In the Era of Therapeutic Hypothermia, How Well Do Studies of Perinatal Neuroprotection Control Temperature?

Abstract

In the era of therapeutic hypothermia, reliable preclinical studies are integral to successfully identify neuroprotective strategies to further improve outcomes of encephalopathy at term. We reviewed preclinical neuroprotection studies reported between January 2014 and June 2016 to assess the use of effective temperature monitoring and control. As a secondary measure, we examined whether studies addressed other methodological issues such as stage of brain development, sex differences, the timing of the treatment relative to the insult, and the histological and functional endpoints used after hypoxia-ischemia. The extent and duration of temperature monitoring was highly inconsistent. Only a minority of papers monitored core (19/61; 31%) or brain temperature (3/61; 5%). Most (40/45) of the neuroprotectants either were likely to affect thermoregulation or their impact is unknown. In 85% of papers neonatal rodents were used (67% at P7); 51% of papers did not report the sex of the animals or tested the effect of potential neuroprotectants on just one sex. In 76% of studies, treatment was before or immediately after the insult (within the first 2 h), and few studies assessed long-term histological and behavioral outcomes. In conclusion, many recent preclinical neonatal studies cannot exclude the possibility that apparent neuroprotection might be related to drug-induced hypothermia or to other methodological choices. Close monitoring and control of brain temperature during, as well as for many days after, experimental hypoxia-ischemia are now critical to reliably develop new ways to improve neurodevelopmental outcomes after perinatal hypoxic-ischemic encephalopathy.

Variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis

“…However, it is also important to note that rodent studies of HT usually only include a formal HT period of up to 5 h, with some natural ongoing hypothermia (rectal temperature < 36 °C) also likely to occur in the nest afterwards 6,27 . As temperature control is generally poorly-reported in rodent neuroprotection studies 65 , comparing the dose an timing of HT to that seen in humans is difficult. Despite this, the largest clinical trials of HIE do not appear to have definitively questioned whether any outcome parameters in asphyxiated infants treated with HT are affected by sex 3,17,18,56,66 .…”

Complex interactions between hypoxia‐ischemia and inflammation in preterm brain injury

“…As previously reviewed, 90 in order to improve preclinical research translation, we must accept and correct current methodological limitations. As previously reviewed, 90 in order to improve preclinical research translation, we must accept and correct current methodological limitations.…”

“…To improve our understanding of the cellular and pathophysiological mechanisms that underlie the complex clinical and epidemiological evidence discussed here, it is essential that researchers focused on perinatal neuroprotection undertake methodologically sound preclinical studies using translational paradigms of preterm brain injury. As previously reviewed, 90 in order to improve preclinical research translation, we must accept and correct current methodological limitations. These include, but are not limited to, inadequate monitoring and maintenance of body temperature, unpragmatic treatment regimes, and failure to report or test the sex of individuals and assess long-term functional and histological outcomes.…”

Ginkgolide B ameliorates NLRP3 inflammasome activation after hypoxic‐ischemic brain injury in the neonatal male rat

“…Approximately 25% of survivors suffer from lifelong neurological deficits including neurodevelopment delays, epilepsy, cognitive issues, and motor skill (Groenendaal and de Vries, 2017). The only recognized beneficial treatment for HIE is hypothermia therapy but many infants still develop significant adverse outcomes (Galinsky et al, 2017; Manley et al, 2017). Therefore, novel therapeutic approaches directed at the pathophysiological mechanisms involved in HIE are urgently needed.…”