REVIEW Pharmacotherapy for Meconium Aspiration

A Asad and R Bhat Division of Neonatology, Department of Pediatrics, University of Illinois at Medical Center, Chicago, IL, USA

with moderate-to-severe MAS. Figure 1 shows the schema of our In this article we have attempted to review the current pharmacological presentation. treatment options for infants with meconium aspiration syndrome with or The treatment options can be divided into general or specific. without persistent pulmonary hypertension. These treatments include The general treatment options are the optimization of ventilation, ventilatory support, surfactant treatment and inhaled nitric oxide (INO), in sedation and alkalanization. The more specific pharmacological addition to older and newer pharmacological treatments. These include therapies are aimed at reducing hypoxia with the use of pulmonary sedatives, muscle relaxants, alkali infusion, antibiotics and the newer vasodilators (inhaled nitric oxide (INO), oral sildenafil and vasodilators. Many aspects of treatment, including ventilatory care, bosentan), and the lung injury by anti-inflammatory agents, surfactant treatment and the use of INO, are reviewed in great detail in this surfactant lavage or replacement. issue. On the other hand, many newer pharmacological modalities of treatment described here have not been evaluated with randomized control trials. We have given an overview of these emerging therapies. Journal of Perinatology (2008) 28, S72–S78; doi:10.1038/jp.2008.160 General management In all newborns with evidence of severe respiratory distress handling is minimized to prevent worsening of gas exchange due to agitation. Sedation and analgesia are used frequently in infants with MAS and persistent pulmonary hypertension to alleviate pain and discomfort that may lead to hypoxia and right-to-left shunting. Introduction Opioids particularly morphine or fentanyl with midazolam are Meconium aspiration syndrome (MAS) is defined as the presence of frequently used across the world (77 to 100%). Major side effects of respiratory distress and hypoxemia associated with the presence of these medications include hypotension, urinary retention, meconium during or just before delivery. Meconium-stained development of tolerance and withdrawal symptoms. Opioids can amniotic fluid is a relatively common occurrence seen in be given either intermittently or as a continuous drip. approximately 10 to 15% of deliveries and approximately 5% of Pharmacokinetics and metabolism of these drugs are well these develop true MAS.1 The most severe cases require assisted studied4,5 but their impact on long-term outcome has not been ventilation for greater than 48 h and are often associated with reported in term infants. Infact, no RCTs are available in term persistent pulmonary hypertension. Several recent publications and infants to support its routine use. other reviews in this issue have described in detail the pathophysiology and different aspects of the management. Our goal Muscle relaxants is to review the pharmacological management of MAS. Prior to 2000, depolarizing muscle relaxants were widely used along with opioids to decrease agitation and subsequent hypoxic Treatment strategies: the past, present and future episodes in ventilated infants. Pancuronium and Vecuronium Various treatment modalities including intrapartum (perineal) and (0.1 mg kgÀ1 hÀ1) are the two most commonly used muscle post-delivery oral suctioning were the routine until recently but two relaxants in neonatal intensive care unit. The benefits of recent randomized controlled trials (RCTs) have shown that none neuromuscular blockade include improved oxygenation, decreased of these techniques have decreased the incidence of MAS.2,3 These oxygen consumption and decreased accidental extubations. approaches are well covered by different authors in this special However, a prospective multicenter observational study by issue. We will focus primarily on different treatments in the Walsh-Sukys et al.6 showed considerable variations in muscle management of infants admitted to neonatal intensive care unit relaxant use between centers (33 to 98%). Use of muscle relaxants was also associated with increased mortality (Odds ratio: 1.95, Correspondence: Dr R Bhat, Department of Pediatrics, M/C 856, University of Illinois at Chicago Medical Center, 840 S Wood Street, Chicago, IL 60612, USA. confidence interval: 0.74, 5.18). In their series, 41% (total E-mail: [email protected] N ¼ 385) of the cases had MAS as the primary diagnosis. The side Pharmacotherapy for MAS A Asad and R Bhat S73

General • Sedation Analgesia • Muscle Relaxants • Alkalinization

Infection & Inflammation Pharmacotherapy Pulmonary hypertension of • Antibiotics MAS • Vasodilators • Anti-inflammatory agents • Hemodynamic stabilizers

Pulmonary care • Surfactant treatment • Surfactant lavage • Ventilator support

Figure 1 Management of MAS. effects of nondepolarizing agents include cardiovascular effects oxygenation. It is noted that these drugs were not studied from histamine release, though this is less common in neonates independently of each other. Hypotension is frequently secondary to and also tachycardia (vagolytic effect). Neuromuscular blockade heavy sedation and the use of high mean airway pressure. can also mask seizures especially in infants depressed at birth. No Dopamine and dobutamine are the two most frequently used randomized control studies are available at this time. inotropes in neonates. High doses of dopamine Neonatologists are urged to consider the risks and beneﬁts of (>10mgkgÀ1 minÀ1) on its own can also contribute to neuromuscular blockade prior to their use. pulmonary vasoconstriction.12

Alkalinization Pulmonary vasodilators Increasing the pH from 7.45 to 7.5 either by hyperventilation or by Regulation of pulmonary vascular tone is a dynamic process and sodium bicarbonate infusion has been shown to produce depends on the balance between various endogenous constrictors pulmonary vasodilatation both in animal models and human (endothelin and thrombaxane) and dilators (nitric oxide (NO) and 7,8 newborns. However, both hyperventilation and sodium prostaglandins). Majority of these substances are produced by the bicarbonate infusion should be used with caution in newborns due pulmonary endothelium. In addition, arterial oxygen and carbon 9,10 to their adverse effects on cerebral and coronary circulation. dioxide tension, and lung volume play a major role in the Sodium bicarbonate infusion can increase intracellular acidosis regulation of pulmonary vascular tone. Pulmonary hypertension in and worsen myocardial perfusion and cardiac output. patients with MAS is secondary to hypoxia, acidosis, release of the Hyperventilation may also increase barotrauma and volutrauma, inflammatory mediators and alveolar atelectasis. Thus the 11 and increase the risk for chronic lung disease. Hypocarbia below pulmonary hypertension of MAS should ideally be treated with 25 mm Hg can also result in hearing loss secondary to injury to adequate ventilation and pulmonary vasodilators. The problem 10 6 hair cells. Walsh-Sukys et al. reported an increased need for until recently was the inability to find such a truly selective extracoporeal membrane oxygenation (ECMO) and oxygen at pulmonary vasodilator. We will briefly review the past and present 28 days in patients treated with sodium bicarbonate. Neither pulmonary vasodilators used in MAS. Table 1 shows dosages of hyperventilation nor alkali infusion have been vigorously tested in various pulmonary vasodilators used in pulmonary hypertension. a RCT. Fortunately their use seems to be on the decline since the availability of INO. Tolazoline Initial management has also traditionally included inotropic Tolazoline is a nonspecific vasodilator, which had been used for support to assist cardiac function against suprasystemic pulmonary the treatment of pulmonary hypertension at least two decades pressures. Once again, there is no randomized study to support this before the introduction of INO. Lee and Hox31 showed that practice. Drummond et al.8 were able to show in a case series that tolazoline led to pulmonary vasodilatation even in the absence of dopamine infusion along with tolazoline and hyperventilation endothelium. Whereas Curtis et al.32 showed in the animal model helped reduce pulmonary pressure. The combination of tolazoline that the vasodilatation produced was independent of NO and dopamine had a variable and unpredictable effect on production. Its mechanism of action is directly on the vascular

Journal of Perinatology Pharmacotherapy for MAS A Asad and R Bhat S74

Table 1 Pulmonary vasodilators Several of these agents are being used in adults with severe pulmonary arterial hypertension. Milrinone, dipyridamole, Tolazoline IV 0.5–2 mg kgÀ1 13,14 (Not available in USA) NEB 1–2.5 mg kgÀ115 zaprinast and sildenafil (Viagra) have all been used in newborns but the number of patients treated so far are few and no large Magnesium sulfate IV 200 mg kgÀ1 bolus control studies are available to date. 20–150 mg kgÀ1 hÀ116 Diltiazem IV 1–2 q12 to q6 h17 Milrinone. Milrinone is a PDE-3-specific inhibitor and is one of the earliest drugs studied in newborns. It acts synergistically with PDE inhibitors INO inducing pulmonary vasodilatation, but in addition it is also a Dipyridamole IV 0.3–0.6 mg kgÀ118–21 systemic vasodilator and has positive myocardial inotropic activity. À1 À1 Esoprostenol/ IV 2–5 ng kg min increments of It is frequently used in newborns, pediatric and adult patients prostacyclin 2–5ngkgÀ1 q15 min22–24 À1 25 following cardiac surgery. Inhaled milrinone has been tried in ET 50 ng kg can be repeated 2 Â adults with pulmonary hypertension undergoing cardiac surgery. Milrinone IV Term À1 In a recent case report, milrinone was successfully used in four Loading 75 mcg kg Â 60 min 35 Maintenance 0.5–0.75 mcg kgÀ1 minÀ1 infants who failed to respond to INO. Pharmacokinetics of <30 GA milrinone have not been studied in newborns. Milrinone may have Loading 0.75 mcg kgÀ1 minÀ1 over 3 h limited role with the advent of more specific PDE-5 inhibitors, for Maintenance 0.2 mcg kgÀ1 minÀ126 example, sildenafil. Sildenafil PO 0.25–1 mg kgÀ1 27,28 Tezosentan IV 5 mg hÀ1 for 30 min, 1 mg hÀ1 for 24–72 h29 Dipyridamole. Dipyridamole is a selective PDE-5 inhibitor. In Adenosine UVC 25–50 mgkgÀ1 minÀ130 experimental models it has been shown to augment and prolong 36 Abbreviations: ET, endotracheal; IV, intravenous; GA, gestational age; NEB, nebulized; the response of NO in post-cardiac surgery patients. However, PO, per oral; UVC, through umbilical vein catheter. augmentation response is not consistent and in some pediatric See the text for details on each drug. studies decrease in pulmonary vascular resistance of >20% is noted in only half the treated cases. Dipyridamole has been shown to help smooth muscle through direct a-adrenergic antagonistic action. in attenuating the rebound phenomenon seen after discontinuation Tolazoline can be given intravenously as well as by intratracheal 18,19 33,34 of INO therapy in pediatric patients. Dosage of dipyridamole route. There is still no consensus on the dose of tolazoline at ranged from 0.3 to 0.6 mg kgÀ1.18–21 which pulmonary vasodilatation can be maximized while eliminating the severe systemic hypotension. Severe systemic hypotension is the Zaprinast. Zaprinast is a more selective inhibitor of PDE-5 and most common and severe adverse effect. The drug is currently not was one of the original inhibitors studied along with dipyridamole. available in the United States and is not recommended for the Intravenous administration showed, in a fetal lamb model, to treatment of MAS with pulmonary hypertension. decrease pulmonary arterial resistance as well as a potentiation of 36–38 INO inhaled NO-mediated pulmonary vasodilatation. The concern An ideal pulmonary vasodilator should (a) decrease pulmonary with intravenous administration was that at moderate-to-high vascular resistance but not systemic vascular resistance, (b) rapidly doses systemic vasodilatation was noted. Aerosolized drug therapy relieve hypoxia, acidosis and vasoconstriction, (c) have no or has been shown to have less systemic side effects, preferential delivery to better ventilated areas of the lungs and a potentiation of minimal systemic effects and (d) be rapidly metabolized or cleared 39,40 from the body. INO is a good example of such a drug. Indications the INO effect. and dose of INO are discussed elsewhere in this issue. Sildenafil. The most specific PDE-5 inhibitor currently available Phosphodiesterase inhibitors is sildenafil. It is becoming increasingly popular in the treatment Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze of pulmonary hypertension, especially in post-cardiac surgery cyclic nucleotides and regulate their intracellular level. Both cyclic cases.41 Initial success has been noted in some pediatric cases in adenosine monophosphate and cyclic guanosine monophosphate attenuation of INO-rebound pulmonary hypertension.42 Baquero play a crucial role in cell signaling. They are classified based on et al.,27 in a proof-of-concept, randomized masked study showed their substrate specificities, pharmacological properties and an improvement in oxygenation index and pulse oxygen saturation distribution in the body. PDE inhibitors block the hydrolysis of within 6 to 30 h, and significant increase in survival rate cyclic nucleotides and thus increase intracellular accumulation of (85%, 6/7 infants) in those randomized to receive oral sildenafil. cyclic adenosine monophosphate or cyclic guanosine monophos- In the placebo group only 1/6 (16%) survived. The dose of phate. A brief review of the PDEs’ inhibitors is given below. sildenafil was 1 mg kgÀ1 every 6 h till oxygenation index decreased

Journal of Perinatology Pharmacotherapy for MAS A Asad and R Bhat S75 to <20. Pharmacokinetics and bioavailability of orally pulmonary hypertension in adults. Side effects of the drug include administered sildenafil has not been studied so far in neonates. abnormal liver enzymes. Second-generation ET-A blockers such as A recent report by Martell et al.43 have shown a significant drop in tezosentan and sitaxsentan are being studied both in animal pulmonary pressures within 2 min following intratracheal models and in adults with pulmonary hypertension and/or heart administration of 0.75 or 1.5 mg kgÀ1 dose of sildenafil in piglets failure at this time.29,52 with meconium aspiration. Inotropic support was needed to maintain systemic blood pressure. A multicenter study with a large Adenosine sample size is needed to assess the safety and efficacy of ATP is a purine nucleotide and well-known dilator of systemic and 53 intravenous, oral or intratracheal sildenafil with or without INO. pulmonary vasculature in both fetal and neonatal vessels. ATP Oral sildenafil can be a lifesaving drug in the developing causes vasodilatation by acting on endothelial A2 adenosine countries to treat pulmonary hypertension and also for infants with receptors and subsequent release of NO. Its use in a meconium 53 severe hypoxia and respiratory failure in community hospitals prior lung was studied by Kappa et al. in the porcine model and he to their transfer to a tertiary care center. Both dipyridamole and showed that at low doses it was able to cause an amelioration of sildenafil have been approved for clinical use in adults with the pulmonary hypertension. However, withdrawal of ATP led to pulmonary hypertension. significant rebound and even an overshoot phenomenon. From a randomized placebo-controlled trial of 18 infants, Prostaglandins and prostacyclins Konduri et al.30 showed an improvement in oxygenation only in It has been known that both the fetal and neonatal pulmonary 4/9 (45%) term infants with persistent pulmonary hypertension. vascular bed is sensitive to the arachidonic acid metabolites. The dosage used was 25 to 50 mgkgÀ1 minÀ1 and no systemic side Prostaglandin E1 (PGE1) has been in clinical use for more than effects were observed. It did not decrease the need for ECMO, three decades for maintaining ductal patency, but it is a weak bronchopulmonary dysplasia or mortality. Adenosine does have a pulmonary vasodilator when compared with prostacyclin (PGI2).44 short half-life and rapid metabolism, therefore it should be given PGI2 has been in use to treat adult pulmonary hypertension for through the umbilical venous line directly to right atrium to reach several years and is the first drug to be approved for clinical use. It the pulmonary artery. is a potent pulmonary and systemic vasodilator, and its action is mediated through increased cyclic adenosine monophosphate. It Magnesium sulfate has antiproliferative and antiplatelet adhesion effects. The major Magnesium at high doses is a smooth muscle relaxant and drawback of PGI2 is the need for long-term intravenous infusion vasodilator. It acts by antagonizing calcium entry in to smooth and its very short half-life. Various synthetic analogs of PGI2, muscle cells. Wu et al. have shown that it also suppresses namely treprostinil, iloprost and beraprost, are in clinical use in catecholamine release and alters metabolism of prostaglandins and 54 adults because of their longer half-life and ease of administration, responsiveness of smooth muscles to vasopressors. Owing to its either orally or as aerosol and subcutaneous drip. Aerosolized PGI2 varying modes and site of action, it is a relatively nonspecific 55,56 has been tried in newborns who failed to respond to INO.45 Another vasodilator with a significant risk for systemic hypotension. prostaglandin, PGD2 has been evaluated in newborns with However, in clinical trials in children who have failed conventional pulmonary hypertension but is yet to show any clinical benefit.46 therapies, significant improvement has been shown in both oxygenation and oxygenation index without significant 16,56 Endothelin antagonists hypotension. Magnesium sulfate also has sedative and Endothelins are vasoconstrictors derived from the endothelial cells. antithrombotic activities. In third world countries where INO is not Of the two major types of endothelins, ET-1 mediates easily available, this multifaceted drug can be used to alleviate vasoconstriction and smooth muscle cell proliferation through hypoxia. RCTs have not been done so far. ET-A receptors. ET-A receptors have been found on smooth muscle cells in pulmonary arteries.47 Endothelins are involved in maintaining the pulmonary vascular tone in the neonatal period. Future pulmonary vasodilators Recent studies have reported elevated ET-1 level48 and an Table 2 shows some of the newer pulmonary vasodilators currently upregulation of ET-1 gene expression in the pulmonary undergoing investigation. 22,49 vasculature following MAS. In adults with pulmonary Table 2 Emerging pulmonary vasodilators hypertension, the combined ET-A and ET-B receptor antagonist bosentan has been used successfully.50,51 In pediatric and neonatal 1 Superoxide dismutase populations information is limited to case reports. The drug is 2 Vasoactive intestinal peptide currently available only in oral formulation, which may hinder its 3 Adrenomedulline 4 Arginine use in critically ill newborns. Bosentan is approved by the FDA for

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Arginine antibiotic treatment did not alter duration of tachypnea, L-arginine infusion is being studied as an adjunct for NO as well as oxygen support and the need for nasal continuous positive airway for its potential use in the weaning process. L-arginine is a required pressure between the treated and untreated infants. Of the substrate for NO synthesis and under oxidative stress conditions it 306 infants, 2-month follow-up data were available only for increases the activity of nitric oxide synthase.57 It also helps to 259 infants. None of these infants required ventilator support and preserve endogenous nitric oxide synthase activity thus has none had perinatal risk factors. The use of antibiotics gave no potential for helping in the weaning of NO. RCTs of L-arginine in advantage in terms of oxygen supplementation, severity of persistent pulmonary hypertension are still lacking. respiratory distress or mortality. Two other prospective studies from Shankar et al.68 and Krishnan et al.69 from India also concluded Superoxide dismutase that routine post-natal antibiotic therapy is of no benefit. These Superoxide dismuatse is an endogenous scavenger and potent studies do support the current view that routine antibiotic therapy anti-inflammatory and anti-oxidative enzyme. There is now a in MAS does not alter clinical course. Currently in our unit only recombinant version (rhSOD) that is commercially available. The infants admitted with MAS requiring ventilatory support or infants rhSOD is being studied as an adjunct with INO therapy. admitted with risk factors (prolonged rupture of membranes, 58 Steinhorn et al. initially showed how single dose administration chorioamnionitis or positive antenatal group B beta streptococcus of rhSOD in a lamb model with and without INO led to selective screen) receive antibiotics after obtaining initial cultures. pulmonary vasodilatation. In view of these anti-inflammatory and pulmonary vasodilator effects, rhSOD appears to be an exciting Anti-inflammatory agents new addition to treat pulmonary hypertension in MAS. Steroids. Although the initial phase of deterioration in the lung mechanics is because of the mechanical obstruction and surfactant Other drugs inactivation, the persistence of the dysfunction is thought to be Surfactant. Meconium contents are highly viscous and consist of because of activation of the inflammatory cascade. Chemical desquamated epithelial cells and inspissated intestinal secretions. pneumonitis is the second cardinal finding in MAS. Khan et al.70 The large glycoproteins in meconium cause increased in 2002 showed histological and biochemical evidence of adhesiveness.59 Rubin et al.60 in 1996 reported that the mucociliary meconium-induced airway dysfunction in a murine model. Our transportability of meconium was lower than that of sputum own animal studies in newborn rabbits following tracheal clearance in cystic fibrosis patients. Meconium constituents instillation of meconium showed significant increase in several especially the fatty acids and other soluble proteins and bilirubin cytokines namely TNFa, IL-8 and IL-1b in tracheal aspirate.71 are direct inhibitors of surfactant.61,62 Two small randomized This was associated with significant apoptosis.72 As inflammation is control studies have reported significant improvement in one of the major findings in MAS; several investigators have oxygenation and decrease in barotrauma with surfactant attempted to treat MAS with steroids. Steroids are potent anti- treatment.63,64 Readers are referred to excellent reviews on inflammatory medications. Glucocorticoids, particularly surfactant therapy and lavage in meconium aspiration in this dexamethasone, has been shown to improve oxygenation and lung issue. function in animal models of MAS73 and in at least one uncontrolled study of human newborns with MAS.74 A recent Antibiotics Cochrane review75 found two small RCTs (a 3rd study was The use of antibiotics in MAS has been controversial. Initial unpublished) and the meta-analysis of the data showed no use was advocated as it was believed that stress caused the passage differences in mortality, chronic lung disease and length of stay. of meconium and the most likely reason for perinatal stress The major weaknesses in these studies were small sample size and was an infection, hence the need to treat with antibiotics. This lack of long-term follow-up. Owing to the lack of consistent was substantiated in 1967 when Bryan65 showed that sterile short-term benefit as well as recent concerns about its long-term meconium was never fatal on its own, but when given outcome, dexamethasone cannot be recommended at this time as intratracheally along with Escherichia coli it reduced the number an anti-inflammatory agent in MAS. of organisms needed to cause death. A more recent in vitro study In summary the recent advances in pharmacological treatment by Eidelman et al.66 showed once again that clear amniotic fluid namely INO and surfactant has certainly decreased the need for was inhibitory for bacterial growth but in the presence of ECMO in MAS infants. However there is a definite need for further meconium b-Streptococci grew at much faster rate. It is still multicenter studies to evaluate some of the specific and nonspecific controversial whether every infant with meconium aspiration therapies discussed in this review. As MAS is a major cause of needs antibiotic therapy. Few prospective RCTs are available from mortality and morbidity in the developing countries, studies outside the United States for comparison of antibiotic use. In a focusing on prevention and early treatment should be continued to prospective RCT of non-ventilated infants Lin et al.67 showed that alleviate this tragedy.

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