Suggested Therapy for MALIGNANT HYPERTHERMIA EMERGENCY

* Revised 1995 *
LOOK FOR:
Tachycardia Muscle Stiffness Hypercarbia Tachypnea Cardiac Arrhythmias Respiratory and Metabolic
Acidosis Fever Unstable or Rising Blood Pressure Cyanosis or Mottling Myoglobinuria
-----------------------------------------------------------------------Acute Phase Treatment

1.Immediately discontinue all volatile inhalation anesthetics and succinylcholine. Hyperventilate with
100% oxygen at high gas flows; at least 10 L/min. The circle system and CO2 absorbent need not be
changed. 2.Administer dantrolene sodium 2-3 mg/kg initial bolus rapidly with increments up to 10 mg/kg
total. Continue to administer dantrolene until signs of MH (e.g. tachycardia, rigidity, increased end-tidal
CO2, and temperature elevation) are controlled. Occasionally, a total dose greater than 10 mg/kg may be
needed. Each vial of dantrolene contains 20 mg of dantrolene and 3 grams mannitol. Each vial should be
mixed with 60 mL of sterile water for injection USP without a bacteriostatic agent. 3.Administer
bicarbonate to correct metabolic acidosis as guided by blood gas analysis. In the absence of blood gas
analysis, 1-2 mEq/kg should be administered. 4.Simultaneous with the above, actively cool the
hyperthermic patient. Use IV cold saline (not Ringer's lactate) 15 mL/kg q 15 min X 3.
1.Lavage stomach, bladder, rectum and open cavities with iced saline as appropriate. 2.Surface cool with
ice and hypothermia blanket. 3.Monitor closely since overvigorous treatment may lead to hypothermia.
5.Arrhythmias will usually respond to treatment of acidosis and hyperkalemia. If they persist or are life
threatening, standard anti-arrhythmic agents may be used, with the exception of calcium channel blockers
(may cause hyperkalemia and CV collapse). 6.Determine and monitor end-tidal CO2, arterial, central or
femoral venous blood gases, serum potassium, calcium, clotting studies and urine output. 7.Hyperkalemia
is common and should be treated with hyperventilation, bicarbonate, intravenous glucose and insulin (10
units regular insulin in 50 mL 50% glucose titrated to potassium level or 0.15 u/kg regular insulin in 1
cc/kg 50% glucose). Life threatening hyperkalemia may also be treated with calcium administration (e.g. 25 mg/kg of CaCl2). 8.Ensure urine output of greater than 2 mL/kg/hr by hydration and/or administration of
mannitol of furosemide. Consider central venous or PA monitoring because of fluid shifts and
hemodynamic instability that may occur. 9.Sudden Unexpected Cardiac Arrest in Children: Children less
than about 10 years of age who experience sudden cardiac arrest after succinylcholine in the absence of
hypoxemia and anesthetic overdose should be treated for acute hyperkalemia first. In this situation calcium
chloride should be administered along with other means to reduce serum potassium. They should be
presumed to have subclinical muscular dystrophy and a neurologist should be consulted.
-----------------------------------------------------------------------Post Acute Phase

1.Observe the patient in an ICU setting for at least 24 hours since recrudescence of MH may occur,
particularly following a fulminant case resistant to treatment. 2.Administer dantrolene 1 mg/kg IV q 6
hours for 24-48 hours post episode. After that, oral dantrolene 1 mg/kg q 6 hours may be used for 24 hours
as necessary. 3.Follow ABG, CK, potassium, calcium, urine and serum myoglobin, clotting studies and core
body temperature until such time as they return to normal values (e.g. q 6 hours). Central temperature (e.g.
rectal, esophageal) should be continuously monitored until stable. 4.Counsel the patient and family
regarding MH and further precautions. Refer the patient to MHAUS. Fill out an Adverse Metabolic
Reaction to Anesthesia (AMRA) report available through the North American Malignant Hyperthermia
Registry (717) 531-6936.
-----------------------------------------------------------------------CAUTION: This protocol may not apply to every patient and must of necessity be altered according to
specific patient needs.
-----------------------------------------------------------------------Names of on-call physicians available to consult in MH emergencies may be obtained 24 hours a day
through:
MH EMERGENCY HOTLINE
1 800 MH HYPER
(1 800 644-9737)
Outside the United States call:
315-428-7924
For Non-Emergency or Patient Referral Calls
MHAUS
(607)674-7901
32 South Main Street
PO Box 1069
Sherburne, NY 13460-1069
MH INFO-BY-FAX:
1-800-440-9990
-----------------------------------------------------------------------MPWC-2 5/95/20K
Last modified: 01 September 1995

Dantrolene Sodium - The Specific Treatment for Malignant Hyperthermia

WHAT IS MALIGNANT HYPERTHERMIA?
MH is a chain reaction of symptoms (a syndrome) triggered in susceptible individuals by commonly used
general anesthetics and, possibly, some other drugs. The symptoms include a greatly increased body
metabolism, muscle rigidity and high fever. Death may result from cardiac arrest, brain damage, internal
hemorrhaging or failure of other body systems.
All of the volatile inhalation anesthetics are triggers, and the muscle relaxant succinylcholine is also a
trigger. Nitrous oxide is not a trigger.
------------------------------------------------------------------------

HOW IS MH TREATED?
MH had a mortality rate of nearly 80 percent at the time it was identified in 1960. Treatment consisted only
of cooling the patient and treating the specific symptoms, but not the underlying cause.
Since 1979, the antidote drug dantrolene sodium has been available for the treatment of MH and has
contributed greatly to a dramatic decline in mortality. The syndrome must be identified and treated early for
a successful outcome. Dantrolene sodium (Dantrium IV) is manufactured by Procter & Gamble
Pharmaceuticals.
-----------------------------------------------------------------------HOW DOES DANTROLENE WORK?
Dantrolene is thought to reduce muscle tone and metabolism by preventing the ongoing release of calcium
from the storage sites in muscle (the sarcoplasmic reticulum). In MH, intracellular calcium levels are
elevated and therefore dantrolene counteracts this abnormality.
Fortunately, muscle calcium is not reduced to a level as to render the muscle flaccid and without tone. It is
therefore not a muscle relaxant in the same sense as curare or analogs of curare. Dantrolene does not
significantly potentiate the effects of non- depolarizing relaxants or prevent the ability to reverse curariform
drugs with anticholinesterase agents.
Dantrolene may cause significant muscle weakness in patients with pre-existing muscle disease and should
be used with extreme caution in those patients.
When used with calcium channel blockers, dantrolene may produce life-threatening hyperkalemia and
myocardial depression. Otherwise there does not appear to be significant negative interaction with other
drugs.
Once a patient has been successfully treated with intravenous dantrolene, he or she may be switched to oral
dantrolene for several days.
-----------------------------------------------------------------------WHO SHOULD STOCK DANTROLENE SODIUM?
Dantrolene should be available for the treatment of potential MH cases anywhere general anesthesia is
administered, including hospitals and outpatient surgery centers.
-----------------------------------------------------------------------HOW MUCH DANTROLENE SHOULD BE KEPT IN STOCK?
Although most cases of MH respond to 2.5-4.0 mg/kg of dantrolene initially, some patients need
significantly more to bring the episode under control. In addition, recrudescence is a possibility within the
first few days of treatment. Finally, because of the need for continued treatment for at least 48 hours after
MH at a dose of about 1 mg/kg every 4 hours, the Malignant Hyperthermia Association of the United States
(MHAUS) recommends that 36 vials be stocked.
-----------------------------------------------------------------------WHERE SHOULD DANTROLENE BE KEPT?

Dantrolene should be kept in or very close to the operating room, so that it is available immediately if MH
occurs. A supply of sterile water for injection USP (without a bacteriostatic agent) should be kept nearby to
mix with dantrolene before injection.
-----------------------------------------------------------------------ARE THERE ANY ADVANTAGES IN SHARING A SUPPLY OF DANTROLENE?
Absolutely not. Minutes count in an MH emergency. The Professional Advisory Council of MHAUS
strongly recommends that an adequate supply of dantrolene be available whenever general anesthesia is
administered.
Responsibility for treatment rests with the facility where the surgery is performed and, therefore, sharing is
not a good alternative.
-----------------------------------------------------------------------DOESN'T DANTROLENE OUTDATE TOO QUICKLY AND COST TOO MUCH TO KEEP ON HAND
FOR AN OCCURRENCE WHICH IS NOT VERY LIKELY TO HAPPEN?
No. At present, dantrolene has a shelf life of three years from the date of manufacture. Although fulminant
MH episodes are unusual, they do happen; and, sadly, patients still die from MH.
-----------------------------------------------------------------------IS PRE-TREATMENT WITH DANTROLENE NECESSARY?
Although pre-treatment with dantrolene for known susceptibles is not usually necessary, in some situations,
such as the patient who survived a crisis, some experts recommend pre-treatment with 2 mg/kg
intravenously prior to induction of anesthesia.
-----------------------------------------------------------------------WHAT IS THE COST OF DANTROLENE?
Dantrolene's 1993 price is approximately $46/vial. Even considering some loss of shelf life during
transportation from plant to hospital, the cost of maintaining 36 vials in stock is less than $600 per year -- a
tiny fraction of most hospital budgets and a very small price to pay for safety.
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------MHAUS HOTLINE Names and phone numbers of on-call anesthesiologists available to consult in MH
emergencies may be obtained 24 hours a day through:
Medic Alert Foundation International
(209) 634-4917 Ask for Index Zero
-----------------------------------------------------------------------This brochure was written and produced by the MALIGNANT HYPERTHERMIA ASSOCIATION OF
THE UNITED STATES (MHAUS). MHAUS serves MH-susceptible individuals and medical
professionals. MHAUS is a non-profit organization under IRS Code 501(c)(3). Its services are provided
free. It operates solely on contributed funds. All contributions are tax- deductible and should be sent to:

MHAUS
PO Box 191
Westport, CT 06881-0191
(203) 847-0407
-----------------------------------------------------------------------The information in this brochure is intended as a general description of MH and not as a specific
recommendation for patient care or management. Consult a qualified physician for further information.
4/93

<Picture: University of Wisconsin Mascot>

University of Wisconsin Anesthesia Topics
------------------------------------------------------------------------

SEIZURE POTENTIAL OF ANESTHETIC DRUGS

R McGucken

Drugs which increase seizure threshold:

Barbiturates (except methohexital)
Benzodiazepines
Isoflurane

Drugs which decrease seizure threshold:

Etomidate
Methohexital
Enflurane (especially in children).

Drugs with no effect or mixed results on the seizure threshold:

Ketamine
Propofol (if anything it appears to increase the seizure threshold)
Fentanyl, Sufentanil, Alfentanil.

Bob McGucken, 1993-94

Anesthesiology, V 87, No 2, August 1997

Influence of Acute Pain Induced by Activation of Cutaneous Nociceptors on Ventilatory Control

Elise Sarton, M.D.

Resident, Department of Anesthesiology, Leiden University Hospital.
Albert Dahan, M.D., Ph.D.
Associate Professor of Anesthesiology, Department of Anesthesiology, Leiden University Hospital.
Luc Teppema, Ph.D.
Associate Professor of Physiology Department of Physiology, Leiden University.
Aad Berkenbosch, Ph.D.
Associate Professor of Physiology Department of Physiology, Leiden University.
Maarten van den Elsen, M.D.
Staff Anesthesiologist, Department of Anesthesiology, Leiden University Hospital.
Jack van Kleef, M.D., Ph.D.
Professor of Anesthesiology and Chairman, Department of Anesthesiology, Leiden University Hospital.

Background: Although many studies show that pain increases breathing, they give little information on the
mechanism by which pain interacts with ventilatory control. The authors quantified the effect of
experimentally induced acute pain from activation of cutaneous nociceptors on the ventilatory control
system.
Methods: In eight volunteers, the influence of pain on various stimuli was assessed: room air breathing,
normoxia (end-tidal pressure of carbon dioxide (PETCO2) clamped, normoxic and hyperoxic hypercapnia,
acute hypoxia, and sustained hypoxia (duration, 15-18 min; end-tidal pressure of oxygen, approximately 53
mmHg). Noxious stimulation was administered in the form of a 1-Hz electric current applied to the skin
over the tibial bone.
Results: While volunteers breathed room air, pain increased ventilation ([Vdot]I) from 10.9 1.7 to 12.9
2.5 l/min-1 (P < 0.05) and reduced PETCO2 from 38.3 2.3 to 36.0 2.3 mmHg (P < 0.05). The increase
in [Vdot]I due to pain did not differ among the different stimuli. This resulted in a parallel leftward-shift of
the [Vdot]I-carbon dioxide response curve in normoxia and hyperoxia, and in a parallel shift to higher
[Vdot]I levels in acute and sustained hypoxia.

Conclusions: These data indicate that acute cutaneous pain of moderate intensity interacted with the
ventilatory control system without modifying the central and peripheral chemoreflex loop and the central
modulation of the hypoxia-related output of the peripheral chemoreflex loop. Pain causes a chemoreflexindependent tonic ventilatory drive. (Key words: Measurement techniques: dynamic end-tidal forcing;
isocapnia. Pain, acute: transcutaneous electric stimulation. Respiration: hypercapnic response; hyperoxia;
hypoxic response; short-term potentiation of breathing.)
-----------------------------------------------------------------------Received from Leiden University Medical Center, Leiden, The Netherlands. Submitted for publication
January 2, 1997. Accepted for publication March 24, 1997.
Address reprint requests to Dr. Dahan: Department of Anesthesiology, Leiden University Hospital (AZL
P5), P.O. Box 9600, 2300 RC Leiden, The Netherlands. Address electronic mail to:
dahan@rullf2.leidenuniv.nl
Anesthesiology
1997; 87:289-96
1997 American Society of Anesthesiologists, Inc.
Lippincott-Raven Publishers

Anesthesiology, V 87, No 2, August 1997

Dose Comparison of Remifentanil and Alfentanil for Loss of Consciousness

Rajiv Jhaveri, M.D.

Assistant Professor of Anesthesiology, Duke University Medical Center, Durham, North Carolina.
Pradip Joshi, M.D., F.R.C.A.
Visiting Associate in Anesthesiology, Duke University Medical Center, Durham, North Carolina. Current
address: Consultant Anaesthetist, Frimley Park Hospital NHS Trust, Frimley, Camberley, Surrey, England.
Randall Batenhorst, Pharm.D.
Director, International Anesthesia/Analgesia Research, Glaxo-Wellcome Inc., Research Triangle Park,
North Carolina.
Verna Baughman, M.D.
Associate Professor of Anesthesiology, University of Illinois, Chicago, Illinois.
Peter S. A. Glass, M.B.Ch.B., F.F.A.(SA)
Associate Professor of Anesthesiology, Duke University Medical Center, Durham, North Carolina.

Background: This study evaluated the efficacy and safety of remifentanil, a potent mu agonist opioid with
a rapid onset and offset of effect, as a sole induction agent for loss of consciousness (LOC) and compared it
with alfentanil.
Methods: Remifentanil and alfentanil were administered intravenously over 2 min in ascending doses
(remifentanil 2, 3, 4, 5, 6, 8, 10, 15, 20 g/kg; alfentanil 40, 60, 80, 100, 120, 160, 200 g/kg) to
unpremedicated healthy patients. Patients were observed for rigidity and LOC for 30 s after the end of
infusion. If patients had not lost consciousness, 2 mgkg-1min-1 thiopental was administered until LOC
was achieved. Arterial blood samples, obtained at specified time intervals, were analyzed for remifentanil
and alfentanil whole-blood concentration. Blood pressure and heart rate were also recorded at preset time
intervals.
Results: Neither drug could reliably produce LOC. With both drugs, there was a dose-dependent decrease
in thiopental requirements and a dose-dependent increase in the incidence and severity of rigidity (P <
0.05). The median effective dose (ED50) for LOC with remifentanil was 12 g/kg, and for alfentanil it was
176 g/kg. The median effective concentration (EC50; whole-blood concentration) of remifentanil was
53.8 ng/ml and for alfentanil it was 1,012 ng/ml. Minimal hemodynamic changes were observed after either
drug was given.
Conclusions: Remifentanil is 15 times more potent than alfentanil, based on the ED50 to achieve loss of
response to a verbal command and 20 times more potent than alfentanil based on the EC50. Neither opioid
is suitable as a sole induction agent. (Key words: Anesthetics, intravenous: remifentanil; alfentanil.
Analgesics: remifentanil; alfentanil. Potency, anesthetic: median effective dose (ED50); median effective
concentration (EC50); remifentanil; alfentanil.)
-----------------------------------------------------------------------Received from the Department of Anesthesia, Duke University Medical Center, Durham, North Carolina.
Submitted for publication June 17, 1996. Accepted March 18, 1997. Supported in part by a grant from
Glaxo-Wellcome Inc., Research Triangle Park, Durham, North Carolina. Presented in part at the October
1993 annual meeting of the American Society of Anesthesiologists, Washington, D.C.
Address reprint requests to Dr. Glass: Department of Anesthesiology, P.O. Box 3094, Duke University
Medical Center, Durham, North Carolina 27710. Address electronic mail to: Glass003@mc.duke.edu
Anesthesiology
1997; 87:253-9
1997 American Society of Anesthesiologists, Inc.
Lippincott-Raven Publishers

Anesthesiology, V 87, No 2, August 1997

A Comparison of Remifentanil and Morphine Sulfate for Acute Postoperative Analgesia after Total
Intravenous Anesthesia with Remifentanil and Propofol

Joel Yarmush, M.D.

Assistant Professor of Anesthesiology, Department of Anesthesiology, University of Medicine and
Dentistry-New Jersey Medical School, Newark, New Jersey.
Robert D'Angelo, M.D.
Assistant Professor of Anesthesiology, Section on Obstetrical Anesthesia, Bowman-Gray School of
Medicine, Winston Salem, North Carolina.
Barbara Kirkhart, B.S.
Clinical Program Head, Glaxo Wellcome Inc., Research Triangle Park, North Carolina.
Colleen O'Leary, M.D.
Assistant Professor of Anesthesiology, Department of Anesthesiology, SUNY Health Science Center,
Syracuse, New York.
Melvin C. Pitts, II, M.D.
Assistant Professor of Anesthesiology, Department of Anesthesiology, Emory University, Atlanta, Georgia.
George Graf, M.D.
Clinical Assistant Professor of Anesthesiology, Department of Anesthesiology, University of California at
Los Angeles, Los Angeles, California.
Peter Sebel, M.D., Ph.D.
Professor of Anesthesiology, Department of Anesthesiology, Emory University, Atlanta, Georgia.
W. David Watkins, M.D., Ph.D.
Professor of Anesthesiology, Department of Anesthesiology, University of Pittsburgh Medical Center,
Pittsburgh, Pennsylvania.
Rafael Miguel, M.D.
Associate Professor of Anesthesiology, Department of Anesthesiology, University of South Florida, Tampa,
Florida.
James Streisand, M.D.
Associate Professor of Anesthesiology, Department of Anesthesiology, University of Utah, Salt Lake City,
Utah.
Laurie K. Maysick, D.O.
Assistant Professor of Anesthesiology and Critical Care Medicine, Department of Anesthesiology,
Montefiore Medical Center, Bronx, New York.
Dragomir Vujic, M.D.
Assistant Professor of Anesthesiology, Department of Anesthesiology, University of Medicine and
Dentistry-New Jersey Medical School, Newark, New Jersey.

Background: The transition from remifentanil intraoperative anesthesia to postoperative analgesia must be
planned carefully due to the short duration of action (3-10 min) of remifentanil hydrochloride, a potent,
esterase-metabolized -opioid agonist. This study compared the efficacy and safety of transition regimens
using remifentanil or morphine sulfate for immediate postoperative pain relief in patients who had surgery
under general anesthesia with remifentanil/propofol.
Methods: One hundred fifty patients who had received open-label remifentanil and propofol for
intraoperative anesthesia participated in this multicenter, double-blind, double-dummy study and were
randomly assigned to either the remifentanil (R) group or the morphine sulfate (M) group. Twenty minutes
before the anticipated end of surgery, the propofol infusion was decreased by 50%, and patients received
either a placebo bolus (R group) or a bolus of 0.15 mg/kg morphine (M group). At the end of surgery, the
propofol and remifentanil maintenance infusions were discontinued and the analgesic infusion was started:
either 0.1 gkg-1min-1 remifentanil (R group) or placebo analgesic infusion (M group). During the 25
min after tracheal extubation, remifentanil titrations in increments of 0.025 gkg-1min-1 and placebo
boluses (R group), or 2 mg intravenous morphine boluses and placebo rate increases (M group) were
administered as necessary at 5-min intervals to control pain. Patients received the 0.075 mg/kg intravenous
morphine bolus (R group) or placebo (M group) at 25 and 30 min after extubation, and the analgesic
infusion was discontinued at 35 min. From 35 to 65 minutes after extubation, both groups received 2-6 mg
open-label morphine analgesia every 5 min as needed.
Results: Successful analgesia, defined as no or mild pain with adequate respiration (respiratory rate [RR]
>=8 breaths/min and pulse oximetry >= 90%), was achieved in more patients in the R group than in the M
group (58% vs. 33%, respectively) at 25 min after extubation (P < 0.05). The median remifentanil rate for
successful analgesia was 0.125 gkg-1min-1 (range, 0.05-0.23 gkg-1min-1), and the median number of
2-mg morphine boluses used was 2 (range, 0-5 boluses). At 35 min after extubation, >= 74% of patients in
both groups experienced moderate to severe pain. Median recovery times from the end of surgery were
similar between groups. Transient respiratory depression, apnea, or both were the most frequent adverse
events (14% for the R group vs. 6% for the M group; P > 0.05).
Conclusions: Remifentanil provided safe and effective postoperative analgesia when administered at a
final rate of 0.05-0.23 gkg-1min-1 in the immediate postextubation period. Remifentanil provided more
effective postoperative analgesia than did intraoperative treatment with morphine (0.15 mg/kg) followed by
morphine boluses (<= five 2-mg boluses). The effects of remifentanil dissipated rapidly after ending the
infusion, and alternate analgesia was required. Further studies are underway to define transition regimens
that will improve postoperative analgesia in patients receiving anesthesia with remifentanil. (Key words:
Analgesics, opioids: remifentanil; morphine. Pain, postoperative: prevention; control. Pain management.
Double-blind method. )
-----------------------------------------------------------------------Received from University of Medicine and Dentistry--New Jersey Medical School, Newark, New Jersey;
Bowman-Gray School of Medicine, Winston-Salem, North Carolina; SUNY Health Science Center,
Syracuse, New York; Emory University, Atlanta, Georgia; University of California at Los Angeles;
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; University of South Florida, Tampa,
Florida; University of Utah, Salt Lake City, Utah; and Montefiore Medical Center, Bronx, New York.
Submitted for publication November 4, 1996. Accepted for publication March 24, 1997. Results of this
study were presented in part at the Annual Meeting of the International Anesthesia Research Society, March
1996, Washington DC; the World Congress of Anesthesiologists, April 1996, Melbourne, Australia; Annual
Meeting of the American Association of Nurse Anesthetists, August 1996, Baltimore, Maryland. The design
and execution of this study, along with data collection and analysis, were performed in cooperation with

members of Glaxo Wellcome Inc. under the direction of Barbara Kirkhart. Financial support for this work
was provided by a grant from Glaxo Wellcome Inc.
Address reprint requests to Dr. Yarmush: Department of Anesthesiology, UMD-New Jersey Medical
School, Newark, New Jersey 07103.
Anesthesiology
1997; 87:235-43
1997 American Society of Anesthesiologists, Inc.
Lippincott-Raven Publishers

Anesthesiology, V 87, No 2, August 1997

Volume Kinetics of Ringer Solution, Dextran 70, and Hypertonic Saline in Male Volunteers

Christer Svensn, M.D.

Attending Anesthetist.
Robert G. Hahn, M.D., Ph.D.
Professor of Anesthesiology, Karolinska Institute.

Background. A knowledge of the distribution of different fluids given by intravenous infusion is basic to
the understanding of the effects of fluid therapy. Therefore, a mathematical model was tested to analyze the
volume kinetics of three types of fluids.
Methods. The authors infused 25 ml/kg of Ringer acetate solution, 5 ml/kg of 6% dextran 70 in 0.9%
NaCl, and 3 ml/kg of 7.5% NaCl over 30 min in 8 male volunteers aged from 25 to 36 years (mean, 31
years) and measured the changes in total hemoglobin, serum albumin, and total blood water over time. The
changes were expressed as fractioned dilution and then plotted against time. The curves were fitted to a
one-volume and a two-volume model, which allowed an estimation of the size of the body fluid space
expanded by the fluid (V) and the elimination rate constant (kr) to be made.
Results. The changes in blood water concentration indicated a mean size of V of 5.9 l ( 0.8, SEM) for
Ringer's solution, 2.6 ( 0.3) l for dextran, and 1.2 ( 0.1) l for hypertonic saline. The corresponding values
of kr were 94 ( 42), 12 ( 6), and 30 ( 4) ml/min, respectively. Blood hemoglobin indicated a degree of
dilution similar to that indicated by blood water. Serum albumin indicated a more pronounced dilution,
which resulted in a larger expandable volume and a greater mean square error for the curvefitting. The
larger volume obtained for serum albumin can probably be explained by a loss of intravascular albumin
into the tissues along with the infused fluid.
Conclusions. The distribution of intravenous fluids can be analyzed by a kinetic model adapted for fluid
spaces, but slightly different results are obtained, depending on the marker used to indicate dilution of the
primary fluid space. Analysis and simulation of plasma volume expansion by this model is a tool that can
help the anesthetist to better plan fluid therapy. (Key words: Dextrans. Fluid therapy. Hemodilution.
Pharmacokinetics. Saline solution, hypertonic. Serum albumin. Water/blood.)

-----------------------------------------------------------------------Received from the Department of Anesthesia, South Hospital, Stockholm, Sweden. Submitted for
publication January 20, 1997. Accepted for publication April 1, 1997. Supported by the Swedish Medical
Research Council (Project 10853). Presented in part at the 11th World Congress of Anaesthesiologists,
Sydney, Australia, April 14-20, 1996.
Address reprint requests to Dr. Hahn: Department of Anesthesia, Sder Hospital, S-118 83 Stockholm,
Sweden. Address electronic mail to: Robert.Hahn@anest.sos.sll.se
Anesthesiology
1997; 87:204-12
1997 American Society of Anesthesiologists, Inc.
Lippincott-Raven Publishers

Anesthesiology, V 87, No 2, August 1997

Reduction by Fentanyl of the CP50 Values of Propofol and Hemodynamic Responses to Various Noxious
Stimuli

Tomiei Kazama, M.D.

Associate Professor.
Kazuyuki Ikeda, M.D., Ph.D., F.R.C.A.
Professor and Chairman.
Koji Morita, Ph.D.
Assistant Professor.

Background: Propofol and fentanyl infusion rates should be varied according to the patient's
responsiveness to stimulation to maintain satisfactory anesthetic and operative conditions. However,
somatic and autonomic responses to various noxious stimuli have not been investigated systematically for
intravenous propofol and fentanyl anesthesia.
Methods: Propofol and fentanyl were administered via computer-assisted continuous infusion to provide
stable concentrations and to allow equilibration between plasma-blood and effect-site concentrations. The
propofol concentrations needed to suppress eye opening to verbal command and motor responses after 50Hz electric tetanic stimulation, laryngoscopy, tracheal intubation, and skin incision in 50% or 95% of
patients (Cp50 and Cp95) were determined at fentanyl concentrations of 0.0, 1.0, 2.0, 3.0, and 4.0 ng/ml in
133 patients undergoing lower abdominal surgery. The ability of propofol with fentanyl to suppress
hemodynamic reactions in response to various noxious stimuli also was evaluated by measuring arterial
blood pressure and heart rate before and after stimulation.

Results: The various Cp50 values for propofol alone (no fentanyl) for the various stimuli increased in the
following order: Cp50loss of consciousness, 4.4 g/ml (range, 3.8-5.0); Cp50tetanus, 9.3 g/ml (range,
8.3-10.4); Cp50laryngoscopy, 9.8 g/ml (range, 8.9-10.8); Cp50skin incision, 10.0 g/ml (range, 8.1-12.2);
and Cp50intubation, 17.4 g/ml (range, 15.1-20.1; 95% confidence interval). The reduction of Cp50loss of
consciousness with fentanyl was minimal; 11% at 1 ng/ml of fentanyl and 17% at 3 ng/ml of fentanyl. A
plasma fentanyl concentration of 1 ng/ml (3 ng/ml) resulted in a 31-34% (50-55%) reduction of the
propofol Cp50s for tetanus, laryngoscopy, intubation, and skin incision. Propofol alone depresses
prestimulation blood pressure but had no influence on the magnitude blood pressure or heart rate increase
to stimulation. Propofol used with fentanyl attenuated the systolic blood pressure increases to various
noxious stimuli in a dose-dependent fashion.
Conclusions: The authors successfully defined the propofol concentration required for various stimuli.
Tracheal intubation was the strongest stimulus. The absence of somatic reactions for propofol does not
guarantee hemodynamic stability without fentanyl. Propofol with fentanyl was able to suppress motor and
hemodynamic reactions to various noxious stimuli. (Key words: Anesthetics, intravenous: fentanyl;
propofol. Anesthetic techniques: tetanic stimulation; tracheal intubation. Anesthetic potency:
hemodynamics; motor reaction.)
-----------------------------------------------------------------------Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine,
Hamamatsu, Japan. Submitted for publication July 5, 1996. Accepted for publication April 24, 1997.
Address reprint requests to Dr. Kazama: Department of Anesthesiology and Intensive Care, Hamamatsu
University School of Medicine, 3600 Handa-Cho, Hamamatsu, Japan 431-31.
Anesthesiology
1997; 87:213-27
1997 American Society of Anesthesiologists, Inc.
Lippincott-Raven Publishers

Anesthesiology, V 87, No 1, July 1997

Remifentanil versus Remifentanil/midazolam for Ambulatory Surgery during Monitored Anesthesia Care

Martin I. Gold, M.D.

Professor of Anesthesiology, Department of Anesthesiology, University of Miami, Miami, Florida.
W. David Watkins, M.D., Ph.D.
Professor of Anesthesiology, Department of Anesthesiology, University of Pittsburgh Medical Center,
Pittsburgh, Pennsylvania.
Yung-Fong Sung, M.D.
Professor of Anesthesiology, Department of Anesthesiology, The Emory Clinic, Atlanta, Georgia.
Joel Yarmush, M.D.

Assistant Professor of Anesthesiology, Department of Anesthesiology, UMD New Jersey Medical School,
Newark, New Jersey.
Frances Chung, M.D.
Professor of Anaesthesiology, Department of Anaesthaesiology, Toronto Hospital, Toronto, Ontario,
Canada.
Nonita T. Uy, M.D.
Associate Professor of Anesthesiology, Department of Anesthesiology, Magee-Womens Hospital,
Pittsburgh, Pennsylvania.
Walter Maurer, M.D.
Professor of Anesthesiology, Department of Anesthesiology, Cleveland Clinic Foundation, Cleveland,
Ohio.
Marcia Y. Clarke, B.S.
Glaxo Wellcome Inc., Research Triangle Park, North Carolina.
Brenda D. Jamerson, Pharm.D.
Glaxo Wellcome Inc., Research Triangle Park, North Carolina.

Background: This study was designed to define the appropriate dose of remifentanil hydrochloride alone
or combined with midazolam to provide satisfactory comfort and maintain adequate respiration for a
monitored anesthesia care setting.
Methods: One hundred fifty-nine patients scheduled for outpatient surgery participated in this multicenter,
double-blind study. Patients were randomly assigned to one of two groups: remifentanil, 1 g/kg, given
over 30 s followed by a continuous infusion of 0.1 gkg-1min-1 (remifentanil); remifentanil, 0.5 g/kg,
given over 30 s followed by a continuous infusion of 0.05 gkg-1min-1 (remifentanil + midazolam). Five
minutes after the start of the infusion, patients received a loading dose of saline placebo (remifentanil) or
midazolam, 1 mg, (remifentanil + midazolam). If patients were not oversedated, a second dose of placebo
or midazolam, 1 mg, was given. Remifentanil was titrated (in increments of 50% from the initial rate) to
limit patient discomfort or pain intraoperatively, and the infusion was terminated at the completion of skin
closure.
Results: At the time of the local anesthetic, most patients in the remifentanil and remifentanil + midazolam
groups experienced no pain (66% and 60%, respectively) and no discomfort (66% and 65%, respectively).
The final mean ( SD) remifentanil infusion rates were 0.12 0.05 gkg-1min-1 (remifentanil) and 0.07
0.03 gkg-1min-1 (remifentanil + midazolam). Fewer patients in the remifentanil + midazolam group
experienced nausea compared with the remifentanil group (16% vs. 36%, respectively; P < 0.05). Four
patients (5%) in the remifentanil group and two patients (2%) in the remifentanil + midazolam group
experienced brief periods of oxygen desaturation (SpO2 < 90%) and hypoventilation (< 8 breaths/min).
Conclusions: Remifentanil alone or combined with midazolam provided adequate analgesia and
maintained adequate respiration at the doses reported. The low dose of remifentanil combined with 2 mg
midazolam, compared with remifentanil alone, resulted in fewer side effects, slightly greater sedation, and

less anxiety. (Key words: Anesthetics, intravenous: remifentanil; midazolam. Analgesics, opioids:
remifentanil. Anesthesia adjuvants: midazolam. Ambulatory care. Anesthesia recovery period. Anesthetic,
local.)
-----------------------------------------------------------------------Received from University of Miami, Anesthesia Service, Veterans Administration Medical Center, Miami,
Florida. Submitted for publication September 23, 1996. Accepted for publication March 4, 1997. Financial
support for this study was provided by a grant from Glaxo Wellcome Inc., Research Triangle Park, North
Carolina.
Address reprint requests to Dr. Gold: University of Miami, Anesthesia Service 139, Veterans
Administration Medical Center, 1201 NW 16th Street, Miami, Florida 33125.
Anesthesiology
1997; 87:51-7
1997 American Society of Anesthesiologists, Inc.
Lippincott-Raven Publishers

Anesthesiology, V 87, No 1, July 1997

Intracuff Pressures Do Not Predict Laryngopharyngeal Discomfort after Use of the Laryngeal Mask Airway

Armin Rieger, M.D., D.E.A.A.

Head of the Department of Anesthesia and Intensive Care Medicine, German Red Cross Hospital, Neuwied,
Germany.
Bergit Brunne, M.D.
Intern, Department of Anesthesiology and Operative Intensive Care Medicine, University Medical Center
Benjamin Franklin, Free University of Berlin, Germany.
Hans Walter Striebel, M.D., D.E.A.A.
Assistant Professor in Anesthesiology, Head of the Department of Anesthesiology, Intensive Care and
Emergency Medicine, Municipal Hospital Frankfurt-Hoechst, Frankfurt, Germany.

Background: The laryngeal mask airway (LMA) is a large foreign body that exerts pressure on the
pharyngeal mucosa, which may lead to throat discomfort. To determine whether intracuff pressures are
associated with such discomfort, a randomized, double-blind study was performed to determine the effect
of high versus low intracuff pressures.
Methods: Seventy healthy women were randomly allocated to two groups with different LMA intracuff
pressures: 30 mmHg (low pressure) or 180 mmHg (high pressure). Pressures were controlled with a
microprocessor-controlled monitor. Insertion of the LMA was performed by one investigator and facilitated

with propofol and verified fiberoptically. Anesthesia was maintained with enflurane and nitrous oxide. The
LMAs were removed while the patients were still asleep. Patients assessed their laryngopharyngeal
complaints (sore throat, dysphagia, hoarseness) at 8, 24, and 48 h after operation on a 101-point numerical
rating scale.
Results: No significant difference was found in the overall incidence of complaints between both groups
(low pressure: 50%; high pressure: 42%). On the day of surgery, dysphagia (38%) was more frequent than
sore throat (16%) or hoarseness (6%) (P < 0.05) within the high-pressure group. In the low-pressure group,
the incidence of these complaints was not significantly different (33%, 20%, and 23%, respectively). On
the following day, dysphagia was still present in 20% of the women in both groups, and other symptoms
comprised 10% or less of the reported complaints.
Conclusions: Differences in LMA intracuff pressures did not influence either the incidence or severity of
laryngopharyngeal complaints. (Key words: Airway: management. Complications: dysphagia, hoarseness,
sore throat. Laryngeal mask airway: cuff pressure.)
-----------------------------------------------------------------------Received from the University Medical Center Benjamin Franklin, Berlin, Germany. Submitted for
publication September 30, 1996. Accepted for publication March 11, 1997. The CDR 2000 cuff pressure
monitor was provided by LogoMed GmbH, Windhagen, Germany.
Address reprint requests to Dr. Rieger: Abteilung fr Anaesthesie und Intensivmedizin, DRK-Krankenhaus Neuwied, Marktstrae 74, D-56564 Neuwied, Germany.
Anesthesiology
1997; 87:63-67
1997 American Society of Anesthesiologists, Inc.
Lippincott-Raven Publishers

Anesthesiology, V 87, No 1, July 1997

Obstetric Anesthesia Work Force Survey, 1981 versus 1992

Joy L. Hawkins, M.D.

Associate Professor of Anesthesiology.
Charles P. Gibbs, M.D.
Professor of Anesthesiology.
Miriam Orleans, Ph.D.
Professor of Preventive Medicine and Biometrics.
Gallice Martin-Salvaj, M.D.
Professional Research Assistant in Anesthesiology.
Brenda Beaty, M.S.P.H.

Professional Research Assistant, Preventive Medicine and Biometrics.

Background: In 1981, with support from the American Society of Anesthesiologists and the American
College of Obstetricians and Gynecologists, anesthesia and obstetric providers were surveyed to identify
the personnel and methods used to provide obstetric anesthesia in the United States. The survey was
expanded and repeated in 1992 with support from the same organizations.
Methods: Comments and questions from the American Society of Anesthesiologists Committee on
Obstetrical Anesthesia and the American College of Obstetricians and Gynecologists Committee on
Obstetric Practice were added to the original survey instrument to include newer issues while allowing
comparison with data from 1981. Using the American Hospital Association registry of hospitals, hospitals
were differentiated by number of births per year (stratum I, >=1,500 births; stratum II, 500-1,499 births;
stratum III, <500 births) and by U.S. census region. A stratified random sample of hospitals was selected.
Two copies of the survey were sent to the administrator of each hospital, one for the chief of obstetrics and
one for the chief of anesthesiology.
Results: Compared with 1981 data, there was an overall reduction in the number of hospitals providing
obstetric care (from 4,163 to 3,545), with the decrease occurring in the smallest units (56% of stratum III
hospitals in 1981 compared with 45% in 1992). More women received some type of labor analgesia, and
there was a 100% increase in the use of epidural analgesia. However, regional analgesia was unavailable in
20% of the smallest hospitals. Spinal analgesia for labor was used in 4% of parturients. In 1981,
obstetricians provided 30% of epidural analgesia for labor; they provided only 2% in 1992. Regional
anesthesia was used for 78-85% (depending on strata) of patients undergoing cesarean section, resulting in
a marked decrease in the use of general anesthesia. Anesthesia for cesarean section was provided by nurse
anesthetists without the medical direction of an anesthesiologist in only 4% of stratum I hospitals but in
59% of stratum III hospitals. Anesthesia personnel provided neonatal resuscitation in 10% of cesarean
deliveries compared with 23% in 1981.
Conclusions: Compared with 1981, analgesia is more often used by parturients during labor, and general
anesthesia is used less often in patients having cesarean section deliveries. In the smallest hospitals,
regional analgesia for labor is still unavailable to many parturients, and more than one half of anesthetics
for cesarean section are provided by nurse anesthetists without medical direction by an anesthesiologist.
Obstetricians are less likely to personally provide epidural analgesia for their patients. Anesthesia personnel
are less involved in newborn resuscitation. (Key words: Anesthesia: obstetric. Manpower.)
-----------------------------------------------------------------------Received from the Department of Anesthesiology, University of Colorado Health Sciences Center,
Denver, Colorado. Submitted for publication April 18, 1996. Accepted for publication March 5, 1997.
Funded by the American Society of Anesthesiologists and the American College of Obstetricians and
Gynecologists. Presented in part at the annual meeting of the American Society of Anesthesiologists, San
Francisco, California, October 15-19, 1994.
Address reprint requests to Dr. Hawkins: Department of Anesthesiology, University of Colorado Health
Sciences Center, Denver, Colorado. Address electronic mail to: jlhawkins@ski.uhcolorado.edu
Anesthesiology
1997; 87:135-43
1997 American Society of Anesthesiologists, Inc.
Lippincott-Raven Publishers

Anesthesiology, V 87, No 1, July 1997

An Algorithm for Assessing Intraoperative Mean Arterial Pressure Lability

David L. Reich, M.D.

Associate Professor of Anesthesiology.
Todd K. Osinski, B.S.
Medical Student.
Carol Bodian, Dr.P.H.
Associate Professor of Biomathematical Sciences.
Marina Krol, Ph.D.
Assistant Professor of Anesthesiology.
Kaya Sarier, M.D.
Assistant Professor of Anesthesiology.
Ram Roth, M.D.
Instructor of Anesthesiology.
Steven N. Konstadt, M.D.
Associate Professor of Anesthesiology.

Background: Intraoperative blood pressure lability may be related to risk factors, hypovolemia, light
anesthesia, and morbid outcomes, but the measurements of lability in previous studies have been limited by
imprecise and infrequent data collection methods. Computerized intraoperative data acquisition systems
have provided an opportunity to readdress the issue of intraoperative blood pressure lability with more
abundant and precise data. This study sought to derive and validate an algorithm (expert system) to
measure mean arterial pressure (MAP) lability.
Methods: Two hundred thirty-nine computerized anesthesia records were reviewed retrospectively. Three
anesthesiologists separately rated MAP as very stable, average, or very labile. The parameters of a
computer algorithm that measured the change of median MAP between consecutive 2-min epochs were
optimized to achieve the best possible agreement among the anesthesiologists. The algorithm was then
validated on 229 additional anesthesia records.
Results: The proportion of consecutive 2-min epochs in which the absolute value of the fractional change
of median MAP exceeded 0.06 (i.e., 6%) correlated strongly with the anesthesiologists' ratings (r = 0.78; P
< 0.0001). The optimal sensitivity and specificity of the algorithm for detecting MAP lability were 98% and
59%, respectively.

Conclusions: One potential application of expert systems to anesthesia practice is a "smart alarm" to
detect blood pressure lability. It may also provide a better tool to assess the relation between lability and
outcome than has been available previously. (Key words: Blood pressure. Computers: expert systems
monitoring, hemodynamic. Surgery, cardiac: coronary artery bypass grafting.)
-----------------------------------------------------------------------Received from the Departments of Anesthesiology and Biomathematical Sciences, Mount Sinai School of
Medicine, New York, New York. Submitted for publication August 28, 1996. Accepted for publication
March 4, 1997.
Address reprint requests to Dr. Reich: Department of Anesthesiology, Box 1010, Mount Sinai Medical
Center, One Gustave L. Levy Place, New York, New York 10029-6574. Address electronic mail to:
dreich@smtplink.mssm.edu
Anesthesiology
1997; 87:156-61
1997 American Society of Anesthesiologists, Inc.
Lippincott-Raven Publishers