University of Colorado Denver

Anesthetic Toxicity

Broadly, our research interests focus on mechanisms by which anesthetic drugs interact with neurotransmitter systems in the central nervous system to produce both pharmacological and toxicological effects. Our primary interests thus far have centered on the identification and characterization of neurotoxic properties of commonly used intravenous and inhalational anesthetics with special emphasis on NMDA antagonist class of general anesthetics. It had extended to include several studies that have looked at the pharmacological ways of protection against this type of neurotoxicity.

Funding: National Institutes of Neurological Disease and Stroke and National Institute of General Medicine (R01), American Heart Association

Publications:

  1. Jevtovic-Todorovic J. (2017) Anesthetics and cognitive impairments in developing children: What is our responsibility? JAMA Pediatrics – In Press
  2. Dalla Massara L, Osuru HP, Oklopcic A, Milanovic D, Joksimovic SM, Caputo V, DiGruccio MR, Ori C, Wang G, Todorovic SM, Jevtovic-Todorovic V (2016) General anesthesia causes epigenetic histone modulation of c-Fos and brain-derived neurotrophic factor, target genes important for neuronal development in the immature rat hippocampus. Anesthesiology 124, 1311-1327.
  3. Obradovic AL, Scarpa J, Osuru HP, Weaver JL, Park JY, Pathirathna S, Peterkin A, Lim Y, Jagodic MM, Todorovic SM, Jevtovic-Todorovic V (2015) Silencing the α2 subunit of γ-aminobutyric acid type A receptors in rat dorsal root ganglia reveals its major role in antinociception posttraumatic nerve injury. Anesthesiology 123, 654-667.
  4. Sanchez V, Feinstein SD, Lunardi N, Joksovic PM, Boscolo A, Todorovic SM, Jevtovic-Todorovic V (2011) General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology 115, 992-1002.

Neuronal Injury Program

The Neuronal Injury Program is a collaborative multidisciplinary group of PhD and MD faculty from various departments at the University of Colorado Anschutz Medical Campus. By combining in vivo animal models of ischemic/traumatic brain injury, neurophysiology, neurobehavioral, histological and molecular approaches we hope to identify targets to improve functional outcome after an insult to the brain. Current projects in our lab focus on ion channel involvement in injury, with a particular emphasis on synaptic plasticity deficits in the hippocampus and cerebellum. We combine this with in vivo pharmacological and genetic manipulations to improve memory or motor function. We also study the contribution of age-dependent neuronal and glial responses to differences in recovery between juveniles and adults.

Faculty:

Paco S. Herson, NIP Director, Professor, Department of Anesthesiology
Nidia Quillinan, Assistant Professor, Department of Anesthesiology
James E. Orfila, Instructor, Department of Anesthesiology
Krista M. Rodgers, Instructor, Department of Anesthesiology
Robert M. Dietz, Assistant Professor, Neonatology, Department of Pediatrics
Andra Dingman, Assistant Professor, Pediatric Neurology, Department of Pediatrics

Funding: National Institutes of Neurological Disease and Stroke (R01s, K01, K08, K12). National Institute of General Medicine (R01), American Heart Association

Publications:

  1. Deng G, Orfila JE, Dietz RM, Rodgers KM, Moreno-Garcia M, Coultrap SJ, Quillinan N, Traystman RJ, Bayer KU, Herson PS (2017) Inhibition of autonomous CaMKII activity decreases neuronal damage and provides long-term functional recovery after resuscitation from cardiac arrest. Cell Reports 18, 1109-1117
  2. Quillinan N, Deng G, Shimizu K, Cruz-Torres I, Schroeder C, Traystman RJ, Herson PS (2016) Long-lasting impairments in Purkinje neuron long-term depression following cardiac arrest and cardiopulmonary resuscitation in mice. Journal of Cerebral Blood Flow & Metab 37, 3053-3064.
  3. Shimizu T, Dietz RM, Cruz-Torres I, Strnad F, Garske AK, Moreno-Garcia M, Venna VR, Quillinan N, Herson PS (2016) Extended therapeutic window of a novel peptide inhibitor of TRPM2 channels following focal cerebral ischemia. Experimental Neurology 283, 151-156.
  4. Ahrendsen, JT, Grewal, HS, Hickey, SP, Culp CC, Gould EA, Shimizu T, Strnad FA, Traystman RJ, Herson PS, Macklin WB (2016) Juvenile striatal white matter is resistant to ischemia-induced damage. Glia 64, 1972-1986.
  5. Dietz RM, Deng G, Orfila JE, Hui X, Traystman RJ, Herson PS (2016) Therapeutic hypothermia protects against ischemia-induced impairment of synaptic plasticity following juvenile cardiac arrest in a sex-dependent manner. Neuroscience 325, 132-141.

Molecular Mechanisms of anesthesia and pain

We are interested in deciphering the roles of voltage-gated calcium channels (VGCC) in molecular mechanisms of anesthesia and pain processing. We use sophisticated biophysical techniques to measure membrane currents from acutely dissociated sensory neurons and intact brain and spinal cord slices. We also have cell lines available that express recombinant ion channel proteins which allow studies of the relationship between structure and function. At the system level, we use virally-mediated knockdown, mouse genetics and pharmacological blockers to establish the role of various subtypes of VGCCs on pain sensation and anesthetic endpoints using behavioral assays and electroencephalographic (EEG) recordings.

Funding: NIH R01 grants from NINDS, NIDA and NIGMS.

Publications:

  1. Todorovic SM. Is diabetic nerve pain caused by dysregulated ion channels in sensory neurons? Diabetes. 2015, 64(12):3987-9.
  2. Joksimovic SJ, Eggan P, Izumi Y, Joksimovic SLj, Tesic V, Dietz RM, Orfila JE, DiGruccio MR, Herson PS, Jevtovic-Todorovic V, Zorumski CF, Todorovic SM. The role of T-type calcium channels in the subiculum: to burst or not to burst? J Physiol, 2017, 000.00:1-22.
  3. DiGruccio MR, Joksimovic S, Joksovic PM, Lunardi N, Salajegheh R, Jevtovic-Todorovic V, Beenhakker MP, Goodkin HP, Todorovic SM. Hyperexcitability of rat thalamocortical networks after exposure to general anesthesia during brain development. The Journal of Neuroscience, 2015, 35(4):1481-92.
  4. Orestes P, Osuru HP, McIntire WE, Jacus MO, Salajegheh R, Jagodic MM, Choe W, Lee J, Lee SS, Rose KE, Poiro N, Digruccio MR, Krishnan K, Covey DF, Lee JH, Barrett PQ, Jevtovic-Todorovic V, Todorovic SM. Reversal of neuropathic pain by targeting glycosylation of CaV3.2 T-type calcium channels. Diabetes 2013, 62:3828-3838.
  5. Jacus MO, Uebele VN, Renger JJ and Todorovic SM. Presynaptic CaV3.2 channels regulate excitatory neurotransmission in nociceptive dorsal horn neurons. The Journal of Neuroscience 2012; 32(27):9374-82.

Oxygen and light sensors: circadian mechanisms in cardioprotection

Our research has been directed towards identifying cellular adaptive mechanisms during hypoxic conditions such as myocardial ischemia – one of the leading causes of morbidity and mortality worldwide. Adenosine signaling has been implicated in cardiac adaptation to limited oxygen availability. In a wide search for adenosine receptor elicited cardioadaptive responses, we identified the circadian rhythm protein period 2 (PER2) as an adenosine signaling target. Here we found that Per2-/-mice had larger infarct sizes and a limited ability to use carbohydrates for oxygen-efficient glycolysis compared to wild-type mice. This impairment was caused by a failure to stabilize the oxygen sensor hypoxia-inducible factor-1 alpha (HIF1A). Moreover, stabilization of PER2 in the heart by exposing mice to intense light resulted in the transcriptional induction of HIF1A regulated glycolytic enzymes and PER2-dependent cardioprotection from ischemia. Ongoing studies are directed towards elucidating the role of the light regulated circadian rhythm protein PER2 as oxygen and metabolic sensor during conditions of limited oxygen availability. The long-term goal of our studies is to introduce circadian (PER2) enhancer strategies into the hospital to prevent or treat hypoxic conditions such as myocardial ischemia in patients (https://clinicaltrials.gov; NCT02490397).

Funding: NIH R01 grant from NHLBI

Publications:

  1. Eckle T, Hartmann K, Bonney S, Reithel S, Mittelbronn M, Walker LA, Lowes BD, Han J, Borchers CH, Buttrick PM, Kominsky DJ, Colgan SP and Eltzschig HK. 2012. Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. Nat Med.18(5):774-82. PMC3378044. Corresponding author.
  2. Bonney S, Kominsky, DJ, Brodsky K, Eltzschig HK, Walker L, Eckle T. 2013. Cardiac Per2 functions as novel link between fatty acid metabolism and myocardial inflammation during ischemia and reperfusion injury of the heart. PLoS One. 20;8(8):e71493. PMCID: PMC3748049
  3. Brainard J, Gobel M, Scott B, Koeppen M, Eckle T. 2015. Health Implications of Disrupted Circadian Rhythms and the Potential for Daylight as Therapy. Anesthesiology. May;122(5):1170-5. PMC4632990
  4. Bartman C, Oyama Y, Brodsky K, Khailova L, Koeppen M and Eckle T. 2017. Intense light-elicited upregulation of miR-21 facilitates glycolysis and cardioprotection through Per2-dependent mechanisms. PLoS One. Apr 27;12(4):e0176243.
  5. Oyama Y, Bartman CM, Gile J, Eckle T. 2017. Circadian MicroRNAs in Cardioprotection. Curr Pharm Des. 23(25):3723-3730. PMCID: PMC5638700

Clinical Outcomes Research

The overarching goal of our research is to use principles of perioperative goal-directed therapy to improve patient outcomes. While our initial focus was on research in perioperative hemodynamic monitoring including echocardiography, we have expanded these efforts to using preoperatively collected data to provide safe pain therapy even after patients have been discharged from the hospital. Our research is highly collaborative, and we collaborate successfully with researchers in internal medicine, family medicine, cardiology, neurology, surgery, psychiatry, pediatrics, as well as basic science. A principal focus of our group is to provide meaningful mentoring to medical students, trainees, and junior faculty – we have brought >10 mentees to their first peer-reviewed publications and have received grant support from ARCS and IARS for our students.

Funding: NIH - National Institute on Drug Abuse (K23), Colorado Department of Health Care Policy & Financing, Achievement Rewards for College Scientists (ARCS) Foundation, International Anesthesia Research Society (Scholars Award).

Publications:

  1. Karsten Bartels , Lena M Mayes, Colleen Dingmann, Kenneth J Bullard, Christian J Hopfer, Ingrid A Binswanger. Opioid Use and Storage Patterns by Patients after Hospital Discharge following Surgery. PLoS One. 2016 Jan 29;11(1):e0147972.
  2. Ana Fernandez-Bustamante, Gyorgy Frendl, Juraj Sprung, Daryl J Kor, Bala Subramaniam, Ricardo Martinez Ruiz, Jae-Woo Lee, William G. Henderson, Angela Moss, Nitin Mehdiratta, Megan M. Colwell, Karsten Bartels, Kerstin Kolodzie, Jadelis Giquel, Marcos Francisco Vidal Melo. Multicenter prospective assessment of postoperative pulmonary complications, early mortality and hospital stay by the Perioperative Research Network (PRN) investigators. JAMA Surgery. 2017 Feb 1;152(2):157-166.
  3. Jason Brainard, Benjamin K. Scott, Breandan L. Sullivan, Ana Fernandez-Bustamante, Jerome R. Piccoli, Morris G. Gebbink, and Karsten Bartels. Heated Humidified High-Flow Nasal Cannula Oxygen After Thoracic Surgery – A Randomized Prospective Clinical Pilot Trial. Journal of Critical Care. 2017 Apr 19;40:225-228.
  4. Janine Hoerauf, Angela F. Moss, Ana Fernandez-Bustamante, Karsten Bartels. Study Design Rigor in Animal-Experimental Research Published in Anesthesia Journals. Anesth Analg. 2018 Jan;126(1):217-222.
  5. Karsten Bartels, Ana Fernandez-Bustamante, Shannon McWilliams, Christian Hopfer, Susan K. Mikulich-Gilbertson. Long-Term Opioid Use After Inpatient Surgery – A Retrospective Cohort Study. Drug Alcohol Depend. In press 2018.

Pediatric Anesthesia

The Section of Pediatric Anesthesia under the leadership of Tom Majcher, continues to pursue high-level scientific investigations and expand a documented track record of research and scholarship. We collaborate extensively with investigators at Children’s Hospital Colorado, and with other centers Nationally and Internationally. The focus of our research areas include; Pharmacokinetics and drug analytics in children, multi-center collaborative neurodevelopmental and behavioral outcome studies related to anesthesia in young children, international registries of regional anesthesia and airway management, spine surgery clinical outcomes and clinical research outcomes in congenital cardiac anesthesia. Additionally, we conduct research in acute and chronic pain management in children. We have 15 clinicians engaged in clinical research, some researchers are funded by external entities and we produce 25- 35 peer reviewed manuscripts in specialist anesthesiology journals annually.

Publications:

  1. Fiadjoe JE, Nishisaki A, Jagannathan N, Hunyady AI, Greenberg RS, Reynolds PI, Matuszczak ME, Rehman MA, Polaner DM, Szmuk P, Nadkarni VM, McGowan FX Jr, Litman RS, Kovatsis PG. Airway management complications in children with difficult tracheal intubation from the Pediatric Difficult Intubation (PeDI) registry: a prospective cohort analysis. Lancet Respir Med. Lancet Respir Med. 2016 Jan; 4(1):37-48. PMID: 26705976
  2. Christensen LK, Armstead VE, Bilyeu DP, Johnson KE, Friesen RH. Hemodynamic responses and plasma phenylephrine concentrations associated with intranasal phenylephrine in children. Paediatr Anaesth. 2017 Jul;27(7):768-773. PMID: 28504321
  3. McCann ME, Withington DE, Arnup SJ, Davidson AJ, Disma N, Frawley G, Morton NS, Bell G, Hunt RW, Bellinger DC, Polaner DM, Leo A, Absalom AR, von Ungern-Sternberg BS, Izzo F, Szmuk P, Young V, Soriano SG, de Graaff JC; and The GAS Consortium. Differences in Blood Pressure in Infants After General Anesthesia Compared to Awake Regional Anesthesia (GAS Study-A Prospective Randomized Trial). Anesth Analg. 2017 May 4. PMID: 28489641
  4. Cohen M, Zuk J, McKay N, Erickson M, Pan Z, Galinkin J. Intrathecal Morphine Versus Extended-Release Epidural Morphine for Postoperative Pain Control in Pediatric Patients Undergoing Posterior Spinal Fusion. Anesth Analg. 2017 Jun;124(6):2030-2037. PMID: 28448398
  5. Klawitter J, Sempio C, Mörlein S, De Bloois E, Klepacki J, Henthorn T, Leehey MA, Hoffenberg EJ, Knupp K, Wang GS, Hopfer C, Kinney G, Bowler R, Foreman N, Galinkin J, Christians U, Klawitter J. An Atmospheric Pressure Ionization MS/MS Assay using Online Extraction for the Analysis of 11 Cannabinoids and Metabolites in Human Plasma and Urine. Ther Drug Monit. 2017 Jun 19. PMID: 28640062.
  6. McRobb CM, Ing RJ, Lawson DS, Jaggers J, Twite M. Retrospective analysis of eliminating modified ultrafiltration after pediatric cardiopulmonary bypass. Perfusion. Perfusion. 2016 Mar;32(2):97-109. PMID: 27708000