Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Pharmacognosy wikipedia , lookup
Prescription costs wikipedia , lookup
Adherence (medicine) wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Neuropharmacology wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Drug interaction wikipedia , lookup
Theralizumab wikipedia , lookup
History of general anesthesia wikipedia , lookup
The antagonism of nondepolarizing neuromuscular blockade TOM E. JENKINS, CRNA Winston-Salem, North Carolina The antagonism of the nondepolarizing neuromuscular blockade is accomplished many times in a given day. Fortunately, the incidents of complications are low. If they do occur and are not recognized and treated properly, however, the results can be serious. In this article, the author reviews the curariform group of drugs, anticholinesterases, and anticholinergics, evaluating the antagonism of the nondepolarizing neuromuscular blockade. The return of normal neuromuscular function, following paralysis with one of the nondepolarizing neuromuscular blockers, is a complex polypharmacological occurrence. The anesthetist must not only administer the proper mixture of anticholinesterase and anticholinergic drugs; but, he or she must also be able to assess the effectiveness of the reversal. The anesthetist must also be cognizant of the possible complications that may ensue. The antagonism of a neuromuscular blockade cannot be accomplished safely and effectively without knowledge of drugs and their sites of action. The neuromuscular junction The neuromuscular junction (Figure 1) is the site of action for nondepolarizing muscle relaxants and their antagonists. At this point, the 452 efferent nerve fiber invaginates the muscle membrane. The electrical impulse from the nerve fiber is transmitted to the muscle by acetylcholine. The acetylcholine stimulates the receptor sites of the muscle membrane, causing the muscle to contract. Before the acetylcholine can cause a second action potential, cholinesterase hydrolyses it.1 The curariform drugs To produce deep muscular relaxation by means of an inhalational anesthetic, it is usually necessary to establish a depth of anesthesia in which the medullary centers of respiration and circulation are severely depressed. The use of the neuromuscular blocking drugs makes it possible to obtain adequate surgical relaxation with a much lower concentration of inhalational anesthetics. The classification and modes of action of these drugs are divided into two types: those which prevent depolarization of the motor end-plate and those which depolarize it.2 The curariform group of drugs prevents depolarization of the muscle fiber. These include tubocurarine (dTc), gallamine, and pancuronium. They bind to the receptor sites, preventing acetylcholine from combining with the receptors and creating an action potential across the neuromuscular junction.1 Until 75-85% of the receptors are blocked, there is no interference with neuromuscular transmission. Clinically, we view the action of the curari- Journal of the American Association of Nurse Anesthetists Figure 1. Neuromuscular Junction I Muscle nuclei form drugs as resembling an iceberg. Most of the receptors must be blocked before there is any decrease in twitch response. The anesthetist works at the top 20-25% of the iceberg; only this small fraction of receptors must be reblocked as the curariform agent is eliminated. 3 The onset of neuromuscular blockade is first seen as motor weakness. Depending upon the dosage given, this weakness progresses until the muscle becomes totally flaccid and inexcitable. Small, rapidly moving muscles (such as those of the toes, eyes, and ears) are involved before those of the limbs, neck and trunk. Finally, the intercostals and diaphragm are paralyzed. Facial and diaphragmatic muscles are the first to recover, followed in order by muscles of the legs, arms, shoulder girdle, trunk, larynx, hands, feet and pharynx.4 The average duration of the curariform drugs is 20-30 min.5 The curariform blockade may be enhanced by inhalation anesthetics, acidosis, certain antibiotics and idiosyncratic response of the patient. October/1980 Anticholinesterases Anticholinesterases inhibit the action of cholinesterase in acetylcholine hydrolysis. The result is the re-establishment of neuromuscular transmission. 5 Randall and Lehmann0 found that the anticurare action of phenyltrialkalammonium compounds could not be attributed to cholinesterase inhibition. They suggested that a direct acetylcholine-like stimulant action of anticholinesterases could account for this activity. There are two other possible reasons for the anticurare action of the anticholinesterases. One may be the direct stimulation of the motor nerve terminal, which causes an increased release of acetylcholine. The second may be the displace. ment of the curariform agent from the receptor site, permitting the redistribution, elimination and destruction of the curariform drug. 7 Edrophonium is a rapid-acting phenyltrialkalammonium compound. Its effects are manifested in 30-60 sec when administered intravenously. The peak effect is seen in 1-2 min and lasts from 5-10 min. The recommended dose for antagonism of a competitive blockade is 0.3 mg/kg. 5 453 Katz 7 demonstrated that, in more than half of curarized patients, edrophonium failed to restore twitch height to control with usual doses (10-20 mg). Artusio and associates 8 reported that unless the respiratory minute volume was 20% of control or greater, edrophonium could not fully reverse the effects of tubocurarine. Doughty and Wylie 9 found that, in patients who receive 140-160 mg of gallamine, edrophonium (20-40 mg) could not adequately restore respiratory function. Katz 7 attempted to demonstrate recurarization in ten patients using edrophonium. The twitch was abolished with tubocurarine, using a 0.1 mg/ kg test dose, followed by 0.5 mg/kg curarization dose. An abrupt increase in twitch height was observed in every patient following administration of 10 mg of edrophonium. This in turn was followed by either a return to a spontaneous rate of recovery, or by a slightly greater rate of recovery. In no patient did the twitch height (recorded for another 45-70 min) decrease following the increase produced by edrophonium. It should be pointed out, however, that edrophonium, when used as the sole antagonist, is a poor choice of an anticholinesterase due to its short duration of action. Neostigmine is the most widely used of the anticholinesterases because of its antagonism of nondepolarizing muscle blockade. It enhances cholinergic action by facilitating the transmission of impulses across the neuromuscular junction, and inhibits the destruction of acetylcholine by cholinesterase. It has been shown that neostigmine may cause paralysis when given in the absence of a curariform drug. This depolarizing muscle blockade has been demonstrated with doses of 3.75-5.0 mg of neostigmine. The presence of even the smallest quantity of a curariform drug will normally prevent such an occurrence. 10 The inhibition of the destruction of acetylcholine not only affects the skeletal muscles, but it also induces widespread activity throughout the body. These cholinergic actions are of such a variety that they are placed into two main groups, nicotinic and muscarinic. (Table I). To have an antagonist with as few side effects as possible, an antimuscarinic is administered with, just after, or just prior to the injection of the anticholinesterase. If an overdose of the anticholinesterase is given or the effect of the antimuscarinic drug does not last as long as the anticholinesterase, a cholinergic crisis may occur (Table II). 4 Foldes 11 published a review of the pharmacology of neuromuscular blocking agents in man. This study demonstrates that the full effects of neostigmine are reached within 2-4 min. Others have found the duration of neostigmine is at least 60 min and, at times, 150 min.12. 13 A significantly larger amount of neostigmine is needed to antagonize a blockade produced by gallamine than to antagonize a blockade produced by tubocurarine or pancuronium. 14 In Katz' 1967 study,7 a dosage of 2.5 mg neostigmine was adequate for reversal of 85% of the patients paralyzed with tubocurarine, and all the patients paralyzed with pancuronium. If an initial dose of 2.5 mg of neostigmine does not antagonize the neuromuscular blockade after 5 min., it is recommended that, small doses of neostigmine be given until a total of 5 mg has been Table II Cholinergic Crisis Muscarinic Salivation Lacrimation Diaphoresis Bradycardia Hypotension Bronchoconstriction Nicotinic Muscle weakness Fasiculation Skeletal muscle paralysis Respiratory paralysis (Goodman and Gilman, 1974) Table I Cholinergic Receptors Muscarinic 1. Stimulation or inhibition of smooth muscles 2. Stimulation of exocrine glands 3. Slows cardiac conduction 4. Decreases myocardial contractility Nicotinic 1. Stimulates autonomic ganglia (sympathetic and parasympathetic) 2. Stimulates adrenal medulla to release catecholamines 3. Stimulates skeletal muscles at the motor end plate (Maree, S. Cardiovascular Pharmacology: A Manual for Nurse Anesthetists) 454 Journal of the American Association of Nurse Anesthetists administered. More than 5 mg will increase the likelihood of creating a depolarizing neostigmine blockade. Pyridostigmine facilitates the transmission of impulses across the neuromuscular junction by inhibiting the hydrolysis of acetylcholine by cholinesterase. Katz15 found pyridostigmine to be more effective than edrophonium and equal to or more effective than neostigmine because there is a wider margin of safety and the oropharyngeal secretions are less. Pyridostigmine was found to cause less bradycardia, and with it the incidences of arrhythmias were less as compared to neostigmine. 16 The anticurare dose of pyridostigmine is 0.15-0.25 mg/kg. An average dose of 0.2 mg/kg is usually sufficient.5 If a repeat dose is needed, it should be one-fifth of the original dose but not to exceed 2 mg. 1 5 The duration of action for pyridostigmine is longer than that of neostigmine; the onset of action for pyridostigmine is seen in 14-15 min. Anticholinergics Reversing neuromuscular blockade by the use of peripherally-acting anticholinesterases has always entailed the use of an anticholinergic agent. The anticholinergic protects against the muscarinic effects of the anticholinesterase. 7 Atropine is a tertiary amide having two actions. The most important therapeutic action is the inhibition of smooth muscles and glands innervated by the post-ganglionic cholinergic nerves. Atropine also has a central nervous system activity."' The timing of atropine administration in conjunction with an anticholinesterase has been a long-standing controversial issue. Most anesthetists are aware of the confusion and irrational behavior that can result from the persistence of the effect of the belladonna alkaloids, such as atropine. It is not widely appreciated that these drugs may, in some cases, be responsible for the patient failing to awaken after anesthesia has been discontinued. This syndrome results because the anticholinergic effects of belladonna drugs within the central nervous system are completely unopposed, giving rise to the signs and symptoms of a central anticholinergic syndrome (Table III).'" All of these effects, including prolonged stupor following the use of the belladonna drugs as part of the reversal, can be quickly terminated by an injection of physostigmine.' 7 Glycopyrrolate, a quaternary ammonium, does not cross the blood-brain barrier, and therefore, exerts no influence on the central nervous system October/ 9S0 Table III The Central Anticholinergic Syndrome Agitation Restlessness Confusion Combativeness Plucking & picking Uncooperativeness Hysterical behavior Memory disturbance Visual aberration Visual hallucinations Auditory hallucinations Delirium Dysarthria Vertigo Atoxia Hyperreflexia Opisthotonos Convulsions Stupor Coma (Longo, 1966) (CNS). Glycopyrrolate also diminishes the volume and free acidity of gastric secretion and controls excessive pharyngeal, tracheal and bronchial secretion. The onset of action from intravenous injection of glycopyrrolate is seen within one minute. The recommended dose of glycopyrrolate for its antimuscarinic effects is 0.2 mg (1.0 ml) for each 1.0 mg of neostigmine or the equivalent dose of pyridostigmine. 18 A 1977 study of glycopyrrolate revealed that the drug provides equal short-term and better long-term protection against cholinergic-induced bradycardia than that provided by atropine. 7 There is also a considerable reduction in the degree of initial tachycardia produced by atropine when given in equipotent doses. When 0.2 mg of glycopyrrolate was given intravenously to healthy, awake volunteers, it did not cause a significant tachycardia but did cause a significant reduction in salivary secretions. 2 0 Antagonist compounds The ideal antagonist for neuromuscular blockade should be effective against the nondepolarizing muscle relaxants. Its effects should develop rapidly, preferably following a single dose. The duration should be long enough to prevent any "recurarization." This reversing compound should have a selective action at the pharmacological receptor site. The side effects of the compound should also be pharmacologically reversible by appropriate agents. The ideal compound, therefore, should consist of one or more reversible anticholinesterases and one or more plarasympatholytic (atropine-like) agents. This agent's sole purpose is to antagonize the undesirable side effects of the anticholinergic agents. 21 Neostigmine and atropine in combination is perhaps the most commonly used anticholines- 45 5 terase/anticholinergic pairing. Rosner and associates22 found that both the previous and concomitant administrations of atropine with neostigmine were safe, provided that oxygenation was maintained. They recommend 20 mcg/kg of neostigmine mixed with atropine 6 mcg/kg, given slowly over 60 sec. The simultaneous administration is a safe and effective means to terminate a nondepolarizing neuromuscular blockade 23 It should be pointed out, however, that cardiac arrest and even death have been reported with the use of atropine/neostigmine mixture. It has been postulated that the cardiac arrests can be the result of the cholinergic action of neostigmine and the initial central vagal stimulation of atropine. A sudden, parasympathetic dominance may also be responsible for the arrests. 20 Theoretically, because the doses of belladonna drugs used for reversal are large and are given at the end of the surgical procedure, the chance that the patient will show signs and symptoms of a central anticholinergic syndrome is certainly enhanced. 17 The short duration of action of atropine is perhaps its biggest disadvantage (Figure 2).10 This difference in length of action will leave the muscarinic receptors vulnerable to the effects of neostigmine. This parasympathetic dominance could cause bradycardia, which could lead to hypotension and shock. The increased muscarinic tone has the possibility of placing certain surgical patients in undue risk. In 1968, Bell and Lewis reported a high incidence of surgical bowel anastomosis leaks (36%) in patients receiving neostigmine. 2 4* Neostigmine and glycopyrrolate. Klingenmaier and others found that the combination of glycopyrrolate and neostigmine caused small and slow changes in heart rate. 25 Furthermore, this compound caused less arrhythmias than did the neostigmine-atropine mixture. The small changes in heart rate were attributed to the parallel onset of action of the two components. 20 (See Figure 3.1 6) Glycopyrrolate offers the same protection against neostigmine-induced bradycardia as does atropine with less tachycardia. The reversing compound should contain 0.2 mg of glycopyrrolate for each 1 mg of neostigmine. 28 The rapid intravenous injection of this compound has been found to be as effective, and is safer and smoother than the neostigmine-atropine combination. 25 Pyridostigmine and glycopyrrolate. When pyridostigmine was substituted for neostigmine, using atropine to combat the muscarinic effects of pyridostigmine (Figure 418), the resulting mixture did not work well. It was effective for the antagonism of neuromuscular blockade but had too many unwanted side effects, primarily due to the difference in onset and duration of action of the two agents. Gyermek 80 found that the combination of pyFigure 3. Glycopyrrolate and Neostigmine Schematic pattern (effect vs. time) of changes inheart rate when glycopyrrolate and neostigmine are combined (Gyermek, 1977). *Editor's note: More recent findings have refuted this condition. Figure 2. Atropine and Neostigmine Schematic pattern (effect vs. time) of changes in heart rate when atropine and neostigmine are combined (Gyermek, 1977). 456 Figure 4. Atropine and Pyridostigmine Schematic pattern (effect vs. time) of changes in heart rate when atropine and pyridostigmine are combined (Gyermek, 1977). Journal of the American Association of Nurse Anesthetists ridostigmine and glycopyrrolate approached the ideal compound for antagonism of neuromuscular blockade. Both agents have approximately the same onset of action. The pyridostigmine bradycardia is well paralleled with the glycopyrrolate tachycardia (Figure 51 "). This factor and others including the decrease in arrhythmias (due to the mild muscarinic action of pyridostigmine),2 8 the lack of central nervous system effects, and greater antisialogogue effects make this compound very desirable for the antagonism of the nondepolarizing neuromuscular blockade. 2 7 The disadvantage of this compound lies in its slow (12-15 min.) onset of action. Compensation for this can be made by simply initiating the reversal process a little earlier. Winnie and others1 7 note that with 10 mg of pyridostigmine, a dose of 0.3 mg glycopyrrolate is optimal. With each increase of 2.5 mg of pyridostigmine, 0.1 mg of glycopyrrolate should be added to the mixture. Gyermek's studies 30 show that the pyridostigmine-glycopyrrolate compound provides a smooth, safe and effective means of antagonizing a neuromuscular blockade produced by tubocurarine.' Winnie and others17 have found the same to be true for the antagonism of blockades produced with pancuronium. Pyridostigmine, endrophonium and glycopyrrolate. Gyermek's studies'" also indicate that there is a need to increase the onset of action of the antagonist mixture. If edrophonium is added to the mixture, the onset of action will be faster. Of the pharmacological agents presently available, the ideal reversal mixture should contain the following agents: edrophonium, pyridostigmine, and glycopyrrolate. Suitable amounts of these ingredients can easily be mixed in one syringe using 1.5-2.0 ml of edrophonium, pyridostigmine and glycopyrrolate (edrophonium 0.2-0.4 mg/kg; pyridostigmine 0.10.16 mg/kg; glycopyrrolate 0.004-0.006 mg/kg). For an average patient weighing 70 kg, usually 4-6 ml of this mixture injected slowly will antagonize the nondepolarizing neuromuscular blockade. Evaluation of antagonism Until short-acting nondepolarizing relaxants are available, the anesthetist must antagonize the long-acting neuromuscular blockers. Evaluating the effects of an antagonist regimen can be accom- Figure 5. Glycopyrrolate and Pyridostigmine Schematic pattern (effect vs. time) of changes in heart rate when glycopyrrolate and pyridostigmine are combined (Gyermek, 1977). plished in many ways. Katz1 5 defines the criterion for adequate reversal of the nondepolarizing muscle relaxants as: the twitch height returning to the control level and a well-sustained tetanic contraction at 30 Hertz. Walts, Levin and Dillon8' found that when there was 90% recovery of twitch force, 16 out of 20 patients had 90% or better recovery of vital capacity. The other four had 80.5% recovery of vital capacity. (The vital capacity allows the patient enough lung volume to deep breathe and cough.) The minute volume may be adequate before vital capacity is restored.8 2 Others recommend the use of the "train-offour"* for evaluating the return of normal function of the neuromuscular junction.8 3 This method does not require a central response nor does it cause the degree of discomfort usually associated with tetanic stimulation. If the fourth response is 60% of the first, the respiratory muscular function should be more than adequate. However, 70% of the receptors can be occupied with nondepolarizing muscle relaxants, and a normal "train-of-four" may still be demonstrated.8 4 Miller3" has compared the reaction of the per. ipheral nerve stimulator to muscle function and the number of receptors occupied by nondepolarizing muscle relaxants (Table IV). He showed that a normal "train-of-four" correlates with 70-75% of receptor occupancy. This also paralleled a normal expiratory flow rate and vital capacity. The ability to sustain contraction in response to a high frequency tetanic stimulation (100 Hertz or more) is probably the most sensitive index of antagonism of neuromuscular blockade, but is too 8" painful for general clinical use. Factors that influence antagonism There are many factors which determine the degree and speed of recovery of a nondepolarized *Editor's note: In the April 1980 issue of the AANA Journal, Dr. Richard Jones expanded on the advantages of the "train of four" technique in his article on the Use of the Peripheral Ner'e Stimulator. October/1980 457 Table IV Suggested correlations between test of Neuromuscular Transmission Estimated Receptors Occupied (%) Peripheral Nerve Stimulation Ventilation Reduced twitch height and sustained tetanus at 30 Hz for five seconds. Normal tidal volume 75-80 Normal train-of-four Normal expiratory flow rate and vital capacity 70-75 Sustained tetanus at 100 Hz for five seconds Normal inspiratory flow rate 50 Sustained tetanus at 200 Hz for five seconds Normal head lift and hand grip test 33 (Miller, 1976) Table V Interaction of antibiotics, muscle relaxants, neostigmine & calcium Neuromuscular block from antibioticalone, antagonized by: Increase in neuromuscular block of: Antibiotics Neostigmine Calcium D TC V muscle relaxants, neostigmine & calcium Table Interaction Neomycinof antibiotic=, Sometimes Sometimes Yes Streptomycin Sometimes Sometimes Yes Gentamicin Sometimes Yes Yes Kanamycin Sometimes Sometimes Yes Paromomycin Yes Yes Yes Viomycin Yes Yes Yes Polymyxin A No No Yes Polymyxin B No* No Yes Colistin No Sometimes Yes ** Tetracycline No Yes Lincomycin Partially Partially Yes Clindamycin Partially Partially Yes Neuromuscular block from antibiotic and tubocurarine antagonized by: SCH Neostigmine Calcium Yes Yes Usually Yes Sometimes Sometimes Yes Yes No No* No Partially Partially Partially Usually Usually Yes Sometimes Yes Yes No No Sometimes Partially Partially Partially ** Yes ** ** ** Yes Yes No ** ** * Block augmented by neostigmine ** Not studied (Miller, 1976) blockade. At the time the reversal is given, the degree of spontaneous recovery will determine the speed of complete antagonism. The amount of spontaneous recovery appears to be a far more important factor in the quantity of antagonist administered than does the total dose of muscle relaxant given. 40 In studying neostigmine antagonism of tubocurarine-induced neuromuscular blockade, Miller and others" have found that respiratory acidosis and metabolic alkalosis limit and oppose neostigmine's antagonistic effects. This may be seen when a narcotic is given immediately postoperatively, and the patient hypoventilates. 88 458 Some believe that recurarization may occur in patients whlo have been hypothermic. McKlveen 3" was unable to confirm this hypothesis in a study of dogs. From studies of hypothermia and its effects on the antagonism of neuromuscular blockade, it appears that hypothermia, per se, does not affect the ability or the amount of anticholinesterase needed. Still others believe that hypothermia decreases the ability of the curariform drugs to block the receptors. If excess amounts of the curariform drugs are given, it is possible to create a neuromuscular blockade too intense for the average Journal of the American Association of Nurse Anesthetists antagonist regimen to reverse.35 This is easily done in patients who are anephric. Miller and Cullen 40 feel that the important measures in preventing "recurarization" are the following: (1) the use of small doses of nondepolarizing muscle relaxants in combination with an inhalation agent to potentiate their effects, (2) more precise monitoring of the neuromuscular blockade, and (3) the use of pyridostigmine as an antagonist of the neuromuscular blockade. Several articles have reviewed the effects of electrolyte imbalance on the antagonism of a nondepolarizing blockade. These articles report on a variety of effects, therefore making it difficult to draw concrete conclusions. Studies of dehydrated patients who have electrolyte imbalances are needed to clarify these confusing, and often opposing, opinions.3 5 The relationship of potassium, calcium, and magnesium to neuromuscular blockade and its antagonism appears to be of prime interest. Perhaps, the best assumption that can be made now is that there may be unfamiliar responses to the curariform drugs and their antagonists in patients who present with electrolyte imbalances. It has been well documented that certain antibiotics enhance nondepolarizing muscle blockade (Table V).35 The particular mechanism of the antibiotic-induced neuromuscular blockade is not known,4 1 but is probably different for various antibiotics. Becker and Miller 4 2 suggest the administration of 5 mg/70 kg of neostigmine with 2 mg of atropine, in divided (oses, to antagonize an antibiotic-enhanced or induced neuromuscular blockade. If this regimen fails, I gm/70 kg calcium chloride may be given in divided doses, with careful ECG monitoring. If these two efforts still fail to produce antagonism, ventilatory assistance should be continued until the neuromuscular blockade spontaneously terminates. Conclusions Until such time as a short-acting, nondepolariz- ing mscle relaxant is availab~le, the anesthetist must antagonize thle long-acting, nondepolarizing drugs. The antagotnit cormpond wrhich is most effective and h~as t~e least side effects is a mixtre of edrophon im, pyridostigmine and glycopyrrolate. The effectiveness of the antagonism is best seen in the return of adeqate hand grip and the patient's ability to lift hiis or her head. Both of these measres of nelromuscullar blockade correspond withi the adeqacy of respiratory function. October/1 9804 If a reasonable attempt to restore normal function of the neuromuscular junction fails, ventilatory support should be continued. There is no report of permanent paralysis from the curariform group of drugs. In the well-oxygenated patient, the tincture of time will antagonize the most stubborn of neuromuscular blocks. REFERENCES (1) Guyton, A. 1976. Textbook of Medical Physiology, 5th Ed., Saunders, Philadelphia. p. 1194. (2) Modell, W., Schild, H. and Wilson, A. 1976. Applied Pharmacology (American Edition), 11th Ed. Saunders, Philadelphia. p. 925. (3) Dripps, R., Eckenhoff, J. and Vandam, 1977. Introduction to Anesthesia: Principles of Safe Practice, 5th Ed., Saunders, Philadelphia. p. 557. (4) Goodman, L. and Gilman, A. 1975. The Pharmacological Basis of Therapeutics. 5th Ed. MacMillan. New York. (5) Collins, V. 1976. Principles of Anesthesiology. 2nd Ed., I.ea and Febiger, Philadelphia. p. 1671. (6) Randall, L. and Lehmann, G. 1950. Pharmacological Properties of Neostigmine Analogues. J. Pharmac. Exp. Ther. 99:16. (7) Katz, R. 1967. Neuromuscular Effects of d-Tuhocurarine, Edrophonium and Neostigmine in Man. Anesthesiology. 28(2): 327-335. (8) Artusio, j., Marbury, B. and Crews, M. 1951. A Quantitative Study of d-Tubocurarine, (Tri Diethyl Aniinoethoxy) 1, 2, 3, Lenzent (Flaxidil) and a Series of Tri-methyl and Dimethylethyl-ammonium Compounds in Anesthetized Man. Ann. N.Y. Acad. Sci. 54: 512-518. (9) Doughty, A. and Wylie, W. 1952. Antidotes of "True" Curarizing Agents. Brit. J. Anaesth. 24: 66. (10) Wylie, W. and Churchill-Davidson, H. 1972. A Practice of Anaesthesia. 3rd Ed. Yearbook Medical Publishers. (11) Folds, F. 1960. rhe Pharmacology of Neuromuscular Blocking Agents in Man. Clin. Pharmacol. Ther. 1: 345. (12) Smith, C., Mead, j. and tinna, K. 1957. Antagonism of Tubocuranine 111: Tine Course of Action of Pyridostigmine, Neostigmine and Edrophonium in Viva and in Vitro. J. Pharnacologv Ex p. T/ier. 1: 200-215. (13) Blitt, C., Moon, B. and Kartchner, D. 1976. Duration of Action of Neostigmine in Man. Canadian Anaesthesiology Society Jourall. 23 (1) : 80-84. (14) Miller, R., Larson, C. and Way, W. 1972. Comparative Antagonism of cl-Tubocurarine-, Gallamine-, and Pancuroniuminduced Neuronuscular Blockades by Neostigmine. Anest hesiology. 37: 503-509. 15) Katz. R. 1967. Pyridostigmine (Mestinon®) as an Antagonist of Anesthesiology. 28: 528-534. (16) Gvyermek, 1.. 1977. Clinical Pharmacology of the Reversal of Neuromuscular Block. International Journal of Clinical Pharrncolov. : 356-362. (17) Winnie, A., Mahor, R., Shaker, M. and Samayaji, R. 1977. Pyridostigm nrc for Reversal. A nest hsiloy JReiec. October: 16-24. (1) Phyvsiinrs' D~sk Referenrc. 1977. Medlical Economics Company. Oraell, New j-rsey. (19)) I.og~o, V. 1966. Behlavioral andi Electrocncephalorahic Effects of Ano~ie andl Related Compounds. Phrnacol Rev. 1: 96T-91. (20) Mirakhlr, R.. Dundec, J. andi Clark, R. 1977. Glycopyrrolate-Nost Kigine Mixtire for Antagonism of Nourouscular lockaec: Comparisln with Atropine-Neostimine Mlixture. lnrt. . Atnaesth. 49: 8325. (21) crmelk, I.. 1978il. 'Ihe Glycopyrrolat-Pyiost igmine Comnationl. A cstesiology Revie. March: 19-22. .. (-Iulbocurarine. 459 Rosner, V., Kepes, E. and Foldes, F. 1971. The Effects of Neostigmine on Heart Rate and Rhythm. Brit. (22) (38) Hughes, R. Balance on Neuromuscular 1. Anaesth. 43: 1066. 42: 658-668. (39) McKlveen, (23) Ovassapian, A. 1969. Effects of Administration of Atropine and Neostigmine in Man. Anesth. Analg. 48: 219-223. (24) Bell, C. and Lewis. C. 1968. Effects of Neostigmine on Integrity of Ileorectal Anastomosis Brit. Med. J. (25) son, Klingenmaier. R. Mixture 1972. R., Thompson, D. and WatBlockade with a Neuromuscular H., Bullard, Reversal of Neostigmine of and Glycopyrrolate. Anesthesia and 1973. (26) Ramamurthy, S., Shaker, M. and Winnie, A. 1972. Glycopyrrolate as a Substitute for Atropine in Neostigmine Reversal of Muscle Relaxant Drugs. Canadian Anaesthesiology So- Jr., Blockade Sokol, M., Absence of Recurarization in Gergis, Upon Acid-base Cats. Brit. J. S. and Anaesth. Dretchen, Rewarming. K. Anesthesi- ology. 38: 153-156. (40) Miller, R. and Cullen, D. 1976. Renal Failure and Postoperative Respiratory Failure: Recurarization? Brit. J. Anaesth. 48: 253-256. (41) Pittinger, C., Eryasa, Y. and Adamson, R. 1970. Antibiotic Paralysis. Anesthesia and Analgesia. 49: 487-501. Induced Analgesia. 51(3) : 468.472. Influence of Changes in 1970. The Atropine and (42) Becker, L. and Miller, R. Nondepolarizing Neuromuscular 1975. Clindamycin Enhances a Blockade. Abstract of Scientific Papers. 1975. Annual Meeting of the A.S.A. 203-204. ciety Journal. 19(4): 399-411. (27) Ostheimer, G. 1977. A Comparison of Glycopyrrolate and Atropine During Reversal of Nondepolarizing Neuromuscular Block with Neostigmine. Anesthesia and Analgesia. 56(2): 182- ACKNOWLEDGMENT 186. as a (28) Zsigmond, E. 1972. Pyridostigmine: A Safe and Effective Anesthetized Man. Clinical Antagonist to d-Tubocurarine in Pharmacology and Therapeutics. 13 (1): 155.156. The author wishes to thank Thomas Irving, M.D., for his and assistance; Charles Gregg, MI). for his assistance support technical proof reader; Toni Brock, CRNA, for her photography; and Gail Jenkins, grammatical proofreader, typist and wife. (29) Miller, R., Van Nyhuis, L., Eger, E., Vietz, T. and Way, W. 1974. Comparative Times to Peak Effect and Duration of Action of Neostigmine and Pyridostigmine. Anesthesiology. 41(1): 27-33. (30) Gyermek, L. 1975. Clinical Studies in Reversal of the Neuromuscular Blockade Produced by Parcuronium Bromide. I. The Effects of Glycopyrrolate and Pyridostigmine. Current Therapeutic Research. 18 (3): 377-385. (31) WaIts, L., Levine, N. and Dillon, J. 1970. Assessment of Recovery from Curare. JAMA 213: 1894-1896. (32) Perotti, J. 1977. A Review of d-Tubocurarine in Clinical Usage. AANA Journal 45 (2): 182-185. (33) Ali, H., Wilson, R., Savarese, J. and Kitz, R. 1975. The Effects of Tubocurarine on Indirectly Elicited Train-of-Four Muscle Response and Respiratory Measurements in Humans. I) Brit. J. Anaesth. 47: 570-573. (34) Wand, B. and Wand, D. 1972. The Relationship Between the Response to "Train-of-Four" Stimulation and Receptor Occlusion during Competitive ology. 37: 413-416. Neuromuscular Block. Anesthesi- (35) Miller, R. 1976. Antagonism of Neuromuscular Blockade. Anesthesiology. 44 (4) : 318-328. (36) Gissen, A. and Katz, R. 1969. Twitch, Tetanus, and Posttetanic Potentiation as Indices of Nerve Muscle Block in Man. Anesthesiology. 30: 481-487. (37) Miller, R., Van Nyhuis, L., Eger, E. and Way, W. 1975. Effects of Acid-base Balance on Neostigmine Antagonism d -Tubocurarine-induced Neuromuscular Blockade. Anesthe- The of siology. 42: 377-383. AUTHOR Ton Jenkins, CRNA, holds an Associate Degree in Applied Science (Nursing) from Pitt Technical Institute in Greenville, North Carolina. He is a recent gradIuate of the Bowman Gray School of Medicine of Wake Forest University and North Carolina Baptist Hospital School of Nurse Anesthesia, and is cur- rently practicing in North Carolina. 'Ihis paper was researched when Mr. Jenkins was a senior student in anesthesia; it was sulbnitted at the recommendation of Sandra M. Maree, CRNA, BS, assistant director of the North Carolina Baptist Hospital School of Nurse Anesthesia. Journal of the American Association of Nurse Anesthetists We've just ,improved your esophageal stethoscope... ~,1~111~ ae r' 4 _ I I - -- - - - - - ~ -~ I - - - ~- I I InnOVar®Injection 1* FOR INTRAVENOUS OR INTRAMUSCULAR USE ONLY The two components of INNOVAR injection, fentanyl and droperidol, have different pharmacologic actions. Before administering INNOVAR injection, the user should familiarize himself with the special properties of each drug. particularly the widely differing durations of action. DESCRIPTION: Each ml. contains (in a 1:50 ratio): Fentanyl ............. ........ ........... .................... ............... 0.05 mg. as the citrate Warning: May be habit forming Droperidol ... . ................................................................ ............. 2.5 mg. Lactic acid for adjustment of pH to 3.5 ± 0.3 ACTIONS: INNOVAR injection is a combination drug containing a narcotic analgesic, fentanyl, and a neuroleptic (major tranquilizer), droperidol. The combined effect, sometimes referred to as neuroleptanalgesia, is characterized by general quiescence, reduced motor activity, and profound analgesia; complete loss of consciousness usually does not occur from use of INNOVAR injection alone. The incidence of early postoperative pain and emesis may be reduced. A. Fentanyl is a narcotic analgesic with actions qualitatively similar to those of morphine and meperidine. Fentanyl in a dose ofO. 1 mg. (2.0 ml.) is approximately equivalent in analgesic activity to 10 mg. of morphine or 75 mg. of meperidine. The principal actions of therapeutic value are analgesia and sedation. Alterations in respiratory rate and alveolar ventilation, associated with narcotic analgesics, may last longer than the analgesic effect. As thedose of narcotic is increased, the decrease in pulmonary exchange becomes greater. Large doses may produce apnea. Fentanyl appears to have less emetic activity than other narcotic analgesics.Histamineassays,and skin wheal testing in man, as well as in viv testing in dogs indicate that histamine release rarely occurs with fentanyl. Fentanyl may cause muscle rigidity, particularly involving the muscles of respiration.It may also produce other signsand symptoms characteristic of narcotic analgesicsincluding euphoria, miosis, bradycardia, and bronchoconstriction. The onset of action of fentanyl is almost immediate when the drug is given intravenously; however, maximal analgesic and respiratory depressant effect may not be noted for several minutes. The usual duration of action of the analgesic effect is 30 to 60 minutes fter a single I. V. dose of up to 0.1 mg. Following intramuscularadministration, the onset of action is from seven to eight minutes, and the duration of action is from one to two hours. As with longer-acting narcotic analgesics, the duration of the respiratory depressant effect of SUBLIMAZE (fentanyl) may be longer than the analgesic effect. The following observations have been reported concerning altered respiratory response to CO stimulation following administration of fentanyl to man: I. DIMINISHED SENSITIVITY TO CO STIMULATION MAY PERSIST LONGER THAN DEPRESSION OF RESPIRATORY RATE. Fentanyl frequently slows the respiratory rate but this effect is seldomnoted for over 30 minutes regardlessof the dose administered. 2. Duration and degree of respiratory depression is dose related. 3. The peak respiratory depressant effect of a single intravenous dose of fentanyl is noted 5 to 15 minutes following injection. 4. Altered sensitivity to CO stimulation has been demonstrated for up to four hours following a single intravenousdose of 0.6 mg. (12 ml.) fentanylto healthy volunteers. Seealso WARNINGS and PRECAUTIONS concerning respiratory depression. B. Droperidol producesmarked tranquilization and sedation. It also produces an antiemetic effect as evidenced by the antagonismof apomorphine in dogs. It potentiates other CNS depressants. It also produces mild alpha-adrenergic blockade, peripheral vascular dilatation and reduction of the pressor effect of epinephrine. Droperidol can produce hypotension and decreased peripheral vascular resistance. It may decrease pulmonary arterial pressure (particularly if it is abnormally high). It may reduce the incidence of epinephrine-induced arrhythmias bu t does not prevent other cardiac arrhythmias. The onset of action is from three to ten minutes following intravenous or intramuscular administration. The full effect, however, may not be apparentfor 30 minutes. The duration of the sedative and tranquilizing effects generally is two to four hours. Alteration of consciousness may persist as long as 12 hours. This is in contrast to the much shorter duration of fentanyl. INDICATIONS: INNOVAR injection is indicated to produce tranquilization and analgesia for surgical and diagnosticprocedures. It may be used as an anestheticpremedication, for the induction of anesthesia., and as an adjunct in the maintenanceof general and regional anesthesia. If the supplementation of analgesia is necessary, SUBLIMAZEa (fentanyl) injection alone rather than the combination drug INNOVAR injection, shouldusually be used; see Dosage and AdministrationSection. CONTRAINDICATIONS: INNOVAR injection is contraindicated in patients with known intolerance to either component. WARNINGS: AS WITH OTHER CN6 DEPRESSANTS, PATIENTS WHO HAVE RECEIVED INNOVAR INJECTION SHOULD HAVE APPROPRIATE SURVEILLANCE. RESUSCITATIVE EQUIPMENT AND A NARCOTIC ANTAGONIST SHOULD BE READILY AVAILABLE TO MANAGE APNEA. See also discussionof narcoticantagonistsin PRECAUTIONS and OVERDOSAGE. FLUIDS AND OTHER COUNTERMEASURES TO MANAGE HYPOTENSION SHOULD ALSO BE AVAILABLE. The respiratory depressant effect of narcotics persists longer than the measured analgesic effect. When used with INNOVAR injection, the total dose of all narcotic analgesics administered should be considered by the practitioner before ordering narcotic analgesics during recovery from anesthesia. It is recommended that narcotics, when required, be used in reduced doses initially, as low as (4 to A those usually recommended. INNOVAR injection may cause muscle rigidits, particularly involving the muscles of respiration. This effect is due to the fentanyl component and is related to the speed of injection. Its incidence can be reduced hy the use of slow intravenous injection. Once the effect occurs, it is managed by the use of assisted or controlled respiration and, if necessary, by a neuromuscular blocking agent compatible with the patient's condition. Drug Dependence: Fentanyl, the narcotic analgesic component, can produce drug dependenceof the morphine type and therefore has the potentialfor being abused. Severe and unpredictable potentiation by-MAO inhibitors has been reported with narcotic analgesics. Since the safety of fentanyl in this regard has not been established, the use of INNOVAR injection or SUBLIMAZE (fentanyl) in patients who have received MAO inhibitors within 14 days is not recommended. Head Injurls and Increased Intrracenial Pressure: INNOVAR injection should be used with caution in patients who may be particularly susceptible to respiratory depression such as comatose patients who may have a head injury or brain tumor. In addition, INNOVAR injection may obscure the clinical course of patients with head injury. Usage in Children: The safety of INNOVAR injection in children younger than two years of age has not been established. Usage Ia Prgnancy: The safeuseof INNOVAR injection hasnot beenestablished with respectto possible adverse effects uponfetal development. Therefore,it should be usedin womenof childbearing potential only when,in the judgment of the physician, the potential benefits outweigh the possible hazards. Thereareinsufficient dataregarding placentaltransferandfetaleffects; therefore,safety for the infant in obstetrics hasnot been established. PRECAUTIONS: Theinitial doseof INNOVAR injection should be appropriately reducedIn elderly, debilitated and other poor-risk patients. Theeffectof theinitial doseshould be considered in determining incremental doses. Certainforms of conduction anesthesia, such asspinal anesthesia andsomeperidural anesthetics, can alter respiration by blocking intercostalnerves,andcancauseperipheral vasodilation andhypotension because of sympathetic blockade. Through othermechanisms (seeActions), fentanyl anddroperidol also depress respiration andblood pressure. Therefore,whenINNOVAR injection is usedto supplement these forms of anesthesia, the anesthetist mustbe familiar with the physiological alterations involved, and be prepared to managethemin thepatientsselectedfor this form of anesthesia. If hypotension occurs, the possibility of hypovolemia should be considered andmanagedwith appropriate parenteral fluid therapy.Repositioning the patientto improve venousreturn to the heartshould be considered whenoperative conditions permit. It should be notedthatin spinal and peridural anesthesia, tilting the patientinto a headdown position etun mayresult a higher level iofthemovng anesthesia than as nd isndesirable. psitonigso execisd houdin h ipai vesasCre wedstosheheat. well as impair venous return to the heart. Care should be exercised in the moving and positioning of patients because of a possibility of orthostatic hypotension. If volume expansion with fluids plus these other countermeasuresdo not correctthe hypotension, then the administration of pressor agents other than epinephrine should be considered. Epinephrine may paradoxically decrease the blood pressurein patientstreated with INNOVAR injection due to the alpha-adrenergic blocking action of droperidol. The droperidol component of INNOVAR injection may decrease pulmonary arterial pressure. This fact should be consideredby those who conduct diagnosticor surgicalprocedureswhere interpretationof pulmonary arterial pressure measurementsmight determinefinal managementof the patient. Vital signsshouldbe monitored routinely. INNOVAR injection, and SUBLIMAZE (fentanyl), should be used with caution in patientswith chronic obstructive pulmonary disease, patients with decreased respiratory reserve, and others with potentially compromised ventilation. In such patients narcotics may additionally decrease respiratory drive and increaseairway resistance.During anesthesiathis can be managedby assistedor controlled respiration. Postoperativerespiratory depression causedby narcotic analgesics can be reversed by narcotic antagonists. Appropriate surveillance should be maintained because the duration of respiratory depression of doses of fentanyl (asSUBLIMA ZE (fentanyl) or INNOVAR) employed during anesthesia may be longer than the duration of the narcotic antagonist action. Consult individual prescribing information (levallorphan. nalorphine and naloxone) before employing narcotic antagonists. Should respiration be compromised by muscle rigidity, assistedor controlled respiration and possibly a neuromuscular blocking agent will be required. The occurrenceof muscle rigidity is related to the speed of intravenousinjection and the incidence can be reducedby slow intravenousinjection, Other CNS depressantdrugs (e.g. barbiturates, tranquilizers, narcotics, and general anesthetics)have additive or potentiating effects with INNOVAR injection. When patients have received such drugs, the dose of INNOVAR injection required will be less than usual. Likewise, following the administration of INNOVAR injection, the dose of other CNS depressantdrugsshould be reduced. INNOVAR injection should be administeredwith caution to patients with liver and kidney dysfunction because of the importance of these organs in the metabolism and excretion of drugs. The fentanyl component may produce bradycardia, which may be treated with atropine; however, INNOVAR injection should be used with caution in patients with cardiac bradyarrhythmias. When the EEG is used for postoperative monitoring, it may be found that the EEG patternreturnsto normal slowly. ADVERSE REACTIONS: The most common serious adverse reactions reported to occur with INNOVAR injection are respiratory depression, apnes, muscular rigidity, and hypotension; if these remain untreated, respiratoryarrest, circulatory depression orcardiac arrestcould occur. Extrapyramidal symptoms (dystonia, akathisia, and oculogyric crisis) have been observed following administration of INNOVAR injection. Restlessness, hyperactivity and anxiety which can be either the result of inadequate tranquilization or part of the symptom complex of akathisia may occur. When extrapyramidal symptomsoccur, they can usuallybe controlled with anti-Parkinson agents. Elevated blood pressure, with and without preexisting hypertension, has been reported following administration of INNOVAR injection. This might be due to unexplained alterationsof sympathetic activity following large doses; however, it is also frequently attributed to anesthetic or surgical stimulation during light anesthesia. Other adversereactionsthat have been reported are dizziness, chills and/or shivering, twitching, blurred vision, laryngospasm, bronchospasm, bradycardia, tachycardia, nausea and emesis. diaphoresis. emergence delirium, and postoperative hallucinatory episodes (sometimes associated with transient periodsof mentaldepression). Postoperativedrowsiness is alsofrequently reported. DOSAGE AND ADMINISTRATION: Dosage should be individuali:ed. Some of the factors to be considered in determining dose are age, body weight, physicalstatus, underlying pathological condition, use of other drugs, the type of anesthesia to be used. and the surgical procedureinvolved. Vital signs shouldbe monitored routinely. Most patients who have received INNOVAR injection do not require narcotic analgesics during the immediate postoperativeperiod. It is recommendedthat narcotic analgesics, when required, be used initially in reduced doses, as low as '4 to ' those usuallyrecommended. Usual Adult Dosage: I. Premedication--(o be appropriately modified in the elderly, dbilitated, and those who have received other depressantdrugs)-0. 5 to 2.0 ml. may be administeredintramuscularly 45 to 60 minutes prior to surgerywith or without atropine. II. Adjunct to General Anesthesia-Induction-I ml. per 20 to 25 pounds of btody weightmay be administered slowly intravenously.Smaller doses may be adequate. The total amount of INNOVAR injection administeredshould be carefully titrated to obtain the desired effect basedon the individual patient's response. There are severalmethods of administration of INNOVAR injection for induction of anesthesia. A. Intravenous injection-To allow for the variable needs of patients INNOVAR injection may he administered intravenously in fractional pu.ts of the calculated dose. With the onset of somnolence, the general anesthetic may be administered. B. Intravenousdrip-10 ml. of INNOVAR injection are added to 250 ml, of 5% dextrose in water and the drip given rapidly until the onset of somnolence At that time, the drip may be either slowed or stopped and the general anesthetic administered. Maintenance-INNOVAR injection is not indicated as the sole agent for the maintenance of surgical anesthesia It is customarily used in combination with other measuressuch as nitrous oxide-oxygen. other inhalation anesthetics,and/or topicalor regionalanesthesia. To prevent the possibility of excessive accumulationof the relatively long-actingdroperidol component, SUBLIMAZE (fentanyl) aloneshould be used in increments of 0.025 to 0.05 mg. (0.5 to I.0 ml.) for the maintenanceof analgesia in patients initially given INNOVAR injection as an adjunct to general anesthesia. (See SUBLIMAZE (fentanyl) package insert for additional prescribing information.) However, in prolonged operations, additional 0,5 to 1.0 ml amounts of INNOVAR injection may be administered with caution intravenously if changesin the patient'scondition indicate lightening of tranquilization and analgesia. III. Use Without a General Anesthetic in Diagnostic Procedures-Administer the usual I.M. premedication (0.5 to 2.0 ml.) 45 to 60 minutes before the procedure. Tb prevent the possibility of excessive accumulation of the relatively long-acting droperidol component, SUBLIMAZE (fentanyl) aloneshould be used in increments of 0.025 to 0.05 mg. (0.5 to 1.0 mi.) for the maintenance of analgesia in patients initially given INNOVAR injection. (See SUBLIMAZE (fentanyl) packageinsert for additional information). However, in prolonged operations, additional 0.5 to 1.0 ml. amounts of INNOVAR injection may be administeredwith caution intravenously if changes in the patient's condition indicate lightening of tranquilization and analgesia. Note: When INNOVAR injection is used in certain proceduressuch as bronchoscopy,appropriate topical anesthesiais still necessary. IV. Adjunct to Regional Anesthesia-I to 2 ml. may be administered intramuscularly or slowly intravenouslywhen additional sedationand analgesia are required. Usual Children's Desage: I. Premedication---O25 ml. per 20 Ibs. body weight administeredintrunuscularli 45 to 60 minutes prior to surgery with or without atropine. II. Adjunct to General Anesthesia-The total combined dosefor induction andmaintenance averages0 5 ml. per 20 Ibs. bodyweight. Following induction with INNOVAR injection, SUBLIMAZE (fentanyl) alonein a doseof (, to A that recommended in the adult dosagesectionshould usually be usedwhen indicated to avoid thepossibility of excessiveaccumulation of droperidol. However, in prolonged operations, additional increments of INNOVAR injection may be administered with caution when changesin the patient's condition indicate lightening of tranquilization andanalgesia. See Warnings and Precautionsfor use of INNOVAR injection with other CNS depressants,and in patientswith alteredresponse. OVERDOSAGE: Manlfestations: Themanifestations of INNOVAR injection overdosagearean extension of its pharmacologic actions. Treatment: In the presenceof hypoventilation or apnea,oxygen shouldbe administered and respiraion should be assistedor controlled as indicated. A patentairway mustbe maintained; an oropharyngeal airway or endotrachealtube might be indicated. If depressedrespiration is associatedwith muscular rigidity, an intravenous neuromuscular blocking agentmight be required to facilitate assistedor controlled respiration. The patient should be carefully observedfor 24 hours; bodywarmth and adequate fluid intake should be maintained. If hypotension occurs and is severe or persists,the possibility of hypovolemia should be considered andmanaged with appropriate parenteral fluid therapy. A specific narcotic antagonistsuchas nalorphine. levallorphan or naloxone should he available for useas indicated to manage respiratory depression causedby the narcotic component fentanyl. This doesnot preclude the use of more immediate counter-measures. The duration of respiratory depression following overdose of tentanyl may he longer than the duration of narcotic antagonist action. Consult the packageinsertsof the individual narcotic antagonists for details aboutuse. ® HOW SUPPLIED: INNOVAR injection is supplied in 2 ml. and5 ml.ampuls, in packages of 10. U.S. PatentNo. 3,141,823 Rev. 1/80 Sublimznaz (fentanyl) injection ~R DESCRIPTION: Each mi. contains: Fentanyl ............................................................ 0.05 mg as the citrate Warning: May be habit forming. Sodium hydroxide for adjustment of pH to 4.0-7.5. FOR INTRAVENOUS OR INTRAMUSCULAR USE ONLY ACTIONS: SUBLIMAZE (fentanyl) is a narcotic analgesic with actionsqualitatively similar to those of morphine and meperidine. SUBLIMAZE (fentanyl) in a dose of 0.1 mg. (2.0 ml.) is approximately equivalent in analgesic activity to 10 mg. of morphine or 75 mg. of meperidine. The principal actionsof therapeutic value are analgesia and sedation. Alterations in respiratory rate and alveolar ventilation, associatedwith narcotic analgesics, may last longer than the analgesiceffect. As the dose of narcotic is increased, the decrease in pulmonary exchange becomes greater. Large doses may produce apnea. SUBLIMAZE (fentanyl) appears to have less emetic activity than other narcotic analgesics. Histamine assays and skinwheal testing in man, as well as in in vivo testing in dogs, indicatethat histaminerelease rarely occurs with SUBLIMAZE (fentanyl). SUBLIMAZE (fentanyl) may cause muscle rigidity, particularly involving the musclesof respiration. It may also produce other signs and symptomscharacteristic of narcotic analgesics including euphoria., miosis, bradycardia, and bronchoconstriction. The onset of action of SUBLIMAZE (fentanyl) is almost immediate when the drug is given intravenously; however, the maximal analgesicand respiratory depressant effect may not be noted for several minutes. The usual durationof action of the analgesic effect is 30 to 60 minutes after a single I.V. dose of up to 0. I mg. Following intramuscularadministration, the onset of action is from seve to eight minutes, and the durationof action is oneto two hours. As with longer acting narcotic analgesics,the durationof the respiratory depressanteffect of SUBLIMAZE (fentanyl) may be longer than the analgesic effect. The following observationshave been reported concerningaltered respiratory response to COs stimulation following administrationof fentanyl to man: I. DIMINISHED SENSITIVITY TO COs STIMULATION MAY PERSIST LONGER THAN DEPRESSION OF RESPIRATORY RATE. Fentanyl frequently slows the respiratory rate, but this effect is seldom noted for over 30 minutesregardlessof the dose administered. 2. Duration anddegree of respiratory depressionis dose related. 3 The peak respiratory depressanteffect of a single intravenousdose of fentanyl is noted 5 to 15 minutes following injection. 4. Altered sensitivity to COs stimulation has been demonstratedfor up to four hoursfollowing a single intravenousdose of 0.6 mg. (12 ml.) fentanylto healthy volunteers. See also WARNINGS and PRECAUTIONS concerningrespiratory depression. INDICATIONS: SUBLIMAZE (fentanyl) is indicated: -for analgesic action of short duration during the anesthetic periods, premedication, induction, and maintenance,and in the immediate post-operativeperiod (recovery room) as the need arises. - for use as a narcoticanalgesicsupplementin general or regional anesthesia. -for administration with a neuroleptic such as INAPSINE (droperidol) injection as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia. CONTRAINDICATIONS: SUBLIMAZE (fentanyl) is contraindicatedin patientswith known intoleranceto the drug. WARNINGS: AS WITH OTHER CNS DEPRESSANTS, PATIENTS WHO HAVE RECEIVED SUBLIMAZE (FENTANYL) SHOULD HAVE APPROPRIATE SURVEILLANCE. RESUSCITATIVE EQUIPMENT AND A NARCOTIC ANTAGONIST SHOULD BE READILY AVAILABLE TO MANAGE APNEA. See also discussionof narcotic antagonistsin Precautionsand Overdosage. If SUBLIMAZE (fentanyl) is administeredwith a tranquilizer such as INAPSINE (droperidol), the user should familiarize himself with the specialproperties of each drug, particularly the widely differing durations of action. In addition, when such a combination is used fluids and other countermeasures to manage hypotension should be available. As with other potent narrotics. the respiratory depressant effect of SUBLIMA ZE (fentanyl) persists longer than the measured analgesic effect. The total dose of all narcotic analgesics administered should he considered hv the practitioner before onlering narcotic analgesics during recover /fromn anesthesia. It is recommended that narcotics, when required, should he used in reduced doses initially,as low as 'i to 'A those usually recommended. SUBLIMAZE (fentanyl) may cause muscle rigidity, particularly involving the muscles of respiration. The effect is related to the speed of injection and its incidencecan be reduced by the use of slow intravenousinjection. Once the effect occurs, it is managed by the use of assisted or controlled respiration and, if necessary,by a neuromuscularblocking agent compatible with the patient'scondition. Dru Depeadence: SUBLIMAZE (fentanyl) can produce drug dependenceof the morphine type and therefore has the potential for being abused. Severe and unpredictable potentiation by MAO inhibitors has been reported with narcotic analgesics. Since the safetyof fentanyl in thisregard has not been established, the use of SUBLIMAZE (fentanyl) in patientswho have received MAO inhibitors within 14days is not recommended. Head Ijuaries and lacreased InlacranialPressure: SUBLIMAZE (fentanyl) should be used with caution in patientswho may be particularly susceptibleto respiratorydepression,such as comatose patients who may have a head injury or brain tumor. In addition. SUBLIMAZE (fentanyl) may obscure the clinical courseof patientswith head injury. Usage in Chldren: The safety of SUBLIMAZE (fentanyl) in children younger than two years of age has not been established. Usage n Pregnancy: The safe use of SUBLIMAZE (fentanyl) has not been established with respect to possibleadverseeffects upon fetal development. Therefore, it should be used in women of childbearing potential only when, in the judgment of the physician, the potential benefits outweigh the possible hazards. There are insufficient data regarding placental transfer and fetal effects; therefore, safety for the infant in obstetricshas not been established. PRECAUTIONS: The initial dose of SUBLIMAZE (fentanyl) should be appropriately reduced in elderly, debilitated and other poor-risk patients. The effect of the initial dose should be considered in determining incremental doses. Certain forms of conductionanesthesia,such as spinal anesthesiaand some peridural anesthetics, can alter respiration by blocking intercostalnerves. Through other mechanisms(seeActions) SUBLIMAZE (fentanyl) can also alter respiration. Therefore, when SUBLIMAZE (fentanyl) is used to supplement these forms of anesthesia,the anesthetistshouldbe familiar with the physiological alterations involved, and be prepared to manage them in the patientsselectedfor theseforms of anesthesia. When used with a tranquilizer such as INAPSINE (dropendol), blood pressure maybe altered andhypotension can occur. Vital signsshould be monitored routinely. SUBLIMAZE (fentanyl) should be used with caution in patients with chronic obstructive pulmonary disease, patients with decreased respiratory reserve, and others with potentially compromised respiration. In such patients, narcotics may additionally decrease respiratory drive and increase airway resistance. During anesthesia, this can be managed by assisted or controlled respiration. Respiratory depressioncausedby narcotic analgesicscan be reversedby narcotic antagonsts. Appropriate surveillance should be maintained becausethe duration of respiratory depressionof dosesof fentanyl employed during anesthesia may be longer than theduration of the narcotic antagonist action. Consult individual prescribing information (levallorphan, nalorphine and naloxone)before employing narcotic antagonists Whena tranquilizer suchas INAPSINE (droperidol) is usedwith SUBLIMAZE (fentanyl), pulmonary arterial pressure maybe decreased. This fact shouldbe considered by thosewho conduct diagnostic and surgical procedures whereinterpretation of pulmonary arterial pressuremeasurements might determine final management of thepatient. Other CNS depressant drugs (e.g. barbiturates,tranquilizers, narcotics, andgeneral anesthetics)will haveadditive or potentiating effects with SUBLIMAZE (fentanyl). When pataents havereceived such drugs, the doseof SUBLIMAZE (fentanyl) required will be less than usual.Likewise, following the administration of SUBLIMAZE (fentanyl), thedoseof other CNSdepressant drugs should be reduced. SUBLIMAZE (fentanyl) should be administered with caution to patientswith liver andkidney dysfunction because of the importance of theseorgansin themetabolism andexcretion of drugs. SUBLIMAZE (fentanyl) may producebradycardia,which may be treatedwith atropine; however, SUBLIMAZE (fentanyl) should be usedwith caution in patientswith cardiac bradyarrhythmias. WhenSUBLIMAZE (fentanyl) is usedwith a tranquilizer such as INAPSINE (droperidol), hypotension can occur. If this occurs, the possibility of hypovolemia should be considered andmanaged with appropriateparenteralfluid therapy. Repositioning thepatientto improve venousreturnto the heartshould be considered when operative conditions permit. Care should he exercised in moving and positioning of patients becauseof the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, the administration of pressor agents other than epinephrine should be considered. Because of the alpha-adrenergic blocking action of INAPSINE (droperidol), epinephrine may paradoxically decrease the blood pressurein patients treated with INAPSINE (droperidoll When INAPSINE (droperidol) is used with SUBLIMAZE (fentanyl) andthe EEG is used for postoperative monitoring, it may be foundthat the EEG patternreturns to normal slowly. ADVERSE REACTIONS: As with other narcotic analgesics,the most common serious adverse reactions reported to occur with SUBLIMAZE (fentanyl) are respiratory depression,apnea, muscular rigidity, and bradycardia;if these remain untreated, respiratory arrest,circulatory depressionor cardiac arrest could occur. Other adversereactions that have been reported are hypotension, dizziness, blurred vision, nausea, emesis, laryngospasm, anddiaphoresis. When a tranquilizer such as INAPSINE (droperidol) is used with SUBLIMAZE (fentanyl), the following adverse reactions can occur: chills and/or shivering, restlessness, and postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression); extrapyramidal symptoms (dystonia, akathisia, and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptomscan usually be controlled.with anti-parkinson agents. Postoperative drowsinessis also frequently reported following the use of INAPSINE (droperidol). Elevated blood pressure, with and without preexisting hypertension, has been reported following administration of SUBLIMAZE (fentanyl) combined with INAPSINE (droperidol). This might be due to unexplained alterations in sympathetic activity following large doses; however, it is aho frequently attributedto anesthetic andsurgical stimulation during light anesthesia. DOSAGE AND ADMINISTRATION: Dosage should be individualized. Some of the factors to be considered in determining the dose are age, body weight, physicalstatus, underlying pathological condition, use of other drugs, type of anesthesia to be used, andthe surgical procedure involved. Vital signsshouldbe monitored routinely. UssulAdulDosaye: I. Premedication (to be appropriately modified in the elderly, debilitated, and those who have received other depressant drugs)-0.05 to 0.1 mg. (I to 2 ml.) may be administeredintramuscularly 30 to 60 minutes prior to surgery. II. Adjunct to General Anesthesia Induction-0.05 to 0.1I mg. (I to 2 ml.) may be administered initially intravenously and may be repeated at 2 to 3 minute intervals until desired effect is achieved. A reduced dose as low as 0.025 to 0.05 mg. (0.5 to I ml.) is recommendedin elderly and poor-risk patients. Maintenance-0.025 to 0.05 mg. (0.5 to I ml.) may be administered intravenously or intramuscularly when movement and/or changesin vital signsindicate surgical stressor lighteningof analgesia. If INNO VAR injection is administered in addition to SUBLIMAZE (fentanyl). the calculation of the recommendeddose of SUBLIMAZE (fentanyl) should include the fentanyl contained in the INNO VAR injection. SeeINNO VAR injection Package Insert for full prescribinginformation. III. Adjunct to Regional Anesthesia-O.05 to 0.1 mg. (I to 2 ml.) may be administered intramuscularly or slowly intravenouslywhen additional analgesia is required. IV. Postoperaively (recovery room)-0.0S to 0. mg. (I to 2 ml.) may be administered intramuscularly for the control of pain, tachypnea andemergence delirium. The dose may be repeated in one to two hours as needed. Usual Children's Do : For induction andmaintenance in children two to 12 years of age, a reduced dose as low as 0.02 to 0.03 mg. (0.4to 0.6 ml.) per 20 to 25 pounds isrecommended. See W rnings and Precautions for use of SUBLIMAZE (fentanyl) with other CNS depressants, and In patients with altered response. OVERDOSAGE: Mas tatdions: The manifestationsof SUBLIMAZE (fentanyl) overdosage are an extension of its pharmacologic actions. Treatumes: In the presence of hypoventilation or apnea, oxygen should be administeredand respiration should be assistedor controlled as indicated. A patent airway must be maintained; an oropharyngeal airway or endotracheal tube might be indicated. If depressedrespiration is associated with muscular rigidity, an intravenous neuromuscular blocking agent might be required to facilitate assistedor controlled respiration. The patient should be carefully observed for 24 hours; body warmth and adequate fluid intake should be maintained. If hypotension occurs and is severe or persists, the possibility of hypovolemia shouldbe considered and managed with appropriate paenteral fluid therapy. A specific narcotic antagonistsuch as nalorphine, levallorphan, or naloxone should be available for use as indicated to managerespiratory depression.This does not preclude the use of more immediate countermeasures.The duration of respiratorydepression following overdosageof fentanyl may be longer than the duration of narcotic antagonistaction. Consult the packageinsert of the individual narcotic antagonists for details about use. SHOW SUPPLIED: 2 ml. and 5 ml. ampuls-packages of 10. U.S. Patent No. 3,164,600 Rev. 1/80 Committed to research... because so much remains to be done. H JANSSEN PHARMACEUTICA INC., NewBrunswick. NewJersey 08903 0 hyethri U an. N hyohem. Co ipa:dgta . ~ backlighted LC . 0spaelsehocp fole F ~ ~ n ahtr Ihryga ihsno ihsno " 4 _ r l W r w Remove the Block Yourself Reverse with REGONOL pyridostigmine bromide Regonol rapidly restores full neuromuscular transmission. It produces fewer oropharyngeal secretions and less bradycardia than neostigmine. Brief Summary (Please consult full package insert, enclosed in every package, before using Regonol). INDICATIONS-Regonol (pyridostigmine bromide) is useful as a reversal agent or antagonist to nondepolarizing muscle relaxants. CONTRAINDICATIONS-Known hypersensitivity to anticholinesterase agents; intestinal and urinary obstructions of mechanical type. WARNINGS-Use with particular caution in patients with bronchial asthma or cardiac dysrhythmias. Transient bradycardia may occur and be relieved by atropine sulfate. Atropine should also be used with caution in patients with cardiac dysrhythmias. Because of the possibility of hypersensitivity in an occasional patient, atropine and antishock medication should always be readily available. Usage in Pregnancy-The safety of pyridostigmine bromide during pregnancy or lactation in humans has not been established. Therefore its use in women who are pregnant requires weighing the drug's potential benefits against its possible hazards to mother and child. ADVERSE REACTIONS-Side effects are most commonly related to overdosage and generally are of two varieties, muscarinic and nicotinic. Among the former group are nausea, vomiting, diarrhea, abdominal cramps, increased peristalsis, increased salivation, increased bronchial secretions, miosis and diaphoresis. Nicotinic side effects are comprised chiefly of muscle cramps, fasciculation and weakness. Muscarinic side effects can usually be counteracted by atropine. As with any compound containing the bromide radical, a skin rash may be seen in an occasional patient. Such reactions usually subside promptly upon discontinuance of the medication. Thrombophlebitis has been reported subsequent to intravenous administration. DOSAGE AND ADMINISTRATION-Prior or simultaneous administration of atropine sulfate (0.6 to 1.2 mg; IV) is recommended to minimize the side effects (excessive secretions, bradycardia). Usually 10 or 20 mg of pyridostigmine bromide will be sufficient for antagonism of the effects of the nondepolarizing muscle relaxants. Although full recovery may occur within 15 minutes in most patients, others may require a half hour or more. Satisfactory reversal can be evident by adequate voluntary respiration, respiratory measurements and use of a peripheral nerve stimulator device. It is recommended that the patient be well ventilated and a patent airway maintained until complete recovery of normal respiration is assured. Once satisfactory reversal has been attained, recurarization has not been reported. Failure of pyridostigmine bromide to provide prompt (within 30 minutes) reversal may occur, e.g. in the presence of extreme debilitation, carcinomatosis, or with concomitant use of certain broad spectrum antibiotics or anesthetic agents, notably ether. CAUTION-Federal law prohibits dispensing without a prescription. HOW SUPPLIED-Regonol is available in: 2 ml ampuls-5 mg/ml boxes of 10. NDC 0052-0460-10 organon A PART OFAzOna INC Organon Pharmaceuticals . A Division of Organon Inc. West Orange, N.J. 07052 r A' ;rmi r.iS r' ; oTh4 r foU, .: l ~ l rr-. rr. y °q j, r'1 !; r !I,, sj r' "v ikFr~rfi v + pfZf , "f jr r ' l ! r1 J :' ° '. : ~Y~~~~~~~~~~~~~ a.3<r~ t_'5 ~~~ ~ ~,,t~~~ ~rs y ~o ~ C~ " 4 a+'~3 a wtiti\) "Y- ?. r ~ rJ\ " J, Jr. ..y7*.U ,~r " J,Or'.4lYG o /c }}E f,4 )i , i''r ., / _br : '!ir . .,:>. :" t),t. r' ,p,t" '"« 1.< S; 3 i ,r " ",, ±t " y"Y} s r; .. S4i. ~,. '/ t y;f wyA. ¢ , A . 'J S. \ -, Q' ~ n ° 4:c \e+C 4%O .ffr p"-r ~ ,r 5,' ~r F>.;Y"!Q vtd ~ 1 ~ f & , ^. ,t ~t :",d 'x r r + . 4w,"Y . .. , .\.""C:t ' . ,,i 9 Fr / i''., - tmS" 'i. "4- f 4% - j 9 C,.F NURSE ANESTHETISTS Openings for nurse anesthetists ina 521-bed university affiliated teaching hospital. Candidates must We can offer you the opportunity for personal and professional growth in the largest privately funded non-profit civilian hospital in Virginia. Norfolk General Hospital has established itself as the tertiary acute - care hospital for all of Virginia. The opportunities for career fulfillment are endless. Continuing education emphasized.A 644-bed facility located near the shores of the beautiful Chesapeake Bay and minutes from the relaxtion on the Oceanfront of Virginia Beach.......................... We offer competitive salaries, tuition reimbursement, paid annual leave and more.....For additional information contact personnel be qualified graduate nurse anesthetists with CRNA certification or be CRNA eligible with current licensure. Excellent benefits and salary. For more information, write or call collect: Betsy Jessup, RN Nurse Recruiter Personnel Office GEORGETOWN UNIVERSITY Washington, D.C. 20057 i Paulette M. Mason Norfolk General Hospital 600 Gresham Drive Norfolk, Virginia 23507 Call Collect: 800-446-8158 202/625-3270 An Equal Opportunity/Affirmative Action Employer 00 anestesia afety Last~at th AecaSoitofnshioissCneto.Oi yea JUNE 1979 NUBAJN® WAS INTRODUCED nalbuphine HCI TODAY PYICLANS ARE USING NUBAJN AS A SAFE AND EFFECTIVE ALTERNATIVE TO MEPERIDINE HCI (DEMEROL") The analgesic potency of NUBAJN Iscompar t that of meperidine HCI. It may be administerd In indivdual doses of 10 mg/70 kg up to 20* v h maximum daily dose of 160 mg. Onset effect are comparable to that of meperdfr : r (50-150 mg). anpa FOR LESS RESPIRATORY DEPRESSION POTENTIAL At dosages of 10 mg/70 kgS NUBAIN 'i to morphine inrespiratory dpeso.At increase respiratory depression, as does (see Precautions). x FOR A LOW LEVEL OF SIDE EFFECT Inclinical trials, NUBAIN caused voiin h meperidine HCI or morphine. less This. is arn iR tflOe consideration for the general surge :or anesthesiologist. FOR FAVORABLE HEMODYNAMKCPC L NUBAIN has the effect of slightly I cardiac work load and can be used Ml (use cautiously where emesis isIrYOl'a) t FOR LONGER DURATiON OF ACT O9N *ICW MAY PROVIDE GREATER PATIENT CQ #P UNINTERRUPTED SLEEP LONGER DAYflME RELIEF The analgesic effect of NUBAJN lasts hours, so the patient has fewv~ i activties and may sleep better. NUBAIN isan Endio registered U.S. trademwk' $ k }r4 V Jp & bfI I NUBAIN" nalbuphine HCI information Briefsummary of fullprescribing canalsobe toseverepain.NUBAIN Forthereliefofmoderate INDICATIONS to surgicalanesthesia, usedforpreoperative analgesia,as a supplement andforobstetricalanalgesiaduringlabor. topatientswho shouldnotbeadministered NUBAIN CONTRAINDICATIONS toit arehypersensitive NUBAIN hasbeenshowntohavealowabuse WARNINGS DrugDependence with When compared tothat ofpentazocine whichis approximate potential that it has beenreported drugswhicharenotmixedagonist-antagonists, potentialforabusewouldbe lessthan thatof codeineand nalbuphine's andphysical dependence andtolerancemay propoxyphene. Psychological cautionshouldbe followtheabuse or misuseofnalbuphineTherefore, it for emotionallyunstablepatients,or for observedin prescribing of narcoticabuse Such patientsshouldbe individuals with a history whenlong-term therapyis contemplatedCareshould closelysupervised which of administration betakentoavoidincreasesin dosageorfrequency Abrupt in susceptibleindividuals mightresultin physicaldependence. use has beenfollowedby following prolonged of NUBAIN discontinuation i.e.,abdominalcramps.nauseaand symptomsof narcoticwithdrawal, rhinorrhea, lacrimation. restlessness,anxietyelevatedtemperavomiting, mayimpairthe Patients NUBAIN UseinAmbulatory tureandpiloerection for the performance of potentially mentalorphysicalabilitiesrequired Therefore, tasks suchas drivinga caroroperatingmachinery. dangerous patientswho withcautiontoambulatory NUBAIN shouldbeadministered shouldbewarnedtoavoidsuchhazards Usein EmergencyProcedures untilrecovered fromNUBAIN effects Maintain patientunderobservation dangeroustasks Use in that wouldaffect drivingor otherpotentially administration topatientsunder18 Clinicalexperience tosupport Children (other than labor)Safe yearsisnotavailableatpresentUseinPregnancy animal has notbeenestablishedAlthough use of NUBAIN in pregnancy reproductive studieshavenotrevealed teratogenic orembryotoxic effects, to pregnant womenwhen.in the nalbuphine shouldonlybeadministered thepossible the potentialbenefitsoutweigh of thephysician, ludgement and Delivery NUBAIN can producerespiratory hazards UseDuringLabor depressionin the neonate It shouldbe used withcautionin women delveringpremature infants HeadInjuryand Increased Intracranial Pressure Thepossiblerespiratory depressant effectsandthe potentialof fluidpressure(resultingfrom potentanalgesicstoelevatecerebrospinal vasodilation following CO,retention) maybemarkedly exaggerated inthe presenceofheadinluryintracranial lesionsor a pre-existing increasein intracranal pressureFurthermore, potentanalgesicscanproduce effects whichmayobscurethe clinicalcourseof patients withhead injuries Therefore. NUBAIN shouldbe used in these circumstances onlywhen essential,and then shouldbe administeredwith extremecaution InteractionWithOtherCentralNervousSystemDepressants Although NUBAIN possesses narcoticantagonistactivitythereis evidencethat in nondependent patientsit will not antagonizea narcoticanalgesic administered lust before,concurrently orlustafteraninlectionofNUBAIN Therefore, patients receiving a narcoticanalgesic,generalanesthetics. phenothiazines. or othertranquilizers, sedatives,hypnotics, orotherCNS depressants (includingalcohol) concomitantly withNUBAIN mayexhibit an additiveeffect.Whensuchcombined therapyis contemplated, thedoseof oneorbothagents shouldbereduced PRECAUTIONS Impaired Respiration Attheusualadultdoseof 10mg/70 kg,NUBAIN causes somerespiratory depression approximately equalto that producedby equaldoses of morphineHowever, in contrastto morphine, respiratorydepression is notappreciably increased withhigher doses of NUBAIN Respiratory depressioninducedby NUBAIN can be reversedby NARCAN (naloxone hydrochlonde) whenindicatedNUBAIN shouldbeadministered withcaution atlowdosestopatientswithimpaired respiration (e.g. fromothermedication, uremia,bronchial asthma,severe infection, cyanosisorrespiratory obstructions) Impaired RenalorHepatic Function BecauseNUBAIN is metabolized in theliverandexcretedbythe kidneys, patientswithrenalorliverdysfunction mayoverreact tocustomary doses.Therefore, intheseindividuals, NUBAIN shouldbeusedwithcaution andadministered inreducedamountsMyocardial InfarctionAswithall potentanalgesics, NUBAIN shouldbe used withcautionin patientswith myocardial infarction whohavenauseaorvomitingBiliaryTractSurgery As withall narcoticanalgesics,NUBAIN shouldbe usedwithcautionin patientsaboutto undergo surgery of thebiliary tractsince it maycause spasmofthesphincter of Odds ADVERSE REACTIONS Themostfrequentadversereactionin 1066patients treatedwithNUBAIN is sedation(381)36% Lessfrequentreactionsare: sweaty/clammy (99) 9%. nausea/vomiting (68) 6% dizziness/vertigo (58) 5%,drymouth(44) 4%,and headache(27) 3% Otheradverse reactionswhichmayoccur(reported incidenceof 1%or less) are:CNS Effectsnervousness, depression, restlessness,crying,euphoria, floating, hostilityunusualdreams,confusion, faintness,hallucinations, dysphorna, feelingof heaviness,numbness,tingling, unrealityTheincidenceof psychotomimetic effects,suchas unrealitydepersonalization, delusions, dysphoria andhallucinations has beenshownto be lessthan thatwhich occurs with pentazocne Cardiovascular Hypertension, hypotension, bradycardia.tachycardia. gastrolntestinal Cramps, dyspepsia, bitter taste.Respiration Depression, dyspnea,asthma Dermatological Itching, burning,urticaria Miscellaneous Speech difficulty urinary urgency. blurredvision,flushing and warmth Patients Dependent on Narcotics Patients whohave been takingnarcotics chronicallymay experience withdrawalsymptoms uponthe administration of NUBAIN If unduly troublesome, narcotic withdrawalsymptomscan becontrolled bythe slow intravenousadministration ofsmall increments of morphine,untilrelief occurs.If the previousanalgesic was morphine,meperidine, codeine,or other narcotic with similar duration of activity one-fourth of the anticipated dose ofNUBAIN can be administered initiallyand thepatient observedfor signs of withdrawal.ie. abdominal cramps, nausea and vomiting,lacrimation. rhrnorrhea.anxiety restlessness, elevationof temperature or piloerection If untoward symptoms do not occur, progressively larger doses maybe triedat appropriate intervals untilthe desiredlevel of analgesia is obtained with NUBAIN Management of OverdosegeThe immediateintravenous administration of NARCAN' (naloxonehydrochlonde) is a specificantidote Oxygen,intravenous fluids, vasopressors and othersupportivemeasures shouldbe used as indicated. Theadministration ofsingle doses of 72mg ofNUBAIN intramuscularly to eightnormalsubjects has been reportedto have resulted primarilyin symptomsofsleepiness and milddysphoria 6094-28S EDO-835B680 &ndoLoborobories.Inc. eSut ryDof th uPor Com pany Garden City, New York 11530 -..- Specializing In Critical Care Personnel M TIONML NEDICIL REGISTRY provides opportunity to travel, with expenses paid, plus income while you for look Shangri-la. your If professional you are a *L * CR.N.A. and are interested in temporary assignments with the possibility of permanent placement, send your resume, passport-type photo and professional referencs to GARY W SMITH. President Natlional Medical Registry 776 StateStreet Suite 101 Ukiah. California 95482 OR CALL TOLL FREE (800) 358-9132 In California, call collect (707) 468-9187 ARNOLD SLADEN, M.D. Professor of Clinical Anesthesiology & Director, Surgical Intensive Care University of Pittsburgh Honorary Consultant