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* 6 CE Crdits AANA Journal Course AANA Journal Course: Advanced scientific concepts: Update for nurse anesthetists - Part IV- The autonomic nervous system and anesthesia TURRY L ft IRIE, CRNA, MNH -oaa~ Im*. !le ?thsr .*p il review thec basic wntomiy and physiology of the aufonmc ner system bncludling receptor physiology. Pahophyslologicalsituatikms that ~c autonomic fzictlon and their pharmacologcalconideratlona wil be dscvaet. The review willjou p*wl on the bnrenuctlon ofl cost yn iuvstheul qem win adwts wihthe wtonounlc nerwnws system. Secc atwunic nervous system agonise: and setagois will not be considered In this reviekw. Objectives distin. .hesympathetc system pinasypa ti nervous ervus Stm. 1. Identfy anatomical features that 2. identIfy Individual sympathetic and pars. symathticreceptor type andFW phcoi cal response to stimulation. 3. Uist pathpyaliogloal processes th~at alter adrnrgic density and function. 4. Dsrodbe the mechanisms by whc voaile and Intraveous anesthetics and ajncts affet autoi activty. 5 Dgibe. the autonomically controlled uhanges tht occurr with conk monly, employed regional anesthetic tcn - Anatomy of the atnmc newvous "sstem Jb Involuntary or muaoc ner v system (ANS) is asp~ticaed arugeu of nervous tissue responalbi(fbt manance of internal hoostatls. 'The mow~UltoE15 of the autonoinic = "meU system are *As Pert ef the "ANA O~inug Zutf., Pr 5s s, . en has for'#pwm conuin education credft. The course will Cori .enultt of aix eucwulavw rtcle, ach. with s sNit-tea sar n eafor rendlsng. At the conclusion of the sin-pert serie, s fines exwminatio, will be printed- in the Mild Jamm." cf ts p~glse of the exaninetio~n will $ield the participant 6 CE Credits. October/November 1987/Vol. 55/No. 5 under the involuntary control of the hypothalamus and the medulla oblongata, although the cerebral cortex can also affect autonomic activity. The autonomic nervous system is divided into the sympathetic and parasympathetic nervous systems. Generally speaking, these subdivisions of the autonomic nervous system exhibit opposing effects on the various organ systems of the body (Table I). In general the sympathetic nervous system (SNS) consists of a preganglionic axon from the spinal cord, a sympathetic ganglion, a postganglionic axon and, finally, an end-organ upon which the SNS exerts its effect. The preganglionic fibers are myelinated and their cell bodies are located in the intermediolateral horn of the spinal cord extending from the first thoracic level to the third lumbar level of the spinal cord. The preganglionic fibers and anterior nerve root pass from the spinal cord into a spinal nerve. Once the spinal nerve exits the spinal column, the preganglionic fibers pass through the white rami into one of 22 pairs of ganglia (the sympathetic chain). Upon entering the sympathetic chain the pregangli- onic fibers may (1) synapse with the corresponding paravertebral ganglion, (2) ascend or descend the paravertebral ganglia to synapse with higher or lower ganglia, or (3) traverse the ganglia intact and synapse with Table I Autonomic effects on various organs of the body Organ Effect of sympathetic stimulation Effect of parasympathetic stimulation Eye: Pupil Ciliary muscle Glands: Nasal Lacrimal Parotid Submaxillary Gastric Pancreatic Sweat glands Apocrine glands Heart: Muscle Dilated Slight relaxation Vasoconstriction and slight secretion Constricted Contracted Stimulation of thin, copious secretion (containing many enzymes for enzymesecreting glands) Copious sweating (cholinergic) Thick, odoriferous secretion Increased rate Increased force of contraction Dilated (112); constricted (o) Dilated Mildly constricted Decreased peristalsis and tone Increased tone Glucose released Relaxed Decreased output Relaxed Excited Ejaculation None None Slowed rate Decreased force of atrial contraction Dilated Constricted ? Dilated Increased peristalsis and tone Relaxed Slight glycogen synthesis Contracted None Excited Relaxed Erection Constricted Constricted (adrenergic oc) Dilated (adrenergic R) Dilated (cholinergic) Constricted Increased Increased Increased up to 100% Increased Increased Excited Increased glycogenolysis Increased strength None None Coronaries Lungs: Bronchi Blood vessels Gut: Lumen Sphincter Liver Gallbladder and bile ducts Kidney Bladder: Detrusor Trigone Penis Systemic blood vessels: Abdominal Muscle Skin Blood: Coagulation Glucose Basal metabolism Adrenal cortical secretion Mental activity Piloerector muscles Skeletal muscle None None None None None None None None Reprinted from Guyton AC: Textbook of Medical Physiology, 6th edition, Philadelphia, W. B. Saunders Company, 1981, with permission from the publisher and author. _1 _ _ ~___ Journal of the American Association of Nurse Anesthetist prevertebral (peripheral) ganglia. Once the relay occurs with the unmyelinated postganglionic fiber at either the paravertebral or prevertebral ganglia, the postganglionic fiber is distributed to various effector organs throughout the body (Figure 1). Of importance is the fact that numerous postganglionic fibers pass back from the sympathetic chain into spinal nerves via the gray rami. These fibers pass with skeletal nerves to all parts of the body to control piloerector functions, blood vessels and sweat glands. To the anesthetist employing regional anesthetic techniques, an understanding of the segmental distribu- tion of sympathetic innervation is imperative. Sympathetic pathways that have their origin in the different segments of the spinal cord are not consistently distributed to the same area of the body as spinal nerves from Figure 1 The sympathetic nervous system Dashed lines represent postganglionic fibers in the gray rami leading into the spinal nerves for distribution to blood vessels, sweat glands and pilo-erector muscles. the same segment. Since the SNS contains afferent sensory fibers from visceral organs, the anesthetist whose knowledge is limited to an understanding of the sensory dermatomes may find that visceral analgesia is inadequate. For example, from Figure 2 it appears that a spinal or epidural block to the T-12 sensory dermatome level would provide adequate analgesia for surgery on the genitals; however, by understanding the sympathetic fiber distribution (Figure 3) it becomes apparent that a T-10 block is necessary to assure visceral analgesia. With this understanding it is not surprising that a patient may complain of discomfort during manipulation of visceral organs despite what seems to be a sufficient somatic block. Anatomically the parasympathetic nervous system (PNS) is analogous to the SNS in that it consists of a myelinated preganglionic axon and an unmyelinated postganglionic axon that innervates the effector organ. Cell bodies of the preganglionic axons have their origins in the cranial nerves III, VII, IX, X, and sacral nerves 1, 2, 3, and 4 (Figure 4). In contrast to the SNS, the postganglionic fibers of the PNS have their cell bodies Figure 2 Representative skin dermatomes Indicating levels of sensory innervation from corresponding spinal nerves C Ce c. .t Reprinted from Guyton AC: Textbook of Medical Physiology, 6th edition, Philadelphia, W. B. Saunders Company, 1981, with permission from the publisher and author. October/November 1987/Vol. 55/No. 5 Y/ is . . • I /-"' Reprinted from Lebovitz PW, Newberg LA, and Gillette MT: Clinical Anesthesia Procedures at the Massachusetts General Hospital, 2nd edition, Boston, Little, Brown and Company, 1982, with permission from the publisher. in ganglia located in close proximity to or within the effector organ. Cranial nerve X (vagus) makes the largest contribution to the PNS in that it is responsible for all of the functions of the cranial outflow except for innervation to the eye, lacrimal glands, and parotid glands; cranial nerves III, VII, and XI support these functions. As illustrated in Figure 4, the sacral outflow finds its distribution to the lower colon, rectum, bladder and the erectile tissue of the genitals. Visceral afferent fibers are conveyed in the PNS as they are in a similar manner in the ANS. Pain from the heart, lung and alimentary tract is conveyed via the vagus nerve while pain from the bladder, prostate, rectum and uterus is conveyed via the sacral components of the PNS. The laboring parturient illustrates this distribution. During the first stage of labor, pain impulses from cervical dilation travel via visceral afferent fibers that accompany sympathetic fibers to enter the spinal cord at the tenth, eleventh and tweiU tdracic segmnats and the first hibar segment. When labor proremes to the second stag. and stretching of the perineum occurs, impulses travel along visceral aflrent fibers that accompany the sacral Chemical neurotranamitters and receptor physiology Preganglionic neurons of the SNS and PNS secrete acetylcholine. Release of acetylcholine from preganglionic neurons will activate both parasympathetic and sympathetic postganglionic neurons. Traditionally, neurons secreting acetylcholine are referred to as cholinergic fibers. Acetylcholine is synthesized in the cytoplasm within the axons of cholinergic nerves from choline and acetyl coenzyme A. The enzyme choilne acetyltransferase is responsible for catalyzing this combination. Acetylcholine is stored in intracellular vesicles at the presynaptic nerve ending and is released in response to an electrical impulse down the nerve. Acetylcholine released from presynapac vesicles traverses the synaptic cleft to depolarize the postsynaptic neuron by combining with postsynaptic receptors. This receptor binding is reversible and very brief (1 maec), as acetylcholine is rapidly hydrolyzed by the enzyme acetylclwineterase parasympathetic fibers. Figure 3 Spinal levels of sympathetic connector cells THORACIC Fi7:ii I MEAD SALIVARY HEART Th.-5 EYE EY Th 1-2 Th.I-3 3 ,UpPER. LIMP LUNGSJ "Th. I-6% Th2-6 SOPI4AGS '4 5 '4/,, Th4-b6 b 7 STOMACH ';LIVER;' G. s. PANCREAS 9 10 SSUPRA-, RENAL Th.I0-U4 §~, ;-'1 'ii Th7.'~,ML SMALL APPENDIX COLON 5" GONADS' Th.IOII / :T .LOWER// 2 - L.2 l.2UTERUS' 4h.11 ' LIMP RECTUM I SPLADOER TIL/ - 0/ :th.12 Th.-L.2 EY 0KIDN L.I -2 2 LUMBAR Reprinted from Last RJ: Anatomy, Regional and Applied, 7th edition, New York, Churchill Livingstone, inc., 1984, wIth permission from the publisher. Journaul of the American Assocation of Nuu Anesthetist that is prsent in large amounts around the receptor. Of the ietabo lits from acetyicholine hydrolysis, choline is transported back into the nerve ending for forther synthesis of acetylcholine. Fostsynaptic cholinrgic receptors are divided into muscarinic receptors or nicotinic receptors depending on their activation by either muscarine or nicotine. Cioslinergic nicotinic receptors are located at the ganglia of both the sympathetic and parasympathetic nervous systems (including the adrenal medulla) and at the neuromuscular junction. In chemical structure, nicotinic receptors at the neuromuscular junction may differ somewhat from nicotinic receptors located at autonomic ganglia. This subtle diference may explain the specificity of some drugs (for example, muscle relaxants) to one particular anatomical location of nicotinic receptors. boline rgic nnucarinic receptors are located at all effector organs stimulated by the postganglionic neurons of the parasympathetic nervous system and at the sympathetic postganglionic synapse to the sweat glands. Table II Physiological response of effeotor tissues to cholinergic nerve transmission Tissue Eye Sphincter muscle (iris) Ciliary muscle Response Contraction- miosis Contraction-for near vision as part of the convergenceaccommodation reflex Heart S-A node Atria A-V node Ventricle Decrease in heart rate (vagus) Decrease in contractility Decrease in conduction velocity, A-V block Possible slight decrease in contractility Lung Bronchial smooth muscle Bronchial glands Stimulation - bronchoconstriction Stimulation - increased secretions Stomach Motility and tone Sphincters Secretions Increase Relaxation Stimulation Intestine Motility and tone Sphincters Secretions Increase Relaxation Stimulation Bladder Detrusor Trigone and Internal sphincter Contraction Relaxation Sex Organs Erection (male) Sweat Glands Increased secretion Adrenal Medulla Secretion of norepinephrine and epinephrlne Exocrine Glands Pancreas Salivary Lacrimal Pharyngeal Increased Increased Increased Increased secretion secretion secretion secretion Reprinted from Wood M and Wood AJJ: Drugs and Anesthesia, Pharmacology for Anesthesiologists, Baltimore, Williams & Wilkins, 1982, with permission from the publisher. October/November 1997/Vol. 53/No. 5 Knowledge of the anatomical location of cholinergic receptors and response to stimulation allows prediction of responses to various cholinergic agonists and antagonists employed in anesthesia. Table II summarizes the physiological responses to cholinergic receptor stimulation. The primary postganglionic neurotransmitterof the SNS is norepinephrine. Effector organ receptors that a minor role. The two enzymes important for catecholamine metabolism are monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT). MAO occurs in large quantities within the cytoplasm of the sympathetic neurons while COMT occurs outside of the sympathetic respond to catecholamines and catecholamine-like drugs different receptor types, alpha and beta. Alpha and beta are referred to as adrenergic receptors. Epinephrine, norepinephrine and dopamine are endogenous catecholamines. Norepinephrine is found mainly in the sympathetic nerves of the peripheral and central nervous system. Dopamine, the immediate precursor to norepinephrine, is found in the SNS, central nervous system and eye. Epinephrine is the primary catecholamine of the adrenal medulla and is released in response to sympathetic stimulation. Approximately 80% of the adrenal receptors more recently have been further divided into alpha 1, alpha 2, beta 1, and beta 2 receptors depending on drug specificity and response to stimulation. Alpha 1 receptors, located primarily in vascular smooth muscle, exert a vasoconstrictor response when stimulated. Alpha 2 receptors are located both presynaptically and postsynaptically. Stimulation of the postsynaptic alpha 2 receptor will cause vasoconstriction while stimulation of the presynaptic receptor inhibits further release of norepinephrine from the nerve terminal. Alpha 2 receptors have also been identified in the central nervous system where receptor stimulation reduces sympathetic outflow and receptor inhibition increases sympathetic outflow. Currently the understanding of beta receptor physiology exceeds the understanding of alpha receptor physiology, so there is a greater comprehension of specific beta 1and beta 2 responses throughout the body. Beta adrenergic receptors have been identified in the heart, arterial smooth muscle, bronchial smooth muscle, liver, skeletal muscle, pancreas, genitourinary smooth muscle, kidney and uterus. Dopamine receptors, although not well understood, should be mentioned as they are responsible for vasomotor tone in the splanchnic and renal vascular beds. Adrenergic receptor type and response to stimulation are listed in Table medullary sympathomimetic amine isepinephrine. The pathway for catecholamine synthesis is illustrated in Figure 5. Once synthesized, the SNS neurotransmitter norepinephrine is stored in synaptic vesicles at the sympathetic nerve terminal and is released in response to an action potential. The initiating impulse allows the influx of calcium, which facilitates the release of norepinephrine into the synaptic cleft for effector organ receptor interaction. The action of norepinephrine is terminated via three mechanisms (Figure 6). Re-uptake of the neurotransmitter back into the presynaptic nerve terminal is the primary mechanism of termination, while diffusion away from the receptor and metabolism play Figure 5 Pathway for biosynthesis of norepinephrine and epinephrine Originally it was postulated that the adrenergic response to catecholamines was exerted through two m. A number of circumstances alter receptor physiology and function. A comprehensive understanding of factors that alter receptor function, coupled with an PHENYLALANINE TYROSINE 4, DOPA neuron. tyrosine hydroxylase dope decarboxylase DOPAMINE dopamine-R-hydroxylase NOREPINEPHRINI E Phenylethanolamine N-methyl transferase EPINEPHRINE Reprinted from Wood M and Wood AJJ: Drugs and Anesthesia, Pharmacology for Anesthesiologists, Baltimore, Williams & Wilkins, 1982, with permission from the publisher. understanding of normal receptor function and response, will allow for the provision of optimal anesthesia care. Many factors will increase the number of receptors at the effector organ (up regulation). Conversely, a decrement of receptor concentration may also be observed (down regulation). Since sympathomimetics are used with some frequency in the operating room, it is essential that the anesthesia provider is cognizant of situations that affect receptor concentrations. For example, the patient chronically taking beta adrenergic antagonists such as propranolol will demonstrate increased receptor concentrations that persist for several days following the drug's discontinuation. Inadequate anesthesia may allow an increased release of catecholamines with Journal of the American Association of Nurse Anesthetists stimulation deserves special mention, as this age group represents a significant portion of the patient population undergoing surgery and anesthesia. The number of adrenergic receptors decreases with age. Decreasing adrenergic activity would be expected to result in increased receptor density with a concomitant supersensitive response to adrenergic agonists. This phenomenon is attenuated in the elderly patient, which may explain the reduced physiological response to adrenergic stimulation in this patient population. Other pathophysiological problems that should alert the anesthetist to altered autonomic function include pheochromocytoma and a host of dysautonomias, including Shy-Drager syndrome, Riley-Day syndrome, Lsch-Nyhan syndrome, Gill familial dysautonomia, diabetic dysautonomla, and the dysautonomia of spinal cord transection. With pheochmnocytoma, exaggerated and many times lethal complications associated with sympathetic excess should be expected. The dysautono- stimulation; or the administration of a sympathomimetic to susceptible patients may lead to adrenergic hypersensitivity with possible catastrophic results. Conversely, the patient chronically exposed to a beta adrenergic agonist such as terbutaline may have a reduced number of receptors with resultant tachyphylaxis to sympathomimetics. Still other examples of adrenergic receptor alteration exist that illustrate the clinical importance of drugreceptor interaction. Withdrawal from alcohol after chronic abuse results in a hyperadrenergic state with exaggerated responses to sympathomimetic drugs. Hyperthyroidism, denervation, increased sodium conor guanethi- surmption and chronic use of aheamines dine are associated with increased adrenergic receptor density. Factors that reduce adrenergic receptor density include hypothyroidism, elevated progesterone levels, and excessive adrenergic stimulation. The response of the geriatric patient to adrenergic Figure 6 Diagrammatic representation of the fate of norepinephrine at the sympathetic nerve terminal Norepinephrine (NE) is released from the nerve endings and acts on the adrenergic receptor. Some NE enters the circulation where it is O-methyiated (COMT) and deaminated (MAO), but most NE is removed by reuptake into the neuron where it is stored in the dense core vesicles or destroyed by MAO. reuptake deanimoted metabolites MAO N // Tyrosine -* dopo reuptoke dopamine -e Storage vesicles -+ 0 N© Release NE 5-- +NE---+ N N NEI / Adrenergic receptors Circulation I Effector COMT cell 0-Methyloted Metobolites Reprinted from Wood M and Wood AJJ: Drugs and Anesthesia, Pharmacology for Anesthesiologists, Baltimore, Williams & Wilkins, 1982, with permission from the publisher. October/Nevember 1917/ Vol. 53/No. 5 ms exhiit fkaurs reflecting hypoflnction of the sym pathetic nervous system, such as orthostatic hypotension and beat-to-beat variability of heart rate. In response o sympathetic hypofunction, these patients may have increased adrenergic receptor density and pole teal superswositivity to sympthanim -s anesthetic nanagemmt for thes Specific particularsyndromes is beyond the scope of this review; however, thy are mentioned here to alert the anesthetit to situations that e pal consideration. Mre sM Inhalation anesthti and autonomic funoton wt A bough fhlly undestood, d3 inhalatlc agents affect autooomic function via a number of mechanisms. These effects are reflcted in the ability of volatile anesthetics to depress central nervous system outflow, Table III Responses evoked by selective stimulation of adrenergic receptors Alpha-i (postsynaptic) receptors Vasoconstriction Mydriasis Relaxation of gastrointestinal tract Contraction of gastrointestinal sphincters Contraction of bladder sphincter to depress Impulses through the preganglionic neuron and to depress autonomic ganglionic activity (Figure 7). his well documuened tat the halogmated neseic decrase plasma ctechdlamine concentrations, and this reduction may be secondary to an alteration In ctechiolamnl3 metabolism and/or a reduction in sympathetic outflow. An Mr mechmniain by which inhalation agents affect autononic activity is via a variable interaction with adrmrgic receptors and adenylate cyclase activity. For example, In the lung, Inhalation agents activate adenylate cyclase with concomitant smooth muscle relaxation. Conversely, adenylate cyclase activity is reduced In the myocardlum. Halothane, enflurane and, to a lesser extent, isoflurane attenuate the baroreceptor control of the heart rate. The volatile anesthetics' ability to attenuate baroreceptor reflex control of the heart rate becomes Important In certain clinical siturr tions, such u hypovolemia, as normal reflex activity is obtunded. The most drantic illustration of the inhalation anathetics' ability to depres atenmic ativity is seen when these aents are delivred In con- centrations sufficient to block the adrenergicspoe to surgical skin Incision (MAC, BAR). In theory this Figure 7 The effects of the halogenated anesthetIcs oh the central and peripheral sympathetic nervous systems Alpha-2 (presynaptic) receptors Inhibition of norepinephrine release Central nervous system Alpha-2 (postsynaptic) receptors Platelet aggregation ®" 1Q 0 Beta-i (postsynaptic) receptors Increased conduction velocity Increased automaticity Increased contractility Preganglionic neuron Beta-2 (postsynaptic) receptors Vasodilation Bronchodilation Gastrointestinal relaxation Uterine relaxation Bladder relaxation Glycogenolysis Lipolysis Dopamine-1 (postsynaptic) receptors Vasodilation Dopamine-2 (presynaptic) receptors Inhibition of norepinephrine release Reprinted from Stoelting RK: Pharmacology and Physiology in Anesthetic Practice, Philadelphia, J. B. Lippincott Co., 1987, with permission from the publisher. 448 Nicotinic ptthway 'Atuscarinic pathwa Ganglion () Postgangionic neuron or adrenal medulla 1 2 3 - 4 - depression depression depression (nicotinic pathway) no effect Reprinted from Clinics in Anaesthesiology, Philadelphia, W. B. Saunders Company, 1983, wIth permission from the publisher. Jewm.1 of the Amrrlean Aeasefeion of Nuru A+retiua mydriasis and vasoconstriction of systemic and pulmonary capillary beds reflect the interplay of nitrous oxide with the autonomic nervous system. In summary, the volatile anesthetics' interaction with the autonomic nervous system are predictable. Generally these agents reduce autonomic activity although autonomnic tition is evident at some points in the reflex arc. In the patient with pre-existing autonomic dysfunction, exaggerated responses to the volatile anesthetics may be evident. The ability of the inhalation anesthtics to depress autonoinic activity is desirable in most clinical situations with the exception of situations where normal autonomic reflex responses might be desirable, such as, hypovolemia. Understanding the inhalation anesthletic/aitonoic nervous system interaction will allow the anesthetist to plan optimal delivery effect might seem ideal; however, concentrations required to prevent the adrenergic response to skin incision are not tolerated by all patients. Inhalation anesthetics produce some degree of sym pathetic stimulation. For example, isoflurane possesses beta agoniatic properties. The sensitization of the myocardium to catecholamines by inhalation agents, particularly halothane, may be related to stimulation of a receptors in the heart. Prolonged inhalation anesthesia, lasting 5-6 hours, is associated with an increased heart rate, cardiac output and right atral pressure. This may reflect a time-related increase in sympathetic nervous system activity. When employing nitrous oxide alone in or in cozmbization with a volatile anesthetic, the autonomic effect of N20 should be considered. Elevations of plasma catecholamine levels, Table IV Chollnoceptlve sites that Interact with neuromuscular blocking drugs Type receptor Nicotinic Function Location Relaxant interactions Neuromuscular junctionpostsynaptic Initiates depolarization in Nicotinic Neuromuscular junctionpresynaptic Maintains ACh release during high-frequency stimulation Succinyicholine stimulates; nondepolarizers block Nicotinic Autonomic ganglion; ganglion cell bodies Initiates depolarization of ganglion cell Succinyicholine stimulates; fazadinium and dtubocurarine block Nicotinic Postganglionic neuron terminal; autonomic Positive feedback for Succinylcholine stimulates; d-tubocurarine and other nondepolarizers may block muscle end plate transmitter release nerves Muscarinic Sinus node of heart Slows cardiac rate Succinyicholine stimulates; nondepolarizers block Succinyicholine stimulates; gallamine, fazadinium, pancuronlum, and alcuronum block Muscarinic (Mj) Autonomic ganglia; interneuron cell bodies Inhibits depolarization by hyperpolarizatlon Pancuronlum and gallamine block Muscarinic (Me) Autonomic ganglia; ganglion cell bodies Augments depolarization by slow, delayed depolarization Atropine blocks; not affected by nondepolarizing relaxants Muscarinic Postganglion neuron terminal; autonomic Negative feedback for Pancuronlum and transmitter release gallamine block nerves Esteratic AChE Hydrolysis of ACh by clinically used relaxants Not significantly affected Esteratic Pseudocholinesterase Hydrolysis of ACh; weakly inhibited by vecuronlum and atracurlum Inhibited by pancuronium Abbreviations used: Ach, acetyicholine; AChE, scetyicholinesterase. Reprinted from Miller RD: Anesthesia, 2nd edition, New York, Churchill Livingatone, inc., 1986, with permission from the publisher. e ,e ~d )..,.;""Q ': i.,a:,~ 'ri!: :m ' . : ,-i t-i O e f No :il" b.r 1IM?/Vol 35/No, 5 :I :::I: ;" r of volatile agents while avoiding or minimizing the sequelae of autonomic depression or stimulation. of the agent that is best suited for individual patient needs. Neuromuscular blockers Many neuromuscular blocking drugs show structural similarities to acetylcholine. It is predictable and observable that many of the neuromuscular blocking agents used clinically in anesthesia will affect cholinergic receptors not only at the neuromuscular junction, but throughout the body. Examples of such activity are observed frequently with the administration of succinylcholine, particularly in children. Stimulation of muscarinic receptors in the heart by succinylcholine may cause bradycardia, junctional rhythms and possibly sinus arrest. Succinylcholine may also stimulate cholinergic nicotinic receptors at the autonomic ganglia causing elevations in heart rate and blood pressure. Autonomic activity of neuromuscular blockers is not limited to succinylcholine. Non-depolarizing neuromuscular blockers interact with nicotinic and muscarinic receptors to produce possible undesirable side effects. For example, the tachycardia associated with the administration of pancuronium is secondary to pancuro- Narcotic and non-narcotic nium's ability to block muscarinic receptors in the heart. Neuromuscular blockers may exert their autonomic effects via the parasympathetic or sympathetic nervous system by interacting at various cholinergic sites (Table IV). Experimentally, if large enough doses are given, all muscle relaxants will exert cholinergic effects. In the range of clinical doses not all neuromuscular blocking drugs demonstrate autonomic activity. Interestingly, muscarinic receptors outside the myocardium, such as those in the bowel, bladder, bronchi and pupils, are not affected by neuromuscular blockers. Understanding the autonomic side effects of the various neuromuscular blockers employed in anesthesia will allow selection of the agent that will provide optimum anesthesia care. For example, in the patient presenting to the operating room with a history of mitral valve regurgitation where reductions in heart rate could be detrimental, pancuronium might be the muscle relaxant of choice. Conversely, in the patient presenting with ischemic heart disease where increases in heart rate might exacerbate ischemia leading to injury, vecuro- nium might be the muscle relaxant ideally suited. In summary, neuromuscular blocking drugs may cause autonomic changes through ganglionic (nicotinic) stimulation, ganglionic (nicotinic) blockade, muscarinic stimulation or muscarinic blockade. In the clinical set- ting this receptor interaction will be reflected in a variety of cardiac rhythms. The practicing anesthetist should be cognizant of the autonomic action of specific neuromuscular blocking agents in order to assure selection anesthetics and adjuncts Intravenous anesthetics and adjuncts may affect autonomic activity in a variety of ways, either directly or indirectly. The hypotension associated with the administration of some narcotics, such as morphine and the ultra-short acting barbiturate sodium thiopental, is due partly to depression of central sympathetic outflow. Interaction with the peripheral components of the autonomic nervous system, such as adrenergic receptors, has not been demonstrated. With the exception of meperidine, the narcotic analgesics produce a decrease in heart rate. This negative chronotropic effect is related to stimulation of the vagal nucleus in the medulla and can be attenuated by the administration of anticholin- ergics or by incorporating the autonomic effects of pancuronium into the anesthetic plan. Because of their ability to reduce heart rate and therefore reduce myocardial oxygen requirements, nar- cotics are ideally suited for most clinical situations. When the analgesic properties of the narcotic are desirable but a reduction in heart rate may be detrimental, as in mitral regurgitation, a muscle relaxant with vagolytic properties might be selected to offset this negative chronotropic effect. Among the intravenous anesthetic induction agents employed frequently in anesthesia, ketamine is unique in its ability to increase sympathetic activity. Ketamine increases cardiac output, blood pressure and heart rate. Possible mechanisms of action include increases in central sympathetic outflow and prevention of the reuptake of catecholamines. Indeed, increased circulating levels of epinephrine and norepinephrine are found after the administration of ketamine. These autonomic effects, while beneficial to the hypovolemic patient, may be detrimental to the patient with ischemic heart disease. Also reflecting ketamine's interaction with the autonomic nervous system is its ability to relax bronchial smooth muscle and to potentiate the effects of epinephrine on bronchial smooth muscle. Etomidate has recently replaced ketamine in many situations where preservation of hemodynamic variables is desirable. The cardiovascular stability observed with etomidate probably reflects little sympathetic inhibition or stimulation by this induction agent. In situations where great fluctuations in hemodynamic variables could be detrimental, etomidate could be the induction agent of choice. The benzodiazepines as a class exhibit very minor effects on the autonomic nervous system. They probably have no direct sympatholytic action; however, by reliev- Journal of the American Association of Nurse Anesthetists ing anxiety they may indirectly reduce sympathetic activity. There exists minimal evidence that diazepam may activate postganglionic mechanisms to produce vasodilation. Although direct effects may not exist or be minimal at best, benzodiazepines are useful because of their ability to allay anxiety and indirectly reduce sympathetic activity. This action may be beneficial to the patient in whom increases in heart rate and sympathetic tone might be detrimental. Many patients presenting for anesthesia may be taking psychotropic drugs. The interaction between psychotropic drugs and the autonomic nervous system should therefore be appreciated. The antipsychotics, including phenothiazines, butyrophenones and the thioxanthenes, are capable of producing hypotension via alpha adrenergic blockade. These agents also exhibit some anticholinergic activity. The tricyclic antidepressants, like the psychotropic agents, possess some anticholinergic activity. A more important consideration with the tricyclic antidepressants is their ability to sensitize the heart to catecholamines. The MAO inhibitors, although having less anticholinergic activity than either the psychotropic agents or the tricyclic antidepressants, probably have the most profound effect on sympathetic activity. Chronic administration of MAO inhibitors results in a measurable increase in catecholamine levels. Concomitant administration of a sympathomimetic drug to a patient on an MAO inhibitor could result in a hypertensive crisis. Currently it is recommended that MAO inhibitors be discontinued two to three weeks prior to anesthesia. Lithium carbonate should be mentioned, as it is frequently used to treat chronic manic depressive illness. It can affect autonomic activity by reducing the release of neurotransmitters both centrally and peripherally. Because many patients may arrive in the operating room with a history of amphetamine or cocaine abuse, it is Ghportant to understand the interaction of these drugs with the autonomic nervous system. Acutely, these drugs enhance the release of catecholamines and block their reuptake. Clinically, this may be apparent as a hyperdynamic state and arrhythmias. Fatal arrhythmias with acute cocaine usage are well documented. This possible complication should be paramount in the anesthetist's mind with regard to the patient who is acutely intoxicated with amphetamines or cocaine. Chronic abuse of cocaine or amphetamines results in eventual depletion of catecholamines. These patients will have diminished or variable sympathetic responses. Predictions of the actions of other pharmacologic agents that affect autonomic activity will be uncertain. October/November 1987/Vol. 55/No. 5 Regional anesthetic techniques and autonomic function Without question, regional anesthetics greatly influence autonomic function. This influence is exemplified when performing spinal and epidural anesthesia. The sympathetic blockade that accompanies these particular techniques can have detrimental consequences if not anticipated by the anesthesia practitioner. The effects of autonomic blockade that are of paramount importance to the anesthetist are hypotension and bradycardia. As noted previously, the sympathetic fibers exit the spinal column from the first thoracic level to the third lumbar level. The reader is referred again to Figure 3 for an illustration of sympathetic fiber distribution. Depending on the level of blockade that is achieved with spinal or epidural anesthesia, the degree of sympathetic blockade and thus hypotension can be either minimal or of significant degree. In fact, the magnitude of hypotension reflects the level of sympathetic blockade. Generally, with spinal anesthesia the level of sympathetic blockade will be two or three dermatomes higher than the level of sensory blockade. This differential blockade is attributedto the smaller size and degree of myelination of the sympathetic nerve fibers compared to the sensory and motor fibers. The hypotension that occurs with spinal and epidural anesthesia can be attributed primarily to an increase in venous capacitance and therefore reduced venous return to the heart. Arterial vasodilation contributes to a lesser degree. Hypotension can be minimized by anticipating the problem, assuring normovolemia before instituting the technique and employing maneuvers, such as placing the patient in the Trendelenburg position, that will improve venous return. Occasionally pharmacological support may be required in the patient who does not respond to more conservative measures. Bradycardia may occur during spinal or epidural anesthesia if the level of sympathetic block ascends to include the upper thoracic segments one through five. Blockade of this sympathetic influence to the heart leaves the parasympathetic influence unopposed and may further exacerbate hypotension. Prompt treatment with an anticholinergic (atropine) or a sympathomimetic (ephedrine) may be required. When contrasting the degree of sympathetic blockade between spinal and epidural anesthesia, there is an unwarranted belief by many practitioners that the degree of hypotension that occurs with epidural anesthesia is less than that which occurs with spinal anesthesia. Actually, the magnitude of hypotension for the same level of sympathetic blockade is similar but occurs more slowly with epidural anesthesia. There is controversy surrounding differential blockade with epidural anesthesia. As mentioned previously, spinal anesthesia produces a sympathetic block that is higher than the sensory block. This difference probably does not exist with epidural anesthesia where the level of sympathetic blockade closely parallels the level of sensory blockade. The fact that sympathetic blockade occurs more slowly with epidural blockade may be to the anesthetist's advantage in situations where a more controlled reduc- tion in blood pressure is desirable. The autonomnic nervous system is affected by other regional anesthetic techniques. Stellate ganglion, lumbar sympathetic, brachial plexus and celiac plexus blocks can interrupt autonomic pathways to discrete areas of the body. A stellate ganglion block, for example, will produce the classic manifestations of Hornet's syndrome (ptosis, myosis, anhydrosis and enoplthalmoe). The fact that localized areas of sympathetic neve distribution can be interrupted by these blocks makes them usei inthe diaposis and treatment of autoswic dystrophies and in the treatnunt of disease processes associated with visceral pain. The extreme alterations in hemuodynmmic variables that can occur with spinal and eptl itnesthsla are essentially non-existent With peripheral nerve blocks. This resicts the discrete autonomic blockade that can be accomplished with these tedmhh~e. jats arlynot benign ommintheir upoe ability to rete alter autonowic n function. The speclfic mechanism of interaction ismno deine foramt anetheics however, the au tonomically cotrolled physilogical responses to mast agnts are somewhat predictable. Understanding the physiologic rsoesto either sympateteic or parasympathetic p -., sloo the urgnic exe t.o t -m ftbed. (4)Grgeme NM. 1961. P8ysilwdofy~.1Aa Aeha, 3rdad. Buldnmr.. Willinins and Wilki. (5)0luytom AC. 1981. T.~*qfiP*orqMdWPWILOp, Embed. Fhledepblm W. B. Samiders Canyany. (6) Johnson RH and Spuding JM. 1974. Dlwaovnof heAuwwsdc Noyla.Fbhladelpiu: Niackwefl Seaik Pubilcedoms. (7)Labowlw PW, Newberg L.A ad QilhUt M, . 196. Qsk d M ewva PFOcsduDV*.f oa.hu.aUNW Geweal Houisel, 2nd ed. Doimo: Little, Brown andCmy . (5) Mn M.191. Clinical inpyuoats of uwuinrane recepior k cibma in an esha. Aaaeiig. 55:1604171. (9) Manna R1, ed. 1983. Ihalaies Awaueaeiolegy. Clinics in Anmuuduelop M1:2 PhiladelphIa: W. B. Saders Conyan y Lad. (10) Miller RA, ed. 1971. Pfrzusc l&ikl Thpics in Ae sae.Inia dasal Anuasthallopy Clinics 9:3 Boston: Liii., Drown and Conmasy. (U1)Miller RD, ed. 1956. AMedaeaia, 2nd ed. New York: Churchill(12)Wood Mand Wood AU, ad. 196. Drniisadl.swesnl Pwuos i for 4nahanolt. Dulmore: Wilihams and Wilin. , AUTOR Tery R. Schriber, CRNA, BSN, is mwisul a said uuudasdst at Memorlal Medicl Cor of Jadoavlle, Florida. Peionuly,be was on the Unlwsrsly tlsa Msl1 Cr, Depatwuwof Nurse Anemimala NMucan~, Kane City, Kansas, we he alm received his &ukycONO mnwouin edao. Test Yourself 1. Contrast the major anatomical and physiological differences of the sympathetic and parasympathetic nervous system. 2. Describe the cause and effect of "up regulation" and "down regulation" of the sympathetic nervous system. 3. Explain the mechanisms of sympathetic nervous system depression by inhalation agents. 4. Identify the autonomic mechanisms by which neuromuscular blockers can produce either tachycardia or bradycardla. 5. Describe the primary cause of hypotension that can occur with spinal or epidural anesthesia. SUGGESTED READING (1)Day MD. I99W Mowk ~wwwna l s New Yak: t sdihl-Lhri v . (2) B0.$ Ha sihr 819qMa ~ 3 Aiwsu (3) Oman AG, Gooma LS and (BbinwmA, e. 1960. Thwe Pbrmww*oIekdo husk of hewqaica, Now York: Maa~a PublishingCusya ye mo- lw aI" (Answers appear on page 477.) atii4ra, 4th itS.t ks Jourlof the America Associations of Nurse Ansthetista pj A;,r I L k 17, - All of the above. And more. Being a nurse anesthetist in the Air Force also makes you part of the Air Force professional health care team. You'll have the opportunity to grow profes- sionally while you serve your country. And as an Air Force nurse you'll be able to use your education and skills to the fullest. You may also receive financial assistance to pursue higher academic degrees. Qualified nurses have excellent opportunities for advancement. Find out all about Air Force nursing today. It's as easy as ABC. Talk to your Air Force recruiter or call toll-free 1-800-423-USAF (in Calif. 1-800-232-USAF). You can Aim High in the Air Force. A R ^--^lRCE--lR-^ Instead of hydroxyzine Sfaster sedation 1-less pain 2 IS As a standard precaution, prior to the I.V. administration of VERSED in any dose, one should be familiar with all dosing and administration guidelines. Oxygen and resuscitative equipment should be immediately available and a person skilled in maintaining a patent airway and supporting ventilation should be present. For conscious sedation, VERSED should not be given by rapid or single bolus I.V. administration. Lower dosage by 25% to 30% in the elderly and debilitated and in patients with limited pulmonary reserve. However, if narcotic premedication or other CNS depressants are used, lower dosage by 25% to 30% in healthy patients and by a total of 50% to 60% in patients who are over 60 or debilitated. Caution patients about driving or operating hazardous machinery after receiving VERSED. opyrigh 1987 by HomannLa Roche nc All righs reserved Copyright © 1987 by Hoffmann-La Roche Inc. All rights reserved. Instead of diazepam * superior amnestic effect 2 * less pain or phlebitis 1 Instead of thiopental * better hemodynamic stability2 * significantly less apnea * pronounced anterograde amnesia INJECTABLE midailIm HCiBRochi equivalent to 1 mg/mL and 5 mg/mL Please see references and summary of product information on the following page References: 1.Data on file (Doc #069-001, 004,005, 007), Roche Laboratories 2. VERSED" (brand of midazolam HCI/Roche) (, Scientific Summary, Roche Laboratories, Division of Hoffmann-La Roche Inc , Nutley NJ, 1986. VERSED" (brand of midazolam HCI/Roche) lC INJECTION Before prescribing, please consult complete product Information, a summary of which follows: INDICATIONS: IM: preoperative sedation, to impair memory of perioperative events IV: conscious sedation prior to short diagnostic or endoscopic procedures, alone or with a narcotic; induction of general anesthesia before administration of other anesthetic agents, as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia) for short surgical procedures (longer procedures have not been studied) When used IV, VERSED is associated with a high incidence of partial or complete impairment of recall for the next several hours. CONTRAINDICATIONS: Patients with known hypersensitivity to the drug Benzodiazepines are contraindicated in patients with acute narrow angle glaucoma; may be used in open angle glaucoma only if patients are receiving appropriate therapy. WARNINGS: Never use without Individualization of dosage. Prior to IV use in any dose, ensure immediate availability of oxygen and resuscitative equipment for maintenance of a patent airway and support of ventilation. Continuously monitor for early signs of underventilation or apnea, which can lead to hypoxia/cardiac arrest unless effective countermeasures are taken immediately. IV VERSED depresses respiration, and opioid agonists and other sedatives can add to this depression; should be administered as induction agent only by a person trained in general anesthesia For conscious sedation, do not administer IV by rapid or single bolus. Serious cardiorespiratory adverse events have occurred, predominantly in older chronically ill patients and/or with concomitant use of other cardiorespiratory depressant agents These have included respiratory depression, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death Do not administer in shock, coma, acute alcohol intoxication with depression of vital signs Guard against unintended intra-arterial inlection; hazards in humans unknown Avoid extravasation Higher risk surgical or debilitated patients require lower dosages for induction of anesthesia, premedicated or not Patients with chronic obstructive pulmonary disease are unusually sensitive to the respiratory depressant effect of VERSED Patients with chronic renal failure have a 1 5- to 2-fold increase in elimination half-life, total body clearance and volume of distribution of midazolam Patients with congestive heart failure have a 2- to 3-fold increase in the elimination half-life and volume of distribution of midaz(olam Patients over 55 require lower dosages for induction'of anesthesia, premedicated or not Because elderly patients frequently have inefficient function of one or more organ systems, and because dosage requirements have been shown to decrease with age, reduce initial dosage and consider possibility of a profound and/or prolonged effect Concomitant use of barbiturates, alcohol or other CNS depressants may increase the risk of underventilation or apnea and may contribute to profound and/or prolonged drug effect Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation Hypotension occurred more frequently in the conscious sedation studies in patients premedicated with narcotic Gross tests of recovery from the effects of VERSED cannot alone predict reaction time under stress This drug is never used alone during anesthesia, and the contribution of other perioperative drugs and events can vary The decision as to when patients may engage in activities requiring mental alertness must be individualized; it is recommended that no patient should operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until the day after anesthesia, whichever is longer Usage in Pregnancy: An Increased risk of congenital malformations associated with the use of benzodlazeplnes (diazepam and chlordlazepoxide) has been suggested in several studies. If VERSED is used during pregnancy apprise the patient of the potential hazard to the fetus. PRECAUTIONS: General: Increased cough reflex and laryngospasm may occur with peroral endoscopic procedures Use topical anesthetic and make necessary countermeasures available; use narcotic premedication for bronchoscopy Decrease intravenous doses by about 30% for elderly and debilitated patients These patients will also probably take longer to recover completely after VERSED for induction of anesthesia VERSED does not protect against increased intracranial pressure or circulatory effects noted following administration of succinylcholine VERSED does not protect against increased intracranial pressure or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anesthesia Information for patients: Communicate the following information and instructions to the patient when appropriate: 1 Inform your physician about any alcohol consumption and medicine you are now taking, including nonprescription drugs Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol and benzodiazepines 2 Inform your physician if you are pregnant or are planning to become pregnant 3 Inform your physician if you are nursing. Drug interactions The hypnotic effect of intravenous VERSED isaccentuated by premedication, particularly narcotics (eg , morphine, meperidine, fentanyl) and also secobarbital and Innovar (fentanyl and droperidol) Consequently, adjust the dosage of VERSED according to the type and amount of premedication A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular VERSED for premedication VERSED' (brand of midazolam HCI/Roche) The use of VERSED as an induction agent may result in a reduction of the inhalation anesthetic requirement during maintenance of anesthesia Although the possibility of minor interactive effects has not been fully studied. VERSED and pancuronium have been used together in patients without noting clinically significant changes in dosage, onset or duration VERSED does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuronium. or against the increased intracranial pressure noted following administration of succinylcholine VERSED does not cause a clinically significant change in dosage, onset or duration of a single intubating dose of succinylcholine No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam. hydroxyzine, d-tubocurarine, succinylcholine and nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCI and Cetacaine) have been observed Drug/laboratory test interactions Midazolam has not been shown to interfere with clinical laboratory test results Carcinogenesis, mutagenesis, impairment of tertility Midazolam maleate was administered to mice and rats for two years At the highest dose (80 mg/kg/day) female mice had a marked increase in incidence of hepatic tumors and male rats had a small but significant increase in benign thyroid follicular cell tumors These tumors were found after chronic use, whereas human use will ordinarily be of single or several doses Midazolam did not have mutagenic activity in tests that were conducted A reproduction study in rats did not show any impairment of fertility at up to ten ti nes the human IV dose Pregnancy Teratogenic effects Pregnancy Category D See WARNINGS sec tion Midazolam maleate inlectable, at 5 and 10 times the human dose, did not show evidence of teratogenicity in rabbits and rats Labor and delivery The use of injectable VERSED in obstetrics has not been evaluated Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonata, CNS depression, VERSED is not recommended for obstetrical use Nursing mothers It is not known whether i ndazolam is excreted in human milk Because many drugs are excreted in human milk, caution should be exercised when injectable VERSED is administered to a nursing woman Pediatric use Safety and effectiveness of VERSED in children below the age of 18 have not been established ADVERSE REACTIONS: Fluctuations in vital signs following parenteral administration were the most frequently seen findings and included decreased tidal volume and/or respiratory rate decrease (23 3% of patients following IV and 10 8% of patients following IM administration) and apnea (154% of patients fol lowing IVadministration), as well as variations in blood pressure and pulse rate Serious cardiorespiratory adverse events have also occurred (See WARNINGS ) In the conscious sedation studies, hypotension occurred more frequently after IV administration in patients concurrently premedicated with meperdine During clinical investigations, three cases (0 2%) of transient fall in blood pressure greater than 50% were reported during the induction phase Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactvity and combativeness have been reported (See DOSAGE AND ADMINISTRATION ) Following IM injection headache (1 3%), local effects at IM site pain (3 /%), induration (0 5%), redness (0 5%), muscle stiffness (0 3%) Followinl IV rdmrinris tration hiccoughs (3 9%), nausea (2 8%), vornmiting (2 6%). coughirng (13%), "oversedation" (16%), headache (1 5%), drowsiness (1 2%). local effects at the IV site tenderness (5 6%), pain during (5 0%), redness (2 6%), induration (1 7%), phlebitis (0 4%) Other effects (- 1%) rrainly following IV administration Respiratory Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea Cardiovascular Bigeminy premature ventricular contractions, vasovagal episode, tachycardia, nodal rhythm Gastrointestinal Acid taste, excessive salivation, retching CNS/ Neuromuscular Retrograde amnesia, euphoria, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, ataxia, dizziness, dys phoria, slurred speech, dysphonia, paresthesia Special Sense Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual distur bance, difficulty focusing eyes, ears blocked, loss of balance, lightheadedness injection Integumentary Hives, hive-like elevation at inlection site, swelling or feeling of burning, warmth or coldness at inlection site, rash, pruritus Miscellaneous Yawning, lethargy, chills, weakness, toothache, faint feeling, hernatorna Drug Abuse and Dependence Available data concerning the drug abuse and dependence potential of midazolam suggest that its abuse potential is at least equivalent to that of diazepam DOSAGE AND ADMINISTRATION: Individualize dosage Elderly and debilitated patients generally require lower doses Adjust dose of IV VERSED accord ing to type and amount of premedication Excess doses or rapid or single bolus intravenous administration may result in respiratory depression and/or arrest, especially in elderly or debilitated patients (See WARNINGS ) IM use Inlect deep in large muscle mass IV use Administer initial dose over 20 to 30 seconds for induction of general anesthesia For conscious sedation administer initial dose over 2 to 3 minutes May be mixed in the same syringe with morphine sulfate, meperidine, atropine sulfate or scopolamine Compatible with 5% dex trose in water, 09% sodium chloride and lactated Ringer's solution OVERDOSAGE: Manifestations would resemble those observed with other benzodiazepines (e g., sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, untoward effects on vital signs) No specific organ toxicity would be expected ROCHE ROCHE LABORATORIES 'Division of Hoffmann-La Roche Inc ® Nutley, New Jersey 07110 P1 037 TI Nellcor N-200 Leads " Beyond Pulse Oximetry Irrrpre A True Technological Breakthrough. The NELLCOR®N-200 pulse oximeter with C-LOCK" ECG synchronization combines our most advanced oxygen saturation monitor to date, with the ultimate reference of cardiac activity... the ECG. Many more sizeable advantages. The compact, lightweight N-200 opens up space on your anesthesia cart and allows for portable operation. Uncompromising performance, even in low perfusion. By synchronizing the optical signal of the pulse oximeter with the patient's ECG R-wave, C-LOCK provides the key reference point to lock in reliable performance. Especially in cases where it may be difficult for other pulse oximeters to detect or distinguish a peripheral pulse...like low perfusion...the N-200 with C-LOCK keeps on tracking. Slip it into places taller monitors won't fit or detach it from the powerbase and continue monitoring during patient transfer from the OR to the PAR. The next standard In pulse oximetry. From its small size on the outside, to its revolutionary circuitry on the inside, the sturdy N-200 with C-LOCK exemplifies Nellcor's on-going commitment to establishing the highest standards in pulse oximetry. Itcombines the same quality, reliability and accuracy that you have come to expect from the NELLCOR N-100 with the advanced technology of C-LOCK. Plus, it has added features like direct or indirect ECG signal input, trend and event memory, RS-232 communication port and system compatibility with every Nellcor sensor. For additional information, write Nellcor or call toll-free 800 433-1244. (InCalifornia, 800 351-9754.) The NELLCOR N-200. When you look for performance beyond pulse oximetry, look to Nellcor. NELLCOR ® Nellcor Incorporated 0081.0387 25495 Whitesell Street, Hayward, California 94545 415 887-5858 Telex 172 428 IN SHORT SURGICAL PROCEDURES, AN OPTIMAL OPIOID ANESTHETIC FOR 11T IQ £ 1Ia RAPID ONSET OF ACTION for prompt control of hemodynamic response to surgical stimulation* SHORT DURATION OF ANALGESIC ACTION permits titrating to patient response PROMPT RECOVERY In short-stay procedurest EJANSSEN wdI.ledr1n anssa seaurch PHARMACELICA * an ~Mwnsrmuua Int. I 7 JFIAL-G4 0 A PHARMACOKINETIC PROFILE THAT PERMITS FLEXIBILITY OF DOSING TECHNIQUE ¢4 BOLUS/INCREM ENTAL ADMINISTRATION for short procedures lasting up to 30 minutes in spontaneously breathing patients, or for procedures lasting 30 to 60 minutes in intubated patients CONTINUOUS INFUSION for procedures lasting more than 45 minutes in intubated patients *As with %s other oplolds. hypotenson and bradycadls with al potent opild. appropriate postopetive have 6e;;i monitoring#vW also ben obserwd at lower doses. Beaue of the possibilIty of dlayd rp ry , swt uonue weuafter surgery. SIleal muscle rigidity Isrelated to the dose and spied MofM Dosage should be Indivduallaed Ineach case. See following page for brief summary of RAPID-ACTING Alfenta (alfentanil HCI) Injection G AN OPTIMAL OPIOID ANESTHETIC FOR MOMENT-TO-MOMENT CONTROL BEFORE PRESCRIBING, PLEASE CONSULT COMPLETE PRESCRIBING INFORMATION, OFWHICH THEFOLLOWING IS A BRIEF SUMMARY. Labor and Delvery: Thereare insufficient datato support the use of ALFENTA in laborand delivery Placental transfer ofthe drughas been reported;therefore,use in laborand deliveryis not recommended. N M iauuw oniinuwouuin vuoivuiusin hfin eu innifiIL i none a Y ° ., 1 A ' ,Y ' i ?' 1 Y., A I, s le wrg oiers: suy ounine women unergoingIUIostaUIII rwU mIPI tU UUI l IIIonUII, significant levels CAUTION: Federal LawProhibits Dispensing Without Prescription ofALFENTA were detectedin colostrum fourhoursafteradministration of60 pg/kg ofALFENTA, withno DESCRIPTION: ALFENTA is a sterile,nonpyrogenic, preservative freeaqueoussolutioncontaining alfentanil detectablelevelspresentafter28 hours.Caution shouldbeexercisedwhenALFENTA is administered toa hydrochloride equivalent to 500 pg per mlofalfentanil baseforintravenous injection. Thesolution, which nursingwoman. contains sodiumchloride forisotonicity, hasa pHrangeof4.0-6.0. Pedatri Use: Adequate datato support theuseof ALFENTA inchildren under12yearsofage arenot available presently inpatients withknown is contraindicated hydrochloride) (alfentanil ALFENTA CONTRAINDICATIONS: hypersensitivity tothedrug. ADVERSE REACTIONS: Themostcommonadversereactions, respiratory depression andskeletalmuscle WARNINGS PHARMACOLOGY, effectsofopioidsSee CLINICAL rigidity, areextensionsofknownpharmacological INTHE TRAINED BYPERSONS SPECIFICALLY ONLY SHOULD BE ADMINISTERED ALFENTA WARNINGS: depression andskeletalmusclerigidity ofrespiratory onthemanagement OFRESPIRATORY and PRECAUTIONS ANDINTHEMANAGEMENT ANESTHETIC AGENTS ANDGENERAL USEOFINTRAVENOUS andhypotension asystole,arrhythmias respiratory arrest,bradycardia, depression, Delayedrespiratory OFPOTENT OPIOIDS EFFECTS havealsobeenreported BE SHOULD ANDOXYGEN EQUIPMENT ANDINTUBATION RESUSCITATIVE ANTAGONIST, ANOPIOID fromcontrolled and tablearederived listedinthefollowing incidencesof adversereactions Thereported READILY AVAILABLE trialsinvolved Thecontrolled 1183patients,ofwhom785 receivedALFENTA OFTHEPATIENTopenclinicaltrialsinvolving MONITORING DEPRESSION, RESPIRATORY OFDELAYED OFTHEPOSSIBILITY BECAUSE Incidencesare enflurane, salineplaceboandhalothane. sodium, comparisons withfentanyl,thiopental treatment WELLAFTER SURGERY MUSTCONTINUE incidenceofcertainside adversereactionsreportedThecomparative andnondisturbing basedon disturbing ininitialdosagesup to20 pg/kg maycauseskeletal hydrochloride) administered ALFENTA (alfentanil incidencein clinicaltrials hasa higherreported is influenced bythetypeofuse,e.g.,chestwallrigidity isusuallydose- effects of thetruncalmuscles.Theincidenceandseverityofmusclerigidity musclerigidity, particularly lf e g., nauseaandvomitinghavea higherincidencein patients andbythetypeofsurgery, produce ofa entanilinduction, induction dosages(above130pg/kg)willconsistently of ALFENTA at anesthetic related. Administration surgery gynecologic opioids undergoing with other occursearlierthan onset.Theonsetofmuscularrigidity rigidity withan immediate muscular ALFENTA mayproducemuscular rigidity thatinvolves all skeletalmuscles,including thoseoftheneckand extremities. Theincidence maybereduced by:1)routinemethodsofadministration ofneuromuscular blocking Thiopental Saline agentsforbalanced opioidanesthesia; 2)administration ofupto 1/4 ofthefullparalyzing dose ofa neuroALFENTA Fentanyl Sodium Enflurane Halothane Placebo' muscular blocking agentjustprior to administration ofALFENTA at dosagesupto130 pg/kg; following loss of (N- 785) (N- 243) (N- 6) (N- 55) (N-18) (N-18) consciousness, a fullparalyzing doseofa neuromuscular blocking agentshouldbeadministered; or 3) simulta% % % % % % neousadministration ofALFENTA anda fullparalyzing doseofa neuromuscular blocking agentwhenALFENTA is usedinrapidlyadministered anestheticdosages(above130pg/kg). Gastrointestinal Theneuromuscular blocking agentusedshouldbe appropriate forthepatient's cardiovascular status Nausea 28 44 14 5 0 22 Adequate facilities shouldbe available forpostoperative monitoring andventilation of patientsadministered Vomiting 18 31 11 9 13 17 ALFENTA. Itis essentialthatthesefacilitiesbefullyequipped to handle all degreesofrespiratory depression. Cardiovascular PRECAUTIONS: DELAYED RESPIRATORY DEPRESSION, RESPIRATORY ARREST, BRADYCARDIA, ASYSTOLE, Bradycardia 14 7 8 0 0 0 ARRHYTHMIAS ANDHYPOTENSION HAVE ALSO BEENREPORTED. THEREFORE, VITAL SIGNSMUST BE Tachycardia 12 12 39 36 31 11 MONITORED CONTINUOUSLY Hypotension 10 8 7 7 0 0 Geeral: TheinitialdoseofALFENTA (alfentanil hydrochloride) shouldbeappropriately reducedinelderly Hypertension 18 13 30 20 6 0 anddebilitated patients.Theeffectoftheinitial doseshouldbeconsidered in determining supplemental doses Arrhythmia 2 2 5 4 6 0 Inobesepatients(morethan20%aboveidealtotalbodyweight),thedosageofALFENTA shouldbe determined Musculoskeletal onthebasisofleanbodyweight. ChestWall 17 120 0 0 0 Inoneclinicaltrial,thedoseofALFENTA required toproduceanesthesia,as determined byappearance of Rigidity deltawavesin EEG,was40% loweringeriatric patientsthanthatneededinhealthy youngpatients. SkeletalMuscle 6 2 6 2 0 Inpatients withcompromised liverfunction andingeriatricpatients, theplasmaclearanceofALFENTA Movements maybereducedandpostoperative recovery maybe prolonged. maypro- Respiratory be administered slowly(overthreeminutes).Administration Induction doses ofALFENTA should duceloss ofvasculartoneandhypotension. Consideration shouldbegiventofluidreplacement priorto induction Apnea 7 0 0 0 0 0 Diazepam administered immediately priortoor inconjunction withhighdosesofALFENTA mayproduce Postoperative 2 2 0 0 0 0 Respiratory vasodilation, hypotension andresultindelayedrecovery Depression andasystolehave Severebradycardia maybetreatedwithatropine. produced byALFENTA Bradycardia beensuccessfully treatedwithatropine andconventional resuscitative methods CNS Thehemodynamic effectsofa particular musclerelaxant andthedegreeofskeletalmusclerelaxation Dizziness 3 5 0 0 0 0 required should be considered intheselectionofa neuromuscular blocking agent. Sleepiness/ 2 8 2 0 0 6 Following ananestheticinduction doseofALFENTA, requirements for volatileinhalation anestheticsor Postoperative ALFENTA infusion arereducedby30 to 50%forthefirsthourof maintenance Sedation Administration ofALFENTA infusionshouldbe discontinued at leas 10-15minutes priortothe end Blurred Vision 2 2 0 0 0 0 of surgery. Respiratory depression causedbyopioidanalgesicscanbe reversedbyopioidantagonists suchas 'Fromtwoclinicaltrials,oneinvolving supplemented balanced barbiturate / nitrous oxideanesthesiaand onein naloxone. Becausetheduration ofrespiratory depression produced byALFENTA maylastlongerthanthe dura- healthyvolunteers whodidnotundergosurgery tionoftheopioidantagonist action,appropriate surveillance shouldbemaintained. As withallpotentopioids, Inaddition, otheradversereactionsless frequently reported(1%or less)were: profound analgesiais accompanied byrespiratory depression anddiminished sensitivity toCO stimulation Laryngospasm, bronchospsm, postoperative confusion, headache,shivering, postoperative euphoria, whichmaypersistintoor recurinthepostoperative period.Intraoperative hyperventilation mayfurther alter hypercsrbia,painon intection, urticaria,enditching. postoperative responsetoCO,.Appropriate postoperative monitoring shouldbeemployd, particularly after Somedegree of skeetalmusclerigidityshouldbeexpected with induction doses of AFENTA infusions andlargedoses ofALFENTA, toensurethatadequatespontaneous breathing is established and maintained intheabsenceof stimulation priortodischarging thepatientfromtherecovery area. RU ABUSE ANDDEPENDENCE: ALFENTA (alfentanil hydrochloride) is a Schedule II controlled drugsub Head Inuries: ALFENTA mayobscuretheclinicalcourseofpatientswithheadinjuries, stancethatcanproducedrugdependenceofthemorphine typeandtherefore has thepotential for beingabused Impaired Respiraton: ALFENTA shouldbeusedwithcautioninpatients withpulmonary disease, OVERDOSAGE: Overdosage wouldbe manifested byextensionofthepharmacological actionsof ALFENTA decreased respiratory reserveorpotentially compromised respiration. Insuch patients,opioidsmayadditionally (alfentanil hydrochloride) (see CLINICAL PHARMACOLOGY) as withotherpotentopioidanalgesics.No decreaserespiratory driveandincreaseairway resistanceDuring anesthesia, thiscanbe managed byassisted experience ofoverdosage withALFENTA was reported duringclinicaltrials.Theintravenous LDo of ALFENTA orcontrolled respiration. is43.0-50.8 mg/kginrats,72.2-73.8 mg/kgin mice, 71.8-81.9mg/kginguineapigsand5.5-875 mg/kgin ImpraredHepatic o RenalFunctn: Inpatientswithliverorkidneydysfunction, ALFENTA shouldbe dogs.Intravenous administration ofan opioid antagonist such as loxoneshouldbe employed as a specific administered withcaution duetotheimportance oftheseorgansin themetabolism andexcretion ofALFENTA. antidotetomanagerespiratory depression. DrugInteractloM: Boththemagnitude andduration ofcentralnervous systemandcardiovascular Theduration ofrespiratory depression followingoverdosage withALFENTA maybe longerthanthe effectsmaybeenhanced whenALFENTA is administered in combination withotherCNSdepressants such as duration ofactionoftheopioidantagonistAdministration ofan opioid antagonist shouldnotpreclude immediate barbiturates, tranquilizers, opioids, orinhalation generalanesthetics. Postoperative respiratory depression may establishment ofa patent airway, administration ofoxygen, andassisted orcontrolled ventilation as indicated for beenhanced orprolonged bytheseagents. Insuch casesofcombined treatment, thedose ofoneor bothagents hypoventilation orapnea. I respiratory depression isassociated withmuscular rigidity, a neuromuscular blocking should be reduced. Limitedclinical experience indicatesthatrequirements forvolatileinhalation anesthetics are agent maybe required tofacilitateassistedor controlled ventilation. Intravenous fluidsandvasoactiveagents reduced by 30 to 50%forthefirstsixty(60)minutesfollowing ALFENTA induction. mayberequired to managehemodynmicinstability Perioperative administration ofdrugs affecting hepatic blood floworenzyme function mayreduce plasma DOSAGE ANDADMINISTRATION: Thedosage ofALFENTA (atfentanil hydrochloride) should beindividualized clearance andprolong recovery Carclnogeneat, Metagenee and aRd Impalrmet of ofFertility: Fertilty: No studiesof in eachpatient according to bodyweight,physicalstatus,underlying pathological condition, use ofotherdrugs, Carclogeneis, Mutagenesls Imparment No long-termanimal animalstudies ofALFENTA ALFENTA and andduration of surgical procedure and anesthesia. In obese patients (more than 20% idealtotal havebeenperformed toevaluatecarcinogenic potentialThemicronucleus testinfemalerats andthedominant bodtypei draton of surgical procedue nd esthesia n patis (o than w 2boy t above e detotal lethaltestinfemaleandmalemicerevealed thatsingleintravenous dosesofALFENTA as highas 20 mg/kg ALFENTA shouldbe reducedinelderlyordebilitated patients(see PRECAUTIONS). of Vitalss ns s hould e oniored rot PRECAU 40 timestheupperhuman dose)produced nostructural chromosome mutations orinduction (approximately m ho ul n n testalso revealedno dominant lethalmutationsTheAmesSalmonella typhimurium metabolicactivating mutagenic activity. Pregnancy Category C: ALFENTA has beenshowntohaveanembryocidal effectin ratsandrabbits whengivenindoses 2.5 timestheupperhuman dosefora periodof10daystoover 30 days.Theseeffects couldhavebeenduetomaternal toxicity(decreased foodconsumption withincreasedmortality) following Manufactured by TaylorPharmacal Co for prolongedadministration ofthe drug. Noevidenceofteratogenic effectshas beenobserved afteradministration ofALFENTA in rats or rabbits. anssen Phrmaceu, 1nc . No.4s7,7 Thereare noadequateand well-controlled studies in pregnantwomenALFENTA shouldbe usedduring PHARMACEUTICA PiscatawayNJ 08854 March19874 7619901M pregnancyonlyif the potentialbenefitjustifiesthe potentialriskto thefetus I ARM EUTICA Pscaaway, NJ08854 March 1987 49-7619901-M long-term type he thoe JAN S SE N RPM a Iri_ I 5~ I~-~ i~ -?~ ::~: THE BARD® ALFENTANIL INFUSER FOR I Iz DEDICATED PUMP FOR ALFENTANIL DELIVERY Designed specifically for accurate administration of alfentanil ELIMINATES TIME-CONSUMING CALCULATIONS Calculates flow rate based on infusion rate, patient's body weight and drug concentration ALLOWS INTRAOPERATIVE FLEXIBILITY Convenient rotary switches provide optimal flexibility for bolus or infusion doses SMALL, PORTABLE, BATTERY- OPERATED Incorporates audio and visual safety features ~D~~rrakbacd ~OCCdLOrdYU. U,-i., ~-. ..-i. ;~ ~, i-: i. * i. ::ri : Call 1 (800)343-0366 or your Bard MedSystems' Representative for more Information. 7i --i :r: -c~--- -. ,:;~.r 1' ;ri See preceding page for brief summary of Prescribing Information for ALFENTA® (alfentanil HCI) Injection E. From non-invasive to invasive blood pressure measurement... without skipping a beat. Introducing the Datascope 22001 monitor. Now, when the routine procedure becomes critical, you don't have to waste time changing blood pressure measurement modes by reconnecting the patient to another monitor. The invasive and noninvasive blood pressure measurement functions of the 2200 I monitor are already built-in, along with ECG, temperature and recording capability. Both the invasive and non-invasive measurements can be performed simultaneously, providing more monitoring versatility and application to a variety of clinical needs. What's more, despite its small size, the 22001 includes sophisticated trending. All of a patient's vital atas c pe signs and their progress can be reviewed on the screen at any time. Any trace, value or trend displayed on the monitor screen can be documented and recorded with full annotation. With the 22001 monitor, as with all our products, there is an entire family of Datascope products that function right along with it. The ACCUCAP® CO,/O, monitor and the ACCUSATTM pulse oximeter can be interfaced simultaneously with the 22001 and its recorder. For more information or a demonstration, just call us at (201) 265-8800. Or write Datascope Corp., PO. Box 5, Paramus, NJ 07653. Datascope Corp. * PO. Box 5, Paramus, N.J. 07653-0005, U.S.A. * Tel. (201) 265-8800 (Corporate Headquarters) Datascope B.V. * Postbox 26,3870 CA Hoevelaken, Holland * Tel. 03495-34514 (European Headquarters) Datascope GmbH * AM Wall 190, 2800 Bremen 1,West Germany * Tel. 421-321818/19 Datascope Medical Co. Ltd. * Science Park, Milton Rd, Cambridge CB44BH, England * Tel. 0223-860 333 220-1 © Datascope Corp. 1987 We Have ABetter Electrode Story. And We Can Make ItStick. During stress testing, in the operating room, I.C.U. and C.C.U., even after defibrillation, our high-demand electrodes stay put and provide crisp, clear and accurate tracings. For paramedic or emergency room trauma cases where prep time is limited, our electrodes remain in place and provide a solid base line, a good clean trace and minimal motion artifact. The unique Accutac gel on our high-demand ECG electrodes sticks and performs well during open heart ZL] and other major surgery, the kind of demanding conditions that might cause other electrodes to fail or fall off. For expediency in the emergency room and surgery, high demand electrodes can be prestaged without concern of dryout. Experience the effectiveness Sof our high-demand electrodes S firsthand, receive a free sample kit when you contact Peggy Razzano at 1-800-543-4890 or in Ohio 1-800-762-4810. STravenol a Operating Room Division NDM Products Rareoe: 1.SanfordTJ J, Smith NT,Dec-Sliver H, at al:A comparison of morphine, fentanyl, and sutentanil anesthesiafor cardiacsurgery: Induction, emergence,and estubatlon.AnesfhAnalg 1986:65:259-266. 2. de LangeS. Boscoe MJ. StanleyTh, at al:Comparison of ufentanll-0: and tentanyl- for coronary artery surgery.Anesfveslgy 1982;56:112.11.3. Beneel 0J, RoizenMF, Lampe61, etal Morbidity afteraortic surgery with sufentanl vs Isoffuraneanesthesia, abstracted. Anesthesiology 1986;65(3A).A516. Before prescribing, piease consuit complete prescribing lnformation, ofwhichthefollowing isa briefsommary CAUTION: Federal LawProhibits Dispensing WithoutPrescrption. IESCUIpTION: SUFENTA isasterile, preservative free, aqueous aolution containing aufantani citrate equivalentto 50 jg per mlof suferdanil baseforintravenous iqection. Thesolution hasa pHrange of3.5-.8.. INDICATIOSI AND USA!: SUFENTA (nufantanil cltrata)lsindicated:As en analgesic adjunctIn the maintenance of balanced general anesthesia. Asaprimaryanesthetic agent for theinduction andmaintenance of anesthesia with 100%oxygen In patients undergoing majorsurgical procedures, such ancardIovascular surgery orneurosurgical procedures inthesiftingposition, to provide favorable myocardial andcerebral oxygen balance orwhenextended postoperative ventilation Isanticipated. SEEDOSAGE CHART FORMORE COMPLETE INFORMATION ONTHEUSEOFSUFENTA. CONTUAIMUICATIOUS: SUFENTA is contraindicated Inpatients withknown hypersensitivity to thedrug. WAIINSIND: SIFENTA ebedi beaeelatered edy by pases epeollela balad s - aooet Mtafre eeaa aeatatIsa ad saaraeee d Ue eepratey efleot d ase ep~el. Asopil ategolat, rseaeaottatle ai Mad bestee eqmeae ad uxygenaoesd ba readily a le. SUFENTA maycause skeletal muscle rigidityparticularly ofthetruncal muscles. Theincidence ard severity of musclerigidityIs doserelated. Admimtration of SUFENTA mayproduce muscular rigiditywitha more rapid onset thanthatseeswithfantany.SUFENTA mayproduce muscular rigiditythatInvolves theskeletalmuscles of theneckard extremitie.Theincidence canbe reduced by:1)administration ofupto' . ofthefoll paralyzingdoneof a non-depolarizing neuromuscular blocking agent just priorto administration ofSUFENTA at dosages of up to 8 Mig/kg, 2) admInistration of a full paralyzing doneof a neuromusclar blocking agent whenSUFENTA isusedin anesthetic dosages (abov8 Ng/bg)titratedb stow following lossofconsciousness intravenous nfusion, or,3) sImultaneous administration of SUFENTA anda lull paralyzing dose of a neuroblocking agentwhenSUFENTA Is used Inrapidlyadministered anesthetic dosages (above 8 pg/kg). muscular patients cardiovascular status. Adequate blocking agent should ba compatible with the Theneuromuscular facilities shouldbe available for postoperative monitoring andventilation ofpatients administered SUFENTA. depression. to handle all degrees ofrespiratory ft Isessential thatthesefacilitiesbefully equipped anddebilishould haappropriately reduced In elderly Samuel: Theinitialdosa of SUFENTA MpECAUI~OO: supplemental doses. Vital be considered Indetermining patients. Theeffect oftheInitial dmsashould tated routinely. Nitrousoxidemayproduce cardiovascular depreslonwhengivenwith signsshouldha monitored ighdoses ofSUFENTA (seeCLINICAL PHARMACOLOGY). Thehamodynamic effects of a particular muscle relaxsntandthedegree of skeletal musclerelaxation required shouldha considered in the selectiono a neuromuscular blockingagent.Highdosesof pancurodom mayproduce increases In heart rateduring SUFNTAoxyen aneoth Ia.Bradycardla babeen reportd lofruesnty withSUFENTA-onygn anesthsia by depression caused by opiod analgesics canha reversed and s beenesrponsiveto ptrpine. Respiratory depresson produced by SUFENTA Because the duration of respiratory opioldantagonists suchasneloxone. maylastlongerthan thedurationoftheopiold antagonist action, appropriate surveillance shouldbemaintaned. depression anddiminishedensi Aswith allpotentopionds, profound analgesla Is accompanied by respiratory tivity toCO2 stimulation whichmaypersist Intoor recur Inthepostoperative period.Appropriate postoperative monitoring shouldhaemployed toensure thatadequste spontaneous breathing Inestablished andmaintained System ae. Interaction with OtherCentralNervous pri to dlichrgingthe patientfromthe recovery Depressants: Boththe magnudeendduration of centralnervous system andcardiovascular effects maybe general tranquilizrn, otheropioids, topatients receiving barbiturates, whenSUFENTA Isadministered enhanced anesthetics orotherCNSdepressants. Inouch casesof combined treatment, thedoseofoneor bathagents should bereduced. HeadInjuries:SUFENTA mayobscurethe clinical courseof patientswith heedinjurius. hnpalred Respiration: SUFENTA shouldha usedwith cautionIn patients with pulmonary disease, decreased respiratory res or potentially compromised respiration. Insuchpatients, oplolds mayadditionally decresa respiratory driveandIncrease airwayresistance. Duringanesthesia, this can be managed byassisted or controlled respiration. Impaired Hepatic orRenal Function: Inpatients withliverorkidneydysfunction, SUFENTA shouldbe administered with cautionduntotheimportance oftheseorgans in themetbolism aid excretion TH ANETEI PIAR Sm. .0VIE IZ 50r 0 0 ot 0sm .55.CE nee S PATE KES TAT Y 0r 0r l du** .o . S 55 S *oneg 55. . S. *0 Dermatologlcal: itching,arythmma Cardiovascular: tachycardia, arrhythmia ofSUFENTA. Central NervousSystem: chills nsauw,vomiting Nolong-term animalstudies ot SUFENTA Gastrointestinal: Cerolseaei, Metageeaalasadlmpalraet ofhily: muscle movement intrasopertive respiratory Miscellaneos: apses, postoperative rats revealed that Respiratory: tet in tamale carcinogenic potential. Themicronucleus to evaluate havebeespertormad bronchospasm dose) depression, 2.5timestheupperhuman (approximately ashighas80 Mg/kg doses ofSUFENTA singleIntravenous (sufentanll citrta) isa Schedule II controled drugaubstanca mutations. TheAmesSaknnonella typhinurlum metabolic activating ARM19 AW DEPINENCE: SUFENTA produced no structuralchromosome far being abused. of themorphine typeandthereor ha thepotential forreproduction studies in ratsasdrabbits thatcanproducedrugdependence testalsorevealed mutagenic activity. SeeANIMAL TOXICOLOGY actions ofSUFENTA ofthepharmacological byan astension Overdosage wouldbemanifested OVERDOIME: effectin ratsandrabbitswhen hasbeenshowntohavean embryacidal Pregecoe,CetgeeyC:SUFENTA no experiences of overas with potentopialdanalgesico. However, (seeCLINICAL PHARMACOLOGY) dose for a periodof 10deysto over30 days.Theseeffectswere givenin doses2.5timestheupperhuman 0 LD ofSUFENTA Inmale duringclinicaltrials. Theintravenous dosage with SUFENTA havebeenestablished with increased mortality)tollowing tosicity(decreased food consumption mestprobably dueto maternal for LOns Inotherspecies). Intravenous adminisiatlon (seeANIMALTOXICOLOGY afteradministraratsis 9.34to12.5mg/kg ofthe drug.Noevidence ofteratogenic effectshaveben observed prolonged administration antidote ts manage respiratory as a specific suchasnaloxoneshouldbe employed studiesin pregnantwomen. of a oploidantagonist andwell-controlled lion ofSUFENTA is ratsor rabbits.Theresreno adequate maybelongerthan following overdosage withSUFENTA depression depresuios. Thedurationof respiratory onlyif thepotential benefit justifiesthepotentialrisktothelatus. shouldbeused duringpregnancy SUFENTA shouldnotpreclude of an epiod antagonist Administration durationof actionofthe spisidantagonist. in laboranddelivery. the datato support the useof SUFENTA Labor ad Delvy: Thereare insufficient andventilation oxygen shouldbeadministered In theeventofoverdusage, countermeasures moreimmediate Therefore, such se isnutrecommended anda for hypoventlatlon orapse. A patentairwaymastbemaIntarned, assisted or controlled usindicated Nenteg Metear: itIs not knownwhether this drugis excreted in human milk.Because manydrugsare esopharyngeal airwayor endotracheal tubemaybe indicated. It depressed respiration to associated with excreted Inhuman mitt, caution should beaercisedwhenSUFENTA Is administered to anursingwomen. muscular rigidity,a neuromuscular blocking agentmaybe required tofacilitate assisted orcontrolledrespiremeaures andothersupportive forthetreatmentof hypotension fluidsandvusopressors cardlo- fan. Intravenous in children undertwoyesrsof ageundergoing Paitroi Uis: ThesafetyandefficacyofSUFENTA maybe employed. of cases. in a limitednumber surgery hasbeesdocumented vencular according should he individualized in each cane ADUIfUSTRIO N: The dosage of SUFENTA 1.8 to 13.0 m/kg in D0AS1 AID Is 15.8to 19.0mg/kginmice, LOa of SUFENTA Aelmal Tealy: Theintravenous condition, useof otherdrugs,endtypeof surgical pathological to bodyweightphysicalstatus,underlying performed in rutsendrabbitsgivedose of Reproduction studies guinea pigeand10.1to19.5mg/k indogs. of thedosage (morethan20%aboveidealtotalbodyweight), In obesepatients procedure andanesthesia. materalmortaltyrates dosefor aperiod of 0toover30 daysrevealedhigh upto 2.5timestheupperhuman Inelderly and shouldbe reduced weight.Ousage onthebasisof teasbody shouldbe determined ofthe results. SUFENTA interpretation anymeaningful andanoxia,whichpreclude doeto decreased foodconsumption (seePRECAUTIONS) patients and debilitated depression of oploideare respiratory adversereactions MACTINS: Themootcommon AlVR U.SPatentNo.3,998,834 enthemanagement at PHARMACOLOGY, WARNINGS endPRECAUTIONS skeletal muscle rigidity. SeeCLINICAL 1J8JePr ui I resctions InclinicaltrialstnoNThemoatfequest adverse respirutory depression andskeletalmusclerigidity. NJ09854 1989,March1985 PHARMACEUIICA Piscataway, (7%),hypertension (3%),chestwallrigidity (3%) ing320patients administered SUFENTA were:hypotension andbradycarde (3%).Other adverse reactions witha reported incidence of lessthan1% were: 0 JesaePhiannceua Inc.1987 JPI-715 no DIRS other SEN January Fro 0 Du PotCitclCae. et okae For acute control of ventricular rate... 3revibloc S(esmolol HCI) Precise control Safety enhanced by * Catecholamine levels markedly raised by stress of surgery often remain elevated. Atrial fibrillation, atrial flutter and sinus tachycardia frequently occur in this setting cardioselectivity * Brevibloc® provides rapid, precise control of ventricular rate in atrial fibrillation or flutter, and in noncompensatory sinus tachycardia where, in the judgement of the physician, specific intervention is required Rapid beta blockade, rapidly reversible * Steady-state blood levels within 5 minutes with loading infusion 1 * 9-minute elimination half-life allows substantial reversal of effects within 10-20 minutes of discontinuing infusion in the vast majority of patients 2-5 * Significantly less bronchospastic potential than propranolol 9 * Unique pharmacokinetics and titratability make relative cardioselectivity clinically useful Blood pressure reduction * In patients with SVT, significant decreases in blood pressure occurred in 20-50% of patients. About 12% of SVT patients experienced symptomatic hypotension (mainly dizziness and diaphoresis)-6% of total discontinued 10 * Patients-especially those with low pretreatment blood pressures-should be closely monitored during Brevibloc administration Please see references and brief summary of prescribing information on following page. ®1987 Du Pont Critical Care, Inc Titratabilityimproves control * Administration by continuous infusion and 9-minute elimination half-life allow more accurate titration to meet fast-changing clinical requirements 5-8 Brevibloc A new level ofcontroland safety in IV beta blockade aV N YO >u._.,M ° References: 1.Data on file. Du Pont Critical Care [Steady-state blood levels] 2. Sum CY et al Kinetics of esmolol, an ultra-short-acting beta blocker, and of its malor metabolite Clin Pharmacol Ther 1983;34(4) 427 3. Gold MI, et al: Heart rate and blood pressure effects of esmolol after ketamine induction and intubation Anesthesiology 1986,64 718 4. Greenspan AM, et al Electrophysiology of esmolol Am J Cardiol 1985:56:19F 5. Morganroth J, et al Comparative efficacy and tolerance of esmolol to propranolol for control of supraventricular tachyarrhythmia Am J Cardiol 1985;56 33F 6. Abrams J, et al Efficacy and safety of esmolol vs. propranolol in the treatment of supraventricular tachyarrhythmias-a multicenter doubleblind clinical trial Am Heart J 1985;110913 7. Allin D, et al Intravenous esmolol for the treatment of supraventricular tachycardia results of a multicenter, baseline controlled safety and efficacy study in 160patients Am Heart J 1986;112:498 8. Byrd RC, et al Safety and efficacy of esmolol (ASL-8052: an ultra-short acting beta adrenergic blocking agent) for control of ventricular rate in supraventricular tachycardias. J Am Coll Cardiol 1984:3(2):394 9. Sheppard D; et al Effects of esmolol on airway function in patients with asthma. J Clin Pharmacol 1986;26(3):169 10. Data on file, Du Pont Critical Care [Hypotension] BREVIBLOC* INJECTION (esmolol hydrochloride) 10mLAmpul-2 5 g Brief Summary NOT FOR DIRECT INTRAVENOUS INJECTION BREVIBLOC* MUST BE DILUTED PRIOR TO ITS INFUSION (SEEDOSAGE AND ADMINISTRATION SECTION) INDICATIONS AND USAGE Supraventricular Tbchycardla BREVIBLOCm (esmolol HCI) is indicated for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a shortacting agent is desirable BREVIBLOC® is also indicated in noncompensatory sinus tachycardia where, in the physician's judgement, the rapid heart rate requires specific intervention BREVIBLOC is not intended for use in chronic settings where transfer to another agent is anticipated CONTRAINDICATIONS BREVIBLOC (esmolol HCI) is contraindicated in patients with sinus bradycardia, heart block greater than first degree, cardiogenic shock or overt heart failure (see Warnings) WARNINGS Hypotenslon: Inclinical trials 20-50% of patients treated with BREVIBLOC' (esmolol HCI) have had hypotension, generally defined as systolic pressure less than 90 mmHg and/or diastolic pressure less than 50 mmHg About 12%of the patients have been symptomatic (mainly diaphoresis or dizziness) Hypotension can occur at any dose but is dose-related so that doses beyond 200 mcg/kg/min are not recommended Patients should be closely monitored, especially if pretreatment blood pressure is low Decrease of dose or termination of infusion reverses hypotension, usually within 30 minutes Cardiac Failure: Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure Continued depression of the myocardium with beta blocking agents over a period of time can, in some cases, lead to cardiac failure At the first sign or symptom of impending cardiac failure, the dosage should be reduced or BREVIBLOC* should be withdrawn Although this dosage adjustment or withdrawal may be sufficient because of the short elimination half-life of BREVIBLOC, specific treatment may also be considered (See Overdosage ) Bronchospastic Daeeaea: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Because of its relative betai selectivity and titratability. BREVIBLOC may be used with caution in patients with bronchospastic diseases However, since beta selectivity is not absolute, BREVIBLOC should be carefully titrated to obtain the lowest possible effective dose. In the event of bronchospasm, the infusion should be terminated immediately; a beta2 stimulating agent may be administered if conditions warrant but should be used with particular caution as patients already have rapid ventricular rates Diabetea Melltus and Hypoglycema: BREVIBLOC- should be usedwith caution in diabetic patients requiring a beta-blocking agent Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected PRECAUTIONS General Infusion concentrations of 20 mg/mL were associated with more venous irritation and thrombophlebitis than concentrations of 10 mg/mL Concentrations greater than 10mg/mL should, therefore, be avoided Because the acid metabolite of BREVIBLOC is primarily B excreted unchanged by the kidney BREVIBLOCw(esmolol HCI) should be administered with caution to patients with impaired renal function The elimination half-life of the acid metabolite was prolonged ten-fold and the plasma level was considerably elevated in patients with end-stage renal disease Drug Interactons Catecholamine -depleting drugs, e g , reserpine may have an additive effect when given with beta blocking agentss Patientstreated concurrently with BREVIBLOC* and a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may result in vertigo, syncope, or postural hypotension A study of interaction between BREVIBLOCs and warfarin showed that concomitant administration of BREVIBLOC and warfarin does not alter warfarin plasma levels BREVIBLOC* concentrations were equivocally higher when given with warfarin, but this is not likely to be clinically important • When digoxin and BREVIBLOC (esmolol HCI) were concomitantly administered intravenously to normal volunteers, there was a 10-20% increase in digoxin blood levels at some time points Digoxin did not affect BREVIBLOC' pharmacokinetics When intravenous morphine and BREVIBLOC' were concomitantly administered in normal sublects, no effect on morphine blood levels was seen, but BREVIBLOC* steady-state blood levels were increased by 46% in the presence of morphine No other pharmacokinetic parameters were changed The effect of BREVIBLOC' on the duration of succinylcholine-induced neuromuscular blockade was studied in patients undergoing surgery The onset of neuromuscular blockade by succinylcholine was unaffected by BREVIBLOC*, but the duration of neuromuscular blockade was prolonged from 5 minutes to 8 minutes Although the interactions observed in these studies do not appear to be of major clinical importance, BREVIBLOC' should be titrated with caution in patients being treated concurrently with digoxin, morphine, succinylcholine or warfarin Carclnogeneals, Mutagenesla, Impailment of Fertility Because of its short term usage no carcinogenicity, mutagenicity or reproductive performance studies have been conducted with BREVIBLOCS Pregnancy Category C Teratogenicity studies in ratsat intravenous dosages of BREVIBLOC* up to 3000 mcg/kg/min (ten times themaximum human maintenance dosage) for30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while a dosage of 10,000 mcg/kg/min produced maternal toxicity and lethality. In rabbits, intravenous dosages up to 1000 mcg/kg/min for 30 minutes daily produced no evidence of maternal toxicity embryotoxicity or teratogenicity, while 2500 mcg/ kg/min produced minimal maternal toxicity and increased fetal resorptions There are no adequate and well controlled studies in pregnant women BREVIBLOC* should be used during pregnancy only if the potential benefit lustifies the potential risk to the fetus Nurasng Mothers It is not known whether BREVIBLOC is excreted in human milk, however, caution should be exercised when BREVIBLOC' isadministered to a nursing woman Pediatric Use The safety and effectiveness of BREVIBLOC* in children have not been established ADVERSE REACTIONS Supraventricular Tachycardia The following adverse reaction rates are based on use of BREVIBLOC* (esmolol HCI) in almost 400 clinical trial patients with supraventricular tachycardia In addition, over 600 patients have been exposed in clinical studies of other conditions The most important adverse effect has been hypotension (see Warnings) Most adverse effects have been mild and transient Cardiovascular- Symptomatic hypotension (diaphoresis, dizziness) occurred in 12%of patients, and therapy was discontinued in about 11%,about half of whom were symptomatic Asymptomatic hypotension occurred in about 25% of patients Hypotension resolved during BREVIBLOC infusion in 63% of these patients and within 30 minutes after discontinuation of infusion in 80% of the remaining patients Diaphoresis accompanied hypotension in 10%of patients Peripheral ischemia occurred in approximately 1% of patients Pallor, flushing, bradycardia (heart rate less than 50 beats per minute), chest pain, syncope, pulmonary edema and heart block have each been reported in less than 1%of patients In two patients without supraventricular tachycardia but with serious coronary artery disease (post inferior myocardial infarction or unstable angina), severe bradycardia/sinus pause/asystole has developed, reversible in both cases with discontinuation of treatment Central Nervous System Dizziness has occurred in 3% of patients, somnolence in 3%, confusion, headache, and agitation in about 2%, and fatigue in about 1%of patients Paresthesia, asthenia, depression, abnormal thinking, anxiety anorexia, and lightheadedness were reported in less than 1% of patients One brief (30 second) episode of grand mal seizure has been reported Respiratory-Bronchospasm, wheezing, dyspnea, nasal congestion, rhonchi, and rales have each been reported in less than 1% of patients Gastrointstlinal Nausea was reported in 7% of patients Vomiting has occurred in about 1%of patients Dyspepsia, constipation, dry mouth, and abdominal discomfort have each occurred in less than 1%of patients Taste perversion has also been reported Skin (Infusion Site)- Infusion site reactions including inflammation and induration were reported in about 8% of patients Edema, erythema, skin discoloration, and burning at the infusion site have each occurred in less than 1% of patients MIscelaneoua- Each of the following has been reported in less than 1%of patients Urinary retention, speech disorder, abnormal vision, midscapular pain, rigors, and fever OVERDOSAGE Acute Toxicity A single case of accidental overdosage with BREVIBLOC* (esmolol HCI) has occurred to date A 5000 mcg/kg/mn dose of BREVIBLOC instead of the recommended 500 mcg/kg/min loading dose, was administered over one minute to a patient with atrial flutter Immediately following the infusion, marked decreases in heart rate and blood pressure were observed and the patient became drowsy but could be aroused The infusion rate of BREVIBLOC was decreased a to 5 mcg/kg/ mm and over the next eight minutes the patient's rhythm converted to normalsinus rhythm and the patient started feeling better Hypotension persisted for a period of four minutes after decreasing the dosage of of BREVIBLOC BLO e Thedrowsiness dsapo peared 15 minutes following discontinuation of BREVIBLOC Because of its approximately 9-minute elimination half-life, the first step in the event of toxicity should be to discontinue BREVIBLOC administration Then, based on the harmacologic actions, the following general measures should also be considered Isdycard: Intravenous administration of atropine or another anticholinergic drug Broltholpasm: Intravenous administration of a beta2 stimulating agent and/or a theophylline derivative Cardac Failure: Intravenous administration of a diuretic and/or digitalis glycoside In shock resulting from inadequate cardiac contractility, intravenous administration of dopamine, dobutamine, isoproterenol, or amrinone may be considered DOSAGE AND ADMINISTRATION NOT FOR DIRECT INTRAVENOUS INJECTION BREVIBLOC IS A CONCENTRATED, POTENT DRUG WHICH MUST BE DILUTED PRIOR TO ITS INFUSION BREVIBLOC' SHOULD NOT BE ADMIXED WITH SODIUM BICARBONATE BREVIBLOC' SHOULD NOT BE MIXED WITH OTHER DRUGS PRIOR TO DILUTION IN A SUITABLE INTRAVENOUS FLUID Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit Dilution: Aseptically remove 20 mL from a 500-mL bottle of one of the intravenous fluids (refer to full rescribing information for compatibility with commonly used intravenous fluids) and add the contents of two (2) ampuls of BREVIBLOC* (each containing 25 g esmolol hydrochloride) This yields a final concentration of 10 mg/mL The diluted solution is stable for at least 24 hours at room temperature Note Concentrations of BREVIBLOC greater than 10 mg/mL are likely to produce irritation on continued infusion (see Precautions) BREVIBLOC* has, however, been well tolerated when administered via a central vein Supraventricular Thchycardla In the treatment of supraventricular tachycardia, responses tc BREVIBLOC usually (over 95%) occur within the range of 50 to 200 mcg/kg/min The average effective dosage is approximately 100 mcg/kg/min although dosages as low as 25 mcg/kg/ mmin have been adequate in some patients Dosages as high as 300 mcg/kg/min have been used, but these provide little added effect and an increased rate of adverse effects, and are not recommended Dosage of BREVIBLOC in supraventricular tachycardia must be individualized by titration in which each step consists of a loading dosage followed by a maintenance dosage Toinitiate treatment of a patient with supraventricular tachycardia, administer a loading dosage infusion of 500 mcg/kg/min of BREVIBLOC for one minute followed by a 4 min maintenance infusion of 50 mcg/kg/min If an adequate therapeutic effect is not observed within five minutes, repeat the same loading dosage and follow with a maintenance infusion increased to 100mcg/kg/min Continue itration procedure as above, repeating loading infusion (500 mcg/kg/mmn for 1 minute), increasing maintenance infusion by increments of 50 mcg/kg/min (for 4 minutes) As the desired heart rate or a safety end-point (e g , lowered blood pressure) is approached, omit the loading infusion and reduce incremental dose in maintenance infusion from 50 mcg/kg/min to 25 mcg/kg/min or lower Also, if desired, increase interval between titration steps from 5 to 10 minutes This specific dosage and administration regimen has not been studied intraoperatively and because of the time required for titration, may not be optimal for intraoperative use Maintenance dosages above 200 mcg/kg/min have not been shown to have significantly increased benefits, and the safety of dosages above 300 mcg/kg/mmn has not been studied In the event of an adverse reaction, the dosage of BREVIBLOC* may be reduced or discontinued If a local infusion site reaction develops, an alternative infusion site should be used The use of butterfly needles should be avoided Abrupt cessation of BREVIBLOC® in patients has not been reported to produce the withdrawal effects which may occur with abrupt withdrawal of beta-blockers following chronic use in coronary artery disease (CAD) patients However, caution should still be used in abruptly discontinuing infusions of BREVIBLOC' in CAD patients After achieving an adequate control of the heart rate and a stable clinical status in patients with supraventricular tachycardia, transition to alternative antiarrhythmic agents such as propranolol, digoxin, or verapamil, may be accomplished Distributed by Du Pont Crtlcal Care, Inc. 1600 Waukegan Road Waukegan, Illinois 60085 January, 1987 A43004 AMC 0201 ( .0Qmw- Du Pont Critical Care, Inc. Free Lancing Anesthesia Can Be An Exciting Career Opportunity Barbara England, CRNA It has been for me! During the past five years I've enjoyed the freedom of staying home with my family as long as I want, then accepting rewarding assignments around the country. I've had the opportunity to ski in Vermont, view the beauty of the Rockies, and sun on Floridabeaches. Professional Anesthesia Services, Inc. offers opportunities for free lance anesthetists in almost every state. Compensation is superior to salaries offered by most hospitals and tax benefits abound. A number of our CRNAs are being introduced to new medical technology and most of all, they enjoy being their own boss. Some prefer independence from the political work environment found in many hospitals and clinics. If YOU would like to learn more about working as a free-lance CRNA, let Professional Anesthesia Services help. We're a nationwide company with emphasis on quality anesthesia and we need quality people. Learn more about how our company can serve you by dropping us a line or calling toll-free for more information and literature. It could mean a new life for you! Professional Anesthesia Services, Inc. 4400 Bayou Blvd., Suite 54A * Pensacola FL 32504* 1-800-634-6664 * in Florida 904-479-3211 P.O. Box 12861 * Pensacola, Florida 32576 Specialists In Locum Tenens and Permanent Placements for CRNAs.
