Mild hypothermia ameliorates anesthesia toxicity in the neonatal macaque brain

Sedatives and anesthetics can injure the developing brain. They cause apoptosis of neurons and oligodendrocytes, impair synaptic plasticity, inhibit neurogenesis and trigger long-term neurocognitive deficits. The projected vulnerable period in humans extends from the third trimester of pregnancy to the third year of life. Despite all concerns, there is no ethically and medically acceptable alternative to the use of sedatives and anesthetics for surgeries and painful interventions. Development of measures that prevent injury while allowing the medications to exert their desired actions has enormous translational value. Here we investigated protective potential of hypothermia against histological toxicity of the anesthetic sevoflurane in the developing nonhuman primate brain. Neonatal rhesus monkeys underwent sevoflurane anesthesia over 5 h. Body temperature was regulated in the normothermic (> 36.5 degrees C), mild hypothermic (35-36.5 degrees C) and moderately hypothermic (< 35 degrees C) range. Animals were euthanized at 8 h and brains examined immunohistochemically (activated caspase 3) and stereologically to quantify apoptotic neuronal and oligodendroglial death. Sevoflurane anesthesia was well tolerated at all temperatures, with oxygen saturations, end tidal CO2 and blood gases remaining at optimal levels. Compared to controls, sevoflurane exposed brains displayed significant apoptosis in gray and white matter affecting neurons and oligodendrocytes. Mild hypothermia (35-36.5 degrees C) conferred significant protection from apoptotic brain injury, whereas moderate hypothermia (< 35 degrees C) did not. Hypothermia ameliorates anesthesia-induced apoptosis in the neonatal primate brain within a narrow temperature window (35-36.5 degrees C). Protection is lost at temperatures below 35 degrees C. Given the mild degree of cooling needed to achieve significant brain protection, application of our findings to humans should be explored further.