Treatment of premature infants with pulmonary hypertension and right ventricular dysfunction with milrinone: a case series

Journal of Perinatology (2015) 35, 268 273 2015 Nature America, Inc. All rights reserved 0743-8346/15 www.nature.com/jp ORIGINAL ARTICLE Treatment of premature infants with pulmonary hypertension and right ventricular dysfunction with milrinone: a case series AT James 1, C Bee 1, JD Corcoran 1, PJ McNamara 2,3, O Franklin 4 and AF EL-Khuffash 1,5 OBJECTIVE: Milrinone has been proposed as an effective treatment for pulmonary hypertension (PH) and right ventricular (RV) dysfunction. We aimed to determine the effect of milrinone therapy on clinical and echocardiography parameters of PH in preterm infants with elevated pulmonary pressures. STUDY DESIGN: A retrospective case review was conducted on infants o32 weeks gestation who received milrinone for the treatment of PH and reduced RV function. Echocardiographic data were collected before and after treatment with milrinone, and serial clinical parameters were recorded over a 72h period. RESULT: Seven infants met the inclusion criteria with a median gestation and birth weight of 27.3 weeks and 1140 g, respectively. Four infants had a diagnosis of pulmonary hypoplasia with PH, and three infants were recipients in twin-to-twin transfusion syndrome who also developed PH. Nitric oxide was used in six infants before commencement of milrinone. Milrinone was commenced at a dose of 0.33 μgkg 1 min 1 to 0.5 μgkg 1 min 1 and continued for a median duration of 70 h. Use of milrinone was associated with a fall in oxygenation index and inhaled nitric oxide dose. Following an initial fall in blood pressure over the first 6 h, there was an increase in blood pressure over the subsequent 72 h. Echocardiographic data demonstrated an increase in indicators of myocardial performance and PH. One infant died before discharge. CONCLUSION: This case series suggests that milrinone may be a useful therapy for premature infants with echocardiography findings of PH and/or RH dysfunction. This data support the need for a randomised control trial to confirm its efficacy. Journal of Perinatology (2015) 35, 268 273; doi:10.1038/jp.2014.208; published online 27 November 2014 INTRODUCTION Pulmonary hypertension (PH) in preterm infants is increasingly recognized as a cause of impaired oxygenation despite ventilation and surfactant therapy. The exact incidence of PH in the preterm population is currently unknown because of the confounding effect of respiratory distress syndrome and the lack of robust echocardiography studies in the early transitional period assessing the presence of PH in this population. Right ventricular (RV) dysfunction accompanying PH may have a vital role in determining the risk of mortality in those infants. An enhanced understanding of the specific physiology may add to our understanding of treatment response and factors influencing survival. Two conditions that can lead to PH in the preterm infant are pulmonary hypoplasia secondary to preterm premature rupture of membranes (PPROM) and twin-to-twin transfusion syndrome (TTTS). 1 3 Preterm infants with PPROM have a high perinatal mortality of up to 90%, presumed secondary to abnormalities of airway or vascular developments and associated PH. Early identification of PH and/or RV dysfunction and initiation of treatment may enhance neonatal outcomes. 4 TTTS complicates between 10 and 15% of monochorionic diamniotic twin pregnancies. The RV in recipient fetuses is thought to be vulnerable to changes in loading conditions but data are limited. 5 Inhaled nitric oxide (ino) has been used in preterm infant with PH with little evidence for its efficacy. 6 In addition, the cost associated with the use of ino in some jurisdictions can prohibit its widespread and prolonged use. As a result, exploring new therapeutic options in those conditions is warranted. Milrinone has recently been proposed for therapeutic use in premature infants with PH. 7 Milrinone has pulmonary vasodilatory properties through its actions on phosphodiesterase 3 (PDE3), which acts to increase cyclic adenosine monophosphate, causing relaxation of vascular smooth muscle and increasing cardiac muscle contractility. In term infants with persistent PH of the newborn, milrinone leads to an improvement in pulmonary and systemic hemodynamics in patients with suboptimal response to ino. 8 We report outcomes of seven preterm infants with PH and/ or RV dysfunction identified on echocardiography who were subsequently treated with milrinone. METHODS This retrospective case series was conducted at the neonatal intensive care unit of the Rotunda Hospital, Dublin, Ireland, between January and December 2013. Preterm infants o32 weeks gestation, with an antenatal diagnosis of PPROM or TTTS, who underwent an echocardiogram following birth and received milrinone for a diagnosis of PH and/or RV dysfunction were included. The study was approved by the Rotunda Hospital Research and Ethics Board. Preterm infants with hypoxemia secondary to respiratory distress syndrome following birth are treated with early surfactant. Infants failing to respond to surfactant and ventilation with a clinical picture suggestive of PH accompanied by an antenatal history of PPROM or TTTS are commenced on ino after ruling out conditions such as pneumothoraces. 1 Department of Neonatology, The Rotunda Hospital, Dublin, Ireland; 2 Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Canada; 3 Department of Neonatology, The Hospital for Sick Children, Toronto, Canada; 4 Department of Paediatric Cardiology, Our Lady s Children s Hospital Crumlin, Dublin, Ireland and 5 Department of Paediatrics, Royal College of Surgeons in Ireland, Dublin, Ireland. Correspondence: Dr A EL-Khuffash, Consultant Neonatologist, The Rotunda Hospital, Honorary Clinical Senior Lecturer, Royal College of Surgeons in Ireland, Dublin 1, Ireland. E-mail: afif@physicians.ie Received 7 August 2014; revised 22 September 2014; accepted 14 October 2014; published online 27 November 2014

It is the policy of our unit that all infants receiving ino undergo an echocardiogram within 12 h of commencement to rule out congenital heart disease, determine the degree of PH and assess the presence of RV dysfunction. Infants with evidence of RV dysfunction on the echocardiogram accompanying PH and those with a lack of clinical response to administered ino are commenced on milrinone in an attempt to augment ino action on the pulmonary vasculature and improve RV function. Milrinone is commenced at an initial dose of 0.33 to 0.5 μgkg 1 min 1 and continued depending on clinical response. No loading dose is used in this cohort to minimize the risk of hypotension. Oxygen requirement and ino are weaned in responders according to unit protocol: infants with a response to ino (defined as a fraction of inspired oxygen (FiO 2 ) requirement of 40% to achieve adequate saturation) for 6 to 12 h are deemed suitable for weaning. Initially ino is weaned by 5 ppm every 4 h until 5 ppm is reached. The ino is then weaned by 1ppm every 4 h until discontinued. If there is an increase in oxygen requirements (420%) to maintain adequate saturation or a discrepancy in the pre/post ductal saturations, the weaning regime is held for 4 h. Treatment for premature infants with PH and RV dysfunction The primary outcome was the effect of milrinone on oxygenation over the subsequent 72 h of treatment. We also examined the change in blood pressure, FiO 2, and ino dose over the same time points. In addition, we examined the change in PH and RV function measured by TnECHO before and after milrinone treatment. Other measures included the dose and duration of ino therapy, heart rate, ventilation status including FiO 2 and MAP, and death before discharge. Statistical analysis Demographic, echocardiography and inotrope data were presented using absolute values for each case. Summarized data were presented as medians (inter-quartile range). Serial cardiorespiratory parameters and echocardiography measurements were represented in tabular form and graphically. Paired data comparisons were carried out if indicated using the Wilcoxon signed-ranks test for two groups or the nonparametric analysis of variance for multiple groups. We used SPSS version 21 for analysis. A P-value of o0.05 was considered significant. 269 Clinical data collection The following data were collected from the health-care records: indication for milrinone, time of commencement, initial dose, maximum dose, duration of milrinone, dose and duration of ino treatment, ventilation mode, mean airway pressure (MAP), FiO 2 and details of other inotropes. Cardio-respiratory variables are recorded hourly on all infants receiving invasive ventilator support by the nursing staff. The following hemodynamic variables were collected at baseline (before milrinone commencement) and for a period of 72 h after commencement of milrinone at 1, 6, 12, 24, 48 and 72 h retrospectively from the nursing observation sheets; heart rate, systolic, diastolic and mean blood pressure, and blood gases. Oxygenation index, a measure of the oxygenation dysfunction, was calculated post hoc from information obtained from the records using the following formula: oxygenation index = (mean airway pressure (in cm H 2 O) fraction of inspired oxygen)/(partial pressure of arterial oxygen (in Kpa) 7.5 100). All infants underwent invasive blood pressure monitoring. Creatinine levels were collected from the hospital laboratory records system before commencement of milrinone and after drug discontinuation in all infants. Platelet counts were collected before milrinone treatment, the day after discontinuation and 5 to 7 days after discontinuation. The following outcome data were collected: pulmonary hemorrhage, chronic lung disease (defined as the need for oxygen at 36 weeks corrected gestation), intraventricular hemorrhage (graded based on the Papile classification), periventricular leukomalacia and death before discharge. Echocardiography A targeted neonatal echocardiogram (TnECHO) was performed on all infants with a suggestive history of PH following birth before commencement of milrinone. The TnECHO assessment was based on previously described methodology. 9,10 We assessed the degree of PH as follows: RV systolic pressure was estimated from the tricuspid regurgitant jet, if present, using the modified Bernoulli equation and assuming a right atrial pressure of 5 mm Hg; The inverse ratio between pulmonary artery acceleration time and RV ejection time (RV ejection time:pulmonary artery acceleration time) was also measured. This provides a surrogate estimation of pulmonary vascular resistance, represented by higher values. 11 We confirmed the presence of PH on TnECHO as: RV systolic pressure equal to or greater than the systemic systolic pressure; bowing of the interventricular septum in the LV cavity in systole; bidirectional or right-to-left shunting across the patent ductus arteriosus (PDA) or a RV ejection time: pulmonary artery acceleration time 44. We assessed RV function as follows: right ventricular output; RV four-chamber fractional area change (a measure of the change in RV cavity area from diastole to systole in the four-chamber view); RV systolic and diastolic velocity using tissue Doppler imaging (TDI). RV dysfunction was diagnosed subjectively by a visual examination of the RV-free wall movement following consultation with a pediatric cardiologist. We assessed LV functional parameters as follows: left ventricular output; LV shortening fraction; LV systolic and diastolic velocities using TDI. We measured the mitral valve inflow velocity time index as an estimate of preload and pulmonary venous return. A second echocardiogram was performed after milrinone therapy at a mean of 24 h with the same parameters measured to assess response to milrinone treatment. We used the objective measures described above to provide a baseline pre milrinone treatment to detect treatment response. RESULTS Infant clinical characteristics Seven infants with a diagnosis of PH and/or RV dysfunction who were treated with milrinone were identified. The median (interquartile range) gestational age and birth weight were 27.3 (26.8 to 30.6) weeks and 1140 (890 to 1600) g, respectively. Baseline characteristics and outcomes are shown in Table 1. Four infants were born with pulmonary hypoplasia secondary to PPROM and three were a recipient twin of TTTS. There were no cases of necrotizing enterocolitis or pulmonary hemorrhage. Baseline hemodynamic data are shown in Table 2.Six neonates received ino before commencement of milrinone. Milrinone was initiated at a median time of 9.5 h (inter-quartile range 1.62 to 22.25) following ino treatment. Milrinone was started at a mean dose of 0.5 mcgs kg 1- min 1 for a median duration of 70 h. One infant died before discharge (Case 2) on day 47 of age. This infant had a history of pulmonary hypoplasia and pneumothoraces and was commenced on milrinone on day 29 of life after an episode of acute hypoxemia and echocardiographic finding of PH with RV dysfunction. A transient improvement was achieved in the clinical and echocardiography parameters, but this infant subsequently died 18 days later. The latter three cases were recipient infants of TTTS. Cases 5 and 6 received milrinone therapy for poor RV function, although oxygen needs were low. One infant did not receive ino therapy (Case 7) but showed evidence of significant RV dysfunction on echocardiography. Change in cardiorespiratory parameters An overall reduction in the oxygenation index, dose of ino and FiO 2 was seen after commencement of milrinone (Figure 1).There was an initial fall in systolic, mean and diastolic blood pressure at 6 h, which recovered to baseline levels by 24 h. None of the infants were in receipt of other inotropes prior to, or within the first 6 h of milrinone commencement. Three infants (Cases 1, 4 and 5) received dopamine during milrinone treatment after 6 h. One further infant (Case 3) required dopamine and adrenaline to maintain an adequate blood pressure during milrinone treatment. Change in echocardiography parameters Changes in echocardiography parameters before and after treatment with milrinone are illustrated in Table 3 and Figure 2. Six infants (cases 1 to 6) demonstrated a fall in pulmonary pressure following the administration of milrinone. There was a fall in the RV systolic pressure in three infants, a decrease in the RV ejection time:pulmonary artery acceleration time ratio in four infants, and a change in the PDA peak pressure systolic gradient from negative (right to left) to positive (left to right) in four infants. Shortening fraction and mitral valve velocity time index both increased following administration of milrinone in all infants. This was 2015 Nature America, Inc. Journal of Perinatology (2015), 268 273

Treatment for premature infants with PH and RV dysfunction 270 Table 1. Clinical demographics, diagnosis and outcomes Death pre-discharge Cystic PVL CLD Early IVH Hospital stay (days) Days on oxygen CPAP days Indication Ventilation days Gender Apgar scores (1 min/5 min) Birth weight (grams) Case Gestation (weeks) 1 27 2/7 900 Male 7/9 Pulmonary hypoplasia/ph 21 45 20 85 Yes Yes No No 2 26 6/7 545 Male 7/9 Pulmonary hypoplasia/ph 33 15 47 47 Yes Yes Yes Yes 3 26 3/7 890 Female 1/5 Pulmonary hypoplasia/ph 21 50 92 92 Yes No No No 4 27 2/7 1140 Male 8/9 Pulmonary hypoplasia/ph 6 35 28 76 Yes No No No 5 30 4/7 1600 Male 3/2 TTTS recipient/ph 11 11 11 37 No No Yes No 6 30 6/7 1695 Female 4/8 TTTS recipient/ph 4 4 0 34 No No No No 7 28 5/7 1550 Male 7/9 TTTS recipient 22 23 22 53 Yes No No No Abbreviations: CLD, chronic lung disease; CPAP, continuous positive pressure ventilation; IVH, intraventricular hemorrhage; PH, pulmonary hypertension; PVL, periventricular leucomalacia; TTTS, twin-to-twin transfusion syndrome. Early IVH is defined as IVH in the first 7 days of life. Both infants had a grade I IVH. accompanied by an increase in left ventricular output. TDI demonstrated modest increase in systolic and diastolic velocities of the LV and RV. RV fractional area change did not change over the treatment period (24% (19 to 30) vs 25% (24 to 30)). None of those changes were statistically significant. The PDA closed in two of the study cases during milrinone treatment (cases 6 and 7). There was no clinical deterioration following PDA closure in those two infants, with both demonstrating low pulmonary pressures during the follow-up scan. The PDA spontaneously closed prior to discharge in a further three infants, with all three infants demonstrating left-to-right shunting prior to spontaneous closure. Case 1 required a PDA ligation at three weeks of age and case 2 required medical treatment to achieve closure at 2 weeks of age (Table 3). Both of those infants had leftto-right shunting across the PDA at the time of treatment with no evidence of elevated pulmonary pressures. Case 2 subsequently died 3 weeks later, however, as described above; there was no acute deterioration associated with PDA treatment. Change in laboratory parameters Baseline platelet count pre milrinone treatment was 208 10 3 microl 1 (136 to 239) in the group. There was a decrease to 185 10 3 microl 1 (76 to194) following treatment and a recovery to 213 10 3 microl 1 (150 to 268) 5 to 7 days following treatment (P = 0.005). There was no change in creatinine levels before and after treatment (87 μmol l 1 (50 to 96) vs 76 μmol l 1 (70 to 87), P = 1.0). DISCUSSION PH in preterm infants is an under recognized phenomenon and as such, information on its incidence is lacking. It is most commonly associated with PPROM where mortality ranges from 75 to 90% owing to resultant pulmonary hypoplasia. 12,13 A recent Cochrane review of the use of ino in this population concluded that ino does not appear to be effective in preterm infants with hypoxic respiratory failure and does not improve survival without bronchopulmonary dysplasia. The lack of effect may be related to the under recognition of the accompanying RV dysfunction; in other conditions associated with PH (such as congenital diaphragmatic hernia), RV dysfunction is an independent predictor of mortality. 14 In TTTS, fetal studies have demonstrated abnormal myocardial performance in the recipient twin. Recipient RV and LV are both globally depressed with systolic and diastolic dysfunction as estimated by speckle-tracking echocardiography. 15 The RV of the recipient fetus is known to be vulnerable to altered loading conditions. Interestingly, those changes are not detectable using conventional imaging methods such as fractional shortening. 5 Some longer term follow-up studies conducted on TTTS survivors beyond the first year of life demonstrate no impact on LV or RV function. 16,17 However, early neonatal data on the post natal adaptation of myocardial performance of the recipient infant, the association with clinical instability after birth, response to therapeutic intervention and long-term outcomes does not exist to date. The relative lack of response to ino in preterm infants with PH, coupled with the potentially prohibitive cost, and the need to address RV dysfunction that may accompany PH in those settings have prompted the need to explore newer therapeutic options. Cyclic nucleotide phosphodiesterases (PDE) are a family of enzymes that hydrolyze the phosphodiester bond in camp and cgmp, thereby inhibiting their pulmonary vasodilator properties. Two isoforms, PDE3 and PDE5 are abundantly present in the neonatal lung and have a key role in the pathogenesis of PH. 18 PDE3 has a predominant hydrolyzing effect on camp. Milrinone is a selective PDE3 inhibitor with pharmacological effects, including relaxation of vascular smooth muscle, enhanced myocardial Journal of Perinatology (2015), 268 273 2015 Nature America, Inc.

Treatment for premature infants with PH and RV dysfunction 271 Table 2. Baseline hemodynamic data, milrinone and other inotropes use Case Sys BP Dias BP OI FiO 2 (%) ino (ppm) Starting dose (μ kg 1 min 1 ) Start time (hours of life) Maximum dose (μ kg 1 min 1 ) Duration of treatment (hours) Additional inotropes 1 35 23 42 100 20 0.33 6 0.5 46 Dopamine (6 12 h) 2 66 39 8 29 15 0.5 707 0.5 125 None 3 52 24 13 50 20 0.5 4 1.0 245 Dopamine (6 44 h)/ adrenaline (24 48 h) 4 40 15 14 66 20 0.5 5 0.6 70 Dopamine (6 24 h) 5 48 30 13 35 20 0.5 16 0.75 104 Dopamine (24 48 h) 6 45 32 3 21 20 0.5 25 0.6 34 None 7 34 29 2 21 0 0.5 22 0.5 24 None Abbreviations: BP, blood pressure; FiO 2, fraction of inspired oxygen; ino, inhaled nitric oxide; OI, oxygenation index; ppm, parts per million. Figure 1. Change in clinical parameters after treatment with milrinone. The x axis represents the median baseline values (Pre) and time in hours following milrinone treatment. The changes were not statistically significant (one-way repeated measures ANOVA). Table 3. Echocardiography data before and 24 h post milrinone treatment Case RVSp (mm Hg) RVET/PAAT PDA diameter (mm) PDA systolic gradient (mm Hg) PDA flow direction Before After Before After Before After Before After Before After 1 41.85 NA 5.56 3.33 3.21 3.58 9.19 2.64 Right to left Bidirectional 2 NA NA 4.76 2.86 3.25 3.61 3.58 2.38 Bidirectional Bidirectional 3 NA 32.23 4.35 3.13 2.47 3.1 5.26 7.11 Right to left Bidirectional 4 34.08 17.09 3.57 5.26 3.32 3.2 4.93 5.09 Bidirectional Bidirectional 5 52.73 21.23 3.85 2.56 4.34 4.28 10.32 3.61 Bidirectional Bidirectional 6 70.87 36.47 2.7 3.45 3.26 0 16.89 NA Bidirectional Closed 7 NA 13.67 4.17 4.35 1.43 0 9.68 NA Left to right Closed Abbreviations: NA, not available; PAAT, pulmonary artery acceleration time; PDA, patent ductus arteriosus; RVET, right ventricular ejection time; RVSp, right ventricular systolic pressure. contractility (inotropy) and improved myocardial relaxation (lusitropy). 19,20 In the newborn lamb model, intravenous milrinone augments the action of PGl 2 (prostaglandins) on pulmonary vasculature by significantly shortening the onset and prolonging the duration and degree of pulmonary vasodilation produced by PGI 2. 21,22 Milrinone may also exhibit synergistic effects with ino in lowering PVR. In animal models and clinical pediatric studies, milrinone demonstrates a synergistic effect when used with ino in 2015 Nature America, Inc. Journal of Perinatology (2015), 268 273

272 Treatment for premature infants with PH and RV dysfunction Figure 2. Change in tissue Doppler indices (TDI). None of the changes were statistically significant (Wilcoxon signed-ranks test). lowering pulmonary vascular resistance. 23,24 These pulmonary vasodilatory properties are less well defined in premature infants. The use of milrinone is established in neonates and children following cardiac surgery for the prevention of low cardiac syndrome and the treatment of PH. 25,26 In preterm infants, milrinone administration after PDA ligation averts postoperative cardiorespiratory instability, which is termed as post ligation cardiac syndrome. 26,27 Its use in the setting of PH of the preterm and term newborn has not been formally evaluated and is limited to case series demonstrating improvement in oxygenation when used in infants with PH failing to respond to ino. 28 30 There is only a single randomized controlled trial of milrinone use in premature infants. Paradisis et al. 31 demonstrated that milrinone did not lead to improvement in superior vena cava flow in premature infants during the first 24 h of life. There are many limitations to this study. Most importantly, data are not provided regarding the physiologic contributors to low superior vena cava flow, which is unfortunate as the impact on pulmonary vascular resistance during the transitional period would have revealed important insights. In this case series, the use of milrinone in preterm infants with PH and/or RV dysfunction was associated with an improvement in the oxygenation index, a fall in FiO 2 and a reduction of ino dose in the subsequent 24 h. In addition, there was a reduction in pulmonary pressure assessed by echocardiography, and a concomitant increase in pulmonary venous return (increased mitral valve velocity time index) and left ventricular output. In all infants, closure of the PDA (either spontaneously or following intervention) did not result in hypoxemia or an acute clinical deterioration, suggesting that pulmonary pressures remained low beyond the treatment period with milrinone. The mortality rate of those infants appeared favorable when compared with the literature with only one infant dying prior to discharge. However, all of the infants with PPROM developed chronic lung disease. In our cohort, we examined functional echocardiographic markers by comparing both pre and post milrinone values. Tissue Doppler indices have been shown to be a reliable marker of both systolic and diastolic function in the preterm infant. 32 34 The increase in TDI indices in the RV and LV suggests that the use of milrinone not only helps to reduce the pulmonary vascular resistance, but also has the dual effect of improving myocardial function of the right ventricle. TDI velocities are heavily influenced by loading conditions and as a result, the increase in LV function measured by those parameters may be a consequence of improved preload. This is supported by the increase in mitral valve velocity time index observed in this cohort following milrinone treatment. The improvement in RV function may have resulted from reducing RV exposed afterload as a consequence of lower pulmonary vascular resistance. This increase in function may be a contributor to the improved oxygenation and reduced need of other pulmonary vasodilator therapy. We recognize that there are limitations to this study including the small sample size and retrospective nature of the study design. In addition, our subjective assessment of RV function as a guide to starting milrinone is not ideal. However, there is lack of RV function reference data in preterm infants, and as a result we were unable to benchmark our objective measurements. The results may have been influenced by the use of other inotropic agents or by a delayed effect of ino. As there was no control group, the changes observed over the time period of the study cannot be attributed to milrinone use. CONCLUSION This case series highlights the potential benefit of the use of milrinone in preterm infants with PH and/or RV dysfunction. This study supports the need for a prospective randomised control trial on the efficacy and safety of milrinone before it is used routinely in the clinical care setting of preterm infants. CONFLICT OF INTEREST The authors declare no conflict of interest. Journal of Perinatology (2015), 268 273 2015 Nature America, Inc.

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