Presented at ASA, October 26, 2015 

Rita S. Shah, M.D., Ming Xiong, M.D.,Ph.D., Jing Li, M.D.,Ph.D., Jiang H. Ye, M.D., Alex Y. Bekker, M.D.,Ph.D.
New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, New Jersey, United States


The commonly used general anesthetics propofol and ketamine trigger widespread apoptotic neurodegeneration on the developing brain [1-2]. Dexmedetomi­dine (DEX), a highly selective α2 adrenergic agonist, exerts anti-apoptosis and neuroprotective properties in isoflurane-induced brain injury [3]. We hypothesized that DEX could attenuate neuroapoptosis in fetal rats exposed to intravenous propofol or ketamine.


With IACUC approval, pregnant Sprague-Dawley rats on gestational day 20 were randomly assigned to 6 groups. 1) 6 dams were administered propofol (bolus: 8.0 mg/kg, infusion rate: 1.2 ± 0.2 mg/kg/min) for 1 hour; 2) 6 dams were administered dexmedetomidine (infusion rate 5 microgram·kg−1·h−1 ) for 1 hour followed by 1 hour of propofol infusion; 3) 7 dams were administered ketamine (bolus: 30-40 mg/kg, infusion rate 90 mg·kg−1·h−1 ) for 2 hours; 4) 6 dams were administered dexmedetomidine (infusion rate 5 microgram·kg−1·h−1 ) for 1 hour followed by 2 hours of ketamine infusion; 5) 3 dams were administered dexmedetomidine (infusion rate 5 microgram·kg−1·h−1 for 1 hour); and 6) 3 dams received no medication (control group). To avoid hypoxia and hypercapnia, the dams undergoing propofol or ketamine general anesthesia (groups 1, 2, 3, and 4) were incubated and supported on controlled mechanical ventilation with 1.0 L/minute oxygen supply. Vital signs, including heart rate, arterial oxygen saturation, and pulse distension, were continuously monitored by a pulse oximeter. End-tidal CO2 (EtCO2) was continuously monitored by an Ohmeda CO2 monitor. Temperature was maintained by a heating lamp with a temperature controller. Caesarean sections were performed 6 hours after propofol infusion or 1 hour after ketamine infusion. The fetal brain tissues were harvested and subjected to the Western blot and immunofluorescence staining to assess cleaved caspase-3 levels.<br


After excluding hypoxia as a confounding factor, the maternal vital analysis indicated that the dams under propofol or ketamine general anesthesia with or without DEX were stable. Maternal propofol anesthesia for 1 hour or ketamine anesthesia for 2 hours increased cleaved caspase-3 levels (propofol: 317 ± 15.2% vs. control: 100 ± 18.9%; ketamine 2 h: 1312 ± 20 %. vs. control: 100 ± 30%) in the fetal rat brain tissues. Caspase-3 activation induced by propofol occurred primarily in the cerebral cortex and thalamic regions of the exposed rodent brains. Double staining with antibodies to cleaved caspase-3 and antibodies to NeuN demonstrated that most of the cleaved caspase-3 positive cells were neurons. The pretreatment with DEX attenuated propofol or ketamine-induced increases in cleaved caspase-3 levels (propofol: 340 ± 31.5% vs. propofol + DEX: 83.7% ± 0.7%; ketamine 2 h: 614 ± 87.9% vs. ketamine + DEX: 115 ± 47.2%) in the fetal rat brain tissues. DEX alone did not affect the cleaved caspase-3 levels in the fetal brain.


Premedication with dexmedetomidine attenuates propofol or ketamine induced cerebral apoptosis in fetal rats.