Mild controlled hypothermia in preterm neonates with advanced NEC

Multiple organ dysfunction syndrome (MODS) in infants with necrotizing enterocolitis (NEC) occurs in >80% of infants with advanced NEC. Mortality is directly related to the number of organs that fail and exceeds 60% with >4 organs involved.
There are no specific therapies other than supportive measures for this condition. In an animal model of intestinal failure associated with MODS, mild hypothermia (32–33°C) was beneficial when applied throughout ischemia and reperfusion. Furthermore, when applied as a rescue therapy after reperfusion, hypothermia reduced intestinal injury and distal organ damage and improved survival. Therefore, therapeutic hypothermia may be beneficial in the treatment of infants with NEC.
Studies of term neonates who had hypoxic ischemic encephalopathy (HIE) or were receiving extracorporeal membrane oxygenation have indicated that mild (>33.5°C) hypothermia can be tolerated safely, and these findings are corroborated by the results of recent clinical trials. However, these clinical trials and preparatory studies of safety and efficacy of therapeutic hypothermia were conducted in term infants and no data are available on controlled 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,
In total, 15 preterm infants who were referred for surgical intervention of advanced NEC and failure of at least 3 organs were enrolled. 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. A non-cooled group (n=10) with advanced surgical NEC and MODS was used for comparison.
The 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 showed significant relationships between core temperature and heart rate (p<0.0001), pH (p<0.0001), base excess (p=0.003), and blood clot dynamics. Changes in heart rate, pH and base excess were small and clinically non significant. Despite the effects on coagulation, no infant experienced any hemorrhagic complication. No major clinical problems or adverse events were noted during cooling or rewarming. Comparison with the noncooled group revealed no increase in mortality, bleeding, infection, or need for inotropes in infants who were cooled.
The small sample size included in this study allowed detection only of large and consistent adverse effects. Large-scale studies are needed to detect more subtle consequences of hypothermia and for a closer monitoring of blood loss, coagulation, and transfusion requirements. Analysis of the inflammatory cytokines revealed the absence of an inflammatory response after rewarming. Study and control infants will be monitored for assessment of long-term consequences of hypothermia on neurodevelopment.
In conclusion, this pilot study has suggested that cooling preterm infants with NEC complicated by MODS for periods of up to 48 hours may be considered feasible and safe. From these results, a larger, randomized study should be performed to investigate the efficacy of controlled mild hypothermia in infants with NEC, simultaneously monitoring safety.

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