**3. ECMO and therapeutic hypothermia**

**1. Introduction**

66 Advances in Extra-corporeal Perfusion Therapies

newborns [6, 7].

injury, even if this requires initiation of ECMO.

**2. General aspects of neonatal ECMO**

with high mortality.

Neonatal encephalopathy secondary to perinatal asphyxia is a common condition, with a global incidence varying between 1.3 and 6.6‰ depending on birth location [1]. It is associated with significant mortality (i.e., 23% of all neonatal deaths worldwide) and long-term morbidity, including cerebral palsy and global developmental delay [2–4]. In developed countries, therapeutic hypothermia has become the standard treatment for newborns born at 36 or more weeks of gestational age who have suffered from birth asphyxia and who present with moderate to severe encephalopathy in the first hours of life [5]. Hypothermia treatment has been shown to reduce the risk of death and long-term disability in these

Hemodynamic instability can develop after birth asphyxia and during hypothermia [8], and may be so severe that some of these asphyxiated newborns treated with hypothermia require support with extracorporeal membrane oxygenation (ECMO) [9–11]. First, transient myocardial ischemia and papillary muscle dysfunction due to subendocardial ischemia occur in one-third of asphyxiated newborns [12, 13]. Second, pulmonary vascular resistances in these newborns are high due to hypoxia-induced pulmonary vasoconstriction, and thus pulmonary hypertension frequently co-exists along with the cardiac dysfunction. Acute pulmonary hypertension may lead to a reduction in the right ventricular function, which, if left untreated, subsequently can impair the left ventricular filling, and hence explain a lower cardiac output [14]. In addition, therapeutic hypothermia results in a lower heart rate in these newborns and a reduction of cardiac output, which reflect the adaptation to the decreased tissue demand during hypothermia treatment [15]. Evidence is accumulating that this hemodynamic instability (including hypotension and persistent pulmonary hypertension) and associated metabolic acidosis and hypoxemia have the potential to worsen brain injury in these newborns [16–18], and thus deserve early and optimal management. Therefore, optimizing the hemodynamic profile of these newborns as early as possible is of the utmost importance for decreasing their risk of further brain

The first reported successful use of neonatal ECMO was in 1975 with a newborn who had meconium aspiration syndrome [19]. Since then, the neonatal ECMO field has evolved rapidly along with the indications and contraindications for this therapy. Broadly, ECMO usually is indicated in newborns for disease processes—believed to be reversible—associated

One of the largest randomized clinical trials of ECMO with newborns was undertaken by the United Kingdom collaborative ECMO trial group [20]. This study enrolled a total of 185 newborns with gestational age ≥35 weeks and birth weight ≥2 kg. The main indication for ECMO in this study was severe respiratory failure with an oxygenation index ≥40. The Clinicians raise concern about increased bleeding risk when providing therapeutic hypothermia during ECMO support. However, several studies have reported the short- and long-term outcomes of newborns treated with ECMO and hypothermia without bleeding complications. Hichiba et al. [31] found that newborns with a body weight between 2 and 5 kg, who were treated with ECMO for severe respiratory failure, could receive hypothermia treatment down to 34°C for 12 h while on ECMO without worsening their survival rate, hemodynamic instability, bleeding risk, and thromboembolic complications. Horan et al. [32] found that newborns who were more than 33 weeks of gestation and who were treated with ECMO for severe respiratory failure could receive hypothermia treatment down to 34°C for 48 h during ECMO without worsening their cardiovascular status, nor having major bleeding. Of note, newborns with severe encephalopathy were excluded from both studies. The safety of maintaining hypothermia down to 34°C during ECMO also was observed in 37 newborns after cardiac surgery by Lou et al. [33]; none of the newborns treated with ECMO and hypothermia developed intracranial hemorrhage or a worsening of hemodynamic instability. In addition, Field et al. [22, 34] found that mild hypothermia down to 34°C could be safely maintained during ECMO for 72 h with newborns with meconium aspiration, persistent pulmonary hypertension, or severe cardiorespiratory failure. When they compared the outcomes at 2 years of age of their 45 newborns treated with mild hypothermia to 34°C for 48–72 h during ECMO to the outcomes of their 48 newborns treated only with ECMO, the mild hypothermia treatment did not improve the outcomes of these 45 newborns [22]. However, given the heterogeneity of the initial diagnoses in this studied population of newborns, these results cannot be extrapolated directly to asphyxiated newborns, in whom hypothermia, not in the context of ECMO, has been shown to be of benefit [6, 7]. Therefore, as of now, no evidence exists that the incidence of significant bleeding and the need for inotropes were worsened when hypothermia was provided to newborns during the ECMO course.
