We describe a term neonate treated with whole-body hypothermia several days after birth to counteract refractory hypoxemia due to persistent pulmonary hypertension unresponsive to optimal treatment. This approach was selected to improve oxygenation and protect the brain from the consequences of hypoxemia. In our experience, hypothermia did not worsen pulmonary hypertension, although no beneficial effect on oxygenation was noted. Nevertheless, the favorable neurological outcome of die neonate provides some evidence for neuroprotection against refractory hypoxemia using hypothermia.
Key words: persistent pulmonary hypertension of the neonate, neuroprotection, mechanical ventilation
L’hypothermie thérapeutique pour l’hypoxémie réfractaire post-natale: présentation d’un cas d’un nouveau-né à terme
Nous décrivons un nouveau-né à terme traité par hypothermie du corps entier quelques jours après la naissance afin de neutraliser l’hypoxémie réfractaire due à l’hypertension pulmonaire persistante qui ne répond pas à un traitement optimal. Cette approche a été choisie pour améliorer l’oxygénation et protéger le cerveau contre les conséquences de l’hypoxémie. Dans notre expérience, l’hypothermie n’a pas aggravé l’hypertension artérielle pulmonaire, mais il n’a été noté aucun effet bénéfique sur l’oxygénation. Néanmoins, l’évolution neurologique favorable du nouveau-né a fourni des preuves de neuroprotection contre l’hypoxémie réfractaire à l’aide de l’hypothermie.
Mots clefs: hypertension pulmonaire persistante, neuroprotection
anagement of late preterm and term neonates with moderate-severe hypoxic- ischemic encephalopathy (HIE) following perinatal asphyxia is, hitherto, the only evidence-based application of hypothermia in neonatology as it reduces mortality without increasing major disability in survivors [1, 2]. Other situations such as perinatal arterial ischemic stroke, neonates with HIE beyond the “therapeutic window” of the first 6 hours after birth or less than 36 weeks gestation and those with unexpected postnatal collapse could potentially benefit from this neuroprotective treatment, but, at present, only few or no data is available [2, 3]. This case describes a term neonate treated with whole-body hypothermia several days after birth to counteract refractory hypoxemia and protect the brain from its consequences.
A female, 3.470 g newborn was transferred to our hospital at 10 hours of life for respiratory distress. The baby was bom at 39+4 weeks gestation after caesarian section due to mild fetal distress. Bag and mask ventilation were given at birth, and the 1 and 5 minute Apgar scores were 6 and 9, respectively. Conventional mechanical ventilation was started upon admission to our department while the lung
X-ray was suggestive of transient tachypnea. Temporal improvement in oxygenation was noted following exogenous surfactant administration (Beractant, 100 mg/Kg/dose). Thereafter, oxygen requirements increased significantly, despite optimal ventilation (including high-frequency oscillatory ventilation) and supportive management (sedation-analgesia, inotropes). Following X-rays consistently showed the absence of parenchymal lung disease. Cardiac ultrasound confirmed the clinical diagnosis of persistent pulmonary hypertension of the neonate (PPHN), but inhaled nitric oxide (iNO) at 20 ppm and other adjunctive therapies (oral sildenafil, bosentan) had no clinical effect. Repeat sepsis work-up was negative. Continuing, severe impairment in oxygenation prompted us to apply whole-body hypothermia (Tecotherm Neo®, target rectal temperature 33.5±0.5 °C)for 72 hours starting from day of life (DOL) 6, which was well tolerated. During hypothermia, the respiratory failure slightly improved, in the short term, as indicated by the reduction of alveolar-arterial difference of oxygen (fig. 1). Despite refractory hypoxemia, no clinical seizures were obsewed whereas there were no pathologic findings on head ultrasound scans and amplitude-integrated-EEG. Interestingly, the sleep-wake cycle was lost during cooling but normalized after the end of this treatment. From DOL 14 onwards, oxygenation started to improve (although still with variable) finally allowing weaning from the ventilator (DOL 20) (fig. 1). Brain imaging (ultrasound scan, magnetic resonance imaging) were normal at hospital discharge (DOL 36) as was later neurodevelopment (6 months).
To the best of our knowledge, this is the first case to report the use of whole-body hypothermia in neonates with refractory hypoxemia secondary to PPHN as adjunct to mechanical ventilation and as neuroprotection. PPHN is an important cause of neonatal respiratory failure associated with increased mortality and neurological impairments in survivors .
Hypothermia reduces oxygen consumption as well as C02 production . Moreover, experimental animal data show that hypothermia may protect  or attenuate the ventilator-induce lung injury mitigating the pro-inflammatory response . Improved gas exchange has also been reported in the latter investigations . Similarly, there is evidence – although limited – from studies in critically ill adults suggesting an improvement in oxygenation [81 and ventilation [91 with hypothermia. Therefore, this therapeutic technique could potentially be beneficial in our patient breaking the vicious circle of hypoxemia, PPHN and ventilator-induced lung injury. On the other hand, aggravation of
Figure 1 – Supportive care and serial changes of alveolar-arterial difference of oxygen (AaD02, best and worse) during the first 3 weeks of life (B and C). Initial lung X-rays (A) and snapshot of the a-EEG recording before and during hypothermia (D) are also shown.
CMV: Conventional mechanical ventilation, DOL: Day of life, HFOV: High-frequency oscillatory ventilation, iNO: Inhaled nitric oxide
PPHN was a possible clinical scenario, given the metabolic response to cold stress (increased catecholamines and pulmonary vascular resistance) . In large randomized controlled trials of hypothermia in perinatal asphyxia, PPHN at randomization was considered as an exclusion criterion [21. It is our clinical observation that a slight and temporal improvement in alveolar-arterial difference of oxygen was indeed observed during hypothermia. However, this could be an oxygen extraction issue. At lower temperatures, oxyhemo’ globin dissociation curve is shifted to the left resulting in decreased oxygen release to the tissues which in turn have decreased oxygen demands . Nevertheless, the fact that improved oxygenation was not sustained and, also, that coincided with the application of high frequency ventilation does not allow us to support any significant effect of whole-body hypothermia per se on oxygenation. Yet, this trend towards improvement in oxygenation is in line with the most recent relevant meta-analysis, in which hypothermia was found not to increase the risk of PPHN, at least as indicated by the need for Ino . Extracorporeal membrane oxygenation (ECMO) could be an alternative treatment to PPHN , but no ECMO center was available. Conversely, this invasive intervention encompasses severe risks for the brain. Actually, for this very reason mild hypothermia was preventively attempted for 12 hours in a small cohort of neonates receiving ECMO. Unfortunately, neurodevelopment outcome was not assessed .
We applied therapeutic hypothermia as this is a promising means of neuroprotection in neonates. None the less, two facts merit comment in the present case: the lack of any clinical or other evidence of brain injury (normal head ultrasound scan, a-EEG) when cooling was decided and the application of hypothermia several days after birth. So far, hypothermia is only indicated as early as possible in neonates with evidence of HIE following an acute perinatal event, so as to limit the already activated molecular mechanisms of neuronal damage and death . It is impossible to know whether prolonged hypoxemia triggered such a cascade of events in our neonate. However, therapeutic hypothermia has also been tested in neonatal conditions, independent of neuroprotection. Advanced necrotizing enterocolitis in preterm infants is such an example, where mild hypothermia was applied as an alternative therapy to reduce intestinal injury and distal organ damage . Specific biochemical biomarkers or more sophisticated techniques (e.g., magnetic resonance spectroscopy) could possibly have provided some indications as to the presence of cerebral injury secondary to refractory hypoxemia and the impact of hypothermia. Such techniques, however, are available for use at the bedside only in a few centers . Additionally, our baby-girl was not part of a relevant study and, therefore, no investigations beyond those indicated in everyday clinical practice were performed. Nonetheless, its favorable neurological outcome is encouraging. Since we are not, however, able to know whether and to what extent hypothermia had any neuroprotective effect against hypoxemia related to respiratory failure, this approach needs to be evaluated in large trials.