Dept Of Anesthesiology & Critical Care, University Of Pennsylvania School Of Medicine

More complex than your house wiring

At home lights on or off is typically accomplished by the same switch and circuitry; not so in the brain with respect to return of consciousness after general anesthesia.  Kelz and his associates recently demonstrated that the endogenous orexin system impacts emergence from but not induction of anesthesia with drugs such as isoflurane or sevoflurane.  The authors note that “there are important differences in the neural substrates mediating induction and emergence.”  The authors state that “orexinergic neurons play a critical role in promotion and maintenance of wakefulness.”   They speculate that volatile anesthetics induce anesthesia through potentiation of inhibitory GABAergic projections from the ventrolateral preoptic nucleus to multiple wake-active neural groups.  Emergence requires stabilization of wakefulness and would thus depend to a larger extent on oxinergic signaling.  The authors note that a subset of narcoleptic humans in whom orixogenic signaling is disordered may take hours to emerge from an anesthetic that for most would require minutes.  They conclude that the “neural substrates governing transitions into and out of the anesthetized state need not be identical, that induction and emergence from anesthesia are not mirror opposite processes.” Kelz MB et al: An essential role for orexins in emergence from general anesthesia. Proc Nat Acad Sci 2008;105:1309 – 14

Max Kelz M.D., Ph.D. is Assistant Professor of Anesthesiology and Critical Care at UPENN

David S. Smith, M.D., Ph.D.

A novel approach to analgesia

Hot peppers make it hurt less – Binshtok and colleagues reported one of those very clever experiments that creates envy from those less imaginative.  They used capsaicin to selectively open TRPV1 channels allowing an otherwise impermeant local anesthetic (QX-314) to enter and block the sensory channel with absolutely no motor blockade.  QX-314 is a charged lidocaine derivative that will not penetrate neuronal membranes and thus has no local anesthetic activity when applied to small sensory nerves.  Capsaicin is a selective agonist for the noxious heat sensitive channel TRPV1 but not for motor channels.  The effect of capsaicin on the channel allowed QX-314 access to the local anesthetic site of action and thus blocked further sodium influx though these channels.  Hind paw injection of QX-314 together with capsaicin produced a long acting (> 2h) increase in mechanical and thermal nociceptive thresholds.  When applied near the sciatic nerve there was a long acting decrease in pain sensitivity without motor blockade in contrast to application of lidocaine which produced both sensory and motor block (Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers.  Nature 2007;449:607-610).

David S. Smith, M.D., Ph.D.

Anesthetics and neurodegenerative disease

Are volatile anesthetic drugs associated with neurodegenerative diseases such as Alzheimer's?  What is the relationship between anesthetic drugs and post operative cognitive deficits?  What are amyloidopathy and tauopathy?  What is their relationship to anesthesia?  All of these questions are clearly discussed in a recent review by Roderic and Maryellen Eckenhoff on the topic of "Anesthesia, Amyloid and Alzheimer's": that will appear in Cellscience Reviews (2007;4: http://cellscience.com/reviews14/Anesthesia_Amyloid_Alzheimers.html) The discussion is readable, the concepts current and the accompanying figures are in color.

David S. Smith, M.D., Ph.D.

Truth in Science

The Wall Street Journal (September 14, 2007) contains the headline “Most Science Studies Appear to Be Tainted by Sloppy Analysis” The article is based on the work of epidemiologist John Ioannidis who has claimed that “most publish research findings are wrong (Why Most Published Research Findings Are False; PLoS medicine 2005;2:696-701).  He notes that the probability of a true finding is related to the size of the study, the magnitude of the effect size difference, the number of tested relationships, the number of other studies on the same or a similar question, and the flexibility of design.  The author notes that the prevalent practice of examining a study in isolation from all of the other work in the same area greatly increases the probability that a given result is due to random fluctuation.

David S. Smith, M.D., Ph.D.

Dr Kofke Discusses Deep Circulatory Arrest and Brain Ischemia

In the Ether Way Blog Andy Kofke reviews the UPENN experience on brain preservation during circulatory arrest for aortic arch surgery and how the successes for this operation might apply to other types of surgery that produce a risk for cerebral ischemia (http://mkeamy.typepad.com/anesthesiacaucus/2007/09/deep-hypothermi.html)

Isoflurane effects on memory and learning in rats

In a maternal fetal rat model, we investigated the behavioral and neurotoxic effects of fetal exposure to isoflurane.  Pregnant rats at gestational day 21 were anesthetized with 1.3% isoflurane for 6 hours. Apoptosis was quantified in the hippocampus and cortex at 2 and 18 hour after exposure in the fetal brain and in the postnatal day 5 (P5) pup brain. Spatial memory and learning of the fetal exposed pups were examined with the Morris Water Maze at juvenile and adult ages. Rat fetal exposure to isoflurane at pregnancy day 21 through maternal anesthesia significantly decreased spontaneous apoptosis in the hippocampal CA1 region and in the retrosplenial cortex at 2 hour after exposure, but not at 18 hour or at P5. Fetal exposure to isoflurane did not impair subsequent juvenile or adult postnatal spatial reference memory and learning and, in fact, improved spatial memory in the juvenile rat. These results show that isoflurane exposure during late pregnancy is not neurotoxic to the fetal brain and does not impair memory and learning in the juvenile or adult rat.

Li, Y., Liang, G., Wang, S., Meng, Q., Wang, Q., Wei, H. Effects of fetal exposure to isoflurane on postnatal memory and learning in rats, Neuropharmacology (2007), doi: 10.1016/j.neuropharm.2007.09.005

On upcoming article in Neuropharmacology

Yujuan Li, Ge Liang, Shouping Wang, Qingcheng Meng, Qiujun Wang, Huafeng Wei

Publications 2006 Department of Anesthesiology and Critical Care

Armstead W M: Association between intravascular coagulopathy and outcome after traumatic brain injury.[comment]. Neurology India 2006;54: 347-8

Armstead W M: Differential activation of ERK, p38, and JNK MAPK by nociceptin/orphanin FQ in the potentiation of prostaglandin cerebrovasoconstriction after brain injury. European Journal of Pharmacology 2006;529: 129-35

Armstead W M, Nassar T, Akkawi S, Smith D H, Chen X-H, Cines D B, Higazi A A-R: Neutralizing the neurotoxic effects of exogenous and endogenous tPA. Nature Neuroscience 2006;9: 1150-5

Atkins J H, Johansson J S: Technologies to shape the future: proteomics applications in anesthesiology and critical care medicine. Anesthesia & Analgesia 2006;102: 1207-16

Augoustides J G, Pochettino A, Ochroch E A, Cowie D, Weiner J, Gambone A J, Pinchasik D, Bavaria J E, Jobes D R, Augoustides J G T, Pochettino A, Ochroch E A, Cowie D, Weiner J, Gambone A J, Pinchasik D, Bavaria J E, Jobes D R: Renal dysfunction after thoracic aortic surgery requiring deep hypothermic circulatory arrest: definition, incidence, and clinical predictors. Journal of Cardiothoracic & Vascular Anesthesia 2006;20: 673-7

Augoustides J G T, Hosalkar H H, Milas B L, Acker M, Savino J S: Upper gastrointestinal injuries related to perioperative transesophageal echocardiography: index case, literature review, classification proposal, and call for a registry. Journal of Cardiothoracic & Vascular Anesthesia 2006;20: 379-84

Barnett R: Pro: Veno-veno bypass should routinely be used during liver transplantation.[see comment]. Journal of Cardiothoracic & Vascular Anesthesia 2006;20: 742-3

Byrem W C, Armstead S C, Kobayashi S, Eckenhoff R G, Eckmann D M: A guest molecule-host cavity fitting algorithm to mine PDB for small molecule targets. Biochimica et Biophysica Acta 2006;1764: 1320-4

Carnini A, Eckenhoff M F, Eckenhoff R G: Interactions of volatile anesthetics with neurodegenerative-disease-associated proteins. Anesthesiology Clinics 2006;24: 381-405

Churbanova I Y, Tronin A, Strzalka J, Gog T, Kuzmenko I, Johansson J S, Blasie J K: Monolayers of a model anesthetic-binding membrane protein: formation, characterization, and halothane-binding affinity. Biophysical Journal 2006;90: 3255-66

Cook-Sather S D, Litman R S: Modern fasting guidelines in children. Best Practice & Research Clinical Anaesthesiology 2006;20: 471-81

Cucchiaro G, Adzick S N, Rose J B, Maxwell L, Watcha M: A comparison of epidural bupivacaine-fentanyl and bupivacaine-clonidine in children undergoing the Nuss procedure. Anesthesia & Analgesia103: 322-7

Deutschman C S, Cereda M, Ochroch E A, Raj N R: Sepsis-induced cholestasis, steatosis, hepatocellular injury, and impaired hepatocellular regeneration are enhanced in interleukin-6 -/- mice.[see comment]. Critical Care Medicine 2006;34: 2613-20

Dominguez T E, Helfaer M A: Review of bispectral index monitoring in the emergency department and pediatric intensive care unit. Pediatric Emergency Care 2006;22: 815-21; quiz 822-4

Eckmann D M, Armstead S C: Influence of endothelial glycocalyx degradation and surfactants on air embolism adhesion. Anesthesiology 2006;105: 1220-7

Eckmann D M, Zhang J, Lampe J, Ayyaswamy P S, Eckmann D M, Zhang J, Lampe J, Ayyaswamy P S: Gas embolism and surfactant-based intervention: implications for long-duration space-based activity. Annals of the New York Academy of Sciences 2006;1077: 256-69

Frey T K E, Chopra A, Lin R J, Levy R J, Gruber P, Rheingold S R, Hoehn K S: A child with anterior mediastinal mass supported with veno-arterial extracorporeal membrane oxygenation. Pediatric Critical Care Medicine 2006;7: 479-81

Gavrin J R: The American Medical Association "Pain Management: the Online Series". Journal of Pain & Palliative Care Pharmacotherapy 2006;20: 71-7

Gavrin J R: Palliative care. Anesthesiology Clinics 2006;24: xv-xvi

Gavrin J R: A prototypical gateway to the World Wide Web: Making sense of pain relief. Journal of Pain & Palliative Care Pharmacotherapy 2006;20: 29-31

Hecker J G, Laslett L, Campbell E, Nunnally M, O'Connor A, Ellis J E, Frogel J K, Fleisher L A: Case 2-2006: Catastrophic cardiovascular collapse during carotid endarterectomy. Journal of Cardiothoracic & Vascular Anesthesia 2006;20: 259-68

Huh J W, Franklin M A, Widing A G, Raghupathi R: Regionally distinct patterns of calpain activation and traumatic axonal injury following contusive brain injury in immature rats. Developmental Neuroscience 2006;28: 466-76

Johansson J S: Central nervous system electrical synapses as likely targets for intravenous general anesthetics.[comment]. Anesthesia & Analgesia 2006;102: 1689-91

Kohl B A: Con: Should aspirin be continued after cardiac surgery in the setting of thrombocytopenia?[comment]. Journal of Cardiothoracic & Vascular Anesthesia 2006;20: 114-6

Levine G K, Deutschman C S, Helfaer M A, Margulies S S: Sepsis-induced lung injury in rats increases alveolar epithelial vulnerability to stretch.[see comment]. Critical Care Medicine 2006;34: 1746-51

Li M, Ratcliffe S J, Knoll F, Wu J, Ances B, Mardini W, Floyd T F: Aging: impact upon local cerebral oxygenation and blood flow with acute isovolemic hemodilution. Journal of Neurosurgical Anesthesiology 2006;18: 125-31

Longnecker D E: Resident duty hours reform: are we there yet?[comment]. Academic Medicine 2006;81: 1017-20

Miksa D, Irish E R, Chen D, Composto R J, Eckmann D M: Dextran functionalized surfaces via reductive amination: morphology, wetting, and adhesion. Biomacromolecules 2006;7: 557-64

Muravchick S, Levy R J: Clinical implications of mitochondrial dysfunction. Anesthesiology 2006;105: 819-37

Ochroch E A, Gottschalk A, Troxel A B, Farrar J T: Women suffer more short and long-term pain than men after major thoracotomy. Clinical Journal of Pain 2006;22: 491-8

Pan J Z, Wei H, Hecker J G, Tobias J W, Eckenhoff R G, Eckenhoff M F: Rat brain DNA transcript profile of halothane and isoflurane exposure. Pharmacogenetics & Genomics 2006;16: 171-82

Sadhasivam S, Ganesh A, Robison A, Kaye R, Watcha M F: Validation of the bispectral index monitor for measuring the depth of sedation in children.[see comment]. Anesthesia & Analgesia 2006;102: 383-8

Xi J, Liu R, Rossi M J, Yang J, Loll P J, Dailey W P, Eckenhoff R G: Photoactive analogues of the haloether anesthetics provide high-resolution features from low-affinity interactions. ACS Chemical Biology [Electronic Resource] 2006;1: 377-84

Papers being presented at the 2007 American Society of Anesthesiologists Meeting

The following is a list of papers being presented by members of the Department of Anesthesiology and Critical Care, University of Pennsylvania at the 2007 ASA meeting

John G. Augoustides, M.D., F.A.S.E., Wilson Szeto, M.D., Sam Watcha, Justin Weiner, M.D., Alberto Pochettino, M.D.: Evaluation of Perioperative Epidural Analgesia in Adult Lung Transplantation. Anesthesiology 2007; 107: A885

Albert T. Cheung, M.D., Jacob T. Gutsche, M.D., Patrick J. Moeller, B.S., Benjamin A. Kohl, M.D., Edward Y. Woo, M.D.: Anatomic Constraints to Transesophageal Echocardiographic Imaging of the Aortic Arch Branch Vessels. Anesthesiology 2007; 107: A1319

Scott D. Cook-Sather, M.D., Jonathan M. Beus, B.S.E., Brian P. Ciampa, B.A., Lydia E. Kruge, B.A., Paul R. Gallagher, M.A.: Effects of Overweight & Obesity on Gastric Fluid Characteristics in Children Fasted for Day Surgery. Anesthesiology 2007; 107: A1225

Giovanni Cucchiaro, M.D., Alfredo Gonzalez-Sulser, B.A., Alan P. Kozikowski, Ph.D., Kennet K. Kellar, Ph.D., Yingxian Xiao, Ph.D.: Analgesic Effects of Sazetidine-A, a New Nicotinic Cholinergic Drug. Anesthesiology 2007; 107: A1348

Marni J. Falk, M.D., Zhe Zheng, Ph.D., Scott A. Falk, M.D., Phil G. Morgan, M.D., Margaret M. Sedensky, M.D.: Altered Potassium Channel Expression in Volatile Anesthetic Hypersensitive Mitochondrial Mutants. Anesthesiology 2007; 107: A1917

Arjunan Ganesh, M.B.B.S., Anne Marie Cahill, M.D., Robin Kaye, M.D., Mehernoor F. Watcha, M.D.: Evaluation of Ultrasound Guided Radial Artery Cannulation in Children. Anesthesiology 2007; 107: A238

Harshad G. Gurnaney, M.B.B.S., M.P.H., Mohamad Rehman, M.D., John D. Dormans, M.D., Daniel M. Shhwartz, Ph.D., Mehernoor Watcha, M.D.: Hemodynamic Factors and Evoked Potential Changes during Spinal Fusion Surgery. Anesthesiology 2007; 107: A2066

W. Andrew Kofke, M.D., M.B.A., Jia Guo, M.D., Thuy Tran, B.S., Mary Ellen F. Eckenhoff, Ph.D., Roderic G. Eckenhoff, M.D.: Delayed Cognitive Dysfunction in Mice by Nitrous Oxide. Anesthesiology 2007; 107: A131

Benjamin A. Kohl, M.D., Albert T. Cheung, M.D., Andrew Ochroch, M.D., M.S.C.E: Risk Factors for the Development of Hyperglycemia during and after Cardiac Surgery. Anesthesiology 2007; 107: A967

Richard J. Levy, M.D., David A. Piel, B.S., Clifford S. Deutschman, M.D.: Exogenous Cytochrome c Improves Myocardial Cytochrome Oxidase Activity and Survival in Late Sepsis. Anesthesiology 2007; 107: A1213

Patrick J. Neligan, F.F.A.R.S.C.I., Stephen Porter, M.D., Bryan Maxx, M.D., E. Andrew Ochroch, M.D., Eric Greenblatt, M.D.: Obstructive Sleep Apnea Is Not a Risk Factor for Difficult Intubation in Morbidly Obese Patients. Anesthesiology 2007; 107: A1821

Mohamed Rehman, M.D., Jonathan Beus, B.S., Travis Fosper, Ph.D., Jim Scott, B.S.: Internet Use on Computers Used as Anesthesia Information Management Systems (AIMS). Anesthesiology 2007; 107: A1116

Raymond S. Roginski, M.D., Ph.D.: Decrease in Rate of NMDA-Induced Ca2+ Entry May Explain Neuroprotection by Anti-GRINL1A Antibodies. Anesthesiology 2007; 107: A1562

Laura E. Schleelein, M.D., Ronald S. Litman, D.O.: Hyperthermia in the Pediatric Intensive Care Unit – Is it Malignant Hyperthermia?  Anesthesiology 2007:107:A1223

Ashish C. Sinha, M.D., Ph.D., Benjamin J. Duckles, M.D., E. Andrew Ochroch, M.D., Noel N. Williams, M.D.: A System for Predicting Adverse Outcomes in Bariatric Surgery Using Preoperative Data. Anesthesiology 2007; 107: A191

Ashish C. Sinha, M.D., Ph.D., Min Wang, B.A., Kristoffel R. Dumon, M.D., Noel N. Williams, M.D.: Incidence of Post Operative Nausea and Vomiting in the Extremely Obese after Weight Loss Surgery. Anesthesiology 2007; 107: A1053

Dennis C. Tong, M.D., Jonathan Beus, B.S., Ronald S. Litman, D.O.: The "Institution's Name" Difficult Intubation Registry. Anesthesiology 2007; 107: A1637

Huafeng Wei, M.D., Ph.D., Qiujun Wang, M.D., Ge Liang, M.D., Hui Yang, M.D., Shouping Wang, M.D.: Isoflurane Induced Neurotoxicity in a Cell Model of Huntington Disease. Anesthesiology 2007; 107: A477

Huafeng Wei, M.D., Ph.D., Ge Liang, M.D., Hui Yang, M.D., QiuJun Wang, M.D., Brian Hawkins, Ph.D.: Common Inhalational Anesthetic Isoflurane Induces Apoptosis Via over Activation of IP3 Receptor. Anesthesiology 2007; 107: A478

Isoflurane preconditioning inhibited isoflurane-induced neurotoxicity

The abstract of a recent article from the Department of Anesthesiology and Critical Care, University of Pennsylvania

Huafeng Wei, Ge Liang, Hui Yang

The commonly used inhaled anesthetic isoflurane has been shown to be both neuroprotective and neurotoxic in various cell cultures and animal models. We hypothesize that, like cerebral ischemia, isoflurane is inherently neurotoxic. Limited exposure of isoflurane provides neuroprotection via induction of endogenous neuroprotective mechanisms (preconditioning), while prolonged exposure of isoflurane induces neurotoxicity directly by its inherent neurotoxic effects. To test this hypothesis, we treated rat primary cortical neurons at different days in vitro (DIV) and rat pheochromocytoma neurosecretory (PC12) cells with or without Alzheimer’s mutated presenilin-1 (PS1) with 2.4% isoflurane for 24 h to induce cell damage determined by both MTT (3-(4,5-dimethyithiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) reduction and LDH (lactate dehydrogenase) release assays. For isoflurane preconditioning, we treated the above cells with isoflurane at 0.6%, 1.2% and 2.4% for 60 min, 4 h prior to a prolonged exposure of 2.4% isoflurane for 24 h. One hour of preconditioning with isoflurane dose-dependently inhibited neurotoxicity induced by 2.4% isoflurane for 24 h in both primary cortical neurons and PC12 cells. This neuroprotection was most dramatically observed in matured cortical neurons (DIV 16) and PC12 cells with over expression of Alzheimer’s mutated PS1 (L286V). Preconditioning L286V PC12 cells with equivalent two minimal alveolar concentrations (MAC) of halothane (1.5%), but not sevoflurane (4%), also abolished the neurotoxicity induced by 2.4% isoflurane for 24 h. Overall these results suggest that isoflurane may be both neuroprotective and neurotoxic, depending on the exposure concentrations and duration. Neuroscience Letters In Press, Corrected Proof, Available online 11 August 2007

Remifentanil-induced cerebral blood flow effects in normal humans: dose and ApoE genotype

Kofke WA, Blissitt PA, Rao H, Wang J, Addya K, Detre J.  Department of Anesthesiolgoy and Critical Care, Department of Neurology, University of Pennsylvania, Philadelphia, PA

Anesthesia & Analgesia. 105(1):167-75, 2007 Jul.

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 (Ultiva) infusion at four sequentially increasing doses: 0, 0.05, 0.1, and 0.2 microg x kg(-1) x 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 Paco(2), were detected in all areas. After normalizing for global CBF to correct for Paco(2) effects, the remifentanil-mediated increased CBF in the cingulate persisted, with decreased flow occurring in the hippocampus and amygdala. All these Paco(2)-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.

Abstract from Ovid Medline