ACADEMIC PROGRAM for THE ACADEMY OF ANESTHESIOLOGY

Transcription

ACADEMIC PROGRAM
for
THE ACADEMY OF ANESTHESIOLOGY
Octogintennial Meeting in St. Petersburg, Florida
February 25 – March 1, 2009
George S. Bause, M.D., M.P.H.; Editor
PROGRAM COMMITTEE:
James D. Kindscher, MD, Vice-Chair & CME Organizer
Angela Enright, MB, FRCPC
Vinod Malhotra, MD
George S. Bause, MD, MPH, Chair
William J. Lyle & Associates, Publisher
Cleveland, Ohio 44060
2009
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OFFICERS
PRESIDENT
C. Alvin Head, MD
IMMEDIATE PAST PRESIDENT
Doris K. Cope, MD
PRESIDENT ELECT
William D.B. Pope, MD, FRCPC
VICE PRESIDENT
Katherine E. McGoldrick, MD
TREASURER
Thomas G. Johans, MD
SECRETARY
Andrew D. Rosenberg, MD
MEMBERS - AT - LARGE
Gerald V. Goresky, MDCM, FRCPC (2008)
James S. Gessner, MD (2009)
Mark A. Warner, MD (2010)
Robert H. Bode, Jr., MD (2011)
Douglas R. Bacon, MD, MA (2011)
SITE COMMITTEE
John F. Ryan, MD
William D. Owens, MD
PROGRAM COMMITTEE
George S. Bause, MD, MPH, Chair
James D. Kindscher, MD, Vice-Chair
Vinod Malhotra, MD
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2009 GUEST LIST
Guest Name*
Sponsor
Salvatore J. Basta, MD
George E. Battit, MD
Sorin J. Brull, MD
Anthony J. Cunningham, MD
Laura F. Cavallone, MD
Carl H. Nielsen, MD
James D. Grant, MD
Douglas R. Bacon, MD
Zeev N. Kain, MD, MBA, MA (Hon)
C. Alvin Head, MD
James R. Munis, MD, PhD
The Anesthesia Foundation
May C.M. Pian-Smith, MD, MS
James S. Gessner, MD
Andrea Vannucci, MD
Carl H. Nielsen, MD
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Overview of the 2009 Annual Meeting of the Academy of Anesthesiology:
Participants will receive a comprehensive update on anesthesia care, including muscle
relaxants, pain management, transfusion medicine, basic science developments in anesthesia,
historical and current anesthesia trends and nitric-oxide’s potential use in sickle cell disease.
Target Audience: The meeting is designed for anesthesiologist-members of the Academy
of Anesthesiology and their guests.
Objectives: At the completion of this meeting, participants should be able to:
• Assess the relevance of the Academy of Anesthesia throughout its history.
• Demonstrate how volatile anesthetics inhibit bronchospasm.
• Appraise the value of the sitting position for neurosurgery.
• Examine the physiology and developments in muscle relaxants and reversal agents.
• Evaluate the success of treatment of delirium after cardiac surgery.
• Interpret the historical, constitutional and ethical issues of lethal injection.
• Describe the neurochemical effects of chronic pain at the spinal cord level.
• Discuss the impact of the global oximetry project.
• Rate the value of the US News & World Report on hospital rankings.
• Interpret the characteristics of a real-time recording of an intra-op cardiac arrest.
• Examine new perspectives of inflammatory pain management.
• Describe the special aspects of anesthesia for gorillas.
• Review the innovations in the development of anesthesia by Seishu Hanaoka.
• Judge the new developments in transfusion medicine as it applies to anesthesia practice.
• Compare how muscle relaxants have evolved in the history of anesthesia.
• Differentiate the interactions between pre-synaptic opioid and muscarinic receptors in
the isolated bovine trachea.
• Appraise the elements involved with making a film on pain.
• Dramatize how understanding physiology is essential to the science of life.
• Rate the newest innovations in the treatment of low back pain.
• Interpret PQRS: a new concept in anesthesiology.
• Appraise the value of managing the perioperative stress response in children.
• Judge the role of nitric oxide in the management of sickle cell disease.
Accreditation
All participants are required to sign attendance rosters at the beginning of each day. A
certificate of completion will be provided to all activity participants based on documentation
of actual attendance time.
Physicians: This activity has been planned and implemented in accordance with the Essential
Areas and policies of the Accreditation Council for Continuing Medical Education through
the joint sponsorship of the KU Medical Center Office of Continuing Medical Education and
the Academy of Anesthesiology. The KU Medical Center Office of Continuing Medical
Education is accredited by the ACCME to provide continuing medical education for
physicians.
The KU Medical Center Office of Continuing Medical Education designates this educational
activity for a maximum of 9.0 AMA PRA Category 1 Credit(s) TM. Physicians should only
claim credit commensurate with the extent of their participation in the activity.
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THURSDAY, February 26, 2009
6:30 a.m.
CONTINENTAL BREAKFAST
7:30 a.m.
Academy President— Welcome
C. Alvin Head, MD
7:35 a.m.
Program Committee Chair— Timing & Scheduling
George S. Bause, MD, MPH
7:40 a.m.
CMEs & Opening Remarks— Thursday’s Moderator
James D. Kindscher, MD
7:50 a.m.
The Once and Future ATC/Academy—
Will We Be Relevant 80 Years From Now?
Douglas R. Bacon, MD, MA
8:15 a.m.
Volatile Anesthetics to the Rescue: Inhibition of Bronchospasm
K. Anthony Jones, MD
8:40 a.m.
The Sitting Position in Neurosurgery: Not Yet Obsolete ! Consequences
Anthony J. Cunningham, MD, FFARCSI, FANZCA, FRCPC
9:05 a.m.
To Twitch or Not to Twitch: Neuromuscular Physiology & Developments
in Muscle Relaxants and Reversal Agents
Sorin J. Brull, MD
9:30 a.m.
Coffee Break & Posters Review
Effect of Spinal Cord Ischemia Injury on the Development of Chronic
Pain in the Rat (Thursday Poster A)
W. Scott Jellish M.D., Ph.D.
Placement of Spinal Cord Stimulator Needles:
A Lesson from Pythagoras (Thursday Poster B)
9:50 a.m.
Treatment of Delirium After Cardiac Surgery: A Success Story at Last
Pieter van der Starre, MD, PhD
10:15 a.m.
Lethal Injection Execution: Historical, Constitutional, and Ethical Issues
Kathryn E. McGoldrick, MD
10:40 a.m.
Neurochemical Effects of Chronic Pain at the Spinal Cord Level
H. Michael Marsh, MB, BS
11:05 a.m.
The Global Oximetry Project
11:30 a.m.
Lunch
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FRIDAY, February 27, 2009
6:30 a.m.
7:30 a.m.
Opening Remarks— Friday’s Moderator
7:35 a.m.
US News & World Report Hospital Rankings:
Should I Depend on Them ?
Mark A. Warner, MD
8:00 a.m.
Mechanisms and Treatment of an Intra-Operative Cardiac Arrest
Analyzed with the Continuous Recording of a Full Set of Hemodynamic
and Respiratory Parameters
Andrea Vannucci, MD
8:25 a.m.
New Perspectives on Inflammatory Pain Treatment
8:50 a.m.
Anesthetizing Gorillas: “My Thrilla with a Gorilla”
Morris Brown, MD
9:15 a.m.
Seishu Hanaoka, a Japanese Pioneer in Anesthesiology
Luke M. Kitahata, MD, PhD
9:40 a.m.
Transfusion Medicine: 2009 (Friday Poster A)
How the World’s First Anesthesia Journal Promoted Replacing
“Asphyxial” With Oxygenating Anesthetic Apparatus (Friday Poster B)
10:00 a.m.
What You Say and How You Say It: A Simulation-Based Program to
Teach Residents How to Speak Up Across Authority Gradients
10:25 a.m.
A Brief Journey Through Relaxant History: Are We There Yet ?
10:50 a.m.
Interactions Between Pre-synaptic Opioid and Muscarinic Receptors in
Isolated Bovine Airways?
Kai Rehder, MD
11:15 a.m.
The Making of a Film on Pain ( Anesthesiology )
Theodore H. Stanley, MD
11:40 a.m.
Lunch
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SATURDAY, February 28, 2009
6:30 a.m.
7:30 a.m.
Opening Remarks— Saturday’s Moderator
7:35 a.m.
Just Enough Physiology: Keeping the Science of Life Alive:
Making Physiology Phun Again
8:00 a.m.
New Innovations in the Treatment of Low Back Pain
Carol A. Warfield, MD
8:25 a.m.
PQRS: A New Concept in Anaesthesia
David J. Wilkinson, MB, BS, FRCA, FCARCSI (Hon)
8:50 a.m.
Winning Their Heart and Mind:
The Perioperative Stress Response in Children
9:15 a.m.
Beneficial Effects of Nitric Oxide Breathing in Adult Patients in
Sickle Cell Crisis
C. Alvin Head, MD
9:40 a.m.
Closing Remarks
9:45 a.m.
Coffee Break
10:00 a.m.
Annual Business Meeting
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THURSDAY, February 26, 2009
6:30 a.m.
7:30 a.m.
Academy President— Welcome
C. Alvin Head, MD
7:35 a.m.
Program Committee Chair— Timing & Scheduling
7:40 a.m.
CMEs & Opening Remarks— Thursday’s Moderator
7:50 a.m.
The Once and Future ATC/Academy—
Will We Be Relevant 80 Years From Now?
8:15 a.m.
8:40 a.m.
The Sitting Position in Neurosurgery: Not Yet Obsolete ! Consequences
9:05 a.m.
To Twitch or Not to Twitch: Neuromuscular Physiology & Developments
in Muscle Relaxants and Reversal Agents
Sorin J. Brull, MD
9:30 a.m.
Effect of Spinal Cord Ischemia Injury on the Development of Chronic
Pain in the Rat (Thursday Poster A)
W. Scott Jellish M.D., Ph.D.
Placement of Spinal Cord Stimulator Needles:A Lesson from Pythagoras
(Thursday Poster B)
9:50 a.m.
Treatment of Delirium After Cardiac Surgery: A Success Story at Last
10:15 a.m.
Lethal Injection Execution: Historical, Constitutional, and Ethical Issues
10:40 a.m.
11:05 a.m.
11:30 a.m.
Lunch
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The Once and Future ATC/Academy— Will We Be Relevant 80 Years From Now ?
Douglas R. Bacon, MD, MA; Professor of Anesthesiology and History of Medicine,
Mayo Clinic College of Medicine, Rochester, MN
Eighty years ago, December 1929, seventeen physician specialists in anesthesia from
across the United States and Canada gathered at the Mayo Clinic in Rochester, Minnesota for
a week of clinical demonstrations, discussions, and camaraderie at the invitation of John S.
Lundy. What would be called the Great Depression had just begun. Yet, with confidence
and optimism, these men came together to discover what novel and perhaps new ways their
colleagues were practicing the specialty of anesthesiology. Equally important, the assembled
physicians believed that seeing work in action held relevance beyond the usual formal lantern
slide lecture. By agreeing to meet again, the idea was perpetuated and the face of North
American Anesthesia was changed. Eighty years later, it is easy to comprehend how
important this group was and is to the development of the specialty.
The Anaesthetists Travel Club (ATC) started out as a clinical, scientific and social
organization. It is clear from Lundy’s original notes and correspondence that great effort was
made to insure that the program contained elements that were of interest to members of the
group. Of equal importance to Lundy was how the evenings would be spent—for he
understood the need for these physicians to have some free form discussion. The key was
that these men were socially compatible as well, or the free and open discussion would not
take place and a critical piece of education would fail to happen in the meeting.
By its demise the ATC had actually revolutionized anesthesiology--or had it? What
was the influence of the ATC? Did the group profess to have a political agenda, or is it
simply coincidence that the members of the ATC were the leaders of the formed American
Board of Anesthesiology, and were influential in transforming the New York Society into the
American Society of Anesthetists ?
In December 1952, the ATC died Academy of Anesthesiology was born, interestingly
enough in Rochester, Minnesota. In ways similar to the ATC, Academy membership was
almost a prerequisite for office in either the ASA or the ABA in the 1950s and 60s. Yet, as the
number of anesthesiologists grew, the membership of the Academy remained fixed, with rare
increases. Thus as a proportion of North American anesthesiologists, the academy became
smaller and smaller and thus the ability to influence events ought to have been less. Yet,
there are a significant number of members of the Academy in leadership positions across
North America organized anesthesiology. While no longer a prerequisite, Academy members
continue to serve in leadership positions out of proportion to the size of the Academy.
What challenges does the Academy face in being relevant over the next eight years ?
The one stated objective of the Academy, that the organization provides “…a broad
exchange of ideas among recognized authorities in problems related to clinical and
administrative Anesthesiology. Historical insights will be included. The presentations will be
followed by an open forum discussion with moderators for a free exchange of ideas. No
dogma here”. Thus, the Academy has staid true to its ATC roots. The free exchange of ideas
amongst leading anesthesiologists is the key to continuing relevance of the organization.
Yet, the real challenge to the organization is insuring that members truly are the
leading authorities within the specialty. As the group’s membership is by invitation only, it is
incumbent upon each member to bring only those potential members who can fulfill the
criteria as experts. However, these members need to be socially adept as well, for without a
congenial group, open and free discussion will not occur. Thus, the question of relevance in
the future is truly in the hands of the members today !
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References:
Letter from John S. Lundy, M.D. to R. Stuart Adams, M.D., October 28, 1929. The Collected
Papers of John S. Lundy, M.D., Mayo Foundation Archive, Rochester, MN
Travel Club 1929 file. Collected Papers of John S. Lundy, M.D., Mayo Foundation Archive,
Rochester, MN
MacKenzie RA, Bacon DR. The Academy: The Beginnings. In: Marsh HM, Stephen CR,
Bacon DR (eds) The Anaesthetists' Travel Club--The Academy of Anesthesiology: 75 Years
in
Service to the Specialty. Academy of Anesthesiology 2004, pp 39-51.
Frontispiece. Academy of Anesthesiology Program 2005.
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K. Anthony Jones, MD, Professor & Chair
University of Alabama, Birmingham, AL
Volatile anesthetics (VAs) have complex effects on airway function, including
reversal of bronchospasm, in patients with hyperreactive airway diseases, such as asthma. In
fact, VAs, particularly halothane and sevoflurane, continue to be effective and safe
therapeutic agents in this clinical setting, even when conventional therapies such as the use of
β2 adrenergic receptor agonists are ineffective. The mechanism of this beneficial effect is
multifactorial, but is due in significant part to a direct inhibitory action (~50% in most
studies) on the airway smooth muscle (ASM) cell. Previous work from our laboratory has
demonstrated that the direct inhibitory effects are due largely to inhibition of agonist-induced
activation of the heterotrimeric guanosine 5’-triphosphate (GTP)-binding proteins (Gproteins). This novel mechanism is not a common property of all anesthetic drugs, but is
unique to volatile agents, and is significant at VA concentrations achieved clinically during
the treatment of severe bronchospasm. This presentation will discuss the biochemical and
biophysical mechanisms by which VAs inhibit agonist-promoted guanosine nucleotide
exchange at the alpha (α) subunit of heterotrimeric G-proteins (Gα). This mechanism is
different from that of all other known inhibitors of G-protein coupled receptor (GPCR)heterotrimer signaling in cells.
The presentation will focus on two of the major GPCR-heterotrimer complexes that
mediate bronchoconstriction, the muscarinic and endothelin receptors, and their cognate
heterotrimers. These complexes are highly relevant to human airway disease, as they are
major participants in the airway inflammatory responses characteristic of reactive airway
diseases. The data support the hypothesis of a unique biochemical mechanism characterized
by allosteric disruption of the ability of the nucleotide-free Gα to enhance agonist binding
affinity to the GPCR. Because this class of metabotropic receptor is important in regulating
cellular function in many tissues, including the central nervous system (e.g., muscarinic
receptor regulation of psychosis and consciousness), the elucidation of the VA mechanisms
on GPCRs may have relevance beyond the ASM cell.
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The Sitting Position in Neurosurgery – Not Yet Obsolete!
Consequences
Anthony J. Cunningham, MD, FRCPC; Professor of Anaesthesia,
Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
Controversy continues to surround use of the sitting position for
neurosurgicalprocedures.1-3 The seated position, while presenting a number of challenges for
the Anesthesiologist, offers many surgical advantages for patients undergoing posterior fossa
and cervical spine procedures including improved operator orientation and surgical access to
midline lesions in many posterior fossa cases. Gravitational drainage of venous blood from
the surgical field and lowering of intracranial pressure increases technical ease and allows
more rapid access to bleeding points.4 An unobstructed view of the face allows motor
responses to cranial nerve stimulation to be directly observed in the sitting position, and
access to the anterior chest wall is facilitated in the event of cardiovascular collapse.
Despite the many advantages offered from the surgical perspective, the sitting
position presents unique physiological challenges for the anaesthetist with the potential for
serious complications.1,5 Venous air embolism (VAE), with or without paradoxical air
embolism (PAE), is a major concern in relation to the use of this position.2,6 Haemodynamic
instability with hypotension and potential compromise of cerebral and myocardial perfusion
may occur. Reduction of inhaled volatile anaesthetic agent and decreasing depth of
anaesthesia may predispose the seated patient to the risk of intra-operative awareness.
Peripheral neuropathy1 tension pneumocephalus,7 and quadriplegia 1,2 are additional reported
associated complications.
The haemodynamic effects of anaesthesia in the sitting position may be influenced by
choice of ventilatory technique. Spontaneous ventilation with a volatile anaesthetic agent in
nitrous oxide / oxygen was popular in the 1960s to provide signs of surgical encroachment on
vital medullary and pontine structures.8 The problems of cardiovascular instability and
arterial hypotension associated with the upright position may be aggravated by the depressant
effects of intravenous induction and volatile agents on myocardial contractility during general
anaesthesia and changes in venous return following intermittent positive pressure ventilation.9
The volume of blood accumulating in the venous system may be influenced by patient factors
- body mass index, intravascular volume status, pre-existing hypertension and mode of
ventilation. As much as 1,500 ml may be sequestered in the venous system of the lower
limbs due to the effect of gravity10 and increased diffusion through the capillary walls and
venous dilatation associated with the use of volatile anaesthetic agents.11 Indicator dilution
technique studies have confirmed a 14 % redistribution of blood volume from the intra- to the
extrathoracic compartment in anaesthetized patients after a change from the supine to the
sitting position.12 Concomitant changes in arterial pressure and stroke volume index were
thus attributed to in cardiac preload.
A number of techniques have been advocated to attenuate the haemodynamic effects
of patient placement in the sitting position. Colloid preloading (10 ml/Kg) 30 minutes before
starting general anaesthesia was reported to prevent decreases in systolic and central venous
pressures during sitting patient positioning without adverse effects.13 Compensatory
mechanisms, perhaps mediated by the renin-angiotensin - aldosterone system or the
sympathetic nervous system, may be operative in the awake or anaesthetized state to
attenuate adverse haemodynamic changes associated with the sitting position. Wrapping of
the legs, application of anti-gravity suits and positioning of the knees at right heart level may
all have potential benefits.
12
Drs Chun-Ming Lin and colleagues from Chang Gung Memorial Hospital, Taiwan
compared the effects of patient position on the minimum alveolar concentration (MAC) for
desflurane in a prospective, non-randomized study of 50 relatively young and healthy patients
undergoing cervical spine laminoplasty (supine) and discotomy (sitting). Not unexpectedly,
heart rate and blood pressure were significantly lower in the sitting compared to the supine
position. However, the MAC for desflurane in this cervical spine surgery patient population
did not differ between the sitting and supine positions. The two patient populations were
reported to share the same desflurane concentration. Response relationship based a complex
logistic regression analysis with co-variate adjustment. The implications of the study
findings are obvious. If hypotension following patient positioning using this desfluranebased general anaesthetic technique is treated by reduction in inhaled volatile agent, intraoperative awareness may follow.
What, if any, is the future use of the sitting position in neurosurgery? Alarming
reports of postoperative quadriplegia in young patients14,15 and successful malpractice
liability claims arising from neurological dysfunction secondary to PAE, has resulted in a
worldwide dramatic decline in the use of the sitting position for neurosurgery. Based on a
postal survey of U.K neurosurgical centres, Elton and colleagues16 reported a greater than
50% reduction in the number of neurosurgical units using the sitting position for posterior
fossa surgery, from 53% in 1981 to 20% in 1991. Posterior fossa craniotomies performed in
the sitting position at the Mayo Clinic declined from over 110 per year in the early 1980’s to
less than 50 per year by the mid-decade17 Responses to a recent questionnaire issued to 61
Japanese neurosurgical institutions reflects a similar decline with only 11.5% of centres
reporting continued use of the sitting position.18 As neurosurgeons abandon its application, it
is likely that this trend will continue as trainees in neurosurgery are not exposed to the
relative merits of sitting position surgery.
Will therefore, specific difficult surgical access cases be denied the technical
advantages of the sitting position in the future ? Is the increasing preference for use of
horizontal positions for surgical access to the posterior fossa appropriate, or should limited
use of the sitting position remain in the neurosurgeon’s armamentarium ? Large prospective
randomised controlled trials examining outcomes following neurosurgical procedures
performed in the sitting compared to the prone or lateral positions, which would shed light on
these questions, are unlikely to be undertaken.
References
1. Porter JM, Pidgeon C, Cunningham AJ. The sitting position in neurosurgery: a critical
appraisal. Br J Anaesth 1999; 82: 117-28
2. Anaesthesia for neurosurgery in the sitting position: A practical approach. Anaesth
Intensive Care 2005; 33: 323-331
3. Matjasko J, Petrozza P, Cohen M, Steinberg P. Anesthesia and surgery in the seated
position: analysis of 554 cases. Neurosurgery 1985; 17: 695-702
4. Black S, Cucchiara RF. Tumour surgery. In: Cucchiara RF, Michenfelder JD, eds. Clinical
Neuroanesthesia. Edinburgh: Churchill Livingstone, 1990; 285-308
13
5. Standefer M, Bay JW, Trusso R. The sitting position in neurosurgery: a retrospective
analysis of 488 cases. Neurosurgery 1984; 14: 649-58
6. Papadopoulos G, Kuhly P, Brock M, Rudolph KH, Link J, Eyrich K. Venous and
paradoxical air embolism in the sitting position. A prospective study with transoesophageal
echocardiography. Acta Neurochir 1994; 126: 140-3
7. Toung T, Donham RT, Lehner A, Alano J, Campbell J. Tension pneumocephalus after
posterior fossa craniotomy: a report of four additional cases and review of postoperative
pneumocephalus. Neurosurgery 1983; 12: 164-8
8. Albin MS, Babinski M, Maroon JC, Jannetta PJ. Anaesthetic management of posterior
fossa surgery in the sitting position. Acta Anaesthesia Scand 1976; 20: 117 - 128.
9. Millar RA. Neurosurgical anaesthesia in the sitting position. Br J Anaesthesia 1972; 44:
495-505
10. Michenfelder JD. Complications during Neurosurgery. Anesthesia and the neuromuscular
system II. Auto-Digest Foundation, Anaesthesiology 1974; 16: 17.
11. Bitte EM, GoebertHW. Anaesthesia for Neurosurgery in the sitting position. Proc Med
Surg 1966; 74: 22
12. Buhre W, Weyland A, Bruhre K, Kazmaier S, Mursh K, Schmidt M, Sydow M, Sonntag,
H: Effects of the sitting position on the distribution of blood volume in patients undergoing
neurosurgical procedures. Br J Anaesth 2000; 84: 354-7
13. Akavipat P, Metta P: Does preloading with colloids prevent hemodynamic changes when
neurosurgical patients are subsequently changed to the seated position ?. J Med Assoc Thai
2005; 88: 247-51
14. Wilder BL. Hypothesis: the etiology of mid-cervical quadriplegia after operation with the
patient in the sitting position. Neurosurgery 1982; 11: 530-1
15. Hitselberger WE, House WF. A warning regarding the sitting position for acoustic tumour
surgery. Arch Otolaryngol 1980; 106: 69
16. Elton RJ, Howell RS. The sitting position in neurosurgical anaesthesia: a survey of British
practice in 1991. Br J Anaesth 1994; 73: 247-8
17. Leonard I, Cunningham AJ: The sitting position in neurosurgery. Br J Anaesth 2002
18. Kida H. Nishikawa N. Matsunami K. Kawahito M. Ota M. Miyao S. [Sitting position
questionnaire, in Japanese language] Masui - Japanese Journal of Anesthesiology. 2000; 49:
566-9
14
To Twitch or Not to Twitch:
Neuromuscular Physiology & Developments in Muscle Relaxants and Reversal Agents
Sorin J. Brull, MD; Professor of Anesthesiology
Mayo Clinic College of Medicine, Jacksonville, FL
I. NEUROMUSCULAR JUNCTION
Physiology. The components of the neuromuscular junction are: (a) the presynaptic
region of the motor neuron; (b) the intervening cleft; and (c) the receptors located on the
postsynaptic membrane (motor end plate). Acetylcholine (ACh) is synthesized in the nerve
terminal and is stored in vesicles. Each vesicle stored in the terminal contains a quantum of
ACh. When the nerve is depolarized, ACh is released into the synaptic cleft and diffuses
across the cleft to bind to the ACh receptors on the motor end plate. Each ACh vesicle
contains between 6,000 and 10,000 ACh molecules, and a nerve impulse typically releases
50–60 ACh vesicles. The motor end plate contains approximately 5 million receptors, each
consisting of 5 subunits (2 alpha, 1 beta, 1 delta and 1 epsilon) arranged around a central
channel. Both of the alpha subunits contain ACh recognition sites and need to be occupied by
ACh molecules (or an agonist) for the channel to open. If ACh binds to both alpha subunits,
the opening channel allows passage of Na+ and Ca++ ions into, and K+ ions out of, the
muscle cell leading to a miniature end-plate potential (MEPP). If enough channels are open,
the individual MEPPs summate and the end plate potential reaches threshold. Once this
occurs, a self-propagating muscle action potential is produced and an “all-or-none” muscle
fiber contraction (muscle twitch) will result, followed by relaxation.
Neuromuscular block: Classification.
There are 2 types of neuromuscular blocking dugs (NMBs, “muscle relaxants”) used
in clinical practice: non-depolarizing and depolarizing. Curare is the prototype of the nondepolarizing group (e.g. atracurium, cisatracurium, doxacurium, mivacurium, pancuronium,
pipecuronium, rocuronium, vecuronium, rapacuronium and gantacurium). These agents
(“competitive blockers”) compete with ACh for binding to the alpha subunit of the postsynaptic nicotinic receptor, blocking the action of ACh. Non-depolarizers have no
appreciable agonist activity, resulting in no muscle fiber contraction. By increasing the
concentration of non-depolarizing molecules at the NMJ, the amplitude of the end-plate
potential (EPP) decreases progressively, making the attainment of threshold more difficult.
While both alpha subunits need to be bound by ACh for receptor activation, binding of only
one non-depolarizer molecule to one alpha subunit renders the receptor non-functional. In
addition, some non-depolarizers may also bind to pre-synaptic receptors, opposing
mobilization (reuptake) and release of ACh quanta.
Depolarizing blocking drugs, such as succinylcholine and decamethonium, initially
depolarize the post-synaptic membrane by opening receptor channels, in a similar manner as
ACh. However, because they are not hydrolyzed by acetylcholinesterases (ACh-ase) at the
NMJ, the action of the depolarizer persists, resulting in prolonged end-plate depolarization.
This brief period of consecutive excitations is manifested clinically by transitory muscle
fasciculations, followed shortly by neuromuscular transmission block and flaccid paralysis.
During either a depolarizing or a non-depolarizing block, and despite the inactivation of the
receptors, the muscle continues to respond (and contract) to direct electrical stimulation such
as electrocautery.
15
II. NOVEL NEUROMUSCULAR BLOCKING AGENTS: PHARMACOLOGY
Gantacurium (AV430; GW280430A) – Gantacurium chloride is a rapid-onset, ultrashort acting non-depolarizing neuromuscular blocker used to facilitate tracheal intubation and
maintain skeletal muscle relaxation during brief surgical procedures. It is classified as an
asymmetric, mixed-onium chlorofumarate compound with a potency (ED95) in animals of 64
mcg/kg. A single ED95 dose has an onset under 2 min, and a duration of 3-6 min. At doses of
3 x ED95 onset is under 1 min, with a duration of action of 5-9 min. Hemodynamic effects are
not reported with doses under 25 x ED95; with larger doses, plasma histamine concentrations
increase.
CW002 – another chlorofumarate compound being developed at Cornell by Dr. John
Savarese. It has a rapid onset and an intermediate duration of action. Its non-depolarizing
blocking actions can be reversed immediately by the administration of cysteine, which
degrades the parent compound into products that are 65 times less potent than CW002.
Cysteine then further degrades these metabolites into 2 molecules that are 500 times less
potent than the parent compound – essentially eliminating the risk of drug accumulation. In
laboratory animals (monkey), doses up to 20 times ED95 result in no hemodynamic changes;
in guinea pigs, similar doses result in no changes in pulmonary resistance that were seen with
rapacuronium. Phase I trials are scheduled to start this summer (2009) (personal
communication, Dr. John Savarese).
SZ1677 – a non-steroidal non-depolarizing neuromuscular blocking agent (pyrrolidinium
bromide compound) that is structurally related to rocuronium. It was first synthesized by
Gedeon Richter in Hungary. Its main degradation product is the 17-OH derivative (SZ1823),
which is 27.5 times less potent than SZ1677. The other form, 3-acetoxy derivative (SZ1676),
is considered impurity. SZ1677 has been shown to have less pre-synaptic inhibitory effect
than rocuronium, so it may induce less fade because of less interference with pre-synaptic
acetylcholine release and reuptake. In laboratory animals, doses up to 8 times ED95 had
minimal effects on blood pressure and heart rate. At similar doses, SZ1677 has no vagal
blocking effects. The potency (ED95) of SZ1677 in laboratory animals is 25 mcg/kg, and
when measured at the airway musculature, onset time at this dose is about 1 min (0.5-2 min
range). Spontaneous recovery (recovery 25%-75%) takes an average of 192 sec (range of 80390 sec). It is reported to have significant variability in onset and duration at different muscle
groups, such as peripheral skeletal vs. central airway muscles.
III. REVERSAL OF NEUROMUSCULAR BLOCK:
Spontaneous vs. pharmacologic
Anticholinesterases (neostigmine, pyridostigmine, edrophonium) are agents that
block the degradation of acetylcholine (ACh) and thus increase the available ACh at the
neuromuscular junction, overcoming the competitive neuromuscular blockade. The efficacy
of this mechanism is limited because once the acetylcholinesterase is maximally inhibited,
there is no advantage to using additional anticholinesterase. Furthermore, if the concentration
of the neuromuscular blocker is still high at the neuromuscular junction, the efficacy of the
anticholinesterase is limited. Anticholinesterases may also have significant cardiovascular
side effects.
16
IV. REVERSAL OF NEUROMUSCULAR BLOCK: Pharmacology
Sugammadex, a modified ɤ-cyclodextrin, is the first selective relaxant binding agent
(SRBA). Sugammadex forms very tight complexes in a 1:1 ratio with steroidal
neuromuscular blocking agents (rocuronium > vecuronium >> pancuronium). This guest-host
complex, which exists in equilibrium, is stable because of its very high association rate and
very low dissociation rate. Sugammadex has no effect on acetylcholinesterases or on any
receptor system in the body, eliminating the need for anticholinergic drugs, which have
undesirable adverse effects. Phase 1-3 trials found that sugammadex can antagonize any level
of neuromuscular blockade, including the profound blockade induced by rocuronium, adding
flexibility to the use of nondepolarizing relaxants. Sugammadex rapidly clears from most
organs, except in renal failure.
Cysteine – a non-essential amino acid, synthesized in human body with methionine as a
substrate, has potent antioxidant properties. Cysteine is important in metabolism as a source
of sulfide, and is used in the biosynthesis of glutathione. It has been used as an antidote for
liver damage from excessive alcohol. In doses of 10-20 mg/kg, cysteine will convert the
chlorofumarate muscle relaxant gantacurium into its inactive derivative, reversing the
neuromuscular block. It is reported to have a half-life of 1-2 hrs, and at the doses used for
reversal of neuromuscular block, it has no hemodynamic side effects.
17
Effect of Spinal Cord Ischemia Injury on the Development of Chronic Pain in the Rat
W. Scott Jellish, MD, PhD, Xin Zhang, MD, Matthew Ripsch, BS, Fletcher A. White, PhD
Dept. of Anesthesiology, Loyola University Medical Center, Maywood, Illinois
Background and Purpose
Injury to the central nervous system may produce chronic pain which is often
refractory to conventional treatment. Activation of both microglia and astrocytes is common
after injury and may increase the production of cytokines and nitric oxide producing painful
neuropathy. Other mechanisms include activation of N-methyl-d-aspartate (NMDA) receptors
in the spinal cord dorsal horn. Activation of NMDA receptors by glutamate is thought to be
essential for the initiation of central sensitization and the subsequent hyperexcitability of
dorsal horn neurons in chronic pain.
Using a novel rodent spinal cord ischemia (SCI) injury model, behavioral testing,
immunohistochemistry and high performance liquid chromatography (HPLC), we determined
the degree to which this injury produces tactile hypernociception, affected neuronal and glial
cells, and increased glutamate levels in the cerebrospinal fluid over a 28-day period of time.
We assayed morphine reversal of nociceptive behavior.
Methods
After approval by the Institutional Animal Care Committee, 150-200g female
Sprague-Dawley rats were anesthetized with isoflurane, their abdominal aorta exposed under
normothermic conditions; the aorta was occluded for one hour. After reperfusion, the
abdomen was closed and the animals awakened from anesthesia. A sham procedure was also
performed without aortic occlusion. All animals were behaviorally tested with Von Frey-type
nylon filaments to determine the pre- and post-operative threshold for foot withdrawal (tactile
hypernociception). One additional group (n=6) was tested for nociceptive behavior following
morphine sulfate administration at 14 days (2 mg/kg) and 21 days (10 mg/kg) post-injury.
Animal groups (n=6-8 per time point) were allowed to survive for 1, 7, 14, 21, and 28 days.
On the day of sacrifice, animals were anesthetized with sodium pentobarbital and
CSF was removed from the fourth ventricle. Following removal of CSF, the animals was
euthanized with CO2 and transcardially perfused with 4% paraformeldehyde. The spinal cords
were harvested, sectioned, and histologically processed for both Nissl staining and
immunohistochemistry. Both neuronal and glial cell types were identified and quantified
using the neuronal marker, NeuN and the glial markers, Iba-1 (microglia) and glial fibillary
acidic protein (GFAP; astrocyte).
Foot withdrawal mean thresholds from sham control animals were compared with
treated animals using ANOVA with repeated measures. Total neuron counts, areas of Iba-1and
GFAP stained spinal cord and CSF levels of glutamate were compared between sham and SCI
groups by ANOVA. Differences between groups was assessed at the p < 0.05 level.
Results
Paw withdrawal threshold response to tactile stimulation in SCI animals (50 mN) was
significantly reduced when compared to sham control by 1 week after SCI (75 mN). The
mean threshold force continued to decrease and reached its nadir 14 days after injury (30
mN). By day 49, the mean threshold had begun to return to baseline levels. Neither dose of
18
morphine produced changes in injury-induced behavior. Analysis of NeuN-labeled cells did
not reveal changes in neuron number following SCI. In contrast, both Iba-1 and GFAP
immunostained SCI tissue revealed that activated microglial cells and astrocytes increased 10
fold and over 7 fold, respectively, by post-injury day 14 compared with sham injury (p<0.05).
HPLC measurement of glutamate present in the CSF at the time of sacrifice reached
128±8.62% by post-injury day 14 compared with sham-treated control rats (p<0.001). Postinjury Day 28 glutamate levels in CSF were 102±3.87% (p<0.001).
Summary
SCI produced chronic tactile hypernociception that proved to be morphineinsensitive, but did not produce changes in neuron cell number. Mechanisms of this ischemiainduced hypernociception include the possibility that activated glial cells may release pronociceptive cytokines or chemokines. Coincident with the development of tactile
hypernociception was greatly increased amounts of glutamate in the CSF. Astrocytes are
known to regulate glutamate levels in the CSF via glutamate transporter proteins under
normal conditions. These findings suggest a combination of glial activation and glutamate
transporter malfunction are responsible for chronic tactile hypernociception in the SCIinjured rat.
19
Placement of Spinal Cord Stimulator Needles: A Lesson from Pythagoras
Thomas G. Johans, MD, Pain Management Services, St. Louis, MO
Introduction.
Placement of spinal cord stimulator electrodes in the epidural space can be a very
daunting task when one considers that its dorsal/midline epidural location is of the utmost
importance for successful spinal cord stimulation. To accomplish this critical position in the
epidural space requires a specially designed epidural needle to be placed at a rather oblique
angle. From the design of the needle, the angle of entry is best if kept at 45o from a line
parallel to the epidural space. Placement of standard epidural needles for catheter insertions
for the purposes of anesthesia do not require such an angle leaving the anesthesiologist new
to spinal cord stimulation frustrated over either ventral placement of the electrode due to an
angle that is too acute to inaccessibility of the epidural space due to an angle too obtuse.
Purpose.
The question at hand is how far back from the vertebral level of insertion does one go
such that when an epidural needle is placed it will always achieve a certain angle of epidural
insertion? The purpose of this poster presentation is to demonstrate a technique that will
insure the angle of epidural entry with the help from an Ancient Greek mathematician.
Technique.
While looking at a lateral view of the spine or x-ray image, a right triangle is formed
by a line drawn anterior from the skin perpendicular to the lamina or epidural space (line a), a
line drawn from this skin reference point of line a caudal and perpendicular to line a (line b)
and a line from caudal end of line b to the lamina (line c). The angle between line a and line c
is the angle of insertion (angle α) into the epidural space.
Line b represents the line whose caudal end represents the skin insertion point for the
epidural needle. Using Pythagoras’ theorem, if we knew the length of line a and the angle of
insertion, then the line b could be calculated by multiplying line a with the tangent of angle α.
How do we measure line a? A small gauge spinal needle is placed as a reference needle
perpendicular to the lamina and parallel to the disc space of the target interspace until its tip
touches the edge of the target lamina. Line a is measured by subtracting the length of the
reference needle outside the skin from the actual length of the reference needle.
Since 45o is the angle we wish to achieve and since the tangent of 45o is 1, line b is
equal to line a. Line c , which represents the hypotenuse of this right triangle would be the
length of needle that would be required to perform the insertion.
Conclusion
Variations in the body habitus of the patient— most notably lumbar lordosis and
obesity— will dramatically affect the success of epidural insertion of spinal cord stimulators.
Those who are expert as well as inexperienced physicians should find this technique helpful
in the placement of these spinal cord stimulator electrodes.
20
Treatment of Delirium After Cardiac Surgery: A Success Story at Last.
Pieter van der Starre, Jose Maldonado, Ashley Wysong, Craig Miller, Bruce Reitz
Departments of Anesthesiology, Psychiatry and Cardiothoracic Surgery.
Stanford University School of Medicine, Stanford, CA
Introduction: Delirium is the most common psychiatric syndrome found in the general
hospital setting. Postoperative delirium is reported in 32 - 80% of cardiac surgical patients,
which may increase morbidity and mortality, and prolong ICU and hospital stay.
Dexmedetomidine, a selective α2–adrenergic receptor agonist, may be an attractive alternative
compared with conventional sedation to lower the incidence of postoperative delirium.
Methods: In a prospective, randomized study 90 open-heart surgical patients, including valve
replacements and aortic surgery, were assigned to Dexmedetomidine (loading dose 0.4 µg/kg,
followed by 0.2-0.7 µg/kg/hr), Propofol (25-50 µg/kg/min), or Fentanyl/midazolam (50-150
µg/hr and 0.5-2 mg/hr respectively), started intraoperatively at sternal closure and continued
postoperatively in the ICU. All patients underwent standard neuropsychiatric tests prior to
surgery, and minimally three days postoperatively, aiming at signs of delirium (DSM-IV
criteria, Delirium Rating Scale) and neurocognitive deficits (Foldstein Mini-mental state
examination, trail-making A & B). Particularly duration of ICU and hospital stay.
Results: The incidence of delirium was 3% in the Dexmedetomidine group, 52% in the
Propofol group, and 50% in the Fentanyl/midazolam group (fig 1). In the Dexmedetomidine
group the ICU and hospital stay were significantly shorter, and there was significantly less
opiate use.
Conclusions: Postoperative sedation with dexmedetomidine was beneficial with respect to
almost complete prevention of postoperative delirium and its consequences in cardiac surgical
patients. This effect may be attributed to its specific pharmacological profile, including its
action on a single receptor type with potential neuroprotective properties.
21
% of Patients with Delirium
60%
50%
50%
50%
40%
30%
20%
10%
3%
0%
Dexmedetomidine
Propofol
Midazolam
Figure 1. Incidence of delirium by postoperative sedation group with standard error bars.
22
Lethal-Injection Execution: Historical, Constitutional, and Ethical Issues
Kathryn E. McGoldrick, MD; Professor and Chair of Anesthesiology,
New York Medical College, Valhalla, NY
Execution has evolved over the years from a public spectacle involving violent
torture to more private, “humane” methods, such as hanging, electrocution, and lethal
gassing. In the United States, a recurring question has been whether particular methods of
execution are compatible with the Eighth Amendment to the Constitution, which states;
“Excessive bail shall not be required, nor excessive fines imposed, nor cruel and unusual
punishments inflicted.” The most recent new method of execution to prompt this question is
lethal injection. In 1977, Oklahoma became the first state to adopt lethal injection, and the
nation’s first execution by lethal injection occurred five years later. Currently, the technique is
used in more than 35 states and by the federal government. Two years before the nation’s first
execution by lethal injection took place, William Curran and Ward Casscells wrote a powerful
article in The New England Journal of Medicine arguing that physicians should not
participate, underscoring that lethal injection “…presents the most serious and intimate
challenge in modern American history to active medical participation in state-ordered killing
of human beings…[since] this procedure requires the direct application of biomedical
knowledge and skills in a corruption and exploitation of the healing profession’s role in
society.” The American Medical Association soon followed their lead, characterizing the
participation of physicians in execution by lethal injection unethical. Nonetheless, to this day,
some physicians participate in execution by lethal injection.
In 2008, the U.S. Supreme Court issued a decision, Baze v. Rees, regarding lethal
injection. The 7 to 2 decision, which did not address the constitutionality of the death penalty
itself, agreed that Kentucky’s 3-drug protocol for lethal injection (the issue in this case) is
constitutional as is, but only three justices (Roberts, Kennedy, and Alito) could agree on a
specific standard that executions by lethal injection must meet. Importantly, none of the
justices even hinted that physicians should be required to participate or be present during
executions by lethal injection. Indeed, all the justices who mentioned medical ethics in
issuing their opinion supported medicine’s stand against physician participation.
The vast majority of states use a three-drug combination (sodium thiopental,
pancuronium bromide, and potassium chloride) for execution. Owing to reports about
“botched” executions, there have been suggestions that changing to a one-drug protocol
(extraordinary amounts of sodium thiopental) that produces death quickly and painlessly, as
well as having direct physician (read anesthesiologist) involvement, would render execution
by lethal injection more aesthetically palatable to the public. It would seem that the problem
the state seeks to solve by enlisting physicians is one of the state’s own making by both
refusing to abolish capital punishment and its insistence on execution by lethal injection as
the method of choice. Why “medicalize” the death penalty in order to save it ?
Suggested Reading:
Curran WJ, Casscells W. The ethics of medical participation in capital punishment by
intravenous drug injection. N Engl J Med 1980;302:226-230.
Baze v. Rees, 128 S. Ct. 1520 (2008).
23
Truog RD, Brennan TA. Participation of physicians in capital punishment. N Engl J Med
1993;329:1346-1350.
Koniaris LG, Zimmers TA, Lubarsky DA, Sheldon JP. Inadequate anaesthesia in lethal
injection for execution. Lancet 2005;365:1412-1414.
Gawande A. When law and ethics collide: Why physicians participate in executions. N Engl
J Med 2006;354:1221-1229.
Guidry OF. Message from the President: Observations regarding lethal injection. ASA
Newsletter 2006;70(8):6-8.
Black L, Sade RM. Lethal injection and physicians. JAMA 2007;298:2779-2781.
Curfman GD, Morrissey S, Drazen JM. Physicians and execution. N Engl J Med
2008;358:403-404.
Annas GJ. Toxic tinkering: Lethal-injection execution and the Constitution. N Engl J Med
2008; 359:1512-1518.
24
H. Michael Marsh, MB, BS; Department of Anesthesiology,Wayne State University
Diabetes is a chronic metabolic disorder that affected 21 million Americans (7% of
the population) in 2005. Neurochemical activity at the level of the spinal cord dorsal horn
maybe modified by diabetes in such a way as to promote Chronic Pain behaviors. STZ is an
established agent used to induce animal models of diabetes and neuropathic pain. In this
study a streptozotocin-induced diabetic state in rats was used to observe if there could be a
valid assessment of both chronic pain behaviors and the neurochemical stores in the dorsal
horn and at thalamic and other central nervous system sites that relate to pain (in particular
the periaqueductal grey area PAG, a known regulator of spinal cord functioning). We
hypothesized that STZ-induced diabetes would decrease pain thresholds and modify the
neurochemical profile in the PAG (increased GLU) and the dorsal horn of the lower lumbar
spinal chord (altered glycine GLY).
Sprague-Dawley rats (n=16; 275g av.) were grouped as control or STZ injected
animals. STZ animals were injected with 50mg/kg IP on day 1. Body weight, water and food
consumption, urine output, locomotor activity (LMA), blood glucose and hindpaw
withdrawal thresholds were determined on days 1, 3, and 7 after STZ exposure. On day 7,
animals were sacrificed and brain punches (2mm3) from the PAG and dorsal lumbar spinal
chord were collected and immediately frozen. HR-MAS 1H-MRS of the intact tissue (~4 mg)
was performed with standard CPMG techniques using a Bruker Avance 500 and a custom
LCModel used for absolute quantification of each neurochemical. Five of the 10 STZ animals
demonstrated diabetic symptoms, exhibiting polyuria, polydipsia and polyphagia, as well as
hyperglycemia. By day 7, STZ-treated animals exhibited a 15% decrease in hindpaw
withdraw threshold and a 22% reduction in LMA compared to controls. The PAG and spinal
chord indicated significant mr-visible increases (p<0.05) in lactate and creatine in the STZ
group. The spinal chord of the STZ treated animals also exhibited significantly higher levels
of Aspartate and GLY (p< 0.05).
Increased creatine and lactate in the CNS of STZ-diabetic rats is consistent with
disrupted energy homeostasis, perhaps a hyperglycemic-induced compensatory increase in
storage capacity of high-energy phosphates (creatine) as well as a shift to anaerobic
metabolism. Metabolic dysfunction may cause abnormal PAG functioning, leading to
decreased spinal cord regulation by the brainstem. Increased glycine in the spinal chord may
occur due to loss of PAG inhibition on primary afferents, with increased signaling through the
dorsal horn activating local glycine interneurons in an attempt to modulate dorsal horn neural
activity without PAG input. The acute onset of locomotor/ sensitivity responses support STZ
and not diabetes in the resultant hyperalgesia. The results also suggest caution when
interpreting metabolite/CRE ratios derived from clinical MR scans in diabetics.
Previously presented.
Metabolic profile of the rat brain using streptozotocin as a model for neuropathic pain:
studies with proton magnetic resonance spectroscopy (MRS). Cherro, H. Marsh, G. M.
Mckelvey1, S. O’Leary-Moore, R. M. Guffey, A. Glaeser, F. Ghoddoussi, M. P. Galloway.
Proceedings of the Society for Neuroscience 2008, November, Washington DC, Abstract #
267.
25
Angela Enright MB, FRCPC
President, World Federation of Societies of Anaesthesiologists
Clinical Professor of Anesthesia, University of British Columbia
Victoria, British Columbia, Canada
In 2004, the Quality and Patient Safety Committee of the World Federation of
Societies of Anaesthesiologists (WFSA) decided to embark on a project to introduce pulse
oximetry to places where it was not in widespread use. With support from the Association of
Anaesthetists of Great Britain and Ireland (AAGBI) and GE Healthcare (GE), the Global
Oximetry Project was born. Pilot projects were undertaken in India, Philippines, Uganda and
Vietnam. GE donated oximeters and the team developed training and education materials.
Each site had its own team. National societies of anesthesia and governments supported the
project.
At about the same time, the World Health Organization (WHO) was developing its
Safe Surgery Saves Lives initiative. Members of the WFSA were very involved with this.
WHO recognized that, without safe anesthesia, there could be no safe surgery. Pulse oximetry
was included as an essential monitoring device on the WHO checklist. However it was
recognized that a significant percentage of anesthesia providers throughout the world has no
access to pulse oximetry.
This led to the development of a secondary project between WHO and WFSA similar
to the WFSA pilot project but on a much larger scale. Teams were created to work on
manufacturing a suitable pulse oximeter, finding financial support and developing an
education and training programme. It is hoped to be have everything in place to begin some
pilot projects in the spring of 2009.
26
FRIDAY, February 27, 2009
6:30 a.m.
7:30 a.m.
Opening Remarks— Friday’s Moderator
7:35 a.m.
Mark A. Warner, MD
8:00 a.m.
Mechanisms and Treatment of an Intra-Operative Cardiac Arrest
Analyzed with the Continuous Recording of a Full Set of Hemodynamic
and Respiratory Parameters
Andrea Vannucci, MD
8:25 a.m.
8:50 a.m.
Morris Brown, MD
9:15 a.m.
9:40 a.m.
Transfusion Medicine: 2009 (Friday Poster A)
How the World’s First Anesthesia Journal Promoted Replacing
“Asphyxial” With Oxygenating Anesthetic Apparatus (Friday Poster B)
10:00 a.m.
What You Say and How You Say It: A Simulation-Based Program to
Teach Residents How to Speak Up Across Authority Gradients
10:25 a.m.
10:50 a.m.
Interactions Between Pre-synaptic Opioid and Muscarinic Receptors in
Isolated Bovine Airways?
Kai Rehder, MD
11:15 a.m.
The Making of a Film on Pain ( Anesthesiology )
11:40 a.m.
Lunch
27
Mark A. Warner, MD; Professor & Dean
.
The best selling single weekly magazine in America is Sports Illustrated’s swim suit
edition. The second best selling single is US News & World Report’s (USNWR’s) hospital
edition. Priorities are every thing in life.
USNWR ranks medical centers based on the cumulative scores of 16 specialties
• The hospital-based specialties of anesthesiology, radiology, and pathology are not
scored
• Of the 16 specialties scored, 12 receive index scores that are based on weighted
counts for reputation of the institution’s specialty (⅓) and medical center-based
factors such as mortality from MEDPAR data ((⅓) and hospital characteristics (⅓).
These characteristics include nurse:patient ratios, presence of unique equipment
such as proton beam accelerators, volume of patients, etc.)
• The remaining 4 specialties are scored only on reputation: psychiatry,
rehabilitation, ophthalmology, and rheumatology
Key factors that influence rankings
Medical center factors
1. Discharge volumes (specialty-specific)
2. Mortality data (MEDPAR data)
Reputational factors
1. Specialty society leadership and awards
2. Specialty society presentations
3. Press releases related to presentations and publications
4. Publications
Potential flaws
• 50 specialists in 4 quadrants of US and Canada (200 total) per specialty perform
the rankings
• Response rates range from 24-52% (48-104 specialists annually)
• Medical center data are self-reported
Summary
A small number of specialists determine reputational scores. The response rates can vary
dramatically between geographic quadrants. Academic medical centers that have high patient
numbers and significant numbers of specialists involved in their national societies and their
work reported in the lay press achieve high overall rankings.
28
Mechanisms and Treatment of an Intra-Operative Cardiac Arrest Analyzed with the
Continuous Recording of a Full Set of Hemodynamic and Respiratory Parameters
Andrea Vannucci, MD, DEAA; Assistant Professor & Patient Safety Officer,
Department of Anesthesiology, Washington University, St. Louis, MO
I will present a case of cardiac arrest and prolonged resuscitation following graft
reperfusion during orthotopic liver transplantation (OLT). A full set of intraoperative
hemodynamic and ventilatory data were recorded in real time. These data will be displayed in
a movie format, as they appeared on the operating room monitors. The case will be discussed
in the context of patient’s comorbidities, anesthetic management and intraoperative events,
with particular regard to the etiology and mechanisms that lead to cardiac arrest. The
possibility to assess and monitor the efficacy of CPR will also be addressed.
The patient was a 74 year-old woman with end stage liver disease secondary to
primary biliary cirrhosis (MELD score 21) who underwent a liver transplant procedure
performed with a standard piggy back technique and temporary porto-caval shunt under
general anesthesia.
Hemodynamic monitors included an oximetric pulmonary artery catheter (Opticath®
Catheter, Hospira, U.S.A.) and invasive blood pressure (ABP) via a radial arterial catheter
connected to a FloTrac transducer (Edwards Lifesciences, Irvine, CA). Hemodynamic data
was displayed on a multimodular Philips IntelliVue 70 monitor (Philips Electronics North
America Corporation, USA). Two arterial pressure based cardiac output monitors, LiDCO
plus® (Lidco LTD., Cambridge, UK) and Vigileo® (Edwards Lifesciences, Irvine, CA) were
interfaced to the monitor (with a Philips VueLink® module) allowing for simultaneous
continuous recording of ABP, cardiac output, and hemodynamic parameters. Data from the
Philips IntelliVue monitor were recorded on a laptop using TrendFace data acquisition
software (Version 1.03, Ixcellence GmbH, Germany) while LiDCO data were stored on the
device’s internal drive.
The following signals were recorded and stored in binary data files. Waveforms:
ECG-II, ECG-V, ABP, PAP, CVP, Pleth, CO2, AWP (both ECG leads were recorded at 250Hz
sampling rate and all other waveform signals were recorded at 125 Hz). Numerical signals:
HR, ABP-SYS, ABP-DIA, ABP-MEAN, PAP-SYS, PAP-DIA, PAP-MEAN, CVP-MEAN,
CO, SpO2, EtCO2, PEEP, P airways peak, Tidal Volume, EtIsofluorane, FiO2 (all of them
were recorded at 1Hz sampling rate). The recorded signals were extracted from binary to text
(CSV) files. Each of the CSV files was loaded into MATLAB programming environment
(www.mathworks.com) and data animation was done using an ad hoc written code. Finally, a
movie file was created at 30fps frame rate and compressed in AVI format.
29
A snapshot from the movie file.
30
Laura F. Cavallone, MD; Assistant Professor, Washington University, St Louis, MO
In recent years a concern of the scientific community and the general public with
regard to appropriate clinical management of pain conditions has grown in parallel with
substantial advancements in basic science research in the field of pain.
Many diverse molecules and molecular pathways have been found to play a key role
in the development of pathological pain, leading to an improvement of our understanding of
the mechanisms underlying both peripheral and central sensitization in response to injury.
Further steps in the next few years are expected to translate this knowledge into the
possibility to develop novel effective analgesic drugs, which would possibly prevent
sensitization at the level of the central and peripheral nervous system, therefore interfering
with the genesis of chronic pain.
Possible targets for these medications include protein kinases, in particular mitogenactivated protein kinases (MAPKs)1, voltage gated sodium channels2, NMDA receptors 3,
and group I metabotropic receptors of glutamate (mGlu1 and mGlu5).4,5
The excitatory neurotransmitter glutamate is released in response to inflammation at
multiple levels throughout the nervous system.6 A pro-nociceptive effect of mGlu5
activation, leading to peripheral and central sensitization, has been demonstrated in
inflammatory pain models.5 On the other hand, mGlu5 antagonists have been demonstrated
to have analgesic properties in a variety of pre-clinical pain models.
Studies of mGlu5 antagonists in pain have been so far limited to pre-clinical animal
models because at this time there are no mGlu5 antagonists that are approved for use in
humans for this therapeutic indication.
In 2005, Porter et al.reported that the clinically validated7 non-benzodiazepine
anxiolytic fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2yl)urea] is a highly potent and selective non-competitive antagonist of mGlu5, similar to the
prototypical antagonist MPEP 8. Porter, et al. further validated fenobam’s efficacy in a variety
of rodent models of anxiety; however its efficacy in the treatment of pain remained untested.
We tested the ability of fenobam to act as an analgesic in two inflammatory pain
models in mice, and found that fenobam, as well as MPEP, can prevent formalin-induced
pain behaviors and relieve established CFA-induced thermal hypersensitivity. In mGlu5
knock-out (KO) mice, no effects of fenobam on spontaneous behavior following formalin
injection were observed, while MPEP decreased spontaneous formalin responses. The effects
of fenobam and MPEP on locomotor behavior and motor coordination were also compared.
In conclusion, compelling pre-clinical data suggest that mGlu5 may be a viable target
for the treatment of pathological pain in humans. Indeed, data from our lab suggest that
fenobam is analgesic in two separate inflammatory pain models in rodents and shows
improved selectivity for mGlu5 compared to MPEP. We therefore propose that fenobam may
represent a promising analgesic for treatment of inflammatory pain in humans.9
Research supported by a grant from the National Institute of Neurological Disorders and
Stroke (NINDS - R01 NS42595)
31
References:
1) Ji R-R, et al. (2009) MAP kinase and pain. Brain Res. Rev.
doi:10.1016/j.brainresrev.2008.12.011
2) Krafte DS and Bannon AW. (2008) Sodium channels and nociception: recent concepts and
therapeutic opportunities. Current Opinion in Pharmacology. 8: 50-56.
3) Liu XJ et al. (2008) Treatment of inflammatory and neuropathic pain by uncoupling Src
from the NMDA receptor complex. Nature Medicine, 14(12);1325-1332.
4) Bhave G. et al. (2001) Peripheral group I metabotropic receptors modulate nociception in
mice. Nature Neuroscience, 4 (4); 417-423.
5) Goudet C et al.(2008) Metabotropic receptors for glutamate and GABA in pain. Brain Res
Rev. doi:10.1016/j.brainresrev.2008.12.007
6) Varney M, Gereau RW IV (2002). Metabotropic receptor involvement in models of acute
and persistent pain: prospect for the development of novel analgesics. Cur Drug Targets: CNS
and Neur Dis 1, 283-296
7) Friedmann et al., (1980) Phase II double blind controlled study of a new anxiolytic,
fenobam (McN-3377) vs placebo. Curr Ther Res 27: 144-151.
8) Porter, et al., (2005) Fenobam: A Clinically Validated Nonbenzodiazepine Anxiolytic Is a
Potent, Selective, and Noncompetitive mGlu5 Receptor Antagonist with Inverse Agonist
Activity. JPET 315:711-721.
9) Montana M et al.(2008) The metabotropic glutamate receptor 5 (mGlu5) antagonist
fenobam is analgesic in rodents. 38th Annual Meeting of the Society for Neuroscience,
Washington, DC., Nov 15-19.
32
Morris Brown, MD; Chair of Anesthesiology, Henry Ford Hospital, Detroit, MI
I had the unique opportunity to provide anesthesia for several gorillas at the
Detroit Zoo on multiple occasions as part of an ongoing study of cardiac disease in
species. While not much is know about gorilla health in the wild, it is known that
gorillas housed in zoos, especially older gorillas, have a relatively high incidence of
fibrosing cardiomyopathy. In fact cardiac disease is the leading cause of death in
male captive gorillas.
I will present my experience in providing anesthesia care to both male and female
gorillas while they underwent routine physical examinations and dental care, transesophageal echocardiography, chest radiography, urinalysis, rabies vaccination, tetanus toxoid
administration as well as TB testing. The challenges presented in immobilizing,
anesthetizing, and awakening Western lowland gorillas will be discussed. In addition,
similarities and differences as well as comparison of equipment and techniques used for
human anesthesia will be presented.
33
Luke M. Kitahata, MD, PhD; Professor Emeritus, Yale University, New Haven, CT
Seishu Hanaoka was born in a town of Hirayama in Wakayama prefecture, Japan in
1760. At age 22 he went to Kyoto to study medicine and surgery and returned home in 1785.
While he practiced medicine and surgery in his father's clinic, he had researched extensively
for two decades on experimental herb medicine and on October 13, 1804, Hanaoka gave
general anesthesia to his own wife to perform mastectomy for her breast cancer. The agents
he used to produce general anesthesia was a combination of eight parts of Datura tatura, two
parts each of Aconitum japonicum, Angelia anomala, Ligusticum cacutilobum, Cuidium
officinale, and one part of Arisaem japonicum.
This event in 1804 took place 44 years before William Morton's demonstration of
ether anesthesia for the removal of a neck tumor at the Ether Dome of Massachusetts General
Hospital. In addition to the mastectomy mentioned above, Seishu Hanaoka had performed
other types of surgery under general anesthesia, such as removal of neck tumors, arm tumors,
leg tumors and limb amputations, etc.
Reference
Akitomo Matsuki: Seishu Hanaoka and Mandragora. Tokyo, Japan, Shinkokoeki Publishing
Company, 2006 [written in the Japanese language]
34
Transfusion Medicine: 2009
James D. Kindscher, MD; Professor & Chair, University of Kansas, Kansas City, KS
What’s new in transfusion medicine? This discussion will highlight some of the
recent developments in transfusion therapy to update anesthesiologists in their management
of patients.
Transfusion Risks: Infectious
With the advent of nucleic acid amplification testing, viral infectious disease
transmission in blood has been greatly reduced. Based on the latest estimates, the current risk
for viral disease transmission in blood is:
HBV
HCV
HIV
West Nile Virus
1 in 200,000-480,000
1 in 1,900,000
1 in 2,135,000
None since 2005
Bacterial contamination in platelets remains one of the greatest infectious risks in
blood products. Because platelets are stored for 5-7 days at room temperature in a solution
that supports bacterial growth, the rate of contamination was previously reported as high as 1
in 2,000. Bacterial detection methods were employed by blood banks beginning in 2004.
The current estimates for the risk of bacterial contamination in platelets are 1 in 75,000.
Chagas Disease is caused by Trypanosoma cruzi, a parasite endemic in Latin
America. An estimated 100,000 people in the U.S. are believed to be infected with Chagas
Disease. The chronic carrier form is transmitted in blood with a high rate of infectivity.
Testing began in 2007 for Chagas Disease and transmission rates are now believed to be very
low.
Transfusion Risks: Noninfectious
Acute hemolytic reactions due to incompatible blood transfusion have been one of
the major causes of the 35-40 deaths per year in the U.S. It has been estimated that ABO
incompatible transfusions occur at a rate of 1 in 14,000 to 1 in 38,000. Hospitals now require
two samples of blood from the recipient to verify ABO and Rh type prior to transfusion. In
addition some centers use additional checks, including bar-coded wrist bands, radiofrequency
identification technology and the use of specialized transfusion teams.
Transfusion Related Acute Lung Injury (TRALI) may now represent the greatest risk
in blood transfusions, with estimates of rates 1 in 3,000 to 1 in 5,000. From 2003-2005 it was
believed TRALI resulted in 24 deaths per year in the U.S. A major etiology of TRALI
involves donor antibodies to leukocytes, particularly the HLA Class I antigens. These
antibodies are most frequently found in women who have experienced pregnancy (25% of
women who have had three pregnancies have these antibodies). Based on the SHOT studies
in the United Kingdom and others, blood banks are now utilizing male-FFP for most plasma
transfusions. This has reduced the incidence of TRALI by as much as 75%.
35
Storage Concerns
It is well known that the ATP and 2, 3-DPG levels of stored blood begin to fall within
one week of storage. Red blood cells also lose their flexibility during storage.
A New England Journal of Medicine article (Koch et al 2008; 358:1229-39),
performed at the Cleveland Clinic in cardiac surgery patients, linked increased risks for postoperative complications as well as lower survival to the age of stored blood that was
transfused. Banked RBC’s that were >14 days old represented a significant risk factor for
prolonged ventilation, renal failure, sepsis and in-hospital mortality. These findings were
countered by a study out of Australia by Yap, et al (Ann Thorac Surg 2008; 86:554-9) that
found no difference in risks for cardiac surgery patients based on age of stored blood.
Because blood supplies are constrained and blood banks are continually pressured to
provide the safest and most available products for patients, the issues of storage lesions create
significant concerns within the blood bank community. At present there is no consensus on
risks based on age of stored blood.
Transfusion
The surgical trauma literature, as well as experiences in combat medicine, has led to
new recommendations for management of the bleeding patient. Increasingly, delayed
resuscitation in the pre-hospital setting is recommended to reduce the amount of blood lost
and to conserve coagulation factors. Once the patient is in the operating room and control of
the bleeding is achieved, resuscitation to normal parameters is undertaken. The surgeons may
also elect to perform “damage-control” surgery, limiting the amount of repair to injuries so
that the patient can be stabilized in the ICU. Once stability is achieved, the patient returns to
the OR for definitive repairs.
The belief that most of the coagulopathy in trauma was due to a dilutional process
has been questioned. Previously it had been recommended that FFP and platelet therapy was
not needed until 1-2 blood volumes had been lost. Many authors in surgical trauma have
begun to recommend early aggressive FFP and platelet therapy, based on the finding in some
studies that the INR on arrival to the hospital was frequently already elevated.
Massive transfusion protocols have also been developed, in which packed red blood
cells, FFP and platelets are given in a 1:1:1 ratio to severely bleeding patients. The
application of recombinant factor VIIa to reduce traumatic bleeding is also receiving much
discussion.
36
How the World’s First Anesthesia Journal Promoted
Replacing “Asphyxial” With Oxygenating Anesthetic Apparatus
George S. Bause, MD, MPH; Honorary Curator, Wood Library-Museum of Anesthesiology
Clinical Associate Professor, Case Western Reserve University, Cleveland, OH
In July of 1891, the Hayes Dental & Surgical Manufacturing Company of Pittsburgh
published the inaugural issue of “the only journal in the world devoted chiefly to the Science
of Anaesthesia”— a quarterly titled The Dental and Surgical Microcosm (D&SM) This
journal aimed “to furnish the most advanced thoughts and developments in this chosen field
of literature and science….”1 The D&SM pre-dated Current Researches in Anesthesia and
Analgesia by 32 years and the British Journal of Anaesthesia by 33 years. By decrying use
of 100% nitrous oxide and by promoting aeration and then oxygenation of volatile agents, the
D&SM helped popularize Hayes Anaesthetic Apparatus Nos. 1, 2, and 3, as well as redefine
general anesthesia as having near-atmospheric or higher concentrations of inspired oxygen.1-7
This redefinition stranded America’s leading dental supplier, the “SS White Dental
Mfg. Co.” (SSW-DMC), geographically between manufacturers who were oxygensupplementing anesthetic apparatus (i.e., between Hayes to the West and Hewitt’s suppliers to
the East). Consequently, a reluctant SSW-DMC felt forced into oxygenating its nitrous oxide
machinery. After receiving the blessing of then unknighted Hewitt and his British colleagues
as “ingeniously made” and “absolutely efficient,” oxygen-supplemented nitrous oxide
apparatus from the SSW-DMC would, over the next 20 years, reach corporate branches in
Germany, Russia, Canada, Great Britain and Brazil. During the same two decades, the
“oxygenated” apparatus was even more widely featured at International Dental Congresses in
Paris, St. Louis, Berlin and London.8
References:
1. Hayes SJ: Hayes process of, and improved apparatus for generating and applying
anaesthetics. Dent Surg Microcosm 1891;1(1):cover, 76
2. Hayes SJ: Process of and apparatus for administering anaesthetics. US Patent 257866, May
16, 1882
3. [Hayes SJ]: Hayes process of, and improved apparatus for generating and applying
anaesthetics. Dent Surg Microcosm 1891;1(1):77
4. Hayes SJ: Process of and apparatus for applying anaesthetic vapors. US Patent 509849,
November 28, 1893
5. [Hayes SJ]: Description of apparatus with instructions for operating. Dent Surg Microcosm
1896;5(1):59
6. [Hayes SJ]: Hayes apparatus for oxygenating the air, as seen attached to the apparatus
previously described. Dent Surg Microcosm 1897;6(1):60
7. Bause GS: America's first patented series of bubble-through anesthetic vaporizers:
Reverend Samuel J. Hayes' sermons against asphyxial anesthesia. Anesthesiology
2009;110(1):12-21
8. S.S. White Dental Mfg. Co.: A Century of Service to Dentistry, 1844–1944. Philadelphia,
SSW Dental Mfg. Co., 1944.
37
What You Say and How You Say It: A Simulation-Based Program to Teach Residents
How to Speak-Up Across Authority Gradients
May C. M. Pian-Smith, MD. MS; Dept Anesthesia & Critical Care,
Massachusetts General Hospital, Harvard Medical School, Boston, MA
Introduction: Residents learn medical knowledge and develop clinical judgment within a
system that is hierarchical. Trainees may be compelled to question their teachers if they
disagree, have safety concerns, or when treatment plans are unclear. We have determined
that a simulation-based educational intervention that teaches a diplomatic
“advocacy/inquiry” technique (A/I) improves the frequency and effectiveness with which
residents "speak up" to superiors during simulated OB emergencies. Subsequently we seek
to determine the transferability and longevity of these lessons, by testing if techniques of A/
I are demonstrated by these subjects in a computer-based exercise 2 years later.
Methods: In a simulated OR, anesthesiology trainees were presented with opportunities to
challenge co-workers’ (confederates) scripted directives (e.g., to administer a relatively
contraindicated medication). In debriefing, they were taught strategies from the aviation and
business world, including techniques of advocacy (saying one's observation) and inquiry
(open, curious request for the other's reasoning). Subjects participated in another scenario at
that time with new opportunities to challenge. In this ongoing work, consented subjects are
followed-up 2 years later and are asked to view video vignettes on a website. An
anesthesiologist in the movies asks them to do things that are controversial (eg, place a
spinal in a septic patient; give nalbuphene to a patient on methadone). Their real-time
spontaneous responses are audio-taped. They each view 4 videos and have 2 opportunities
to “speak up” during each case. As with the initial intervention, language is rated by 2
investigators on a 5-pt scale (1: no acknowledgement of problem; 2: oblique answer; 3:
Advocacy or Inquiry; 4: Advocacy and/or Inquiry repeatedly with desire for discussion; 5:
crisp succinct A/I ). A control group (trainees and junior faculty experienced with
simulation but who have not been trained specifically about A/I, from the Feinberg SOM at
Northwestern, Geffen SOM at UCLA and Miller SOM at Miami) is also being studied.
Results: Mean scores for the original resident subjects participating in an immersive
simulation exercise were statistically different, pre- and post-debriefing intervention (2.3 +/1.3 vs 3.6 +/- 1.2). Fourteen subjects (of a projected cohort of 40) have completed the
follow-up study so far. In the on-going follow-up study, the mean time interval between
initial training and follow-up is 24 +/- 4.9 months, and the mean language score for
challenging is 3.0 +/- 1.4. Results from the control group are pending.
Discussion: An immersive simulation-based intervention was developed and improved
"speaking up" by residents across authority gradients during simulated OB emergencies.
We are assessing long-term retention and transferability of such simulation lessons with a
computer-based exercise 2 years later by comparing the results with those from naïve
controls. Ultimately, overcoming communication barriers within the medical hierarchy may
improve learning opportunities and promote patient safety.
Reference: Pian-Smith M, Simon R, Minehart R, Podraza M, Rudolph J, Walzer T, Raemer
D. Teaching Residents the Two-Challenge Rule: A Simulation-based Approach to Improve
Education and Patient Safety. Simulation in Healthcare. (In press)
This work was supported by a Foundation for Anesthesia Education and Research (FAER)
Research in Education Grant (REG)
38
Salvatore J. Basta, MD; Assistant Professor, Harvard University
Chief Massachusetts Eye & Ear Infirmary, Boston, MA
Since the introduction of d-tubocurarine (borrowing from its use in treating tetanus
and electroshock – induced seizures ) into anesthesiology practice in 1945 by Griffith and
Johnson in Montreal and succinylcholine in 1949 by Mayrhofer and Foldes, the remarkable
report of Beecher and Todd and its correct and more broad interpretation and explanation by
Dripps, anesthesiologists have been looking for the perfect neuromuscular blocking agent.
This has lead over the past 67 years to an incredible understanding of neuromuscular
transmission, the neuromuscular junction, and the nicotinic receptor in health and disease.
Anesthesiologists have honed their skills studying pharmacokinetics and pharmacodynamics
with these agents, elucidated the intricacies of relaxant-induced side effects and waged a long
battle of measuring the degree of block and its adequate reversal in order to prevent morbidity
in the PACU and ICUs. With our increased understanding of the subtleties of residual
relaxation and progress with measuring small amounts of residual paralysis, it is rare to read
reports or series about problems resulting from relaxant misuse. At last year’s ASA meeting
there was only one PBLD, one Refresher Course, one panel on on monitoring neuromuscular
function, one panel with new drugs or antagonists as part of a larger panel, and a mere 20
abstracts presented.
However, rare does not mean zero, and “not zero” continues to stimulate research
into how better to measure and thus how better to antagonize neuromuscular blockade and
how better to judge the process complete. The search for a rapid onset, rapid offset
nondepolarizing agent devoid of side effects continues and has spawned newer strategies
(perhaps misguided ) to terminate relaxant function. This is why I would say that when our
children ( residents ?) ask “are we there yet” , we respond “not yet but soon”.
This brief abstract will summarize the two parallel synthetic efforts demonstrating the
old sop that structure begets function and if you know a little chemistry, you will know these
drugs. I will conclude by introducing two new strategies to irreversibly terminate residual
paralysis and the latest potential chemical class which also shows promise as relaxants
( which can also be rapidly destroyed in the body ).
Steroidal Relaxants ( Its all in the A and D rings )
Cardiovascular
Respiratory
Potency and onset
The organs have it
Harder to reverse
Benzylisoquinolinium Esters
Histamine release (red is what you get)
Time management(duration)
Choose your degradation
Consistent, good behavior (ease of reversal )
Cyclodextrins and Steroid Capture
Cholofumaric Acid Esters and Cysteine Destruction
39
Interactions between Pre-synaptic Opioid and
Muscarinic Receptors in Isolated Bovine Airways ?
Kai Rehder, MD; Vail, CO;
Emeritus Professor, Mayo Clinic College of Medicine, Rochester, MN
Introduction. The amount of acetylcholine (ACh) released upon stimulation of
cholinergic nerves is regulated by activities of pre-synaptic receptors, including purinergic, ßadrenergic, opioid and muscarinic receptors. The latter are considered to be the most
important ones. They trigger, when activated by ACh, a negative feedback mechanism by
which further release of ACh is reduced. The negative feedback thus allows contractile
responses to be finely controlled. The receptors are referred to as autoreceptors and their
controlling effect on ACh-release as muscarinic autoregulation. Evidence for this mechanism
stems from observations that in many species the selective M2-antagonists gallamine and
methoctramine enhance electric field stimulation (EFS)-induced contractile response
presumably by increasing ACh-release. ACh-release is increased because the reduced activity
of inhibitory pre-synaptic M2-receptors attenuates the negative feedback. By contrast
activation of pre-synaptic µ- and κ-opioid receptors by opioids attenuates ACh-release and
contractile response to electric stimulation (ES).
In the present study we studied if interactions between pre-synaptic opioid and
muscarinic receptors existed in isolated bovine trachealis muscles. Is the inhibitory effect of
opioids on ACh-release attenuated by reducing the activity of inhibitory pre-synaptic
muscarinic receptors ?
To our knowledge pre-synaptic muscarinic receptors have not been demonstrated in
bovine trachealis muscles. The goals of the study were first to search for presence of presynaptic muscarinic receptors, secondly determine if pre-synaptic muscarinic receptors are of
the M2-subtype and thirdly examine if interactions occur between inhibitory pre-synaptic
muscarinic and opioid receptors in isolated bovine trachealis muscles.
Methods and Procedure . Twenty-nine bovine tracheas were obtained from a local
abattoir. The tracheas were immersed immediately after the death of the animals in aerated
and chilled (4º C) physiologic salt solution (PSS) and transported to the laboratory. Small
muscle strips were prepared and suspended in tissue baths. The strips were contracted
every 5-min for 30-s by electric field stimulation (EFS) or electric stimulation (ES) (32 Hz,
25 V, 0.5 ms). EFS and ES were provided by a direct current amplifier triggered by a
stimulator. The strips were stretched by means of micromanipulators after each stimulation
until constant and maximal contractions were observed (optimal length, lo). Isometric forces
were recorded continuously throughout the study.
Presence of pre-synaptic muscarinic receptors. One pair of muscles was used from
19 animals. The muscles were mounted horizontally in 2-ml water-jacketed tissue baths. They
were superfused with aerated (95% O2 and 5 % CO2) PSS (37 ºC) containing propranolol (106
M), indomethacine (10-5M), and choline chloride (10-6M). One end of the muscles was tied
to a platinum electrode mounted on a force transducer and the other end was tied to a
platinum electrode attached to a micromanipulator. Both muscles were superfused with
aerated PSS at flows of 1-ml/min until lo had been achieved.
Both muscles were then equilibrated with [3H]-choline by superfusion with aerated
PSS (37ºC) at flows of 2-ml/min for 30-min. 15 µCi of [3H]-choline (specific activity 75µCi/
mM) was added to the PSS. During equilibration both muscles were stimulated continuously
by ES (25 HZ, 25V, 0.5ms) to enhance neuronal uptake of [3H]-choline. Following
completion of equilibration, both muscles were washed for 90-min with aerated PSS
containing in addition to the other compounds hemicholinum-3 (10-5M) to inhibit neuronal reuptake of [3H]-choline.
40
The flows of superfusates were reduced to 1-ml/min and collections of superfusates
were started. This time is referred to as time zero (t0). Superfusates were collected separately
from both muscles for 3-min periods in scintillation vials containing 14-ml Opti-fluor ®.
Collections were continued until the end of the study. It was interrupted only for 10-min
periods for incubation with test compounds.
Superfusates were assayed for radioactivity by liquid scintillation counting. Counts
were corrected for background counts. Counts per minutes (CPM) were converted to
disintegrations per minute (DPM) as follows:
(1) DPM = CPM / counting efficiency
DPM were plotted as a function of time. ES-induced release of [3H]-ACh was
calculated by integrating the area bound by spontaneous [3H]-release and [3H]-release
occurring in response to ES. It is expressed as disintegrations.
One of two muscles from each animal served as control and the other as test muscle.
Eighteen minutes after the beginning of the study both muscles were stimulated the first time
by ES (4 Hz, 25 V, 05.ms). At t39 test but not control muscles were incubated with atropine
(10-7M) and at t67 a second ES of test and control muscles followed. ACh-releases determined
for the two stimulations are referred to as A1 and A2, and contractile responses as F1 and F2,
respectively. The ratios of A2/A1 and F2/F1were calculated and compared statistically. The
data for contractile responses and ACh-releases were expressed as mean ± SD.
Determine if pre-synaptic muscarinic receptors are of M2-subtype. From 10 animals,
8 strips each were prepared. One muscle from each animal served as control while the other
seven were used as test muscles. The strips were mounted vertically in eight 25-ml waterjacketed tissue baths containing aerated PSS (37ºC), containing propranolol (10-6M) and
indomethacine (10-5M). One end of the muscles was tied to stationary hooks and the other
end to a force transducer mounted on a micromanipulator. The muscles were stimulated by
EFS through two vertically mounted parallel platinum electrodes (1 x 4 cm). Seven strips
from 5 animals each were incubated with either the M2-specific antagonists gallamine or
methoctramine (log increments from 10-9 to 10-5M). Thirty minutes after addition of each
aliquot, contractile responses to EFS (32Hz, 8Hz, 2Hz, and 0.5 Hz) applied in random order
were determined.
Interactions between muscarinic and opioid receptors. Interactions between presynaptic opioid and muscarinic receptors were studied in 14 pairs of trachealis muscles. After
incubation with atropine (10-7M), ES-induced ACh-releases were determined. Thereafter, test
but not control muscles were incubated with either 10-5M DAMGO (n=7) or 10-5M U-50488
H (n=7). ACh-releases were determined again after a third ES.
Results and Discussion. Presence of pre-synaptic muscarinic receptors. Atropine
(10 M) reduced significantly (p< 0.001) ES-induced contractile responses, presumably by
antagonism of post-synaptic muscarinic receptors. Atropine also resulted in a significantly
(p<0.04) larger ES-induced ACh-release than in control muscles. The increased ACh-release
is presumably the result of reduced activity of inhibitory pre-synaptic muscarinic receptors.
Determination if pre-synaptic muscarinic receptors are of the M2 subtype. At low
concentrations both gallamine and methoctramine are M2-specific antagonists. They attenuate
activity of inhibitory pre-synaptic receptors and thereby the negative feedback by muscarinic
autoregulation. Consequently stimulus-induced ACh-release and contractile response will
increase if muscarinic receptors of the M2-subtype are present. In the present study neither
gallamine nor methoctramine increased contractile response to EFS at any of the 4
stimulating frequencies or at any of the 5 concentrations of gallamine or methoctramine.
Failure to increase EFS-induced contractile responses at any concentration and frequency
-7
41
suggests that no inhibitory pre-synaptic muscarinic receptors of the M2-subtype were present
in the isolated bovine trachealis. The significant (p<0.05) reductions in EFS-induced
contractile responses at 10-5 M of gallamine and methoctramine were due to antagonism of
post-synaptic muscarinic receptors; because both gallamine and methoctramine loose their
M2-specificity at high concentrations.
Interactions between pre-synaptic muscarinic and opioid receptors. The mean A2/A1
was significantly (p=0.0003) larger in control muscles than in muscles treated with DAMGO
(10-5M), demonstrating inhibition of ACh-release by DAMGO. After treatment with the µopioid antagonist naloxone, the mean A3/A1 was significantly (p=0.007) larger than the mean
A2/A1, suggesting that the inhibitory effects of DAMGO were due to stimulation of µ-opioid
receptors. Importantly DAMGO also inhibited significantly (p=0.02) ES-induced AChrelease when muscles were pre-incubated with atropine. Thus attenuating the negative
feedback did not abolish the inhibitory effect of DAMGO on ES-induced ACh-release. These
findings suggest that with DAMGO alone the negative feedback was intact, i. e. DAMGO
did not affect the inhibitory pre-synaptic muscarinic receptors. Thus there appeared to be no
interactions between pre-synaptic muscarinic and µ-opioid receptors.
Similar results were obtained with U-50488 H (10-5M). The mean A2/A1 was significantly
(p=0.0002) larger in control muscles than in muscles treated with U-50488 H , demonstrating
an inhibitory effect of U-50488 H on ACh-release. Treatment with the highly specific κopioid antagonist nor-BNI resulted in a mean A3/A1 which was significantly (p=0.02) larger
than the mean A2/A1, suggesting that the inhibitory effect of U-50488 H was due to
stimulation of κ-opioid receptors. U-50488 H also significantly (p=0.03) inhibited ESinduced ACh-release when muscles were pre-incubated with atropine (10-7M). Thus
attenuating the negative feedback did not abolish the inhibitory effect of U-50488 H on ESinduced ACh-release. Thus there appear to be no interactions between pre-synaptic
muscarinic and κ- opioid receptors.
However, the conclusions must be taken with some caution, because ideally one
would have complete frequency and concentration response curve.
Clinical Implications. There was no evidence for interactions between muscarinic
and opioid receptors. In human airways, inhibitory pre-synaptic muscarinic receptors of the
M2-subtype are present. Hence in humans the effect of opioids on ACh-release will depend on
M2-activity. This may be of clinical interest to anesthesiologists. Certain muscle relaxants
including gallamine and pancuronium are specific M2-antagonists. They attenuate muscarinic
autoregulation and may reduce the inhibitory effects of opioids on ACh-release and thereby
on airway contraction.
42
The Making of a Film on Pain (Anesthesiology)
Theodore H. Stanley, MD; Professor, University of Utah, Salt Lake City, UT
Pain…an inextricable part of life. On one hand it protects our bodies from damage
and on the other it can morph into immense suffering robbing us our identity and humanity.
It is an aspect of life that can literally soften our will to live into cherishing the prospect of
death.
An estimated $100 billion per year is spent in the area of pain and among the leading
health problems visible today such as breast cancer and heart disease, pain’s presence tops
them all - its physical hold and far-reaching breadth of financial and familial stress, is
devastating !
Currently, almost 1/3 our population suffers chronic pain. We can all relate to the
wrenching nature of cancer and the unbelievable pain it can cause at a time in life when
everything is at stake, we can connect immediately to a loved one reeling from the
devastating after effects of a traumatic accident, or the gradual debilitating pain of aging and
disease. Our film carries the viewer on a visual journey through the lives of 3 people and
their involvement with pain, weaving a human story of compassion, despair, comedy, hope
and inspiration starting first with how they arrived at pain, what they have done to receive
relief, how their exposure to the healthcare process and the various people involved in
delivering pain relief care occurred, and finally how they got better.
Our film takes us through pain’s manifestation in the body, why it can linger long
after an injury has healed. We then take a ride to the top of the mountain of inspiration as we
view how the body and mind work together to turn off its excruciating sensation. We are
captivated by the effervescent view of hope – learning for ourselves pain relief’s effect on the
body, how it travels the internal workings of our mind delivering its succor – made possible
through the assistance of myriad drugs, methods and techniques.
Not all is perfect in the land of medicine and even though we have amazing drugs,
and methods for treating pain, the system isn’t always right-on. To this end we examine the
social and cultural obstacles involved in receiving good pain relieving care, some of the
political and financial barriers associated with the medical establishment and a reflection into
the education of pain on the part of the medical practitioner. Currently, pain is not taught in
medical school it is a practice gleaned from many years of specialty in various areas of
medicine such as anesthesiology, internal medicine, and psychology.
We round the film’s close leading up to the horizon of products, technology and
research of the future. There is much peace and hope with which to surround ourselves.
Ultimately we arrive at an education and understanding of pain and pain relief armed with a
proactive stance to take charge of our own care should we find ourselves in the vulnerable
arena of pain.
Our message: We needn’t succumb to suffering !
43
SATURDAY, February 28, 2009
6:30 a.m.
7:30 a.m.
Opening Remarks— Saturday’s Moderator
7:35 a.m.
Just Enough Physiology: Keeping the Science of Life Alive:
Making Physiology Phun Again
8:00 a.m.
8:25 a.m.
8:50 a.m.
Winning Their Heart and Mind:
The Perioperative Stress Response in Children
9:15 a.m.
Beneficial Effects of Nitric Oxide Breathing in Adult Patients in
Sickle Cell Crisis
C. Alvin Head, MD
9:40 a.m.
Closing Remarks
9:45 a.m.
Coffee Break
10:00 a.m.
Annual Business Meeting
44
Just Enough Physiology:
Keeping the Science of Life Alive: Making Physiology Phun Again
James R. Munis, MD, PhD; Assistant Professor
The world has gone molecular. As it should. The cutting edge of research and
therapeutics has long since passed down through the levels of integration; moving from the
whole body to organ systems to tissues, and finally to cells and molecules. Even, perhaps,
penetrating into the nanosphere. Answers to important questions are being found among the
chemical constituents of life. Molecular levers are being pulled that, with exquisite finesse,
fight disease at its tiniest and most vulnerable level.
And then there’s us. Anesthesiologists. Are we an anachronism? We do our work at
the level of organ systems. We’re practical. We’re attentive. That’s our job. But we do that job
by attending to people where our hands and our instruments and our monitors can best touch
their lives: where electrical impulses fire in the brain and heart; where gas mixtures inflate
and exchange with one another in the complex caverns of the lungs; where streams of blood
and oxygen course through the great traffic circle of the vasculature; and even where nerve
and muscle touch to make us move.
To be sure, we may manipulate the body at the molecular level. Some of our drugs
are deliberately targeted there. He wasn’t an anesthesiologist, but Claude Bernard, the father
of experimental physiology, was the first scientist to discover the site of action of any
anesthetically-relevant drug. With characteristic ingenuity, Bernard used simple frog
experiments to show that curare acted not on muscle and not on nerve, but at the junction
between the two. This was decades before Paul Ehrlich taught us about receptors. Watch
carefully what happens during an ECT case with succinylcholine and a leg tourniquet and
direct electrical current delivered to the masseter muscles and you’ll see Bernard’s frog
experiments repeated before your own eyes. Physiology is embedded in history. So we know
where and why some of our drugs act, even at the molecular level. Others, including inhaled
anesthetics, are still just happy accidents. But we also manipulate the body at the grossest
level: prying open airways, ventilating lungs, infusing fluids and blood, and tracking the
impulses and contractions of the heart. We are organ system physiologists to the core.
When a patient is placed under our care, however, the first thing we do is disable
them. The fine-tuned feedback loops of the autonomic nervous system are cut. “The Wisdom
of the Body”, as Walter B. Cannon referred to it, is left helpless and dumb. So we step in to
take over. Our monitors become the afferent limb of the body’s servo-controlled symphony.
Our drugs, our hands, and the tools in our hands, become the efferent limb. During an
anesthetic, we become the conductor of what Cannon first called “homeostasis”; that great
feedback-controlled symphony that maintains what Claude Bernard had earlier named the
interieur milieu.
In the middle of a tough case, though, it doesn’t feel like that. Blood is pouring out,
the pressure is down, and the IV access isn’t enough. We can never escape the earthy,
practical nature of our calling. Medical students notice these things. And they should. I did.
When I was a resident, I enjoyed the sweet irony of working under an attending who, one
minute, was describing the nuances of a new physiologic intervention he had discovered; and
the next, was desperately, expertly, and eventually successfully resuscitating a hemorrhaging
patient. It was all the reward I needed. I had chosen my specialty wisely. There was
something very special about the place where these men and women, whose specialty their
45
own parents couldn’t pronounce, chose to touch, and sometimes even rescue, their patient’s
lives.
That place is at the level of physiology. Not just the physiology of cells and
molecules, but the physiology of whole organs and systems. “The Wisdom of the Body” is
smart where it counts, and it counts where everything comes together. Where blood meets
breath, and where electricity meets muscle. Where the metabolic flame of life in a liver cell is
sustained, in part, by the precision of a respiratory control center many inches and a billion
cells away in the carotid body chemoreceptor. That’s where physiologists work.
What kind of a place is it? I tell medical students it’s a place of overlap. Take a live
body. Subtract from it a dead body. The difference is physiology. There’s more than that, of
course; but for the scientist, it is the definition of function. The science of life.
It only takes one deep hypothermic circulatory arrest to make this point. Invite a
bright student into the OR during the arrest phase. Ask them to tell you if the patient is alive
or dead. There is no pulse, no detectible electrical rhythm in the heart or the brain; no
respiratory movement, no convection of blood; no detectible burning of oxygen or outpouring
of carbon dioxide. And the body is lifelessly cold. Without vital signs, vital sign monitors are
of no use. Without robust metabolism, arterial blood gases are of no use. They say dead men
tell no tales. Neither do their blood gases.
Can the patient be restored to what we call “life” again? Or is it too late? How would
the student know? Maybe some yet-to-be-invented submicroscopic monitor of homeostasis
could tell us whether or not the intracellular house is being kept. But we don’t know. All we
have is the clock. And our experience. And the data of comparative physiology – of
hibernating and hypothermic animals. And the “Q10 Rule”. It’s the sum of those parts, and
not our eyes or our monitors, that give us the confidence to tell the student that “she’ll be
fine”. But our eyes, and the surgeon’s, keep darting back to the clock.
This is as close to the boundary of life and death as we get. It is also a marvelous
place to show a student or a resident where physiology lives - and what physiology is. As the
patient emerges, so, too, does her physiology, but still in a disabled state. We will need to play
the role of central controller in her homeostatic feedback loops again – just as we did on her
way down. Our monitors come to life again in their role as our patient’s afferent limbs; and
our drugs and ventilator as her efferent limbs. We warm her up, wean her back, then allow the
wisdom of her own body to regain its senses and take over again. It’s both pure and applied
physiology.
Bernard never got to see this. Neither did Cannon. I’m sure Guyton did. I never got to
meet him or ask him what he thought, but I can guess. Our students get to see these things,
though, and it’s important that we explain to them what they are seeing. And what they aren’t.
I was fortunate to have teachers and attendings who thought a great deal about what was right
there in front of them, and even more fortunate that they asked me questions about it, too.
Students like this kind of stuff. It’s one of the best things we have to teach them
within the confines of a hospital. But we can’t forget that they’re still young and adventurous.
They’re also attuned to things like mountain climbing, deep sea diving, spaceflight, and
African safaris. Thankfully, so is physiology.
46
That’s why it was so delicious to be in San Diego for a few years. You can find
incredible things there, especially if you have the advantage of being a student. And more
especially, if you have the advantage of being a student who’s willing to play hooky on bright
San Diego days and explore. The city is graced with two zoos, a Sea World, a world-class
organ-system physiology department, high altitude physiologists, comparative physiologists,
Navy-trained sea mammals, and Navy-trained human SEALs. It’s a physiology student’s
dream. For me, it provided four years of physiology stories for my own future students, and I
know they’ll remember my stories long after they’ve forgotten me.
But there’s also another coast. I was a resident once, and during a rare quiet night in
Boston, I noticed something peculiar about the CVP in a patient sitting up in a chair in the
ICU. I asked my attendings about it the next day. They were honest. They didn’t know.
They’re guesses didn’t quite get us to the mark. But I made another guess: I wagered that the
comparative physiologists would know. The same scientists who study giraffes in Africa had
thought about these things. So did the physiologists who study spaceflight and
weightlessness. More food for thought. Now I do sitting cases for neurosurgery almost every
day. I see the same thing, and I ask my residents the same question. The questions keep
coming. For example, I ask them how our sitting patients get venous air embolism when
they’re being mechanically ventilated. They don’t know. Our textbooks don’t know. But the
comparative physiologists do, so we visit the Doctor Dolittles of the world of comparative
physiology to answer the question. What seemed so arcane once turns out to have
medicolegal and practical application to how we think about and measure CPP in the sitting
position. Our residents are good sports about these excursions: they like the neuroanesthesia
rotation, even though they never know where it will take them.
And, of course, there’s history. We have a beautiful medical library at the Mayo
Clinic. It’s in the Plummer Building – named for a colleague of Will and Charlie Mayo who
was particularly inventive. Henry Plummer was the kind of guy who was always looking for
solutions, whether they were from the past or ahead of his time. Inside the massive ornate
reading room of the library are wooden ceiling beams. They have imprinted on them the
names of the great medical scientists of all time: Harvey. Vesalius. Pasteur. Virchow.
Mitchell…. Mitchell? Very few students know who he is. If they read Just Enough
Physiology they will. He was ridiculed for suggesting that the inner mitochondrial membrane
acted like a proton battery to power and keep alight that little flame of life at the end of
oxygen’s journey from the atmosphere. What Ewald Weibel called “The Pathway of
Oxygen”. It is the ultimate answer to why oxygen tanks and oxygen hoses and other green
things in the hospital are so important to us.
Mitchell coupled oxidative phosphorylation and electron transport to that proton
gradient. He went from ridiculous to Nobel laureate within a decade. He wasn’t the only one,
of course. Medical history is full of similar curious cases. To be honest, we can set aside
Mitchell for a second. Very few students know who Claude Bernard or Walter B. Cannon is,
for that matter. That’s our fault. So I provoke the students. I tell them that if (when) one of
them wins a Nobel Prize some day, within two years no contemporary medical student will
even know their name. Even if it’s on a beam in the Plummer Library. They don’t like that.
Maybe it will provoke them to read. “Doctor” derives from the Latin for “docere”: to teach. I
think it may also mean to provoke. Hidden within Just Enough Physiology are a few
provocations. Not too many, I hope, but just enough.
One more story. A little closer to home. One day I was a young faculty member
engaged in an otherwise routine case. It was a long one, and I had time to watch, and time to
47
think. There was an IV in the patient, of course. Since I like history, I remembered that Sir
Ernest Starling (go ahead - ask one of my students who he was) had once opined that there
was one special place in the circulation where the action of the heart neither raised nor
lowered the local blood pressure. The pressure there would be the same whether the heart was
beating or not. Starling called it the “mean systemic pressure”, and thought that it occurred in
the small veins. Guyton made a great deal of mean systemic pressure for other reasons; but in
his era, before controlled circulatory arrest cases, he couldn’t measure it in humans. I thought
it would be a marvelous pressure to know because it was a pure index of cardiovascular
fullness; or as Starling would think of it, the ratio of stressed blood volume to venous
compliance. What if we simply measured it in our patients’ IVs ? What if we measured it
during an isovolemic circulatory arrest case for the repair of a giant cerebral aneurysm to
confirm that IV pressures (PVP) estimate mean circulatory pressure? What if we observed
that all other pressures converged to PVP during isovolemic arrest – just like they had a
century earlier in Starling’s animal experiments; or a half century later in Guyton’s ? It was a
very old idea, but with new and better ways to measure it, and new ways to take advantage of
it. That started a bit of fun, and eventually spawned some studies around the world. And some
controversy. I’m sure there’s a Latin root buried somewhere in the word “hemodynamics”
that translates as “controversy”. For the students, though, I summarize a small hemodynamic
and physiologic adventure like this with a simple equation: History + Physiology = Phun.
At the end of the day, physiology is the real science of life. And anesthesia is applied
physiology. Together, they make for some good stories, and I’ve only tried to pass a few of
them on. I hope not too many, but just enough.
48
Carol A. Warfield, MD; Professor, Harvard University, Boston, MA
Low back pain is a leading cause of disability. In the United States its treatment costs
more than $100 billion in direct and indirect expenses. Seventy-five percent of these costs
can be attributed to the five percent of patients who become disabled due to inadequate relief
of pain. Although there are many nonsurgical treatments for low back pain, those which most
concern anesthesiologists and injection therapies, neuroablative therapies and implantable
devices. Many of these therapies have long been used and include epidural steroid, facet,
trigger and sacroiliac injections, epidural lysis of adhesions, facet rhizotomy, and implantable
spinal cord stimulators and intrathecal pumps. More recently, intradiscal therapies have been
introduced to the armamentarium of tools which anesthesiologists are using to treat low back
pain. These intradiscal therapies include intradiscal steroids, intradiscal electrothermal
therapy (IDET), biacuplasty, and nucleoplasty.
Osteoporosis is a common problem which often results in painful fractures. New
techniques for the treatment of the pain associated with vertebral compression fractures have
been developed. Both vertebroplasty and kyphoplasty involve the injection of
polymethylmethacrylate into the fractured vertebral body.
A description of and rationale for each of these therapies will be discussed in detail
and data on the indications, contraindications, efficacy and complications of each of these
therapies will be presented.
49
David J. Wilkinson, MB, BS, FRCA, FCARCSI (Hon); Chair PQRS Board;
Emeritus Consultant, Barts and the London School of Anaesthesia, London, UK;
Audit is now one of the fundamental aspects of all anaesthetists’ work. This has
traditionally looked as mortality and morbidity as the best indices of how good we are in our
work. In the early 1800s both Snow and Simpson collected this type of data. 1, 2 This tradition
has continued to the present day 3 but has proved to be a useless tool to evaluate any form of
quality in recovery.
Measurement therefore in the recovery phase of anaesthesia has focussed
predominantly on the speed of return to physiological “normality.” The original Aldrete score
4
was modified by the author 5 and then by White 6 and in part led to fast track approaches to
day stay care so that patients could move directly from theatre to step down units without
entering the initial recovery area. This scoring system evolved into the Post Anaesthesia
Discharge Scoring System (PADSS) 7 by the inclusion of intake and output measures together
with the ability to walk.
The concept of a quality measure relating to recovery is not new. Myles in Australia
produced a QoR Score 8 in 1998 which was then modified to a simpler process in 2000. 9 The
first system was very complex and the subsequent, perhaps, an over-simplification did not
appear to have caught the imagination of the profession and has been largely ignored to date.
This paper will outline the creation of a new Post operative Quality of Recovery
Scale (PQRS). It has been created through a multinational taskforce with input from
anaesthetists, neuropsychologists and statisticians. It has been piloted around the world and
has proved to be simple to use and useful.
References:
1. Simpson JY. Anaesthesia, hospitalism and other papers. Edited by WG Simpson. 1871.
Adam & Charles Black. Edinburgh.
2. Ellis RH (ed) The case books of Dr. John Snow. 1994. Wellcome Institute for the History
of Medicine. London.
3. Warner MA. 30 day morbidity and mortality of 45090 outpatients 1988-1990. Anesthesia
and analgesia 1993; 76: S45.
4. Aldrete JA, Kroulik D. A postanesthetic recovery score. Anesthesia and Analgesia 1970;
49: 924-934.
5. Aldrete JA: The post-anesthesia recovery score revisited. Journal of Clinical Anesthesia
1995;7:89 - 91
6. White PR, Song D: New criteria for fast-tracking after outpatient anesthesia: A comparison
with the modified Aldrete Scoring System. Anesthesiology 2002; 96: A23
7. Chung F., Chan VMS., Ong D. A post-anesthetic discharge scoring system for home
readiness after ambulatory surgery. Journal of Clinical Anesthesia 1995; 7: 500-506.
8. Myles PS., Hunt JO., Nightingale CE. Development and psychometric testing of a quality
of recovery score after general anesthesia in adults. Anesthesia and Analgesia 1999; 88: 8390.
9. Myles PS., Reeves MDS., Anderson H., Weeks AM. Measurement of quality of recovery in
5672 patients after anaesthesia and surgery. Anaesthesia and Intensive Care 2000; 28: 276280.
PQRS Board comprises: David Wilkinson (UK) Chair, J Boldt (Germany), F Chung
(Canada), R Hannallah (USA). I Hurtado (Mexico), S Newman (UK), R McKay (USA), C
Royse (Australia), F Servin (France), J Stygall (UK), B Yu (China) and is supported by an
unrestricted educational grant from Baxter.
50
Winning Their Heart and Mind: The Perioperative Stress Response in Children
Zeev N. Kain, MD, MBA
Professor & Chair of Anesthesiology, University of California, Irvine, CA
Of the over five million children who undergo surgery in the United States, it is
estimated that up to 65% will experience significant preoperative anxiety and pain while in
hospital. That is, every year, about 3 million children experience anxiety before surgery and
postoperative pain while in the postoperative anesthesia care unit. Postoperative pain
continues to be prevalent when children return home, with one study indicating that 56% of
children report immediate postoperative pain at home and up to 33% continue to experience
pain one week following surgery. Indeed, up to 50% of all children undergoing surgery
developed postoperative behavioral changes such as sleeping disturbances at 2 weeks after
surgery. In addition to the behavioral manifestations detailed above, several studies have
documented that anxiety prior to surgery is associated with neuroendocrinological changes
such as increased serum cortisol, epinephrine, growth hormone, IL-6, and increased Natural
Killer cells activity, and correlates other physiological manifestations of anxiety such as heart
rate, blood pressure and prolonged recovery and prolonged hospital stay.
Considering the above it is imperative to understand risk factors, interventions and
outcomes of these clinical phenomena. The lecture will briefly cover the above conceptual
framework and some of the studies that have been conducted to date in this area.
51
Beneficial Effects of Nitric Oxide Breathing in Adult Patients in Sickle Cell Crisis
C. Alvin Head, MD, Paul Swerdlow, MD, William A. McDade, MD, PhD, Ratan Mani Joshi,
PhD, Melanie L. Cooper, MD, MPH, James R. Eckman, MD
Author Affiliations: Department of Anesthesiology & Perioperative Medicine, Medical
College of Georgia (Drs Head and Joshi), Department of Internal Medicine, Wayne
State University (Dr Swerdlow), Pritzker School of Medicine, The University of
Chicago (Dr McDade), Department of Family Medicine, Morehouse School of Medicine
(Dr Cooper), Georgia Comprehensive Sickle Cell Center, Emory University (Dr Eckman)
Context: Pain due to recurrent vaso-occlusive crisis (VOC) is the major cause of
hospitalization in patients with sickle cell disease (SCD). Nitric oxide (NO)-based therapies,
such as inhaled NO (INO) or NO-enhancing drugs (e.g., oral arginine or hydroxyurea) have
reported beneficial therapeutic effects. A preliminary assessment of NO breathing in children
with SCD showed a decrease in the pain scores during VOC.1 This study supports the clinical
use of inhaled NO in the treatment of vaso-occlusion in adult patients.
Objective: To determine if NO breathing reduces pain associated with acute VOC in adult
patients with SCD and to determine the safety and efficacy of NO in such a crisis.
Design: Prospective, double-blind, randomized, placebo-controlled multi-center clinical trial
in adult patients with SCD.
Study Setting and Population: Twenty-three patients aged 19 to 50 years with SCD who
were experiencing uncomplicated severe acute VOC were enrolled at 5 institutions.
Intervention: Patients were randomly assigned to receive INO (80 ppm with 21% final
concentration of inspired oxygen; n=9) or placebo (21% inspired oxygen; n=9) for 4 hours.
Main Outcome Measures: Primary outcome was change in pain scores after 4 hours of
inhalation compared with preinhalation, measured on a 10-cm visual analog scale (VAS);
secondary outcome included amount of narcotic used at baseline, 4 hours, and 6 hours. Safety
assessments included measurement of minimum systolic blood pressures, minimum pulse
oximetry reading, maximum concentration of delivered NO2, and maximum concentration of
methemoglobin (metHb).
Results: At baseline, VAS pain scores were similar for NO and placebo groups. NO
breathing resulted in reduced VAS pain score at 4 hours into treatment (NO group: ~6cm;
placebo~ 3 cm, P = .02). No NO gas toxicity was observed (metHb levels < 5%).
Conclusions: NO breathing in adult patients with SCD during acute sickle crisis appears to
be safe and effective in reducing pain.
52
2009 Annual Meeting of Academy of Anesthesiology
February 26 – 28, 2009
Renaissance Vinoy Resorts, St. Petersburg, FL
Faculty and Planning Committee Disclosure Information
Disclosure of Relevant Financial Arrangements
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME) and the American
Nurses Credentialing Center (ANCC), the University of Kansas Medical Center Continuing Education must ensure that
the health and well being of the public is more important than any economic interest, and that activity content is
effective in improving practice, independent of commercial interests, and based on valid content. Individuals with
control over the content of this activity are required to disclose to the learners any relevant financial relationships
within the past 12 months with any proprietary entities producing, marketing, re-selling, or distributing healthcare
goods or services related to the content of the activity (with the exemption of non-profit or governmental organizations
and non-healthcare related companies). This includes any relevant financial arrangements involving their
spouse/partner. Relevant financial relationships may include employment, management position, independent
contractor (including contracted research), consulting, speaking and teaching, membership on advisory committees or
review panels, board membership, etc. The intent of this disclosure is not to prevent an individual with a relevant
financial relationship from being a planning committee member, a teacher, or an author of CME/CNE having control
of, or responsibility for, the development, management, presentation, or evaluation of the CME/CNE activity, but
rather to assist the provider in the identification and resolution of conflict of interest prior to the activity and to provide
the learners with the information they need to determine whether these interests or relationships influenced the content
of the activity.
The following presenter has disclosed a relevant financial relationship with the following commercial entity
producing healthcare goods or services related to the content of his presentation.
C. Alvin Head, MD – He received research funding and royalties from IND-Therapeutics.
The following presenters do not have any relevant financial relationships with any commercial entity producing
healthcare goods or services related to the content of their presentations.
Morris Brown, MD
Sorin J. Brull, MD
W. Scott Jellish MD, Ph.D
Kai Rehder, MD
Andrea Vannucci, MD
Mark A. Warner, MD
The following presenters and planning committee members do not have any relevant financial relationships
with any commercial entity producing healthcare goods or services related to the content of their presentations
or related to the content of the activity.
Vinod V. Malhotra, MD
53

ACADEMIC PROGRAM for THE ACADEMY OF ANESTHESIOLOGY

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