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

Separating analgesic from respiratory effects of narcotics

In a rodent study published in the June 2009 issue of Anesthesiology, Ren et al begins to separate the analgesic from the respiratory effects of narcotics.  They found that administration of Ampakine CX717 attenuated (when given before) or reversed (when given after) an intraperiotoneal dose of fentanyl that would produce apnea.  The authors note that the compound used is considered safe for primate studies and clinical trials for cognitive disorders.  It also crosses the blood brain barrier.  The effect of CX717 does not directly reverse the effect of the narcotic on the respiratory center but rather it accentuates a pathway that is important to generating the respiratory rhythm within the preBotzinger complex.  Ren J et al: Ampakine CX717 protects against fentanyl-induced respiratory depression and lethal apnea in rats.  Anesthesiology 2009;110:1364-70.

 

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

Normothermia Attenuates Cerebral Metabolic Distress In Patients With Aneurysmal Subarachnoid Hemorrhage And Refractory Fever

A team of investigators from PENN MED (including WA Kofke, Department of Anesthesiology and Critical Care) recently investigated the effect of sustained fever (temperature greater than 38.3 deg C despite antipyretics) on the lactate/pyruvate ratio (LPR) of microdialisate samples obtained from brain tissue of patients who had acute subarachnoid hemorrhage (SAH).  An increase in the LPR is considered a marker for increased anaerobic glycolysis, a sign of metabolic stress in brain.  The authors defined an episode of metabolic crisis as an LPR greater than 40.  Reducing body temperature with ice packs and an external cooling device reduced the mean LPR and reduced the percentage of LPR values in the metabolic crisis range.  This was true whether or not ICP was elevated.  The authors concluded that fever control is associated with reduced cerebral metabolic distress in patients with SAH irrespective of ICP (Oddo M et al: Induced normothermia attenuates cerebral metabolic distress in patients with aneurismal subarachnoid hemorrhage and refractory fever.  Stroke 2009;40:1913-1916).

  Dr. Fleisher (Chair, Department of Anesthesiology and Critical Care) points out that this paper has some interesting correlates with several papers showing increased cognitive dysfunction after cardiopulmonary bypass when the body temperature is greater than 37 degrees C: 1) Sahu B et al: Neurocognitive function in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass: The effect of two different rewarming strategies.  J Cardiovasc Vasc Anesth 2009;23:14-21. 2) Grigone AM et al: The rewarming rate and increased peak temperature alter neurocognitive outcome after cardiac surgery.  Anesth Analg 2002;94:4-10. 3) Grocon HP et al: Postoperative hyperthermia is associated with cognitive dysfunction after coronary artery bypass graft surgery.  Stroke 2002;33:537-541

 

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

A New Tool For Understanding The Mechanism Of General Anesthesia

A team of investigators led by Roderic Eckenhoff recently published their identification of a fluorescent anesthetic compound that should assist in obtaining more precise information about the mechanism of anesthetics and allow more rapid testing of potential new anesthetic drugs.  The compound, 1-aminoanthracene, is anesthetic, potentiates GABAergic transmission, and gives the appropriate dissociation constant for binding to the general anesthetic site of horse spleen apoferritin.  Its signal intensity changes as it is displaced from this binding site so it can serve as a marker for site binding competition.  The introductory three paragraphs of their paper provide a focused review of the structural requirements of an anesthetic site of action.  Figure 8 is of particular interest in that it may be one of the first showing the distribution of a general anesthetic molecule within the brain.  Ref: Butts CA et al: Identification of a fluorescent general anesthetic, 1-aminoanthracene.  Proc Nat Acad Sci 2009;106:6501-6501

 

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

Consensus Statement – First international workshop on anesthetics and Alzheimer’s disease

The workshop was held in May, 2008 at the University of Pennsylvania and the consensus document was recently published in Anesthesia and Analgesia.  The statement provides 8 conclusions: 1) The benefits of general anesthetics in allowing surgery and other painful procedures likely outweighs the potentially toxic effects that are currently known.  2) Evidence from animal models suggests that inhaled anesthetic exposure increases the pathologic changes normally associated with Alzheimer’s disease.  For example, in adult wild type rats and mice, isoflurane exposure alone produces decrements in learning and memory that persist for weeks or months.  There are also a number of other well described changes in various animals.  3) In vitro studies provide evidence that inhaled anesthetics interact with recognized pathways of neurodegeneration and produce effects consistent with increased cellular stress.  4) A number of potential mechanisms for the accelerated neuropathyology seen after general anesthetics have been identified.  However the group felt that there is a higher priority to determining the magnitude and presence of anesthetic-induced long term behavioral effects, preferably in humans.  5) The data on the probability of a particular anesthetic drug to cause changes is sparse.  More work is needed; particularly work that directly compares the various anesthetic drugs.  6) Hypothermia during or after anesthesia may be an independent risk factor.  7) The potential effects of anesthesia and surgery at young ages on long term learning and memory have not been examined in clinical studies.  In adults, post operative cognitive decline is well described.  However, the relationship of anesthetic drug to post operative cognitive decline is speculative at best when based on the currently available studies.  8) The long time- course of neurodegenerative diseases coupled with the relatively short period of normal post operative follow-up means that acceleration of Alzheimer’s disease after anesthesia may not have been recognized.  Given the available evidence, the potential for anesthetics to have long term cognitive effects needs serious attention and further study.  In their closing statement the group cautioned against premature, extrapolated conclusions with respect to anesthesia safety.  They felt that “physicians working and publishing in the area have a responsibility to be objective and candid about the limitations surrounding the clinical implications of their work, particularly with in vitro and animal models, as well as with small or retrospective clinical studies.”  The entire statement is only 2.5 pages.  It is clearly written.  I have abstracted only part, it is worth reading in its entirety of you have an interest or concern about these issues.  Baranov D et al: Consensus statement: First international workshop on anesthetics and Alzheimer’s disease.  Anesth Analg 2009;108:1627-30

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

 

Inhalation anesthetics produce damage by disrupting intracellular calcium homeostasis

Huafeng Wei continues his investigations into inhaled agent toxicity.  Using chicken lymphocytes he demonstrated that isoflurane, desflurane and sevoflurane at 2 MAC for 24 hours produced cell damage by increasing cytosolic calcium.  The calcium came from the endoplasmic reticulum.  In IP3 deficient lymphocytes this damage calcium translocation and cell damage did not occur (IP3 is a calcium channel located on the endoplasmic reticulum).  Isoflurane had a much greater effect than did desflurane or sevoflurane.  The clinical significance of these findings are as yet not clear.  The doses and duration of exposure was high for all three agents.  However from a mechanistic viewpoint these findings add to our understanding of the effect of inhaled anesthetics on intracellular calcium control (Yang H et al: Inhalational anesthetics induce cell damage by disruption of intracellular calcium homeostasis with different potencies.  Anesthesiology 2008;109: 1 – 8).

 

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

ASA Abstracts 2008 Department of Anesthesiology and Critical Care, UPENN

John G. Augoustides, Wilson Y. Szeto, Brittany Cornelius,  Elizabeth K. Walsh, Joseph E. Bavaria: Does Ischemia on Presentation Stratify Perioperative Outcome after Acute Stanford Type a Dissection? Anesthesiology 2008; A1422

Albert T. Cheung, Neil Singla, Solomon Aronson: Predicting Clevidipine Dose Requirements in Cardiac Surgery Patients with Perioperative Hypertension. Anesthesiology 2008; A1590

Robert D. Gaiser: Faculty Evaluations, Resident Subtest Scores, and Gender on an Obstetric Anesthesia Rotation. Anesthesiology 2008; A1180

Arjunan Ganesh, Travis Foster,  Scott Adzick, Giovanni Cucchiaro: Efficacy of Addition of Fentanyl to Epidural Bupivacaine for Post-Thoracotomy Analgesia in Infants. Anesthesiology 2008; A1610

Raymond Glassenberg, Roderic Eckenhoff, Jin Xi: Bupivacaine Macrocycle Complexes. Anesthesiology 2008; A651

Jeff E. Mandel: Liquid Injection Closed Circuit Administration of Sevoflurane by Waters’ Canister for Cardioversion. Anesthesiology 2008; A1571

Patrick J. Neligan, Guarav Malhotra, Michael Fraser, Maurizio Cereda, Edward A. Ochroch: Boussignac CPAP Immediately Following Extubation Improves Lung Mechanics in Morbidly Obese Patients. Anesthesiology 2008; A1249

Patrick J. Neligan, Guarav Malhotra, Michael Fraser, Maurizio Cereda, Edward A. Ochroch: Immediately Postoperative Non Invasive Ventilation Improves Lung Mechanics Following Bariatric Surgery. Anesthesiology 2008; A849

Raymond S. Roginski,   Phillip P. Santoiemma: GRINL1A Interactors Cluster to Synaptic Function, Transcription Regulation and Neurologic Diseases. Anesthesiology 2008; A1529

Christopher Ward, Huafeng Wei,  Ge Liang,  Shouping Wang, Yifan Zhao: Neonatal Exposure to Isoflurane Does Not Cause Learning Deficits in the Developing Mouse Brain. Anesthesiology 2008; A201

Huafeng Wei,  Ge Liang,  Hui Yang,  Jing Li, : Suppression of IP₃ Receptor Inhibited Isoflurane Neurotoxicity in Rat Primary Cortical Neurons. Anesthesiology 2008; A329

Huafeng Wei, Yifan Zhao,  Ge Liang,  Qianru Chen, Christopher Ward: Isoflurane Induced Apoptosis by Activation of IP₃ Receptors in Developing Rat Brains. Anesthesiology 2008; A25

A proposed mechanism for isoflurane induced apoptosis

Wei and associates continue their investigations into isoflurane toxicity in this paper from Anesthesiology (2008;108:251 – 260).  Using a variety of cultured cell types they showed that isoflurane activates the endoplasmic reticulum membrane inositol 1,4,5-triphosphate (IP3) receptor.  This activation produces excessive calcium first in the cytosol and then in mitochondria.  It is this higher calcium level that triggers apoptosis.  There was considerable variability in the sensitivity of the various cell lines to isoflurane induced apoptosis.  The authors note that certain cases of familial Alzheimer’s or Huntington disease have enhanced IP3 receptor activity and thus may be more sensitive to the toxic effects of isoflurane.  Recognize the difficulty of extrapolating from cell cultures, to organs or whole animals.  Thus, it is my belief, that further work is necessary before clinical practice is altered by findings such as these (DSS comment).

Huafeng Wei, M.D., Ph.D. is Assistant Professor of Anesthesiology and Critical Care at the University of Pennsylvania

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