Cardiopulmonary bypass and long-term neurocognitive dysfunction in the rat Jan M. Dieleman a, ⁎ , Fellery de Lange a , Ralph J.F. Houston a , Geert-Jan Biessels b , P.R. Bär c , G. Burkhard Mackensen d , Hilary P. Grocott d , Cor J. Kalkman a a Division of Perioperative Care and Emergency Medicine, University Medical Center Utrecht, PO Box 85500, mail stop Q04.2.313, 3508 GA Utrecht, The Netherlands b Division of Neurology and Neurosurgery, University Medical Center Utrecht, The Netherlands c Graduate School Biomedical Sciences, Utrecht University, The Netherlands d Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA Received 1 November 2005; accepted 27 January 2006 Abstract Neurologic and neurocognitive complications after cardiac surgery with cardiopulmonary bypass (CPB) have been reported repeatedly. To better understand its etiology and design protective strategies, an appropriate animal model may prove useful. Although impaired short-term neurocognitive function has been recently demonstrated after CPB in rats, the demonstration of persistent long-term neurocognitive changes would be more relevant from a clinical perspective. We hypothesized that CPB results in long-term impairment of neurocognitive performance in rats. Male rats were exposed to either 60 min of normothermic non-pulsatile CPB, using a roller-pump and a neonatal membrane oxygenator, or to cannulation only (sham animals). Long-term neurocognitive function was assessed at 4 to 7 weeks after CPB (Can test), and again after 12 weeks (Morris water maze) in both operated groups and in a non-operated control group, followed by histologic evaluation of the hippocampus. In separate groups of CPB and sham animals, we also measured TNF-α and IL-6 in plasma. There were no significant differences in long-term neurocognitive performance or histological outcome between the three groups. Cytokine patterns were also similar in both operated groups. We conclude that CPB did not appear to cause long-term neurocognitive dysfunction in this model of CPB in young healthy rats. The lack of long- term deficits may be due to the absence of clinically important etiologic factors such as atheromatous and gaseous embolization in this model. Similar cytokine patterns in both operated groups suggest that surgical trauma rather than exposure of blood to extra-corporeal circuit was probably responsible for the inflammatory response. © 2006 Elsevier Inc. All rights reserved. Keywords: Cardiopulmonary bypass; Cognitive dysfunction; Cerebral injury; Cerebral protection; Inflammatory response; Rat Introduction Neurological complications after cardiac surgery with cardiopulmonary bypass (CPB) have been reported in several clinical studies. Stroke occurs in 3% of patients, but the risk can increase to more than 6% in patients older than 75 years (Roach et al., 1996). In contrast, neurocognitive deficits (NCD), which can be detected by repeated neuropsychological testing, occur in up to 36% of patients after 6 weeks (Newman et al., 2001; Roach et al., 1996). These complications mainly present as deficits in memory and learning capacity, although personality changes or psychiatric pathology such as depression can also manifest. The current opinion about the causative mechanism of neurologic damage after CPB is that it results from cerebral embolization, hypoperfusion, generalized inflammation or a combination of these factors (Grocott et al., 2005; Selnes et al., 1999). To elucidate mechanisms underlying this complication, and to support the development and pre-clinical testing of possible neuroprotective strategies, a reproducible and eco- nomical animal model for CPB is needed. A survival model for extra-corporeal circulation in the rat was recently developed by Grocott et al. (2001). In this model, consistent neurocognitive deficits and immunological changes have been observed 3–12 days after CPB (Grocott et al., 2001; Hindman et al., 2001; Ma et al., 2003; Mackensen et al., 2001; Sato et al., 2002). Life Sciences 79 (2006) 551 – 558 www.elsevier.com/locate/lifescie ⁎ Corresponding author. Tel.: +31 30 2509677; fax: +31 30 2541828. E-mail address: S.Dieleman@UMCUtrecht.nl (J.M. Dieleman). 0024-3205/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2006.01.036