index were unchanged (Table 2, Fig. 2). In patients receiving sildenafil first, by 20 min PA pressure tended to fall (by 10+- 4.1%; p=0.055). Mean systemic arterial pressure fell by 12+- 1.2 mmHg (17+- 1.8%; p<0.001); left atrial and central venous pressures, and cardiac index were unchanged. The addition of nitric oxide resulted in a further reduction in PA pressure to levels which were significantly below baseline (p=0.001) (Table 2, Fig. 2). In infants receiving nitric oxide first, within 20 min of treatment, PVRI fell to 0.54+- 0.16 units below baseline (17+- 5.0%; p=0.01), while SVRI was unchanged. Addition of sildenafil reduced PVRI by a further 0.41+- 0.16 units (16+-5.2%; p=0.04), but also reduced SVRI significantly (by 22+-5.4%; p=0.03; (Table 2, Fig 2)). In infants receiving sildenafil first, PVRI fell by 0.44+-0.16 units (12.8+-5.7%; p=0.03) between 0 and 20 min. However, SVRI also fell by 4.02+-0.58 units (by 23+-2.1%; p<0.001), therefore the pulmonary to systemic vascular resistance ratio was unchanged. The addition of nitric oxide in these infants further reduced PVRI, by 0.25+-0.07 units (7.8+-2.0%; p=0.01), without influencing SVRI. There was no difference in relative reduction of PVRI between the two treatment groups during the first treatment period with nitric oxide or sildenafil alone (p=0.7). Arterial partial pressure of CO2 and pH did not change significantly during any of the therapeutic interventions in either group (Table 2, Fig 3). In patients receiving nitric oxide first, there was a trend towards an improvement in PaO2; and oxygenation index and alveolar-arterial gradient both fell significantly during nitric oxide inhalation alone. However, the addition of intravenous sildenafil in these children reduced PaO2 by 38.2+- 15.9 mmHg (p=0.045) and, as a result, increased the oxygenation index by 1.4+-0.5 (p=0.04) and increased the alveolar-arterial gradient by a mean of 47+-14 mmHg (p=0.03). In those infants receiving sildenafil first, sildenafil reduced the PaO2 by 29.9+-6.9 mmHg (p=0.003), increased the oxygenation index by 2.0+-0.8 (p=0.003) and increased the alveolar-arterial gradient by 30+-6 mmHg (p=0.007). Administration of nitric oxide did not produce any further changes in these variables. Discussion The main goal in study 1 was to see if Sildenafil, as an only treatment option, could reverse refractory hypoxemia in patients with severe PPHN when HFV, ECMO, and iNO were not available. The study’s results showed that Sildenafil was effective in increasing oxygen index and arterial oxygenation without causing fluctuations in systemic blood pressure, although dopamine was administered to all patients. All patients receiving Sildenafil survived without rebound refractory hypoxemia. In study 2 the goal was to see if Sildenafil could decrease the likelihood or completely prevent a rebound of PPHN when iNO is discontinued. The results show that giving Sildenafil before discontinuing iNO decreased pulmonary artery pressures, decreased weaning time from the iNO treatment, and decreased duration on the ventilator. The majority of the placebo group had a rebound of PPHN whereas in the Sildenafil group, none of the patients experienced rebound PPHN. The purpose of study 3 was to see if a treatment option of iNO with the addition of Sildenafil was more effective than the treatment option of Sildenafil with the addition of iNO. It was concluded that iNO with the addition of Sildenail resulted in a greater reduction in pulmonary vascular resistance index than did the treatment option of Sildenafil with the addition of iNO. It was also concluded in this particular study that Sildenafil was linked to reduced systemic blood pressure and arterial oxygenation whereas iNO did not produce any changes to the systemic blood pressure or decreases in oxygenation. Conclusion The use of Sildenafil was an effective treatment option for patients with elevated pulmonary artery pressures in all 3 studies, although Sildenafil was shown to reduce systemic blood pressure as well as the patients’ oxygenation in the last study. In studies 1 and 2, there was a great improvement in oxygenation values. I think Sildenafil is a revolutionary drug that should be more vastly used in the NICU and PICU. It is as effective as iNO, more cost effective, and if combined with iNO, heightens the vasodilatory effects iNO. Despite the drop in systemic blood pressure and oxygenation in Study 3, Sildenafil should be researched further and, if research permits, should be used more frequently with patients. References Baquero, H., Soliz, A., Neira, F., Venegas, M. E., Sola, A. (2006). Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn: A Pilot Randomized Blinded Study. Pediatrics, 117(4), 1077-1083. Retrieved April 22, 2010 from Namachivayam, P., Theilen, U., Butt, W. W., Cooper, S. M., Penny, D. J., Shekerdemian, L. S. (2006). Sildenafil Prevents Rebound Pulmonary Hypertension after Withdrawal of Nitric Oxide in Children. American Journal of Respiratory and Critical Care Medicine, 74, 1042-1047. Retrieved April 22, 2010 from Stocker, C., Penny, D. J., Brizard, C. P., Cochrane, A. D., Soto, R., Shekerdemian, L. S. (2003). Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery Intensive Care Med, 29, 1696-2003. Retrieved April 22, 2010 from

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