Physiological assessment and control in studies evaluating central nervous system injury: should size matter?

I n this issue of Anesthesia & Analgesia, Loepke et al. (1) examined the effect of a 1-h isoflurane exposure on extracerebral physiological variables in postnatal day (PND) 10 mice—an age suggested to mimic the brain maturation of human term infants. Studies were performed in anesthetized mice with and without controlled mechanical ventilation and in parallel groups exposed to a hypoxic-ischemic insult. Mice that were removed from the dam for an identical period of time, but not exposed to prolonged anesthesia, served as controls. Remarkably, mice anesthetized with isoflurane became hypoglycemic, as detected at the end of the 1-h anesthetic exposure. At that time, the mean blood glucose concentrations were 43 mg/dL and 38 mg/dL in spontaneously ventilating and mechanically ventilated mice, respectively. In some mice, blood glucose concentration was less than the 20 mg/dL limit of the assay used. The mean blood glucose concentration was even lower (26 mg/dL) in anesthetized, mechanically ventilated mice exposed to hypoxic-ischemic injury, and the mortality rate was 100%. The normal value for blood glucose in the control group was 108 mg/dL. Unanesthetized controls for either the anesthetic exposure alone or the hypoxic-ischemic injury did not exhibit hypoglycemia. Although the mechanism underlying the isoflurane-mediated hypoglycemia in PND 10 mice remains unclear, the findings may be important. In 2003, Jevtovic-Todovoric et al. (2) reported in the Journal of Neuroscience, that a 6-h exposure of PND 7 rats to isoflurane, either alone or combined with midazolam and nitrous oxide, resulted in neurological deterioration in the developing brain. Needless to say, the report garnered considerable notice. The possibility that exposure to general anesthetics at a critical juncture in brain development could lead to neuronal death paralleled the concept of central nervous system injury in conditions such as the fetal alcohol syndrome, in which exposure to the N-methyl-d-aspartate receptor antagonist ethanol leads to neurodegeneration and a described phenotype (3) and raised important concerns in obstetrics, perinatal medicine, neonatology, and pediatric critical care medicine. Clearly, the findings could have far-reaching implications for clinical care, including anesthesia during pregnancy or delivery, surgery in premature infants, and possibly even sedation or brain-targeted therapies, such as “barbiturate coma” in infants with severe traumatic brain injury, in pediatric intensive care units worldwide. The findings of Jevtovic-Todovoric et al. (2) merit additional investigation in light of these potential ramifications to routine clinical care, as well as possible implications for the interpretation of experimental neonatal or pediatric brain injury studies. The report by Loepke et al. in this issue of the journal (1) describing isoflurane’s effects in developing mice expands on the work of Jevtovic-Todovoric et al. (2), using the perspective of a clinical anesthesiologist who is probing the potential clinical ramifications of the findings. Monitoring and controlling physiological variables in the newborn or developing rodent is challenging. Endotracheal intubation, controlled mechanical ventilation, and the use of invasive continuous arterial blood pressure and oxygen saturation monitoring are technically demanding. Similarly, serial arterial blood gas sampling and assessment of blood chemistries are even more problematic because assay sample volumes are often a physiologically important fraction of the rodent’s total blood volume. Consequently, many experimental studies involving developing rodents may not effectively mirror the current clinical practice of invasive monitoring Accepted for publication July 26, 2005. Address correspondence and reprint requests to Patrick Kochanek, Safar Center for Resuscitation Research, Critical Care Med, Pittsburgh, PA 15260. Address e-mail to kochanekpm@ ccm.upmc.edu.