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From the Departments of *Anesthesiology and Critical Care, Neurosurgery, Neurology, ||Radiology, and ¶Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; Neuroscience ICU, Duke University Medical Center, Durham, North Carolina; #The Center for Functional Neuroimaging, University of Pennsylvania, Philadelphia, Pennsylvania.
Address correspondence to W. Andrew Kofke, MD, MBA, FCCM, Department of Anesthesiology and Critical Care, University of Pennsylvania, 7 Dulles Building, 3400 Spruce St, Philadelphia, PA 19104-4283. Address e mail to kofkea{at}uphs.upenn.edu.
Abstract
BACKGROUND: Opioids have been linked to limbic system activation and, in animals, to neurotoxicity. Limbic system nonpharmacologic activation patterns have been linked to the Apolipoprotein E (ApoE) allelic distribution. We tested the hypothesis that, in the absence of surgery, small doses of remifentanil produce limbic system activation in humans which varies with dose and ApoE genotype.
METHODS: Twenty-seven ASA I–II volunteers received a remifentanil (UltivaTM) infusion at four sequentially increasing doses: 0, 0.05, 0.1, and 0.2 µg · kg–1 · min–1 while receiving 100% oxygen. Cerebral blood flow (CBF) was measured at each dose globally and in the amygdala, cingulate, hippocampus, insula, and thalamus regions by pulsed arterial spin labeling magnetic resonance imaging. ApoE single nucleotide polymorphisms were determined in each subject.
RESULTS: Significant dose-related CBF increases, without correction for Paco2, were detected in all areas. After normalizing for global CBF to correct for Paco2 effects, the remifentanil-mediated increased CBF in the cingulate persisted, with decreased flow occurring in the hippocampus and amygdala. All these Paco2-corrected effects were reversed in the presence of the ApoE4 polymorphism.
CONCLUSION: Remifentanil at sedative doses produces both activating and depressing effects in various limbic system structures. The cingulate cortex seems to have the most susceptibility to remifentanil activation, and ApoE4 seems to produce relative activation of the hippocampus and amygdala.
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