Anesthesia for athletes using performanceenhancing

Anesthesia for athletes using performanceenhancing drugs JOSEPH A. JOYCE, CRNA, BS Kernersville, North Carolina Anabolic-androgenicsteroids are used ...
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Anesthesia for athletes using performanceenhancing drugs JOSEPH A. JOYCE, CRNA, BS Kernersville, North Carolina

Anabolic-androgenicsteroids are used in the

treatment of numerous medical conditions, including Fank oni's anemia, hypogonadism, hereditary angioedema,hypopituitarismand impotence. However, because of their potent anabolicproperties,athletes began to use them to enhance body strength, size and endurance. Despite warningsfrom the medical and scientific communities of dangerousside effects such as Wilm's tumor, hepatocellularcarcinoma, stroke and myocardial infarction,some athletes continue to use anabolic steroids. Among the numerous research publications, only one case report was found which related difficulties in anesthesia administration.This paper presents the physiologic changes associated with anabolic steroid ingestion and applies these changes to the administrationof anesthesia.

Key words: anabolic-androgenic steroids, enzyme induction, steroids, volume of distribution. Historically, the male hormone, testosterone, was first synthesized in 1935 after its anabolic properties were recognized.' An anabolic substance is one which promotes the constructive process by which cells convert simple substances such as amino acids, glucose, etc. into more complex substances such as enzymes, other proteins, fats, etc. Testosterone was

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first used to reverse the catabolic process thus stimulating weight gain in patients who were grossly underweight and those recovering from systemic illnesses. Anabolic steroids were reportedly administered to German troops during World War II to enhance their aggressiveness and later to concentration camp survivors to stimulate weight gain. 2 Because of testosterone's potent androgenic properties, derivatives were developed which attempted to maximize the anabolic properties and at the same time diminish the androgenic properties as much as possible. An androgenic substance is one which stimulates development of male characteristics. In addition to the anabolic properties, these derivatives are longer lasting, more potent erythropoietic stimulants than the parent compound testosterone. Anabolic steroids are used in the treatment of certain types of aplastic anemia, such as Fanconi's anemia, as well as the following conditions: hypogonadism, hereditary angioedema, senile and postmenopausal osteoporosis, corticosteroid-induced catabolism, female-to-male sexual reassignment, hypopituitarism and impotence. Table I lists commonly used anabolic-androgenic steroids along with the recommended dosages for each. By the 1950s, athletes competing in events requiring body strength or endurance began to incorporate anabolic steroids into their training regimens to maximize gains in strength, size or endurance over shorter periods of time.' Anabolic steroid use proliferated over the next 26 years. In 1976, the International Olympic Committee added anabolic steroids to the list of banned substances. Also, in

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Table I Commonly used anabolic-androgenic steroids Generic name

Brand name

Recommended dosage

Oral preparations Testolactone

Teslac®

150 mg PO daily or 100 mg IM 3 times/week 200 mg PO daily 4-8 mg PO daily 2-30 mg PO daily 5 mg PO daily

Calusterone Ethylestrenol Fluoxymesterone Methandrostenolone

Oxandrolone Oxymetholone

Methosorb® Maxibolin® Halotestin® Dianabol®(withdrawn from market by manufacturer, 3/82) Metardren® Oreton Methyl® Anaval® Anadrol-50®

Stanozolol Danazol

Winstrol® Danocrine®

Parenteral preparations Dromostanolone propionate Nandrolone deconate Nandrolone phepropionate Testosterone cypionate Testosterone enanthate Testosterone propionate

Drolban® Deca-Durabolin® Durabolin® Depo-Testosterone® Delatestryl® Oreton*

Methandriol

Anabol®

Methyltestosterone

5-15 mg buccal daily 10-50 mg PO daily 5-10 mg PO daily 5-15 mg PO daily 50-100 mg daily (for anemia) 6 mg PO daily 200-800 mg PO daily 100 mg IM3 times/week 50-100 mg IM every 3-4 weeks 25-50 mg IM weekly 100-400 mg IM every 2-4 weeks 100-400 mg IMevery 2-4 weeks 50 mg IM 3 times/week or 300 mg subcutaneous every 4-6 months 50-100 mg IM 1-2 times/week

IM-intramuscular PO-per os Composite listing derived from: (1) Kibble MW, Ross MB. Adverse effects of anabolic steroids in athletes. Clin Pharm 1987; 6:686-692. (2) Mellion MB. Anabolic steroids in athletes. Am Fernm Physician. 1984; 30:113-119.

1986 and 1987, the National Collegiate Athletic Association and the National Football League, respectively, began to test athletes for anabolic use.' Beginning with the 1989 season, the National Football League penalized players guilty of steroid use. Despite these bans, anabolic steroid use has continued as evidenced by the disqualification of 15 athletes from the 1983 Pan American Games and the disqualification of Ben Johnson during the 1988 Seoul Olympics. A 1988 study by Buckley and associates showed that an estimated 6.6% of high school senior males have at some time used or presently are using anabolic steroids.3 When anabolic steroids were first used by athletes in the 1950s, dosages ingested were predominantly within the medically recommended ranges. However, the adage, "if one is good, two is better" began to encroach and seems to have become accepted among these athletes, as well as their coaches. Athletes, male and female alike, who choose to utilize anabolic steroids as part of their training regimen, currently follow two administration methods.4-6 The first is known as "cycling," where the

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athlete starts with relatively low doses and steadily increases the dosages over a period of weeks, followed by gradual decreases in dosages, again over a period of weeks, to the point of discontinuation." These "cycles" typically encompass 4 to 18 weeks and are followed by a period of time, usually 6 to 8 weeks, during which no anabolic steroids are taken. The second method, employed concurrently, is known as "stacking."" This method involves ingestion of two or more anabolic steroids during a "cycle" theoretically to further enhance the much sought after gains in strength, size or endurance. Both of these methods of administration result in the athlete exceeding the medically recommended dosages by as much as 50- to 150-fold. Anabolic steroid use has been demonstrated to affect many body systems. The major cardiovascular effects include secondary polycythemia, hypertension, hypertrophy of the left ventricle, cardiac muscle lesions and increased cholesterol levels.6 Myocardial infarction and cerebral vascular accident have also been associated with the use of anabolic steroids.10

n

The liver is probably the organ

Journal of the American Association of Nurse Anesthetists

Table II Adverse side effects Cardiovascular Increased low-density lipoprotein Increased high density lipoprotein (HDL) HDL2, HDL3 Decreased apolipoprotein A-1 Decreased apolipoprotein B Hypertension Cardiac muscle lesions Secondary polycythemia Decreased erythrocyte sedimentation rate Decreased platelet aggregation Left ventricular hypertrophy Decreased 2,3 diphosphoglycerate Water retention Increased serum K+, Na+ and Ca++ Decreased serum K+ (if diuretics used) Endocrine Decreased lutenizing hormone Decreased follicle stimulating hormone Decreased thyroid stimulating hormone Decreased adrenocorticotropic hormone Decreased thyroxine Decreased triiodothyronine Decreased free thyroxine Decreased thyroxine-binding globulin Decreased protein-bound iodine Increased serum cortisol Gynecomastia Alopecia Sterility Impotence Precocious puberty

Hyperinsulinism Diminished glucose tolerance secondary to insulin resistance Genitourinary Wilm's tumor Prostatic hypertrophy Prostatic adenocarcinoma Testicular germ cell tumor Hepatic Hepatocellular carcinoma Hepatic angiosarcoma Intrahepatic cholangiocarcinoma Cholestasis Jaundice Peliosis hepatis Skeletal Weakening of tendons Premature epiphysis closure Females only Virilization Excessive facial hair growth Hirsutism Menstrual irregularities Deepening of voice Enlarged clitoris Breast carcinoma Male-pattern baldness Decreased breast size

Composite listing from: (1) Kibble MW, Ross MB. Adverse effects of anabolic steroids in athletes. Clin Pharm. 1987; 6:686-692. (2) Alen M, and Rahkila P. Anabolic-androgenic steroid effects on endocrinology and lipid metabolism. Sports Med. 1988; 6:327-332.

most affected by anabolic steroids. Among the hepatic problems encountered with anabolic steroid use are jaundice, cholestasis, peliosis hepatus (blood-filled lacunae in the liver parenchyma), hepatocellular carcinoma and intrahepatic cholangiocarcinoma.12 Table II contains a more complete list of adverse effects of anabolic steroid use. In addition to using anabolic steroids, many athletes use other drugs in an attempt to counteract some of these adverse side effects. These "associated drugs" are listed in Table III. Many of the adverse side effects listed in Table II are of importance to the anesthetist. Of primary importance is the possibility of hepatic damage and dysfunction which would be indicated by elevated levels of the liver-specific isoenzyme of lactic dehydrogenase (LDH) and alkaline phosphatase. Virtually all of the anabolic steroids currently in use are metabolized by the liver. With continued

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Table III "Associate" drugs commonly used Sympathomimetics-as stimulants Beta blockers-to reduce tremors Human chorionic gonadotropin (Preznyl®)-used to prevent testicular atrophy and maintain endogenous testosterone production either concurrently or immediately after a "cycle." Diuretics (furosemide, hydrochlorothiazide, etc.)to decrease retention Thyroglobulin (Proloid") Composite derived from: (1) Strauss RH, et al. Side effects of anabolic steroids in weight-trained men. Physician and Sports Med. 1983;11:87-96. (2) Deters T.So you want to take steroids? Muscle and Fitness. 1989;50:109-110, 230-233. (3) Brainum J. Growth hormone: Myth vs. fact. Muscle and Fitness. 1988; 49:161-163, 185-188.

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use, anabolic steroids can be destructive to the liver. Oral preparations demonstrate greater hepatic toxicity than parenteral preparations because the oral agents must pass through the liver twice before metabolism is complete." Because of this, the anesthetist should be alerted to the possibility of enzyme induction which will result in increased patient requirements. This is especially true for the athlete just starting or completing a "cycle." In addition, since a large portion of the anesthetist's pharmacologic armament is metabolized by the liver, one should also be aware of the possibility of prolonged drug actions in such a patient. Even in medically recommended doses, administration of anabolic steroids results in retention of sodium, potassium, calcium and water. '. Alen and others have reported significant increases in fat-free weight at least part of which can only be attributed to increased water retention. 7 In short, this results in an increased volume of distribution of many anesthetic medications. Thus, drug requirements for anesthesia may be increased. Reddy and associates speculate that the increased volume of distribution was at least partially responsible for the resistance to muscle relaxation, with depolarizing and nondepolarizing muscle relaxant drugs, demonstrated by a patient undergoing abdominal hysterectomy and bilateral salpingo-oophorectomy as part of sexual reassignment. These authors also speculate that increases in the number of acetylcholine receptors resulting from increased muscle mass, as well as enhanced neuromuscular transmission from stimulation of adrenocorticotrophic hormone and corticosteroids' activity, contributed to the observed resistance to muscle relaxation.' 4 Because of the water retention associated with anabolic steroids, some athletes may use furosemide or some other diuretic to remove the excess water. Use of furosemide without potassium replacement will result in potassium depletion and hypokalemia. Hypokalemia and hyperkalemia, at the extremes, both have profound effects on the myocardium, for which reason the electrocardiogram (ECG) should be closely monitored. Because of the erythropoietic stimulation, anabolic steroids cause a secondary polycythemia which may be further aggravated by the use of diuretics to remove retained water. Polycythemia alone, or in combination with diuretic-induced dehydration especially, increases the viscosity of the blood. This, in turn, increases the workload of the heart, thus increasing the myocardial oxygen requirements. In addition, polycythemia is associated with greater perioperative complications, usually postoperative hemorrhage or thrombosis." Furthermore, in view of the secondary polycythe-

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mia and increased workload of the heart, it should be noted that dehydroepiandrosterone sulfate, a precursor of androstenedione and testosterone, has been shown to result in significant decreases in red cell 2,3-diphosphoglycreate."' This factor shifts the oxygen-dissociation curve to the left. Because of this left shift, the cardiac output must increase in order to maintain adequate tissue oxygenation, thus the workload of the heart is further increased. During the preanesthesia interview, every effort should be made to determine whether any performance-enhancing and/or "associate" drugs have been used by the athlete either currently or within the preceeding 8 weeks. Reassure the athlete that strict confidentiality will be maintained. In any event, obtaining this information may still be difficult since these athletes are extremely protective and quiet about this subject. Projecting a nonjudgmental attitude and explaining the importance of such information to the successful administration of anesthesia may make obtaining this information somewhat easier. Although the "community" of athletes using anabolic steroids is relatively small, the strict "underground" nature of their use warrants inclusion of this information into the preanesthesia interview. In reviewing the patient's laboratory data, particular attention should be paid to the following: sodium, potassium and calcium concentrations; cholesterol levels; high-density lipoprotein/low density lipoprotein (HDL/LDL) ratio; alkaline phosphatase; liver-specific LDH isoenzyme; aspartate transferase; and alanine transferase; along with hemoglobin, hematocrit and red blood cell count, because these values may be elevated and may be the first indication of the need for a more in-depth history (Table IV). The ECG, if present, should be noted for bradycardia, first-degree atrioventricular delay, wandering atrial pacemaker, Wenckeback phenomenon, ST-T wave changes and left or right ventricular hypertrophy, all of which are relatively common among athletes. There are no reported contraindications for spinal or epidural anesthesia for the athletic patient who uses anabolic steroids." If general anesthesia is indicated or desired, one should attempt to minimize the use of drugs requiring metabolism by the liver for clearance if hepatic dysfunction is present as indicated by the laboratory data. Induction with sodium thiopentol is acceptable, keeping in mind the possibility of enzyme induction and the larger volume of distribution. Etomidate has been implicated in suppression of adrenal cortical functioning, which may enhance the effects of prior steroid ingestion and should probably not be used. 1" Anesthesia can be maintained with a nitrous

Journal of the American Association of Nurse Anesthetists

Table IV Guidelines for history

Do you have current problems with: Headache ENleeding gums Muscle weakness SStomach ache after eating Easily fatigued fatty foods Frequent bruises with Hleart pounding louder and minor injuries faster than normal Bothersome itching Rlestlessness especially after bathing Akpathy Increased sweating Irrritability Blurred vision D)rowsiness/depression Nosebleeds that are difficult to stop Do you currently take: Prescribed medicines Pi'ills or injections to Over-the-counter medicines make you bigger Herbal teas, family or stronger remedies, etc. Males only-Do you have current problems with: Change in hair Change in testicle size growth patterns Urine stream that is Breast enlargement weak or slow Females only-Do you have current problems with: Loss of hair on your head Exceptional voice Drastic decrease in change such as breast tissue hoarseness, deepening Drastic increase in Stopping of menstrual muscle mass period

Increased episodes of dizziness or sleeplessness Rectal bleeding Vomiting coffee-ground-like material Color change of bowel movements Urine color Painful urination Frequent urination Trouble emptying bladder

Return of acne that had cleared Change ingenitalia appearance Return of acne Increased hair growth on your face, chest, arms or legs

Reprinted with permission from Duncan DJ, Shaw EB. Anabolic steroids: Implications for the nurse practitioner. Nurse Practitioner 1985;1 0:8-15. oxide/oxygen)'isoflurane regimen. The muscle relaxant of choice for intubation and intraoperative relaxation is atracurium since its metabolism is essentially independent of hepatic function. In conclusion, anabolic steroids occupy a place in the treatment of various medical conditions. However, despite proven deleterious and sometimes fatal consequences of their use, many athletes persist in using them in their training regimens, usually in megadose fashion. More investigation and research is needed to understand the full and long-term effects of anabolic steroid use. REFERENCES (1) Bierly JR. Use of anabolic steroids by athletes. Post-grad Med. 1987 ;82 :67-74. (2) Haupt HA, Rovere (;D. Anabolic steroids: A review of the literature. Am J Sports Med. 1984;12:469-484. (3) Buckley WE, Yesalis CE, Friedl KE, et al. Estimated prevalence of anabolic steroid use among male high school seniors. JA MA. 1988;260:3441-3445. (4) Deters T. So You Want to Take Steroids? Muscle and Fitness. 1989;109-110, 230-233. (5) Duncan DJ, Shaw EB. Anabolic steroids: Implications for the nurse practitioner. Nurse Practitioner 1985; 10:8-15.

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(6) Kibble MW, Ross MB. Adverse effects of anabolic steroids in athletes. Cin Pharm. 1987 ;6~:686-692. (7) Ale'n M. Anabolic steroid effects of liver and red cells. 13r].Sports Med.

1985;l11:15-20.

(8) Lendlers 1W M, 1)e-macker 1)N M, Vos j A, (t al. l)eleterious effects of anabolic steroids on serum lipoproteins, 1)100( pressure and liver function in amateur body builders. Imt] Sports Med. 1988;9: 19-2:3. (9) Appxell 11J. Morphological alterations in myocardiurn after ap~plication of anab~olic steroids. Intl./ Sports Med. 1983;4:6i2. (10) McNutt RA, Ferenchick (;S, Kirlin PC, et al. Acute myocardial infarction in a 22-year-old world class weight lifter using anabolic steroidis. Am ] Cardiol. 1988;62:16i4. (11) Frankle MA, Eichberg R, Zachariah SB!. Anabolic androgenic steroids and a stroke in an athlete: Case report. Arch P/its Med Rehabil 1988;6i9:6i32-633. (12) ILamb 1). Anabolic steroids in athletes: Hlow well do they work and how dangcerous are they. Am I Sports 1984;12:31-38. (13) Stauss Rhi, Wright JE, Finerman (;AM, et al. Side effects of anabolic steroids in weight-trained men. Physician and .SportsMed. 198:1;11:87-96.

Med

(14)

Reddy,.11

Guzman

A, Robalino

J,

et al. Resistance to muscle

relaxants in a patient receiving prolonged testosterone therapy. Anesthesiology. 1989:871-873. (15) Remes K, Vuopio 11,Jarvinen M, et al. Effects of short-term treatment with an anabolic steroid (methandieone) and dehydroepiandrosterone sulfate on plasma hormones, red cell volume and 2,3-diphosphoglycerate in athletes. Scandif Clin Lab Invest.

(16)

1977;37:577-586.

Solomon S. The athlete. Anesthesiology News. April, 1989:13-23.

ADDITIONAL READING (1) Ale~n M, Rahkila P, Reinila M, et al. Androgenic-anabolic steroidl

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effects on serum thyroid, pituitary and steroid hormones in athletes. Am J Sports Med. 1987;15:357-361. (2) Alen M, Rahkila P. Anabolic-androgenic steroid effects on endocrinology and lipid metabolism in athletes. Sports Med. 1988;6:327-332. (3) Cohen JC, Hickman R. Insulin resistance and diminished glucose tolerance in powerlifters ingesting anabolic steroids. ] Clin Endocrinol and Metab. 1987;64:960-963. (4) Creagh, TM, Rubin A, Evans DJ. Hepatic tumors induced by anabolic steroids in an athlete. J Clin Pathol. 1988;41:441-443. (5) Edis AJ, Levitt M. Anabolic steroids and colonic cancer. Med J Australia. 1985;146:426-427. (6) Mellion MB. Anabolic steroids in athletes. Am Fam Physician. 1984;30:113-119. (7) Overly WL, Dankoff JA, Wang BK, et al. Androgens and hepatolcellular carcinoma in an athlete. Ann Intern Med. 1984;100:158-159. (8) Prat J, Gray GF, Stolley PD, et al. Wilm's tumor in an adult associated with androgen abuse. JAMA. 1977;237:2322-2323. (9) Vinchattle K. Steroids almost killed me. Muscle and Fitness. 1990;51:122-123, 203-204.

(10) Wood TO, Cooke PH, Goodship AE. The effect of exercise and anabolic steroids on the mechanical properties and crimp morphology of the rat tendon. Am J Sports Med. 1988;16:153-158.

AUTHOR Joseph A. Joyce, CRNA, BS, holds a bachelor of science degree in Chemistry and is a 1989 graduate of the Charleston Area Medical Center School of Nurse Anesthesia, Charleston, West Virginia. Mr. Joyce is currently a staff anesthetist at Wesley Long Community Hospital in Greensboro, North Carolina.

ACKNOWLEDGEMENTS The author thanks Pat Fleming, CRNA, AANA past-president, and William White, CRNA, BS, for their technical suggestions for the text and Janet M. Joyce and Rhea Griffs for their grammatical and spelling corrections. The author also extends special thanks to Kevin Causey for preparing the manuscript for publication.

".. fIshould die before I wake.." That little gnawing fear expressed in the simple childhood prayer becomes a tragic reality every year for those people afflicted with Malignant Hyperthermla ... many of whom are children. Fatalities resulting from malignant hyperthermia are unexpected, unfair and almost always, unnecessary. Unexpected because the patient-child or adult-shows no outward signs of this genetic disorder. And there is no simple diagnostic test. Most people have never heard of malignant hyperthermia until it strikes. Unfair because it is triggered by the patient's reaction to certain common anesthetics used during surgery. The life-threatening episode that results has nothing whatsoever to do with the condition requiring the surgery. Unnecessary, in most cases, because preparedness and prompt treatment can arrest the episode before it reaches dangerous levels. Persons who know of their susceptibility can have surgery safely using nontriggering anesthetics. When MH strikes unexpectedly during an operation, it can be brought under control by early diagnosis and immediate treatment. As a medical professional, you can combat this silent killer. For the latest information on diagnosing and treating malignant hyperthermia, contact the Malignant Hyperthermia Association of the United States (MHAUS) at (203) 655-3007. It may mean the difference between life or death.

* 144

MHAUS PO. Box 191 Westport. CT 06881-0191

Journal of the American Association of Nurse Anesthetists

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Mean postanesthesia recovery times (min)1 Thiopental/ DIPRIVAN isoflurane Duration of anesthesia 85* 57 Response to commands 3,5* 6.1 Fully oriented 5.5 9.4 Able to tolerate fluids 61 * 130 "Ready" for discharge 138* 206

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CLINtCA PARMACOLOGY). SknnAppendages: Flushing. "3%to10%;"10% orgreater. events is1%-3%; incidence ofunmarked not intheliterature, events only (Adverse Probable Laesthan 1%-Causl Relationship Incidence Itacifzed. ) trials, are seen Inclinical IVADMINISTRATION FOR EMULSION Tachycardia, Cardeovaecular: Trunk Pain. Neck Stiffness, Pain, Chest Pain, asaWhole: Extremities Body ECG, STSegment Abnormal Syncope, Atrial Contractions, Premature Veontricular Contractions, Premature insert) package see information, Forfull prescribing (INDICATIONS Tremor, Paresthesla, Hypertonla/Dystonda, Somnolence, Shivering, Nervous Systeum: Centrel induction Depression. forboth canbeused agent that isanIVanesthetic Injection UAE: DIPRIVAN AND HypersatiDge t vo: Fagidity. Euphoria, Faiue, Moaning, Delirium, Confusion, Dreams, Agitation, outpatient surgery. Abnormal and forinpatient technique anesthetic ofabalanced aspart ofanesthesia maintenance and/or Redness/Discoloration. Hives/Itching, Discomfort, Phlebitis, Inectien Site: Mouth, Swalowing. vation, there because deliveries, section incudingcesarean lorobstetrics, isnot recommended Injection DIPRIVAN Wheezing, Dyspnea, Bronchospasni, Obstruction, Airway Repleery: Upper Myalgia. Mussuloukolotel: (See PRECAUTIONS.) tothefetus. itssatety tosupport data insufficient are and Appendages: Hyoxa. SNd Hyperventilation, Sneezing, Tachypnea, Burning InThroat, been Hypoventilation, has Injection DIPRIVAN because mothers foruse innursing recommended isnot Injection llnnitus.Urogenitl:Urine Pain, Taste Perversion, Dipiopia, Eye Speelal Sease: Ambyoda, Rash, Urticaria. arenot ofpropofol ofsmall amounts absorption oforal and theeffects milk Inhuman lobeexcreted reported Retention, (keen Urine known. (See PRECAUTIONS.) not only Intheliterature, events reported Unknown (Adverse Relationship Inuidenee Leethan 1%- Causal have safety andeffectiveness because patients foruseInpediatric isnot are flakoized.) seen in clinical triais, (See PRECAUTIONS) notbeen established. hofensia. Central Newt 8Axk, Fibrllation, Ventricular Bieminy Edema, pressure Crdiomeuter Arrhythmia, intracranial with increased inpatients atthis time foruse Isnot Injection DIPRIVAN andLocalized Seizures, Hysteria, Insomnia, motonal Lability Depression, arterial NerouSem: AnxietyE inmean decreases cause substantial may Injection because DIPRIVAN cerebral orimpaired Pruritus, andmeie~ Diaphoresis, Respiratory:La .osamSkin Digeidve: Diarrhea. (See PRECAUTIONS.) (shrotonus. pressure. perfusion Incerebral decreases substantial and : Anormal Urine. ystarnus. Uoe Senes: Ear Pain, ypem i p al Con junctival hypersensitivity with aknown orinpatients Iscontraindicated general anesthesia When known. ASUSENDDEPENDENCE: None DRUG orItscomponents. toDIPRIVAN effect titrated tothedesired and Dosage should beIndividualized nduetien: AND ADMINISTRATION: ofgeneral DOSAGE onlybyprsontrained inthe beadministered should DIPRIVAN Injection ASA I classified 55 years ofageand adult patients under status. Most clinical tothepatents ageand according and enrchnment andesygen "Iatrw uilaI ventilation, oflapatent Faclities formnintenance anesthesia. when or when for induction of DIPRIIAN Injection, to 2.5 mg/kg to require 2.0 and II arelikely avaIlabIa beImmediately must ciculatory resuscitation Injection should DiPRIVAN narcotics. For induction, orlintramuscuiar benzodiazepines with oral withbood orplasmaebecausepremedicated IV catheter through thesame should notbecoadministered Injection signs until theclinical the ofthepatient against 40mg every 10seconds) (approximately component betitrated oftheglobular that aggregates have shown Invitro tests been established. hasnot compatibility ofanesthesia. theonset signifi- show The and animals. from humans with blood/plasma/serum occurred vehicle have oftheemulsion treating of Inecton before with the Intravenous use familiar and experienced Illis Important to be cancelis notknown. patients Status ClassesorIV.These those inASA patients and/or debilitated, hypovoiemic elderly, vehicle In The DIPRIMN Injection. whie handling hemaintained meet emnftk Strict should ofDIPRIVAd Injection thedosage ofDIPRIW4A Injection; totheeffects sensitive AND ADMIN- maybemore (See DOSAGE ofmlcroerganlemL. rapid growth of DIPRIVAN Inecion Ies pable conditions according totheir 10seconds) 50% (20 mgevery inthese patients byapproximatei bedecreased Handlng Procedures.) ISTRATION EGU IDE.) DOSAd (See PREATIOaS and should be ofadministration maintenance rate and aslower dose General: Aloer induction PRECAUTONS: Inpatients may beIncreased ofDIPRIVAN Injection theeffects anesthetic agents, aswithmost DOSAGE ASA Ill orIV.(See and those rated disorders, with and/or patients debilitated used Inelderly, toinduction. shortly prior ornarcotic premedicbions Intravenous sedative received hypotensionwhohave forearly signs ofsignificant monitored becontinuously should AND ADMINSTATION.) Patients orIntermittent Injection byInfusion byadministering DIPRIVAN canbemaintained Anesthesia ofklower extremities, Maintenanee: fluid, elevation ofIntrvenous increasing therate may Treatment and/or bradycardia. frequency rate ortheamount and determine theInfusion The patient's clinical will IVbolus Injection. andmaypersistlfor Apna often occurs Induction ofatropine. useof pressor oradministration Injections. caution ofIncremental Injection isanemulsion, Because DIPRIVAN bereuired. support may 60seconds. Vlentilatory than counters, syringe pumps recommended that drop Injection by infusion, Itlls administering DiPRIVAN When diabetic as primary hyperlpoproteinemla, metabolism such oflipid Inpatients withdisorders should beexercised controlled Infusion rates. pumps beused toprovide orvolumetric hyent pemia, andpancreatitis. rate Infusion with in a variable mg/kg/mn administered 01 to 0.2 DiPRIVAN Injection Centlneees leleelen: Is of the awakened patient of evaluation an adequate period never used alone, Injection Is Snce DIPRIVAN surgery. Maintenance underging general forpatients oygen provides anesthesia oxdds and 60%-70% nitrous from the ofthepatient priortodischarge fromgeneral anesthesia satisfactory recovery toensure Indicated

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puogencymwhich limitfathe rate ofinducinosalthoughsricessineslimstion oritrechebrenchalsecrstions dootsappeartobestimulated Pharyngeal andlaryngeal reflmaes arereadily ounded Thetenetofanesthesia maybechangedrapidly with eaonuesne isofluraea is a profoundrespiratory deprseait RESPIRATION MUSTDE MONITOREDCLOSELY AND DUPPORTEDWHEN NECESSARY Acanestheticdoe is increased, tidalvolumedecreaaes aodrespiratory reateunchanged Thisdepe signisperpallyreoesed byasurgical stimoulation, awn at deep e als ofanesthesia Isofurneokse a sighresponse reminiscenof thatsenmwithdiethyleother and onfurane,althoughthe frequancyislse thnmithnfurne Dioodpreegure decrese mithinduction of anesthesia but returnetowardnormalwithsurgicalstimulation Progreseive inraesin depthof anesthesia producecorreeponding decreaseein blood pressureNitrousside diminishesthe inapatoryconcentration of teoflurane reqiredto reacha desiredtenetofanesthesia andmayreducethe aterial hypinen si en reith soflurene,alone Heart rhythmasremarbably stable With controlledvmntilation and normalPeCO., cardiatoutputlismaintainsddespiteincreaingdepthofanethesia primarilylthmugh anincreassinheart rstamhich compeneetes fora reductioninstrobecolumeThehypemcapotarwhich stendespontaneouacventtletionoduring aflurane anesthesi furtherincreasesheart rateandriaisscardiac output ahowe awaealowle sonurne doesnorensitise the myncardium to soogenouely adminietered epinephrinein thedog Limiteddataindicatethat subcutanecus injec lionof 02t mg of opinephrinaItO mL of I.200b00 solution)doesnotproduca an increasein nentriculararhythmia in petienta angtheted withisoflurana Musclerelareation isoftenadequateforinto-abdomcinal operations atnormal mevl of anesthesia Completemuscle peralysia ceobeattainedwith smalldoaasofmusclerelaxante ALL COMMONLYUSEDMUSCLERELAXANTSARE MARKEDLY POTENTIATED WITH4 ISOFLURAPIE, THEEFFECTBEINGMOSTPROPOUND WITH THENONDEPOLARnZ INOTYPE Neotigmiserewersesathe effactofnondepolarising musclerelaaantu nthepresence of sourane All com monlyused musclerelaxants are compatiblewithisolutane 15 Isoflurans can producecromnary aodilationathe arteriolartalevlin selected aimal mdla thedrugieoprobebly alsoa comonary dilatorin humanstantlurne.lbhe someothercoronaryarteriolardiletors, has beanshaoito dinert bloodfromcollteraldependantesyncerdbum tonormallyperfuasdareasin ananimalmodel c'oronary stel") Chonical that hanenotrestahliehed infarctionanddeathasoutcom parrameters stuiesodtemluainmyoardnlechmi, the coronary aleriolar dilationpropxr1 9 l saofltrn is mithcoronarystealormyocardialiectema in palientawithcoronary rtery diseasa Pbarsoaelae: leolurane undergoes minimalbiotransformation in man In Ihe postanesthesia period,only0 17% of the iofluranetakes up can be recoversd so urinarymatabobtea

aesociated

FORANEblolurane,USP)maybe usedlot inductionandmaintenanceof generalanesthesia Adequatedate bane not been devwloped to estabbebh its apphication in obstetricalanesthesia

CONTRAINDICATIONS

sesitivity

Enown to FORANE(icofusene, USP)orto otherhalogenatedagents Enownor suspected geneticsuaceptibilityto malignanthyperthermia

ADVERSE REACTIONS

Aderse reactionsencounteredtinthadminstratonof FORANllteourane, USP)arein generaldagedepgrndette tensionsof phamacophystologic effectaand includerespiratorydepreseton.hypotnsionanderrhyfbmtas Shivering nausea,vomitingcodtaus banebeenobeernedin the postoperatios period Acmith altothergeneralanasthetica. transienteleaftonsin whbite bloodcoonihaebeenobservedowntn the absence of surgical tresa ScePRECAUTIONS for informationrogardtngmalignanthyparthetmie

OVIRDOSAGE

In the enentof onerdoage or wnhatmayappearto be ocerdoage. tt. tollowng actionshouldttlabkti Stopdrugadministration establisha clear airway andinitiate assistedot controlledveniaeiot withpots ioeygeti

DOSAGE AND ADMINISTRATION PremedleelleecPremedication shouldbe selected accordingto the neadof theindividualpetient,tebintg intoaccount that secretiona aremeeklystimulated by FORANEitonurene, USP)endthe heart ratetende lo be increasedThe use

of antichoorgoc drugsin a melter of choice spired Ceecealle: The concentration of isoflurane beingdelivered froma osporiestduring anesthesia should befrown Thismaybecaccomplished byusing at

Inductionotandrecoreryfromisonurane anesthesiaamerapid Isofurenehasamild

INDICAS'IONS AND USAGE

Oeracol: Aswith any potent generalanesthtic, ORANE (eourane. USP shouldolybeadotisteted inan ado quatatyequippedanethenlng nvionmentbthoemho areams Warwththepharmacologyofthedtig ad quatfted by trainitg andeaperienceto managethe anesthetieed patient Ragardlesaeottheeanaethetce empsyed.maintanciteof normal hemudynarocea n portantto teaoidano i nyccatda 45 6 7 isthamia in patientswithcoronaryarterydteae . . . laforesatls te Patten: feoffurane. a. well ac othergeneretanestheticsnay causea slght dacreaseintntlletuiol functonofor2or3dys followinganestheia As withotheranesthetics,smallchangeein moodsandsymptot ay persit for uptoS6daysafter administration Lahereleryitli Transientincreasasto DSPretentionbloodglutcose aodsetoum cteecintne withdecreasein DUN, srmcholesterol andalkralinephocithatasehame bean oberoed Drig Iatsreteea: teotlaata potentiatasftcmacle relaiant effectof allmueclerelacait mostnodalfynondepoetigeng musclerelaxant andMAC (mtnimumalveolatconcentraton)ie reducedby concomitant administtetionof NO Se CLINICAL PHARMACOLOGY Cacslmegeaeels:Swiss fCRmice weregivenisoffuranetodeterminewhstbet u eoxsposute might indiuceoneoplaste tsoflurenewas givenat 112,118and1132MAC too tour in oteroeapoauresand for 24expoeureetothe pups doting the firstnise meebaof ifeThe nicemerebittedat ft monthsof age Thetnctdenceof tumorsin thesemtcewnns the same aseinuntrsetedcontrolmicewhich wre giventheame bacground ge,butnotthe nestheic PrgaaoiayCatge7 c: Iofurane has been shownto heneepossiblearsesthettc-related Ietotc effectin mice when giventodoes Stimeethe humandoes Thereame noadequttae codmellconrotled studiesin pregnantwmeenIeafure shouldbe usedduring pregnancyonlyif the potentialbeneft ustittesthepotential rtekto the fetus Nursing Melaes: Itanot knowcnmwhther thisdrugisemreted inhumanmilk Becastsaneydrugseere ecrsted in humanmilk. caution shouldbe eamised whenisolurane isdministered to anaming oman Udaflgmeat ltyprlaecla: In sosceptible imdivmduals isnlane antethesiamayuiggera siteisalmacle hypermasaaboc steteleadingto highottygendemandandthe clinicaleyndromebnom s malignanthyperthermi The syndrome includesnonepecific featureseuch aemusclerigidity.tchycardia, tachypna cyanocis, arthyfhmiae,and cnstebte bloodpreseer s fhotuldalaobenotedthatmaeyothesenonspeiftc signsmayppear withlightanesthesie.acute hyposia.etc) An tncreaeeis overallmetabobam maybe reflectedin an elenatedtempereture (mhichmayriserapidly earlyorlta in thecaw, butusuallyisnotthe ftrstsign ofaugmentd metabolsm)andanincreaed usge of he CO absorptionesystem (hotscaniaterfPeOsandpH maydecrease,andhyperkatemia dabasedficitmayappea lnea mentincludeediscontinuance of triggering agenrafog , aelfirne, administration of intraenouc dantrotenesodiumi andapplbcation ofesupportine therapy Suchtherapytncludesotgorouseffortfeto restorebodytemperture tonormal, respiratoryandncirculetory support esindtcated, andmanagement of eectrolytetludatdbase drngement ICon suItprecribing informationfor dantfmlcne sodiume intrenenous for additionalinformationon pasientmanagementI Renal fetloremayappear later.end urinefore shouldbe sustainedif possible

vsporisere calibratedspecificallyfor isoflurane.

hI mapoticara from whichdeliveredtvows canbecaclated. sui~chapcaliittes deliveringa saturated input wnhich is thendiluted Thedelimired coccentla lion fromsucha maporiermaybe calculatedusing the foriul % isofurgna-

10Py Fy FT

inhere

P0 P0 P0v FT.

(PA

PV)

Pressureof atmoephere Vaporpressure otsonuane Flo of gasthroughvaporiasr Imimiol htalgasnow (miLmin)

teoflrans conteins nostebilier Nothingin the agentalterscalibratioi oroperationof lths csotniet lnductbos:Inductionwith isofluranein ottygenorit combinationwith oygerinitrousoide iclires maypriotate coughing,breathholding,orlaryngopem Thesedifficultieemaybe avided bytheuscetoaiypntiicieif tiiilta shortactinghbarbiturste Inspiredconcentrations oll6tu 30% isonurneusuallypttoducenotgialaniesthesi ita7lic t0 minutes Malabeas: Surgicallevelsofanesthesia maybesusrainedmwitha lto 26% coincentrstiottwhen nitrausmadc ieus edconcotmtanlyAnaddionatltbtof 0%maybe requaredwhenaoruan aagimen usig orygen atoneIf addedrelatfo isrequired,supplsmental donesofmusclerelaxantamaybe ued Thblevelofbloodpresaureduringmaintenancean iomefuniocfiof urnmconcentrtion in theeabance of oher costcaliogproblems Eocessivmdacreases maybeduetodepthbolansthsia andinscbisnce maybe itrtst by lightening anesthesia

HW SUPPLIED

FORANEt(isonurana, USP).NDC 10018938040ispecbagedinttlt0mLantbt coiliotebustlra 9serege:Storeat roomtemperatureIt" 30"C(6t' D 6F)Iloliariecitaie ii. aditiieni ha beetidemonstrated lo be stableat roomtemperaturefor periodsin socesof tamyears

Referencee IJC Dill.stat, Anesthesiology 6e 273 279. 19t7 2 RFHohey,at .1. Anesthesiology88 21 30.19ee 3 CW Duffinonc sa. Anesthesiology 6D280.292,1987 4 5 Rais.t at. Anesthesiology 59 9t 97.1983 6SStogcffandASKet. Aoesthesiology7 17188 189 8 EJTuimar,to at. Anesthesiology 70 189198 1969 7 DT Mangano.EditorialViems Anesthesiology 70 t17t617D, 1gug Revised2 80

References: GUS Computer Simulation. Registered trademark of Quincy Street Corporation. Phoenix, AZ. References used to generate this program include: 1. Eger El II: Anesthetic Uptake and Action. Baltimore, Williams & Wilkins, 1979. 2. Lowe HJ, Ernst EA: The Quantitative Practice of Anesthesia-Use of Closed Circuit. Baltimore, Williams & Wilkins 1981. 3. Parbrook GD. Davis PD, Parbrook EO: Basic Physics and Measurements in Anesthesia. Baltimore University Park Press, 1982.

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