Caffeine Augments Anesthesia Neurotoxicity in the Fetal Macaque Brain

Kevin K Noguchi,Katie J Schenning,Stephen A Johnson,Gregory A Dissen,Kobe L Masuoka,Lauren D Martin,Chrysanthy Ikonomidou,John W Olney,Sasha L Williams,Francesca M Manzella,Ansgar M Brambrink

doi:10.1038/s41598-018-23560-7

Abstract

Caffeine is the most frequently used medication in premature infants. It is the respiratory stimulant of choice for apnea associated with prematurity and has been called the silver bullet in neonatology because of many proven benefits and few known risks. Research has revealed that sedative/anesthetic drugs trigger apoptotic death of neurons and oligodendrocytes in developing mammalian brains. Here we evaluated the influence of caffeine on the neurotoxicity of anesthesia in developing nonhuman primate brains. Fetal macaques (n = 7–8/group), at a neurodevelopmental age comparable to premature human infants, were exposed in utero for 5 hours to no drug (control), isoflurane, or isoflurane + caffeine and examined for evidence of apoptosis. Isoflurane exposure increased apoptosis 3.3 fold for neurons and 3.4 fold for oligodendrocytes compared to control brains. Isoflurane + caffeine caused neuronal apoptosis to increase 8.0 fold compared to control levels but did not augment oligoapoptosis. Neuronal death was particularly pronounced in the basal ganglia and cerebellum. Higher blood levels of caffeine within the range considered therapeutic and safe for human infants correlated with increased neuroapoptosis. Caffeine markedly augments neurotoxicity of isoflurane in the fetal macaque brain and challenges the assumption that caffeine is safe for premature infants.

Highlights

Sedative, anesthetic, and anti-epileptic[3,4,5] drugs (SADs) frequently used in neonatal medicine can trigger widespread apoptosis of neurons and oligodendrocytes in the developing brain of several animal species and produce long-term neurodevelopmental impairment[6,7,8,9,10]
Animals tolerated induction and maintenance of general anesthesia and their vital signs remained within physiological limits without specific intervention as described previously[4,5]
A subsequent Pearson’s r correlation coefficient revealed a statistically significant positive linear correlation indicating that increasing caffeine levels were correlated with heightened neuroapoptosis (r = 0.8438, p < 0.0001)

Summary

Introduction

Anesthetic, and anti-epileptic[3,4,5] drugs (SADs) frequently used in neonatal medicine can trigger widespread apoptosis of neurons and oligodendrocytes in the developing brain of several animal species (including non-human primates) and produce long-term neurodevelopmental impairment[6,7,8,9,10]. CAF has recently been referred to as the ‘silver bullet of neonatology’[25,26,27] because of its safety and putative therapeutic benefits, including a decrease in prevalence of bronchopulmonary dysplasia[28] and cerebral palsy[29] This has led to CAF being the most commonly used drug in the neonatal intensive care unit (NICU) for premature infants[30]. This practice is concerning in view of recent reports[31,32] demonstrating that administration of CAF to rats causes neuroapoptosis in the developing brain. Non-human primate fetuses at an age comparable to that of premature human infants were exposed for 5 hours to the anesthetic isoflurane (ISO), ISO + CAF, or to no drug (control), and after a 3-hour recovery period their brains were histopathologically examined

Methods

Results

Conclusion