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Millions of children are treated every year with anesthetics and sedatives to facilitate surgical procedures and to provide sedation in emergency and intensive care. In addition to rendering patients insensible to painful stimuli, these compounds have numerous other effects, some of them protective, while others may be deleterious. Accordingly, our laboratory examines the effects of anesthetics and sedatives on the developing brain.
Thousands of infants require complex surgical procedures early in life, such as neurosurgery, surgery for inherent malformations or repair of congenital heart disease, which may predispose them to hemodynamic instability and periods of inadequate supply of oxygen and blood flow (hypoxia-ischemia) to their immature brains, potentially resulting in brain damage and long-term developmental abnormalities. Our research efforts are directed toward improving the detection of hypoxic and hypoxic-ischemic episodes using noninvasive techniques, to identify the mechanisms of hypoxic and hypoxic-ischemic brain injury, to characterize neurological injury and subsequent neurocognitive outcome, as well as to develop treatment strategies, with a special focus on anesthetics.
Mounting evidence from animal studies has implicated all commonly used anesthetics and sedatives to induce widespread neuronal cell death, resulting in long-term neurological abnormalities under certain conditions. These findings have raised serious concerns regarding the safe use of these medications in young children. Our research sets out to clarify the underlying mechanisms of anesthesia-induced neurotoxicity and the selectivity of the phenomenon, which will be critical for assessing its human relevance, and if necessary, for discovering mitigating therapies. Moreover, our preclinical research aims to identify biomarkers of anesthesia-induced developmental neuroapoptosis. Our clinical research efforts are directed toward examining the phenomenon’s long-term brain morphological effects using non-invasive imaging technology. Moreover, we are participating in a multicenter trial, the PANDA study, which investigates the long-term neurobehavioral effects of surgery with anesthesia early in life.
Backeljauw B, Holland SK, Altaye M, Loepke AW. Cognition and Brain Structure Following Early Childhood Surgery with Anesthesia. Pediatrics. 2015; in press.
Osterop SF, Virtanen MA, Loepke JR, Joseph B, Loepke AW, Vutskits L. Developmental stage-dependent impact of midazolam on calbindin, calretinin and parvalbumin expression in the immature rat medial prefrontal cortex during the brain growth spurt. Int J Dev Neurosci. 2015; in press.
Loepke AW, Hansen TG. Is this your (paediatric patient's) brain on (anaesthetic) drugs?: The search for a potential neurological phenotype of anaesthesia-related neurotoxicity in humans. Eur J Anaesthesiol. 2015 May;32(5):298-300.
Lin EP, Lee J-R, Loepke AW. Anesthetics and the developing brain: The yin and yang. Curr Anesthesiol Rep. 2015 Mar 26;5(2):177-189.
Davidson AJ, Becke K, de Graaff J, Giribaldi G, Habre W, Hansen T, Hunt RW, Ing C, Loepke AW, McCann ME, Ormond GD, Pini Prato A, Salvo I, Sun L, Vutskits L, Walker S, Disma N. Anesthesia and the developing brain: a way forward for clinical research. Paediatr Anaesth. 2015 May; 25(5):447-52.
Lin EP, Miles L, Hughes EA, McCann JC, Vorhees CV, McAuliffe JJ, Loepke AW. A combination of mild hypothermia and sevoflurane affords long-term protection in a modified neonatal mouse model of cerebral hypoxia-ischemia. Anes Analg. 2014 Nov;119(5):1158-73.
Deng M, Loepke AW. Anesthetic Neurotoxicity – Preclinical and Clinical Research. J Perioper Sci. 2014 Jul 13;1:6.
Miller JW, Vu D, Chai PJ, Kreutzer J, Hossain MM, Jacobs JP, Loepke AW. Patient and procedural characteristics for successful and failed immediate tracheal extubation in the operating room following cardiac surgery in infancy. Paediatr Anaesth. 2014 Aug;24(8):830-9.
Lei SY, Hache M, Loepke AW. Clinical research into anesthetic neurotoxicity: does anesthesia cause neurological abnormalities in humans? J Neurosurg Anesthesiol. 2014 Oct;26(4):349-57.
Deng M, Hofacer RD, Jiang C, Joseph B, Hughes EA, Danzer SC, Loepke AW. Brain regional vulnerability to anaesthesia-induced neuroapoptosis shifts with age at exposure and extends into adulthood for some regions. Br J Anaesth. 2014 Sep; 113(3):443-451.
Lin EP, Soriano SG, Loepke AW. Anesthetic neurotoxicity. Anesthesiol Clin. 2014 Mar; 32(1):133-155.
Spaeth JP, Loepke AW. (2014). Anesthesia for Left-Sided Obstructive Lesions. Chapter 22 In DB Andropoulos, SA Stayer, IA Russell (Ed.), Anesthesia for Congenital Heart Disease. 3rd Edition. Oxford, UK: Wiley-Blackwell Publishing.
Jevtovic-Todorovic V, Absalom AR, Blomgren K, Brambrink A, Crosby G, Culley DJ, Giffard RG, Herold KF, Loepke AW, Ma D, Orser BA, Planel E, Slikker W Jr., Soriano SG, Stratmann G, Vutskits L, Xie Z, Hemmings HC Jr. Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar. Br J Anaesth. 2013 Aug;111(2):143-51.
Hofacer RD, Deng M, Ward CG, Joseph B, Hughes EA, Jiang C, Danzer SC, Loepke AW. Cell-age specific vulnerability of neurons to anesthetic toxicity. Ann Neurol. 2013 Jun;73(6):695-704.
Istaphanous GK, Ward CG, Nan X, Hughes EA, McCann JC, McAuliffe JJ, Danzer, SC, Loepke AW. Characterization and quantification of isoflurane-induced developmental apoptotic cell death in mouse cerebral cortex. Anes Analg. 2013 Apr;116(4):845-54.
Loepke AW. Single surgical procedure with general anaesthesia early in life is associated with subsequent impaired language development and cognitive function. Evid Based Med. 2013 Aug;18(4):e39.
Loepke AW, Davidson AJ. (2013). Surgery, Anesthesia, and the Immature Brain. Chapter 23 In Coté CJ, Lerman J, and Todres ID (Ed.), A Practice of Anesthesia for Infants and Children, 5th Edition (pp. 492-509). Philadelphia, PA: Saunders Elsevier.
Loepke AW, McCann ME. (2013). Anesthetic-Induced Neurotoxicity. Chapter 24 In P Mongan, T Sloan, Soriano S (Ed.), A Practical Approach to Neuroanesthesia, 1st Edition (pp. 307-316). Philadelphia, PA: Lippincott Williams & Wilkins.
Mintz CD, Wagner M, Loepke AW. Preclinical research into the effects of anesthetics on the developing brain: promises and pitfalls. J Neurosurg Anesthesiol. 2012 Oct;24(4):362-7.
Murphy BL, Hofacer R, Faulkner CR, Loepke AW, Danzer SC. Abnormalities of granule cell dendritic structure are a prominent feature of the intrahippocampal kainic acid model of epilepsy despite reduced postinjury neurogenesis. Epilepsia. 2012 May;53(5):908-21.
Ward CG, Loepke AW. Anesthetics and sedatives: toxic or protective for the developing brain? Pharmacol Res. 2012 Mar; 65:271-4.
Istaphanous GK, Loepke AW. (2012). Pediatric Pulmonary Hypertension. In K Goldschneider, A Davidson, E Wittkugel, Skinner (Ed.), Clinical Pediatric Anesthesia: A Case-Based Handbook, 1st Edition (pp. 341-50). Oxford, UK: Oxford University Press.
Lin EP, Loepke AW. (2012). Cardiac Catheterization. In K Goldschneider, A Davidson, E Wittkugel, Skinner (Ed.), Clinical Pediatric Anesthesia: A Case-Based Handbook, 1st Edition (pp. 321-30). Oxford, UK: Oxford University Press.
Wise-Faberowski L, Loepke AW. Anesthesia during surgical repair for congenital heart disease and the developing brain: neurotoxic or neuroprotective? Paediatr Anaesth. 2011 May;21(5):554-9.
Istaphanous GK, Howard J, Nan X, Hughes EA, McCann JC, McAuliffe JJ, Danzer SC, Loepke AW. Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice. Anesthesiology. 2011 Mar;114(3):578-87.
Loepke AW. Developmental neurotoxicity of sedatives and anesthetics: a concern for neonatal and pediatric critical care medicine? Pediatr Crit Care Med. 2010 Mar;11(2):217-26.
McAuliffe JJ, Loepke AW, Miles L, Joseph B, Hughes E, Vorhees CV. Desflurane, isoflurane, and sevoflurane provide limited neuroprotection against neonatal hypoxia-ischemia in a delayed preconditioning paradigm. Anesthesiology. 2009 Sep;111(3):533-46.
Kurth CD, McCann JC, Wu J, Miles L, Loepke AW. Cerebral oxygen saturation-time threshold for hypoxic-ischemic injury in piglets. Anesth Analg. 2009 Apr;108(4):1268-77.
Loepke AW, Istaphanous GK, McAuliffe JJ, Miles L, Hughes EA, McCann JC, Harlow KE, Kurth CD, Williams MT, Vorhees CV, Danzer SC. The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg. 2009 Jan;108(1):90-104.
Loepke AW, Soriano SG. An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg. 2008 Jun;106(6):1681-707.
Loepke AW, McCann JC, Kurth CD, McAuliffe JJ. The physiologic effects of isoflurane anesthesia in neonatal mice. Anesth Analg. 2006 Jan;102:75-80.
Loepke AW, Golden, JA, McCann JC, Kurth CD. Injury pattern of the neonatal brain after hypothermic low-flow cardiopulmonary bypass in a piglet model. Anesth Analg. 2005 Aug;101:340-8.
Ditsworth D, Priestley MA, Loepke AW, Ramamoorthy C, McCann JC, Staple L, Kurth CD. Apoptotic neuronal death following deep hypothermic circulatory arrest in piglets. Anesthesiology. 2003 May;98:1119-27.
Loepke AW, Priestley MA, Schultz SE, McCann JC, Kurth CD. Desflurane improves neurologic outcome after low-flow cardiopulmonary bypass in newborn pigs. Anesthesiology. 2002 Dec;97:1521-7.
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