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REVIEW Pharmacotherapy for Meconium Aspiration Journal of Perinatology (2008) 28, S72–S78 r 2008 Nature Publishing Group All rights reserved. 0743-8346/08 $30 www.nature.com/jp 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
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