Mild controlled hypothermia in preterm neonates with advanced NEC

Multiple organ dysfunction syndrome (MODS) is a frequent event in infants with necrotizing enterocolitis (NEC) and is associated with significant morbidity and mortality. At present, there are no specific therapies for MODS other than supportive measures. Animal models of intestinal failure associated with MODS showed beneficial effects of mild hypothermia (32–33°C), which was also associated with a prolonged survival when applied throughout ischemia and reperfusion. Furthermore, mild hypothermia as a rescue therapy after reperfusion reduced intestinal injury and distal organ damage and improved survival. Mild hypothermia has been shown as a safe and effective procedure in term infants. However, there are no data on the safety of therapeutic hypothermia in preterm or very low birth weight infants.
On this basis, an English group has conducted a prospective, non randomized pilot study to determine the feasibility and safety of controlled mild hypothermia in preterm infants with NEC and MODS. This exploratory study may represent the starting point for a randomized, controlled trial investigating the efficacy of mild hypothermia in the treatment of preterm infants with NEC and MODS.
In total, 15 preterm infants who were referred for surgical intervention of advanced NEC and failure of =3 organs were included in this study. Three groups (n=5 per group) were cooled to core temperatures of 35.5°C, 34.5°C, and 33.5°C, respectively, for 48 hours before rewarming to 37°C. Infants were carefully monitored to identify adverse effects potentially related to cooling and rewarming. A non-cooled group (n=10) with advanced surgical NEC and MODS was used for comparison.
Overall, gestational age at birth was 27 weeks (range: 26 –30), admission weight was 1.1 kg (1.0 –1.7), and admission age was 31 days (12– 45). Core temperature was maintained within target range for 90% (88%–97%) of the intended time. Statistical analysis disclosed significant relationships between core temperature and heart rate (P<0.0001), pH (P<0.0001) and base excess (P<0.003). However, changes in these parameters were not clinically significant. Decreasing temperature was also associated with blood clot dynamics (longer time to initial clot formation, slower rate of clot formation, and decrease in clot strength; all P<0.001). Importantly, despite the significant effect of hypothermia on coagulation, no infant experienced any hemorrhagic complication. Analysis of cytokine levels supported the absence of an inflammatory response during cooling or rewarming. No major clinical problems or adverse events were noted and the comparison with the non-cooled group did not reveal any increase in mortality, bleeding, or need for inotropes. In conclusion, this study demonstrated that therapeutic controlled hypothermia may be a feasible and safe intervention in preterm, low birth weight infants with NEC and MODS. Adverse neurodevelopmental outcome in infants with NEC is being increasingly recognized but no conclusion can be drawn from this study on the long-term neurological consequences of mild controlled hypothermia. Overall, the results of this small pilot study may represent the basis for the design of larger, randomized trials to investigate efficacy and safety of hypothermia in infants with NEC.

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