Considerations in surgery of the common duct

CURRENT

PROBLEMS EDITORIAL

U RGER,

BOARD

,',lark .Xl. Ilavitc]~, .XI.I). Chairm(m E d w i n 11. I:,Iliscm, .XI.D. O n n a m t (2. J~llian, .XI.l). Alan P. Tidal, .NIiD. O w e n I1. \Vangensteen, M.D.

A Series of Monthly Clinical Monographs

May 1968

CONSIDERATIONS in S U R G E R Y of the C O M M O N D U C T John L. Madden

William j. McCann

Souhel Kandalaft

Bok Y. Lee •

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received his M.D. from the University of Kansas School of Medicine. H e is presently combining a residency in general surgery with graduate work toward a Ph,D. degree in physiology. Doctor Hermreck is a USPHS Postdoctoral Fellow, His research activities involve the cardiovascular system and pancreas,

is Professor of Surgery in the University of Kansas Medical Center. He took his residez,cy training a~ the University of Minnesota, where he received the degree of Ph.D. (Surgery) in 1956. He serves on several committees of the N a t i o n a l Research Council. Doctor Thal's clinical interests

encompass the areas of general and thoracic surgery, and his research activities center about the cardiovascular area and shock.

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THERE ARE FEW PHYSIOLOGIC RESPONSES which match the immediate, dramatic and widespread effects of the natural release or intravenous injection of powerful adrenergic substances. Heart rate and force of myocardial contraction are augmented, the blood pressure rises and the metabolic pace quickens. Clearly, this sympathomimetic reaction is intimately involved in t h e adaptive response to shock-producing injury. Because of their consistent ability to raise blood pressure, the adrenergic drugs have commonly been used in the treatment of shock, although their potentially damaging effects on tissue perfusion have long been known (47). Currently, there is recognition of the importance of maintaining tissue perfusion, rather than arterial pressure per se in shock therapy, and as a consequence, the value of the vasoconstrictor drugs has been seriously questioned. However, recent studies have shown a wide spectrum of activity of the adrenergic drugs. These findings have opened fascinating possibilities of manipulating selectively the cardiovascular system and certain vital metabolic processes by the judicious use of currently ayailable drugs. The present review will ~deal with important conceptual advances in the classification of the adrenergic receptors and with the pharmacologic and metabolic actions of the more common adrenergic stimulating and blocking drugs and will outline some clinical experiences in the treatment of shock. NOTE: Supported by U S P H S G r a n t # 11241-02 a n d also in p a r t by t h e K a w Valley Heart Association:and USPHS Grant # NB07369'01. 3

I. CLASSIFICATION OF ADRENERGIC RECEPTORS In the 1930s, Cannon and Rosenbleuth (24) ix)stulated two hypothetical mediator substances, one excitatory (sYmpathin E) and the other, inhibitory (sympathin l) to explain the varied effects observed with sympathetic stimulation. This classification, however, did not wholly explain the earlier classic work by Dale (36) showing that ergot blocked all the excitatory effects of epinephrine, except those on the heart, but failed to block the inhibitory actions of epinephrine on the circulatory system. Dale was the tirst to clearly differentiate two distinct types of receptors for epinephrine: one receptor, excited by epinephrine to give motor responses, could be "'paralyzed" by eegot alkaloids, whereas the other receptor, which was inhibited by epinephrine, was unaffected by ergot. Ahlquist (1) stimulated further consideration of this proble m by pointing out that not a single known amine fulfilled the requirements for either sympathin E or sympathin I. H e postulated further that the varied effects of sympathetic activity, observed with various amines, were due to stimulation of different receptor types in the effector cells and not to release of different mediator s~bstances. Ahlquist's concept was based on the fo{lowing observation: A series of six closely related sympathominletic amines has one order of potency on the following functions: vasoconstriction, excitation o f the uterus and ureters, contraction of the nictitating membrane, dilation of the pupils and inhibition of the gut. In contrast, this same series of amines have an entirely dilferent order of potency on the following functions: vasodilation, inhibition of the uterus and myocardial stimulation. Ahlquist concluded that variations in the activity of the amines were due to stimulation of dilterefft receptors. On this basis, he class~ed adrenotropic receptors into two distinct t y p t . ~ alpha and beta--and categorized the responses of various effector organs to adrenergic stimuli in a manner outlined in the table. Additional evidence to supportand develop Ahlquist's classification evolved i,when various highly specifie~ adrenergic blocking agents, which p r o d u c e a. diffet:ential blockade Ofr either alpha, o r beta-adrenergic receptor tissue, responses, were :develo .ped~ The relatively nonspecific ergot alkaloids itowards i epinephrine had beenidemonstrated early byl Dale ( 3 6 ) , S011man and Brown ( 1 3 6 ) : Otlaeri!more~selectiVe , drugs :suCh a s Dibenamine (Nickerson and Goodman [!06]),i!phenoxybenzamine/(Mc~an,et al, [95]), and t ''~ " " ' ' "(Memr . . . . . .et:al. [96]), were-devel0ped:subsequently to p h enommme: Ahlqmst s classificatmn,:~:and ::have been reported: to: be very specific alpha-adrenergie: receptorl blocking! a~nts, .

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blocked by DCI. Thus, DCI was the first known beta-adrenergic receptor blocking drug. More specific beta-blocking drugs, such as p1"onethalol (Black and Stephenson [17]), and propranolol (Black et al. [ 16] ), have recently been developed. Although oilier classifications for adrenergie receptors have been proposed by Lands (81 ) and Furchgott (52), the original classification by Ahlquist, with slight modification, is the most widely ac,cepted today. The. adrenergic, drugs to be reviewed will be classified and disRESPON.~ES OF EFFECTOR ORGANS TO ADRENERGIC STIMULI* R ECEPTOR TYPE

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Detrusor Trigone & sphincter Eye

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Pilomotor muscles Sweat glands

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cussed according to the receptor stimulated or blocked (Fig. 2). On this basis, the action of the drug is pr;:dictaSle in~the standard experimental animal preparation or nomaal human. In acute disease states, however, where the blood volume may be severely reduced and the vasomotor centers and adrenergic receptors may already be RG. Z" _,LDiagrammatic ~oncept of biosynthesis of norepinephrine and drug action at the adrc.nergic~hervc~4mding. (Modified and reproduced with permigsion .of Dr. William B~~I;Abrams.)

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under intense stimulation, the action of these drugs may not be entirely predictable. Also, in chronic disease states such as congestive heart failure, either myocardial catecholamine synthesis or binding may be impaired since total norepinephrine content of the heart is decreased (27). The ability of tlie heart in congestive failure to take up catecholamines is not impaired, however, and frequently congestive heart failure is associated with sympathetic hyperactivity. Similarly, norepinbphrine levels within sympathetic ne~'e endings may be decreased in advanced hemorrhagic shock (35). Hyperthyroidism also creatc:s a condition: where cardiac sensitivity to circulating catecholamines is incl~ea~d (37). Chronic use of drugs such as either guanethidine, which blocks spontaneous release of norepinephrine (69), or reserpine, which depletes endogenous norepinephrine (15), will decrease sympathetic activity. Sympathectomy alters the capacity of the organs involved to take up Ha-catecholarnine. but actually enhances their responses to circulating catecholamines (68). Administration of tyramine or foods rich in tyramine, such as cheddar cheese or wine, to a patient who has been on monoamine oxidase inhibitors may cause death resulting from extreme hypertension (94) since patients who have been treated chronically with M A t inhibitors cannot inactivate tyramine, which liberates free norepinephri-r,.e (72). These a n d other conditions limit the ability to predict the response to adrencrgic drugs in certain groups of patients. tt.

THE HEMODYNAMIC AND METABOLIC EFFECTS OF THE ADRENERGIC AGENTS

GENERAL HEMODYNAMIC ACTIONS OF THE ALPHA- AND BETA-.MIMETIC DRUGS

According to the classification devised by Ahlquist, adrenergic stimulating drugs may be termed alpha-mimetic or beta-mimetic depending on the receptor stimulated. Methoxamine represents a prototype of the alpha-mimetic drugs. As illustrated in the ~table, the peripheral vascular tree (veins and arteries) is conceived to be richly populated with, and the heart virtually devoid of alpha-adrenergic receptors. Consequently, this drug produces a response in the peripheral system characterized by intense vasoconstriction ('5)with a marked rise in blood pressure followedby reflex slowing of the heart. Little effect is noted on venous tone in human extremities (42)~ 3,et centra.1 venous pressure increases. There are few, if any, inotropic effects on the heart (58, 59), so cardiac output decreases because of the reflex bradycardia and increased peripheral resistance. Blood flow to most organs is decreased due to the intense vasoconstriction and decreased cardiac output. Isoproterenol, ' at the opposite pole of the adrenergie spectrum, 7

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represents the prototype of a pure beta-mimetic drug. All components o f the cardiovascular system are subserved by beta-adrenergic receptors (see the table, p. 5). The response seen with a beta-mimetic agent is directly opposite to that seen with an alpha-mimetic agent. Arteriolar dilation occurs with a mild increase in systolic blood pressure, but a decrease in diastolic pressure (2). Venoconstriction causes blood to shift centrally (80). Central venous pressure decreases because of the more effective cardiac action (2, 38). Blood flow to most organs is augmented as a result of the fall in peripheral resistance and increase in cardiac output (38) (Fig. 3 ). Unfortunately, only a few adrenergic drugs can be defined neatly as pure ialpha, o r beta-mimetic agents. Most of these agents have varying degrees of alpha and beta activity and .their properties will be discussed later. METABOLIC EFFECTS Recent studies have begun to elucidate the important metabolic effects on the catecholamines. However, the metabolic effects of the adrenergic agents cannot be separated clearly on the basis of alpha or beta receptors. Elevation of blood glucose and lactate, and a decrease in rthe glycogen content of the liver and skeletal muscle (66, 70, 7 7 , 93, 139, 140) has long been known, but the control of vital metabolic processes exercised by catecholamines h a s only recently been subjected to a unitarian hypothesis. The common process underlying the various actions of catecholamines is apparently an acceleration of the synthesis of cyclic 3', 5,-adenosinemonophosphate (cyclic AMP), the formation of which is catalyzedby adenyl cyclase, an enzymestimulated by catechola~ines (Fig. 4). In muscle, cyclic

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AMP converts inactive phosphorylase b to active phosphorylase a, which in turn brings about the breakdown of glycogen t o yield glucose-6 phosphate (52, 70, 79, 116, 139, 140). Since muscle lacks glucose-6-phosphatase, glucose-6-phosphate is metabolized to lactic acid causing an increase in blood lactate levels. In the liver, however, glucose-6,phosphatase is present and converts glucose-6-phosphate to glucose, thereby raising blood glucose. Other hePatic effects of catecholamines, which may be mediated by cyclic A M P , includb increased ketogenesis and inhibition of incorporation of acetate iiato fatty acids and cholesterol (14), stimulation of gluconeogenesis (48) and inhibition of incorporation of amino acids into proteins (114). There is now accumulated evidence suggesting that cyclic AMP may be involved in the inotropic response o f the heart. Murad et al. (101 ) measured the relative potency of several catecholamines, with respect to their ability,~to stimulate cyclic AMP formation by sub•

c~Uular particulate preparations from dog myocardium. The relative potencies were: 1-isoproterenol, 7.8; 1-epinephrine, 1.0; l-norepinephriae, 1.0; and d-epinephrine, 0.12. These values are very similar to the relative in vivo inotropic potencies of these agents (32, 59, 92). Robinson et al. (119) have demonstrated that tissue levels of cyclic AMP in the isolated perfused working rat heart increased approximately fourfold within 3 seconds after inj~tion of a single submaximal dose of epinephrine. In these experiments, the contractile force did not reach a peak until 20 seconds after the injection of epinephrine. The increased tissue level of cyclic AMP and the inotropic effects of epinephrine are both blocked with the beta-adrenergie blocking agent pronethalol (119). Levine and Vogel (83) have reported that intraeardiae injection of cyclic AMP in unanesthetized dogs is followed by marked increase in rate and cardiac output. This may also occur in man (82). The eatecholamines are now thought to control the rate of many vital enzyme reactions through cyclic AMP. Change in the pace of these various enzyme reactions account for a large portion of the metabolic and cardiovascular effects observed with ca"iecholamine administration. On the basis of the studies already referred to, the hypothetical beta receptors seem to be identical with adenyl cycla~ (120). There is also speculation that the alpha receptor may be related to adenyl eyclase (120). There is evidence now that production of cyclic AMP is affected by agents (histamine, vasopressin, ACTH, etc.) other than the cateeholamines (141). Whether or not these homlones interact with the enzyme adenyl eyelase to catalyze the formation of cyclic AMP in a manner similar to the cateeholamines is not clear at present. Recent studies suggest that the methyl xanthines (theophylline and aminophylline) block phosphodiesterase, the enzyme responsible for degradation of cyclic AMP, demonstrating other mechanisms for effecting cyclic AMP tissue levels (23). This action of the methyl xanthines on cyclic AMP may explain why they have catecholaminelike effects on the cardiovascular system. Catecholamines also raise the blood concentration of free fatty acids (23, 66, 70, 88, 1 5 3 ) b y activation of a specific lipase in adipose tissue which converts triglyeerides to glycerol and free fatty acids, This may be accomplished by the activation of the same cyclic AMP system which is involved in glyeogenolysis. It has been demonstrated that epinephrine increases the activity of adenyl eyelase and t h e levels of cyclic AMP in adipose tissue (23, 77, 79), and that derivatives of cyclic AMP have the same lipolytie effects as eatecholamines (23).~ The calorigenie effects, respiratory stimulating effects, vasodilating and vasoconstrieting effects of eateeholamines in general may be:mediated via cyclic AMP (89), Cyclic AMP thus appears to a e t a s a common rate potentiating agent in a host of vital metab01ie processes, a findingwhich:may provide the basis f o r a unitarian molecular theory explaining the faction of the adrenergie agents.

III. THE ALPHA-MIMETIC BETA-MIMETIC SPECTRUM OF ADRENERGIC DRUGS By following Ahlquist's classification, the adrenergic drugs may be arranged into a spectrum extending from the purely alphamimetic through a large group having mixed properties to the opposite pole of the pure beta-mime.fie drugs. Some of the significant properties of the more commonly used agents will now be considered. Methoxamine (Vasoxyl) is, for all practical purposes, a pure alpha-mimetic agent. The hemodynamic effects have already beeu described. It is a potent vasopressor with few, if any, direct effects on the heart. A reflex bradycardia results from its pressor effect. Its metabolic effects have not beea extensively studied. One interesting effect of this drug is that when the reflex vagal slowing of the heart is blocked with atropine, me,thoxamine will further slow the heart. This may be due to the partial beta receptor blocking ability which this drug seems to exhibit in man and the dog (74), since it prolongs ventricular muscle action potentials and refractor), period and slows A-V conduction (53 ). Norephlephr#~e (Levarterenol) is the chemical transmitter of the postganglionic sympathetic nerve endings. It functions in man as a primary alpha-adrenergic stimulant on the peripheral circulation, but also has beta-adrenergic activity on the heart and metabolism (75). The pharmacologic interpretation of the cardiac effects of norepinephrio.e has been debated. Some believe norepinephrine is purely an alpha-adrenergic receptor stimulant and explain its action on the heart by postulating that the heart has undifferentiated receptors (52). Others think that norepinephrine, like epinephrine, has both alpha- and beta-adrenergic receptor stimulating properties since its alpha and beta effects can be selectively blocked by the alpha- and beta-adrenergic blocking agents (97). In the intact individual, norepinephrine is primarily a vasoconstrictor and its action is exerted on the blood vessels of the kidney (30, 135), splanchnic organs (13), cutaneous area (11), brain (59, 126), skeletal muscles (9, 50) and lung (51, 111 ). This generalized vasoconstrictor action leads to an increase in_ peripheral resistance and arterial blood pressure (2). A reflex bradycardia usually results which can be blocked by atropine (11). Cardiac output is increased in the dog (59, 123), but remains the same, or is slightly increased, in man (13, 51, 61, 145) (Fig. 5). This is probably due to the bradycardia (11) and the increase in peripheral resistance. Some confusion has arisen in the literatui'd because both norepinephrine and epinephrine have inotropic ~effects on isolated heart preparations. Yet only epinephrine causes a marked increase in cardiac output in man. This confusion has been resolved with the demonstration that.norepinephrine greatly increases cardiac output i n the human after vagus blockade with tetraethylammonium bromide or atropine (148), Norepinephrine, having a more potent 11

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peripheral vasoconstrictor effect and causing a greater elevation in blood pressure fllan does epinephrine (59, 60), induces an intense reflex bradycardia. Thus, the negative chronotropic effects of the vag~ reflexes mask the direct stimulating effects of norepinephrine, and cardiac output changes very little. Norepinephrine has also been shown t o increase cardiac output considerably in man (150) and in dog (5) after alpha-adrenergie blockade with phenoxybenzamine (Fig. 6). Norepinephrine increases pulmonary, resistance m the dog (6) and man (51, 111 ). Systemic venom constriction, With shifting of blood centrally t o t h e lung, occurs in the dog (118, 121, 127) and possibly in man, since peripheral venous constriction occurs (19, 20, 21, 43). The metabolic effects of norepinephrine are qualitatively similar to those: described under general considerations. Memraminol ( A r a m i n e ) i s a potent v,'Lsopressor and functions to deplete norepinephrine by displacement(128, 129). Therefore, its actions are almost identical to that of norepinephrine with the except i o n that metaraminol appears not to reduce renal blood flow as much as norepinephrineiin~ m a n ( 8 6 ) . It has been shown to liberate norepinephrine and is itself taken up by adrenergie neurons and the heart-in p l a c e of norepinephrine (129). Pretreatment o f subjects with norepinephrine-releasing drugs such as reserpine attenuates or abolishes the action of metaraminol a n d prolonged administration of metaraminol leads to a state of refractoriness to its vasopressor actions (34). T h i s m a y reflect an action as a false transmitter similar to that of alpha-methy]dopa, or because norepinephrine is depleted. I t has b e e n shown :that metaraminol, like norepinephrine, is 12

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released by norepinephrine-releasing drugs (reserpine, guanethidine), while uptake of metaraminol is inhibited by drugs inhibiting norepinephrine uptake (imipramine, guanethidine) (129). Metaraminol, like norepinephrine, may be released from the heart by sympathetic nerve stimulation (33). Sarnoff (124) made some interesting observations on metaraminol. He showed that the vasoconstrictor and myocardial stimulant effects of rnetaraminol were separate and dissociated with small doses i n t h e dog. Clearly, myocardial contractility was improved without vasopressor effects when small doses were used. The metabolic effects of metaraminol are similar to those~seen in norepinephrine. Epinephrine (Adrenalin) is one of the oldest known adrenergie stimulants. Oliver and Schafer (108) i n 1895, showed thepressor action of extracts from the suprarenal gland i(predominant :site of endogenous production of epinephrine). Epinephrine is mainly a beta-adrenergic stimulant at low doses, although i t d 0 e s possess potent alpha-mimetic effects in high doses. When infused:intravenously, epinephrine causes a n increase in heart rate (chronotropic effects) ( 2 , 10, 61). This is presumably the result of the direct action 13

of epinephrine on the sinoatrial node. Also, it has been shown to increase conduction velocity through the atrioventricular node and shorten the refractory period of cardiac muscle. In a standard normotensive preparation, •stroke volume increases as a result of the direct effects of epinephrine on the force of myocardial contractility (inotropic effects) (10, 61 ). Thus, cardiac output increases as a result of the increased stroke volume and heart rate. Total peripheral resistance falls with physiologic doses only, although systolic pressure increases and diastolic pressure remains unchanged, or increases sligdatly, causing a moderate increase in mean blood pressure (2, 10, 6 I). Venous constriction has been demonstrated in the extremities in man (43, 57, 110) and throughout the systemic venous bed in the dog (80), causing a shift of blood centrally in the dog (80) and possibly in man (43). Central venouspressure increases (117), and coronar3' (31 ), cerebral (78, 126), splanchnic (13) and skeletal muscle (9) blood flow increase, whereas renal blood flow (7, 26, 135), and blood flow through skin and mucous membranes decrease (11). Pulmonary vascular resistance is increased in the dog (6). The metabolic effects of epinephrine are similar to those ,already described. Mephentermine (Wyamine) appears to be an alpha- and betaadrenergic stimulant, but its over-all effects are beta-mimetic in nature. Its action on the heart appears to be dependent.on endogenous norepinephrine, since prior treatment of dogs with reserpine abolishes mephentermine, s cardiotonie effects (49). Prolonged administration of this drug leads to a state of myocardial refractoriness possibly because o f nerepinephrine depletion of the heart or other factors not clear at present. When infused, mephentermine increases heart rate and myocardial contractility with a resultant increase in cardiac output (5, 71, 84),: Mephentermine seems to act like isoproterenol on the peripheral circulatiofi by decreasing arterial resistance (5), while artenal••pressure remains the same or is decreased slightly. However, l a r g e doses of mephentermine, in contrast to isoproterenol, will cause :vasoconstriction. It appears to function as a vasoconstrictor since it has been shown in the dog to increase venous retuna to the heart when cardiac :output is maintained constant by right heart bypass-:-(147). Antiarrhythmia effects have also been reported for this agent (109,1 149). The metabolic effects of mephentermine are not known. lsoproterenot ( I s u p r e l ) i s a pure beta-mimetic agent and its hemodynamic effects have already been described. The metaboliceffects of ~oproterenol are somewhat different from those mentioned for norepiUephrine~ and epinephrine:: !It i s as effective a s epinephrine in releasing free,:fatty acids a n d increasing oxygen demands (75), but has very ilitfle~i effect on blood glucose levels (73). The effects of isoproterenoI 0n the:heart are very similar t o those of norepinephrine andepinephrine: on t h e h e a r t when, their peripheral vasoconstricting effects are abolished b y a l p h a adrenergic bl0ckade. .

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OTHER AGENTS Alpha-methyl tyrosine, an analogue of tyrosine, blocks the activity of tyrosine hydroxylase (the enzyme responsible for the conversion of tyrosine to DOPA) (Fig. 7). Tyrosine hydroxylase appears to be the rate-regulating enzyme for eatecholamine synthesis since its con.centration in catecholamine producing tissues is lower than other enzymes involved in catecholamine synthesis (102). It apparently blocks catecholamine synthesis a n d has been used effectively in controlling pheochromocytoma (44). Tyrosine hydroxylase inhibitors will have wide use in studies of adrenergic mechanisms, and potentially in clinical therapeutics. Dopamine is one of the intermediates in eatecholamine synthesis (See Fig. 7). When administered, it has norepinephrine-like effects. Its role in clinical use has not been established. Tyramine induces potent vasopressor effects (72) (See Fig. 7). It is known to cause norepinephrine release. However, it may have to be converted to octopamine for its pharmacologic eff~ts. Its action is potentiated by monoamine oxidase inhibitors. I V . THE ALPHA-ADRENERGIC RECEPTOR BLOCKING AGENTS

Several drugs having alpha-adrenergic receptor blocking properties have been developed. First to be recognized were the e ~ o t alkaloids. but these were considerably less specific than the more recent developed drugs. The synthesis of Dibenamine and later phenoxybenzamine (Dibenzyline) provided long-acting drugs of the haloalkylaminegroup. Phentoltvnine (Regitine), an imidazolini:, is probably not as specific as the longer-acting alpha-blocking drugs, and has a short duration of action. Knowledge of the pharmacologic properties and early clinical experiences with phenoxybenzamine in shock patients derives from the wo:'k of Nickerson (103-105). Skillman et al.(132) have recently studied the physiologic effects of phenoxybenzamine in normal volunteers during control periods and in subjects in whom modest hypovolemia and hypervolemia were induced. The cardiac index was increased two- to threefold in all subjects after a 3-hour period. An increase in eaidiac output was noted in the normovolemic subjects early after infusing phenoxybenzamine and was decreased significantly in 1 hypovolemic subject, but after 2-3 hour,s, the cardiae output was increased in all patients including the hypovolemic subjects. Hypervolemia induced by dextran administration did not appear to alter cardiac output significantly when compared with normovolemic subjects who received phenoxyber~amine alone. Total peripheral resistance fell striking)y after 2 - 3 hours from a mean controlof 1,5.16 to 845 dynes-sec./cm. 5 16

Phenoxybenzamine or Dibenamine given intravenously to healthy, recumbent, normovolemic patients or animals causes minor changes in systolic blood pressure, although diastolic pressure decreases (103). Skillman (132) found orthostatic hypotension to be present up to 24 hours in the patients studied after administration of phenoxybenzamine. This blood pressure reduction is a result of the vasodilation (132) or loss of effective circulatory volume (there is a n exp,'msion of plasma volume but a comparatively larger increase in the dimensions of the va~ular space). The marked increase in cardiac output is probably due to the vasodilation causing lowered resistance coupled with the unbuffered effects of catecholamines on the heart after use of Dibenzyline. l.ilood flow to most organs in the healthy, recumbent, normovolemic patient are not changed with administration of phenoxybenzamine since little sympathetic activity exists under these conditions. Exceptions are resting skeletal muscle or skin exposed to a cool environment (rt×ma temperature) (103). The increase in cardiac output seen in resting states is probably accommodated by these organs. Little change in blt~d flow in warm skin or exercising skeletal muscle (8, 103) occurs since the sympathetic nervous system exerts little control over these organs under these conditions. A marked shift of blood from the pulmonary vascular bed to the systemic vascular bed occurs due to the reduction in systemic vascular tone (103). Also, fluid shifts from the interstitial to the vascular compartment, increasing plasma volume and reducing hematocrit

(I03). The alpha-adrene~ic receptor stimulant properties (vasoconstriction) of norepinephrine and epinephrine are abolished with either phenoxybenzamine or Dibenamine (97)..Selective eltects on a partitular vascular bed may also be produced experimentally. Moyer et al. (99) and more recently Gump e t al. (63) have investigated the effects of selective blockade of the vascular bed of the kidney using phenoxybenzamine. These investigators have confirmed previous in vitro studies demonstrating that Dibenzyline becomes securely and rapidly attached to receptor sites in tissues. Using this approach, organs sensitive to ischemia, such as the kidney, may be protected during intense hypovolemic vasoconstriction; this finding raises interesting therapeutic and experimental implications. The chronotropic and inotropic effects of epinephrine and norepinephrine are enhanced by the alpha-adrenergic blocking agents (97). The tachycardia seen commonly with epinephrine is increased. The bradycardia usuallS, seen with norepinephrine is reversed. These agents cause heat loss secondary to cutaneous vasodilation. Phenoxybenzamine and Dibenamine have varied metabolic effects which are not clearly defined at present. Only slight inhibition o f the hyperglycemia and lactacidemia produced by epinephrine in man and animals are reported (103). Phenoxybenzamine has been shown to 17

with Nethalide in the intact dog severely limits the animal's ability to increase its output in response to rapid volume loading. Another finding of interest is that when propranolol is administered to subjects resting in the supine position, it does not alter ventricular dimensions and does not effect contractility as determined by the myocardial force-velocity relation (137). This would suggest that the sympathetic nervous system has little stimulating effect on the myocardial tissue in the supine, resting man. These findings would seem to restrict the use of beta-adrenergic blocking agents to certain situations, where myocardial function is impaired because of excessive sympathetic activity, such as in some forms of paroxysmal ventrieular tachycardia (142), and hypertrophic subaortic stenosis (65). Reports of symptomatic relief of angina pectoris ,'tftar the administration of beta-blocking agents are numerous (55, 56, 62, 115), and more recently propranolol has been used with success in treatment of arrhythmias (4+5~+ Beta-adrenergic blocking drugs have variable metabolic effects depending on the species and effect studies. Epstein and Braunwald (45), in a recent review, suggest from the available evidence that the adrenergic receptor for phosphorylase activation is a beta receptor and is thus blocked with beta-blocking agents. The effects of betablocking agents oa lipolysis and other metabolic functions have not been fully evaluated. The beta-adrenergic blocking agents have not been used in the treatment of shock in humans.

Vl. ADRENERGIC STIMULATING AND 8LOCKING DRUGS USED IN THE TREATMENT OF SHOCK The concept that shock is a single clinical entity and amenable to therapy by a single pharmacologic agent is untenable in the light of current understanding. Therapeutic approaches are based on momentto-mon,,ent hemodynamie and biochemical measurements and clinical judgment ( 143, 144). On the basis of this information, the particular problem i~ analyzed and an attempt is made to characterize it in physiologic terms. Cardiac function, a primary consideration, is investigated and an adequate atrial filling pressure secured by volume replacement. Equally important are the measurements of ventilation and pulmonary gas exchange which may indicate the need for respiratory assistance. On the basis of this and other information , the vital organ support needed to sustain the patient is usually obvious though not always attainable. For example, in cardiogenie shock the prime aim of treatment may revolve about control of rate or force of contraction. In hemorrhagic shock, volmne support~is o f prime importance. In septic shock, lah.e problem is far more complex, and the selection of appropriate antibiotics, the. drainage of abscesses and the support of blood volume and pressure become important. In 19

current shock therapy then, drug treatment is instituted only as an adjuvant toward a specific goal and not as a panacea fcr this as yet ill-defined entity. Early in this paper, the possibilities of using the adrenergic drugs to manipulate cardiovascular function or the peripheral vascular s~.'stem was stressed. Some of the clinical experiences using these drugs will now be outlined. All the clinical data are complicated by many uncontrolled variables. These include underlying disease process, depth and: duration of lshock, the almost:uniform usage of a number of different forms of treatment concurrently and the Obvious lack of adequate controls. For these reasons, survival rates between different series eannot be compared at the present time and the value of any particular agent can only be surmised until extensive clinical hemodynamic and biochemical data have been collected. The use of the various agents will be considered in relation to the different types of shock, although recent studies make it clear that eases of advanced shock may move from one catego~, to the other. trPOVOLEMIC SHOCK

Hypovolemic shock in its early stages responds well to blood, colloid and balanced saline, but when treatment is delayed or inadequate, the simple phenomenon of fluid lack becomes complicated by intense vasoconstriction and myocardial failure which is refractory to fluid replacement alone, lt is under these circumstances that vag-~dilator drugs appear to be of value. Nickerson (104, 105, 107). the first to use phenoxybenzamine in the treatment o f shock, treated 2 patients with phenoxybenzamine and fluids because of advanced hypovolemie shocL Blood pressure. pulse rate and urine output were markedly improved in these patients and:clinical evidence :~of peripheral sympathetic overactivity was re-versedwith this agent, Lillehei (85) pre~zeated 2 patients with Dibenzylinc prior t o o p e n heart surgery, Both responded dramaticaUy when shock.= occurred 24 hours po~0peratively and they were retreated with, p enoxyoenzamme, p l s nmos, Wilson, :Jablonski and Thai (150) i/!treated severai eases ~of: hypovolemic Shock exhibiting a high . . . . . . res~stan . . . C e; low :.:cardiac output and peripheral: high central venous press u e with !~mg, lkg. .~phengxybenzamme, All these patients were m~advanced h y ~ v o l e m i c ) s h ~ k a n d had:: manifestations of cardiac f~ureii~which prevented further fluid ~therapy.: Mostl wereyoung and r e s ~ n d ~ f a v o ~ b l y t o phenoxybe.nzamine w i t h a marked fall in cen, allowing cardiac output~ ....o be increased by subse uent fluld loadm . Further aug m enta,,fi6n,:ii:Of:cardiac:i output:: c o ~ d ?be:/obtained: if: ~norepinephrinc Was ~ven:iii~i~:~ong!:Wi~: ~.the:il~fluids and :i:p h e n b x y b e n ~ n e : :::ISoproterenol (MacEean '~:,etal!::,i::[90] ):::.hasia~:i:: b~en, u ~ d / in ;advanced "~:~d ,Corn' ...........

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plicated hypovolemic shock. Although survival figures were not encoura~ng, hemodynamie studies indicated that central venous pressure was decreased, urine output increased and cardiac output augmentcd. Far-advanced hypovolemic shock associated with cardiac .failure, low cardiac output, high peripheral resistance and venous pressures appears to be a prime indication for the use of vasodilator drugs and fluid therapy. The current use of vasodilator drugs in shock has been a matter of some contention, which is exemplified by recent work onqaboratory. animals. Muhm and Shumacker (100), studying the effects of phenoxybenzamine, Affonad and Apresoline on renal blood flow in normovolemic and moderately hypovolemic states, showed that vastdilator agents reduce renal blood flow. Mandelbaum, Silbert and Berry (91) examined a similar problem during extracorporeal circulation. These workers maintained a constant pump output and measured renal blood flow directly before and after the administration of large doses of phenoxybenzamine. There was a significant fall iu renal vascular resistance after alpha-adrenergic blockade, but the total peripheral resistance declined to an ever greater degree resulting in a diversion of blood to the areas of lowest resistance. These studies clearly point out the hazards of using these drugs in the presence of hypovolemia without concomitant expansion of the vascular space. The ablation of baroreceptor reflexes results in perfusion~ of nonessential skin and muscular compartments thereby reducing flow to vital structures. The studies have been essentially duplicated for other organs by Pollock et aL (112), studying regional blood flow in dogs which were bled 30 cc./kg, body weight. They f o u n d n o difference in organ blood flow when phenoxybenzamine-treated animals were compared to non-drug-treated animals. Baue et al. (.12)~studied mesenteric blood flow and oxygen consumption in dogs in hemor, rhagic shock treated with phenoxybenzamine andfoUndcardiac out, put and systemic oxygen consumption to increase but without in-. creasing the mesenteric circulation; moreover, mesenteric:oxygen consumption decreased despite phenoxybenzaminetreatment:: Rush~iletilal. (122) found that the u s e of phenoxybenZaminc during hemd~hal -.~ shock was assocmted with decreased oxygen consum fi0n~::~Cr~ed oxygen debt and increased metabolic acidosis. Againi in n0ne:ofi~dSe studies was adequate volumcreplaccmentcarried Out, thereby c r o t mg an experimental c0nditionat vadancelwith t h e i c U r r e n t i d i ~ use of the drug, The :vasoconstriction resp0nse iin Sh~k!isi!atiiibast initially al.vital.Survival-mechanism • a~ed.-ii.at/~thel.rediStl-ibution..iOf blood iflow from the nonessential~muscle masses,.sk~;i~.~t.ahd:i!~:i~d, neys to the essentialcerebral - ~ d c o r o n ~ ' circtflations~ .TO~abrO:at~ ~is reaction by.:..:unselective:i..:vasodilationi~:in:.thel.face:~iof/continumg hypovolemia~wouldl s e e m t O b e undesirable;i~..~d. Clinieali~obSe~atiohs tend .to ;.confi rml.thisinferencei:.:Vasodilation .~in/the ::fa~:: ofi"Coritih~g •

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low cardiac output is disastrous. Current clinical usage of phenoxyb~azamine in shock is predicated on the prior demonstration of an adequate or increased atrial filling pressure. Its usa must be accompanied by continuous intravenous infusion to expand intravascular volume. It also seems clear that beneficial results from generalized vasodilation may be anticipated in clinical shock only when consider:able increases in total blood flow can be secured by increased venous return to compensate for diversien to less critical regions. _The use of norepinephrine or other inotropic drugs to increase cardiac output in patients treated with phenoxybenzamine and fluids may be necessary to accomplish this goal in far-advanced shock. Another alternative is the use of phenoxybenzamine in a selective re~onal fashion a s discussed previously. One question that needs answering is what precisely are the microcirculatory pathways opened u p after alpha-adrenergic blockade with phenoxybenzamine? Are thes~ nutritive or bypass channels? The metabolic acidosis frequently seen after using Dibenzyline in the vasoconstricted: shocked human or animal is thought to be due to washout from t h e mt~scle masses a n d skin and other organs previously isolated b y vasoconstriction, This is only transient and is reversed in amatter of minutes with effective circulation. However, at l ~ s t two other possibilities exist: either precapilla~ shunting is occurring o r phenoxybenzamine may actually decrease oxygen demands in certain tkssaes.

CARDIOGENIC SHOCK Primary failure of left ventricular ejection is most commonly seen as a result iof extensive myocardial infarction, but sometimes it fob lows cardiac arrhythmias with a rapid ventricular response. The cardiae output reaches low levels as the stroke volume declines, and the calculated peripheral resistance generally rises to levels higher than that seen in other forms of shock. The intense activation of the sympatheti.c:.nerv0ussystem~in i~ese patients may rt~sult in severe vaSoc0nstriction i i n the extremities with a i re!alavely htgh central ao~e~ipressure~iThis;~ m litself, m a y ifurther impair myocardial function by?increasing~ithe :resista~a.ce against !which the left Ventricle must eject:~: When •the fall :in ' cardiac ioutput 0Ccursgradually over a long period; i as in'advanced imiual ilstenosis, ~a. cardlacoutput: Wluch is well w i ~ tble leVelS~found~iih'severeshock m a y he,tolerated at'rest. In Sh~k~ however, where thedamage is sudden andseVere, cii:culatory teadjustments OccUrtffprodu~diversionoftheblOodi~fromthe periptiery::~t0:the~ coronary and cerebral -~areas.~ The~venous ~pressure is e i ~ e r r a i s e d orrises rapidly with relatively small ?mfusions of fluid. This sta~:!isi:t0!eratedfori o~yrelatiVely:short periods an.d t h e mortalJ~ r a t e fo!lowmg)myocardia! ~ r c t i o n w i t h isho~ek~varies between 70 ;~di il00%i:Secondary cardlae failure iscomm0n and i-~complicates

many forms of severe shock regardless of origin. Drug therapy has been used to accomplish seemingly opposite ends. Clearly, coronary perfusion pressure must be maintained. Yet, intense vasoconstriction is already present and the Use of vasoconstrictor drugs further adds to the resistance against which the heart must eject as well as ineroasing metabolic demands. Conversely, vasodilator drugs, although lowering the peripheral resistance, may theoretically reduce cerebral and coronary perfusion below critical levels. This dilemma has not yet been resolved. The literature is replete with clinical reports which provide testimonials to the value of vasopressor agents in temporarily elevating the blood pressure in the majority of patients in eardiogenic shock. Few of these reports make any attempt at measuring myocardial function and ti~ue perfusion. No attempt will be made to covet these reports in this review. A few representative current studies where hemod)~namic measurements have been made using various agents will bediscussed. Smulyan et al. (134) evaluated the effects of lavarterenol bitartrate and metaraminol bitartrate in 7 patients in shock due to myocardial infarction. Results from these studies showed that cardiac output was consistently decre,'ksed and total peripheral resistance increased from baseline hemodynamic measurements. Increasing the drug dosage further decreased the cardiac output and increased peripheral resistance. Shubin and Weil (130) studying the effects of these agents in patients in cardiogenic shock, confirmed the fi~dings of Smulyan et al. ( 1 3 4 ) , but suggested if the arterial pressure was maintained at a level approximately 30 ram. Hg below "normal" systolic blood pressure, excessive vasoconstriction was avoided and cardiotonic effects were observed. These studies point out that excessive vasoconstriction, resulting from the infusion of norepinephrine or metaramino! will further decrease an already low cardiac output in cardiogenie shock. These conclusions have been further proved by Gunnar (64) who observed that methoxamine, when given to 7 patients in shock secondary to acute myocardial infarction, caused significant decreases in cardiac output and increases in peripheral resistance, as well as clinical deterioration of the patient. Epinephrine was used by Coffin et al. ( 2 9 ) f o r the treatment of low cardiac output syndromes following corrective valve surgery. Infusions of 0.1 to 0.5#g./kg./min. of epinephrine increased blood pressure and urina D, output and caused improved peripheral circulation with reduction or disappearance of cyanosis and increased warmth,0f extremities. No serious arrhythmias or tachycardia were observed and these authors concluded that the infusion ofilow: doses to Obtain primarily:beta-mimetic effects was satisfactory in thetreatment of postoperatl e low cardiac output syndrome. Udhoji and Weil:(146) observed similar results ::with the~drug: mephentermine in a:~few patients t r e a t e d f o r cardiogenie shock: Cardiac: output lWas increased, 23

pulse rate increased from an average of 93 to 103 beats per minute and peripheral resistance was reduced. No change was noted in central venous pressure or mean arterial blood pressure. MacLean et aL (90) recently reported on the use of isoproterenol in 20 patients

treated for shock, a few of whom were in primary cardiogenie shock. Cardiac output was markedly elevated in these patients, central venous pressure was decreased, and urine output was auimaented ,after administration of isoproterenol. Changes in peripheral resistance were not consistent and, in general, no change was noted. Some of these patients were refractor,] to metaraminol and norepinephrine, but responded to infusion of isoproterenol. Smith et al. (133) recently confirmed MacLean's observations on isoproterenol. These studies have made it clear that the pure alpha-mimetic agent, methoxamine, is not effective in supporting the heart and is not even effective in supporting pressure since elevations in mean aortic pressure are usually modest. The alpha-mimetic agents which are void of inotropic effects, therefore, have virtually no place in the management of a patient in cardiogenic shock. The mixed alpha- and beta-mimetic agents with predominantly alpha,mimetic effects, such as norepinephrine and metaraminol, are effective in supporting pressure but like methoxamine, they increase peripheral resistance and usually decrease cardiac output. Central venous pressure frequently rises and the patient deteriorates despite the increase in blood pressure. However, small infusions may be effective in supporting theheart without excessx've increases in peripheral resistance. The mixed alpha-and beta-mimetic agents with predominantly beta,mimetic effects such as epinephrine or mephentermine seem:to be of some value. And, finally, the pure beta-mimetic agent; isoproterenol, is very effective for supporting the heart without excessive increases in resistance. None o f these agents is without dangerous side effects, however. All willprovoke serious arrhythmias. The beta-minletic agents apPear i t o b e m o r e prone to produce :arrhythmias than the alpha-beta m ~ e d agents; A1/patients receiving these agentsmust be monitored continuously,! and if signsof myocardial irritability are.evident, the ~ g s n i U S t t;e:~istopped.:~ c k e t t (871:)has rep0rted that isoproterenol may~cause Cardiac~a~est~ at .least:in the cat, when:ithe heart is fatigued ~d!!iis:workingat i~high loads a n d h e suggests!this! m a y o c c ~ i n the liUm~: : ! ~ e bet~,m~eti6 agents are notorious in producinga marked taCtiycardiaiandli::C~didatesl .~r~these drugs:usury alrea~ty h a v e a r a~id'i::hea~ rate;i~again li~ti~g:their: use::Pr01onged use iof any: of tlJege~:i:'agentsi:i;:~icUlatiyliso~roterenol;ii~ll produce focal myocar~fis:t75): :~anh;fUaiier a ~ a v a t e .:i.the pre,existing infarction I of~ the The~ final,: and; perhaps most importa.nt, ;question that.:must be raisedli/With: 'the USeIIof ~:!:theiladrenergicils~ulat~g agents in Shock c6nce~:il itll~r~metabolieiieffeCts:;:It:iis~kn0wnl that adrenergic stimu24

lating agents have a calorigenic effect and increase oxygen demands by about 20%. Possibly the metabolic deficits commonly seen in shock patients may be further aggravated even though the cardiovascular performance and tissue perfusion are improved. Drucker (41 a) has shown that metabolic deficits are further aggravated and tolerance to hypovolemia shortened if norepinephrine is given prior to repletion of blood volume. It seems ,almost paradoxical to administer agents which increase systemic oxygen demands when the whole organism is in a state of severe oxygen debt. Clearly, survival under these conditions is limited to cases where the improvement in blood gas transport offsets the increased, demand for oxygen induced by the drug. Various attempts have been made to use the alpha-adrenergic blocking agents in the treatment of cardiogenic shock. Wilson, Jablonski and Thai (150) studied the effects of phenoxybenzamine in the treatment of several patients in cardiogenic shock. In general, peripheral resistance could be markedly reduced, central venous pressure decreased with relief of pulmonary edema, but-cardiac output increased only modestly. However, if norepinephrine was added to the regimen, cardiac output could b e further increased several-fold (See Fig, 6). While a few patients showed dramatic recovery, the majority eventually died despite a transient improvement in hemodynamic measurements. Only further studies will indicate whether or not this therapeutic regimen holds any promise. Physiologically, at least, the workload of the heart should be decreased as suggested b y Sanaoff's (123a) observations.

SEPTIC SHOCK Traumatic and hypovolemic shock often occur in individuals previously well, but septic shock usually accompanies some chronic or subacute disease process. In particular, it may complicate genitourinary infection, biliary disease, pneumonia and peritonitis, and it is often seen during the second or third week after burns. The clinical picture varies considerably; shock may follow dramatically after urologic instrumentation, or it may be a terminal event after prolonged sepsis with long-standing fever, tachycardia, tachypnea a n d a l l the evidence of a prolonged hypermetabolic state, T h e hem.dynamic picture is equally inconstant. Whereas some patients exhibit the typicat features of:high resstance : l o w output shock with pale, mottled skin, cerebral depression, .liguria, others'show a change'of almost opposite characteri T h e s k i n may b e w a r m and dry, the: bloodpressure low :and the cardiac output either within normal m~ge or :mcreased. Hyperventilation i s common: and~ metabolic acidosis may coexist with' increases in cardiac loutput, This seemingly paradoxical situation:is, at least~in part,~ explained by the finding of a raised mixed venous oxygen content. I n some a r e a s there is perfus~on of nonnutri•

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tive vessels, presumably in the form of arteriovenous shunting. At present, septic shock repre,~nts a confused entity which differs from other forms in several vital particulars. While initial hemodynamic

studies indicated that septic, iike hypovolemic and cardiogenic shock, was characterized by a low cardiac output and increased peripheral

resistance, subsequent measurements have revealed a far more complex •picture. Our early studies identified several hemodynamic patterns-(152). Most interesting of all, and quite commonly seen, ,~'as a hyp6rdynb.~lic form where 'the hypotension was associated with a normal or high cardiac output. These findings have recently Seen confirmed by others (131). Also, as judged by the response to fluids, a.relative hypovolemia was often present and, in addition, sorile cases revealed a dominant element of associated cardiac failure. The maj0dty of patients destined to survive responded to fluid.and antibiotic therapy coupled with cardiopulmonary support and drainage of abscesses where indicated. The mortality rate in those failing to respond to these primary forms of treatment is approximately 73%. Clearly, in so heterogenous a group, therapy with vasoconstrictor, inotmpic or vasodilator drugs must be based on hemodynamic measurements. For example, t h e low-output, high-resistance group might be expected to respond to a va,sodilator drug such as phenoxybenzamine. Our studies (152), as well as the more recent reports of Anderson :et al. ( 3 ) confirm this. Conversely, the use of this drug or isoproterenol, in the presence of the low peripheral resistance and high cardiac output form of septic shock, would appear to :be contraindicated. . Rather, an agent selectively closing the multiple arteriovenous shunts in the microcirculation might represent ideal therapy, but such an agent has not yet been introduced: Gilbert et al. (54). in 1955, reported o a e o f the first hemodyna.mic studies of alpha--mi~'etic drugs in septic shock. He found that the control cardiac output was normal or high, and total perip]ler~l resistance was~low. With the infusion o f norepinephdne into 4 of: these patients, a rise in arterial pressure and fail in the cardiac output occurr~ed in 3: Smulyan e t a L (134): studied the effects of norepinephrincand-metaraminol on 8 patients in septic shock. Control cardiac o u t p u t : :was low:in these patients and peripheral resistance near normal .or high' . After: infusion of these agents: cardiac output: was slightiyl ~creased: but :a marked increase ..in peripheral ~resistance occurred;ilf., the:infusion t h e. s e : .... a. g e. n..of t s. . . . . . .was augmente d, c a r d ~acoutput seemed:to :deteriorate i along: With -'.further elevations . in systemic resistance::They~ also Consistently observed:thai, the.-largest increases in resistance:occurredwhen. resistancewas already high and t h a t cardiac Output •Was.rained.when ........ " " '"ltwashighest-and " .... " " " Close to normal,. In:patients "

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who!: ad::,lowcardmc:ioutput and total penpheral resmtance, ~wher¢ thcoretically!an:.:increase in i,cardiac :..output and t o t a l , .peripheral :resistance ~:,. Would : be (desirable; :the i:~former Usually :.decreased and: the latter ~increased excessively,. 26

These results are consistent with the previously mentioned studies where norepinephrine and metaraminol were used to support the heart in advanced hypovolemie shock and eardiogenie shock. Because of their predominant alpha-mimetic effects, excessive vasoconstriction and consequent elevatiot~ in resistance is seen with a decrease in cardiac output. Both norepinephrine and metaraminol in large doses increase blood pressure but at the expense of blood flow. Whether either of these agents could be effective in reducing the postulated arteriovenous shunting in septic shock patients where cardiac output is high and resistance low awaits evaluation in the laboratory and shock centers. One must be aware that these agents have the ability to increase the oxygen demands of tissues under stimulation and, therefore, will be effective in decreasing the mixed venous oxygen 6ontent without necessarily reducing the arteriovenous shunt. MacLean et al. (90) extensively evaluated the effects of the betamimetic agent, isoproterenol, in patients in septic shock. They felt that most of their patients were in heart failure and observed that isoprote~nol augmented the cardiac output, reduced venous pressure, increased hourly urine output, but had little effect on resistance. These results have been confirmed by Kardos (76) who found that isopro.terenol increased blood pressure, decreased pulse rate and central venous pressure while~ elevating hourly urine output in 12 patients, in septic shock. Siegel, Greenspan and DelGuereio (13 I) recently studied several patients in septic shock and found that oxygen consumption was usually decreased, arteriovensus shunting present, and ventricular function hypodynamic or hyperdynamic. Isoproterenol was used in a few of these patients and clearly improved myocardial performance, but had little effects on improving tissue Oxygen uptake. Observations by these investigators confirm that isol~roterenol is effective in improving depressed cardiac performance in septic shock patients and, thus may allow, time for control of thesepsis which is produizing the shock problem. All these studies, and others previously mentior~ed, on patients in septic shock point o u t the complexity of this type of shock and the problems in therapy. Evaluation of therapy in septic shock is difficult and the lack of adequate control studies have made thi_s a formidable task. A laboratory preparatlon which closely parallels human septic shock is clearly.needed. T h e alpha-adrenergic blocking agea t , phenoxybenzanune, " has been used in our laboratory in the~treatment of patients ~in septic ~shock (150, 1 5 1 ) . Peripheral resistance a n d :central ~venous: pressure, ff elevated, could :be: lowered with dibenz~line. C a r d i a c outpUt:.could 0nly be imodestly:elevated, however, if norepinephrine was~added to thedibenzyline and fluid regimen; cardiac output~ Could be increased several times; again "buying time" tmtil: the eps~s could be~controlled. It is obvious when reviewing these studies thatthe ideal therapyis S

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not at hand. What one can hope to accomplish with the stimulating or blocking adrenergic agents, with our present state of knowledge, is to tide over the critically ill patients until sepsis is controlled. Obviously, much work is needed to define this complex entity termed septic shock before any definitive statements can be made concerning therapy. NEUROGENIC SHOCK

Complete transection of the spinal cord or severe injur~ of the cord of such a degree that edema results in functional interruption of the cord, produces a state referred to as spinal shock. This is c h ~ acterized by flaccid paralysis of skeletal muscles below the level of the injury, together with a resultant vasodilation and hypotension resulting from a loss of pc.ripheral vascular resistance. The use of the term shock for this condition is misleading since it bears little relationship to more common forms of shock. Patients with spinal shock customarily remain well oriented, dr),, warm, have good filling of peripheral veins and produce a satisfactow urine output. The I~.~ of autonomic function may be severe enough to render the p~!:i~:;at poikilothemnic, where body temperature tends to rise or fall passivciy depending on ambient conditions of temperature and humidity. The ' con V ent~on,-d clinical findings of hypovolemic shock do not occur in spinal cord inju~, a n d , if present, strongly suggest some associated injury. If,elevation of b l o o d pressure is desirable, any of the alpha, mimetic agents, such as methoxamine, or the mixed alpha- and betamimetic agents withpredominantly alpha-adrenergic effects, such as norepinephrine or ~methoxamine, can be tised t o elevate blood Dressure temporarily, ILLUSTRATIVE CASES USE OF PHENOXYBENZAMINE IN" HYPOVOLE MIC SHOCK

CASE 1.--An 18-year-old girl developed severe hypovolemic shock secondary to'fulminating ulcerative colitis. :She was hospitalized after an episode of sYncope:i~aadi,~diarrhea with blood. Two days after admission, ~e!patient developed moderate abd0minal pain with distentio n and had tiple loose: stools which: contained blood./Severe hypovolemic shock developed rapidly,/ Blood pressure became unobtainablei She was rushed to:the operatin~ room, rapidly transfused, :and an emergency subtotal colectomy was performed. Several liters o f straw, colored fluid were prese n t i n the~abdonaen at the time of operation; the colonwas edematous. hem0rrhagiC and distended With blood. Blood pressure was unobtafnable throughout the operation and extreme vasoconstriction was shown by the paucity of the bleeding. A cut-down on theradial artery revealed only a trickle of blood. 28

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Fro. 8.--Case 1, an 18-year-old girl with severe hypovolemic shock secondary to ulcerative colitis. Early hemodynamic measurements revealed a low cardiac output (C.O.), high total peripheral resistance (TPR) syndrome with a high central venous pressure (CVP). Dibenzyline (1 mg,/kg.) was administered along with fluids, with prompt improvement. Immediately following operation, the blood pressure was 80/40; pulse 120; central venous pressure 16 cm. water; cardiac output 2 L. per minute and calculated total peripheral resistance 3,000 dynes-see, cm. 5 (Fig. 8). The patient's extremities were cold and cyanotic. Peripheral pulses were absent. There was no urine output and further fluid loadi.ng res~,~ted in an elevation of the central venous pressure to 28 cm. water without improvement in the patient's cardiovascular status. Phenoxybenzamine (I mg./kg.) was administered with further fluids. Central venous pressure rapidly decreased to 8 cm. water; cardiac output increased to 5.2 L. per minute and calculated resistance fell to 1,000 (See Fig. 8). Urine output increased from 0 to 50 cc./hr. The extremities became warm; the cyanosis disappeared and periphcral pulses could be palpated. The patient's sensorium improved to the point that she resisted the endotracheaI tube. Approximately 8 hours postoperatively, bright red blood was noted in the nasogastric suction and in the drainage from the ileostomY.~ Three thousand cc. of freshwhole blood were replaced during the following 16' hour period (Fig. 9). Twenty-four hours following surgery, itheipatient again developed oliguria,:cold and cyanotic extremitiesl and became unresponsive. Cardiac output a t t h i s time w a s 2.8 L. perrninute and calculated resistance, 2,500. Retreatment withl 1 mg./kg, phenoxybenzamine and furttaer fluids restored blood pressure and cardiac output (See Fig. 8). Following this, her cardiovascular functi0n returned t o n o r m a l levels. ~She becamc fuHy~ responsive and recovery was anticipated until a number:of severe complications set in. 29

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tems such as skin and muscle mass being perfused at the expense of vital organs such as the brain, heart and kidneys after treatment with phenoxybenzamine? ( 2 ) A r e by.pass channels opened in the form of arteriovenous shunts resulting in nonnutrient perfusion o f tissues? It seems: clear-that a considerable amount of blood is diverted to skin and muscle mass after the use of phenoxybenzamine , but that perfusion t o vital organs is also irnproved, provided cardiac output can beincreased. Evidence for this is shownby the increased urine output and the improvement in the patient's sensorium. Whether or not sig32

FIG. 12 (lelt)...JCase 1. A supine, portable x-ray taken at 19:45 hours on the first postoperative day. Oxygenation could be achieved only after tracheostomy and ventilatory support with the Emerson respirator and 100% oxygen. Diffuse haziness over both pleural spaces can be seen with a pleural effusion on the left side. Fro. 13 (right).::-Case I. A supine, portable x-ray taken on the second postoperative day which again shows haziness over both lung fields. Oxygenation was marginal despite support with the Emerson ventilator and 100% oxygen, nificant arteriovenous shunting in other organs occurs after the use of phenoxybenzamine cannot be answered at this time. An interesting phenomenon previously mentioned is t h e extreme acidosis encountered after administration of phenoxybenzamine i n a patient with severe shock. Prior to administration of Dibenzyline in this patient, the pH was 7.48; Peon, 20; and bicarbonate 16. Shortly edter treatment, the p H dropped to 7.31; Pco2 rose to 29 and bicarbonate was 14 ( S e e Fig. 11). Despite g r e a t improvement in the hemodynamic status, the acidosis continued for several hours. O u r belief is that this is d u e to:washout of various tissues previously iso, lated from the central circulation •because of extreme vasoconstriction. An alternative approach in this case would be the use of the betastimulating agent, isoproterenol (peripheral vasodilator and cardiac stimulant). The results of this treatment may also have been favorable. but perhaps limited by the tachycardia. Use of other-" agents with alpha-adrenergic stimulating properties such as•norepinephrine, metaraminol or methoxamine are contraindicated because of the danger of aggravating an already• severe peripheral vasoconstriction. Multiple organ: dysfunction was present in this patient, probably resulting from the severe shock. A normal hepatogram on admission changed to a total bilirubin of 24.9 m g % ; SGOT of 1,395 units; alkaline phosphatase o f 5.•5 B.L. units; and a cephalin flocculation of 4 in 24 hours. T o t a l p l a t e l e t s were reduced to 32,000 a t one 33

FIG. 1 4 (leIt). Case 1. A supine, portable x-ray taken on the third postoperative day showing clearing of tile haziness on the right side, but a definite infiltrate in the left lower lung field. FIo, 15 (right).: Case 1. Upright, portable x-ray taken on the 20th ~x~stoperafive day. Note clearing of both lung fields in contrast to previous films. A large subphrenic abscess is present on the right side.

point. Multiple bleeding episodes were encountered which were probably indicative of a consumption coagulopathy (See Fig. 9). Fever and a leukocytosis were present with septic episodes despite proper antibiotic coverage and drainage o f ' a subphrenic abscess (See Fig. 10), suggesting reticuloendothelial dysfunction. R esp~atory dysfunction is one of the most dramatic and, frequently, most limiting factor in survival of severe shock. During the immediate postoperative period after treatment with Dibenzyline, this patient was easily oxygenated with an endotracheal tube in place on room air. T h e P o 2 was 1 0 6 : P c o 2 23; and pH 7.33. Ventilation with: 100% oxygen resulted in a Po2 of 450; Pcoa of 20; and pH of 7,48, indicating excellent pulmonary function (See Fig. 11 ). However, at 8 : 2 0 on the first postoperative day, the patient's Po:~ was 67; Pcoa, 34; and p e r c e n t saturation was 88.4 (See Fig. 12). By 19:40 o n the same day, the patient's Po2 was 35 and Pco2, 28 on room air (See Fig. 12). A tracheostomy was performed and controlled ventilation with humidified 100% oxygen on an Emerson respirator resuited in a P o 2 of 100 and Pco2 of 29 in contrast to a Po2 of 450 obtained on the previous day. X-ray examination of t h e chest revealed diffuse haziness over both pleural spaces, with apleural effusion o n the left side ( S e e Fig. 12). The left pleural spacewas t a p p e d a n d about 50 co. of straw-colored fluid was obtained. Bronchoscopy was carried out a n d only minimal secretions were noted. Further problems i n ventilation were encoun34

tered in the following 6-7 days (See Figs. 13-15), and the patient could be only poorly oxygenated with 100% oxygen. Compliance was markedly decreased during this period. The precise pathophysiologic mechanisms for pulmonary dysfunction can only be guessed at, at the present time. The ventilation problems may be due t5 arteriovenous shunting in the lung due to miliary atelectasis, altered ventilation-perfusion due to decreased compliance in certain portions of the lung or impaired diffusion of gases. This case vividly portrays the dilemma of treating the multiple organ dysfunction encountered in advanced shock. The severe cardiovascular dysfunction was clearly reversed with the use of the drug phenox)'benzamine. One then encounters the complex problems of supporting a patient with multiple system failure, due to the insult of severe shock over long periods of time. Whether significant survival ratcs can be obtained in these patients after reversing what was formerly called "irreversible shock" remains to be evaluated. USE OF ISOPROTERENOL IN HYPOVOLEMIC SHOCK CASE 2.---A 68-year-old male represents a case of severe hemorrhagic shock from upper gastrointestinal hemorrhage (Fig. 16). He had a history of chronic alcoholism and previous diagnosis of cirrhosis of the liver, duodenal ulcer and chronic obstructive emphysema. Initial therapy in this patient consisted of whole blood and balanced salt solutions and digitalis. Despite elevation of central venous pressure to 17 cm. of water, the blood pressure remained at 80/40; pulse 100; cardiac output 3.3 L. per minute; calculated resistance 970 dynes-sec./cm. 5 and an hourly urine volume of 3 co. Arterial blood gases at this time revealed Pco2 of 58 and pH of 7.27. Tracheostomy was performed and the patient was placed on i 00% oxygen. The arterial hemoglobin saturation then increased to 80%; Pco,2 to 70 and pH dropped to 7.20. The patient's hemodynamic status failed to improve, however, despite respiratory support. Isoproterenol (0.2 rag./250 co. D-5-W) was then administered by intravenous drip at a rate to maintain the pulse below 140 beats per minute. The cardiac output rose to 7.1 L. per minute; central venous pressure decreased to 12 cm. water and calculated resistance became 1,120; pulse 132 and blood pressure 95/55. The patient's clinical status was greatly improved. Attempts to discontinue the isoproterenol over the next 24 hours resulted in a marked decrease in cardiac output and deterioration. After approximately 36 hours of intermittent support with isoproterenol and fluid therapy, the patient was able to maintain an adequate icardiac output and urine volume without the support of isoproterenol. Bleeding had stopped spontaneously early during therapy, but continued ventilatory support was needed several days after the shock was corrected because o f the severe lung disease.

COMMENTS.--This patientwith hemorrhagic shock, complicated by chronic: lung disease and cirrhosis of the liver, represents an atypical case of hemorrhagic shock. Usually in far, advanced ihypovolemic shock, calculated resistance is high and central venous pres35

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sure is low. The+failure of peripheral resistance to rise in this case was probably due to the arteriovenous shunting which is known to occur inpatients with cirrhosis ~of the liver. This patient's n o r m a l cardiac output was probably iin t h e r a n g e of 7-10 L. per minute; yet initially cardiac output ~of only 3 - 4 L . could be obtained in the face of evid e n c e o f cardiac failure .(CVP 17 era. water). This patient had obvi0usly progressed veryrapidly, because -of his age and underlying disease, fromlearly hemorrhagic shock, which:usually responds.well t011fluid therapy o ~ y , ' to advat~ced hemorrhagic shock with associated cardiac failure.~:iIncreasing the+force ~of myocardial contraction with an inotropic agent seemed the therapy of choice. u S ~ g I s u p r e l , ( stroke ~volume increased from 3 4 , 6 ce. per minute prior toi:infusion of isoproterenol to 53 :cc, +per: minute after isopro36

teren01. Pulse increased from I00 to 132 beats per minute indicating both intotropic and chronotropie effects from isoproterenol. Certain adrenergic receptor stimulating drugs are effective cardiotonic agents under these conditions. Norepinephfine, metaraminol or epinephrine, if used as cardiotonic agents, must be given in low enough concentrations to avoid excessive vasoconstriction. If isoproterenol or mephentermine :are used, continuous monitoring must be accomplis.hed to prevent severe tachycardia or arrhythmias. Phenoxybenzamine was not selected in this case since the peripheral resistance wasnot raised. USE OF METARAMINOL AND METHOXAMINE IN HYPOVOLEMIC SHOCK CxsI-~ 3 . - - A 35-year-old male was admitted in coma and sever hemor-rhagic shock after massive upper gastrointestinal bleeding from esophageal varices. He had a history of alcoholism and previous diagnosis of cirrhosis Of the liver with esophageal varices. Shortly after admission, the patient had a cardiac arrest but was successfully resuscitated with external cardiac ma.~sage. Initial fluid therapy consisted of normal saline, sodium bicarbonate and whole blood. After approximately 2,000 cc. of fluid, thecentral venous pressure was 6 cm. water: cardiac output 9 L. per m~nute; systolic blood pressure of 65 ram. Hg; calculated resistance 478 dy/tes-sec./cm. 6 and pulse 120. Blood gases showed a Pco.~ of 42, arterial hemoglobin saturation of 60% and pH of 6.92 (Fig. 17). A Blakemore-Sengstaken tube was placed to control bleeding; generalized hypothermia was employed; a tracheostomy was performed and the patient placed on a respirator. Thirty minutes after the initial hemodynamic measurements were made, repeat determinations revealed the cardiac output to be 8.1 L, per minute; calculated resistance 301; pulse 125 and central venous pressure 4.5 cm. water and blood pressure 65/25. The arterial pH had increased to 7.14 with the aid of sodium bicarbonate. Several hours after admission, the patient's cardiac output began to decline despite a central venous pressure of 10 cm. water. H e remained semicomatose and was deteriorating clinically, despite intensive treatment. The vasoconstrictor drugs, metaraminol and methoxamine, were tried with the object of raising the peripheral resistance.

COMMENXS.: Cirrhotic patients frequently have a high cardiac output and a low calculated peripheral resistance. Presumably, peripheral artedovenous shunting occurs in these patients sin~ they have an elevated oxygen content in mixed venous blood samples. In this patient, the low arterial ~oxygen saturation despite assisted ventilation probably indicates the development of anatomic shunts in the lungs, as reported in cirrhoticsby Hoffbauer. This patient, after being resuscitated ~from cardiac arrest, exhibited a very high cardiac output and an extremelyloWcalculated resist~ce, T h e severe ~metaboliciacidosis in ~e~face,i~of:. a high!!cardiac:output also ~Supports the thesisi:ofby'passiof nutritive ctlannelS.iEventuaUy, ~ 37

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F [ o 17. Case 3, A 35-year, old male in severe hemorrhagic shock following massive gastrointestinal hemorrhage from esophageal varices Cardiac arrest occurred shortly after admission, and,r~uscitation was successful, Extremely high cardiac output with low resistance: was iniually observed along wifla severe a~tdosis, Administration of Aramine was followed by an increase in pressure,:calculated resistance and slight augmentati0n o f cardiac OutpuL Infusion of Vasoxyl resulted in a decrease in cardiac output, fall m pressure and: peripheral reszstance, N o t e the severe metabohe acidosis despite the high cardiac output, This form o f high 0utput~low resistance shock iis cormaaonly seen i n t h e cirrhotic or septic patient'

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~isicase:: serves: tOi pOint ~u the value o f :cardiac :output determinati0ns,,i!in/~indieat~g~:: drug ~erapy. The id6~d~g::.~;this: patieht ~ d ~m Somepatients Wi~ septic shock with high if!IoUtpUt210W /~eoretically an by abolishing No (agent :iltodat6 has ::ibeefi dtsC0Vered WhiClafulfi/lS: this::cntefionJ . . . . m

ele~atmg:pr~ssure!~d!:t0t~:re~is~n~e,: but~had!n0 effect !0npUlse rate ~di!redueed i~eal~diae::i0utput ! i(Fig~ii!i17 :the 38

Methoxamine was used on two occasions, causing 3 reduction in cardiac output, increase in calculated resistance and decrease in blood pressure. Agents such as methoxamine, which stimulate solely alphaadrenergie receptors, are frequently ineffective even in supporting pressure in these patients. The use of an alpha-adrenergie blocking agent such as phenoxybenzarnine would appear to be contraindicated in cases such as this, where the peripheral vascular resistance is already low.

SUMMARY The current classification of adrenergic receptor drugs has been reviewed. Evidence in support of this classification is presented. The metabolic and hemodynamie aspects o f many currently available agents was stressed as well as their use in various forms of clinical shock, Finally, 3 cases of shock are presented t o illustrate that adrenergie drugs are best selectedl on the basis o f hemodynamie measurements in each individual patient rather than by broad generalization. REFERENCES 1. Ahlquis~, R. P.: A study of the adrenotropic receptors. Am. L Physiol. 153:556, 1948. 2. Allwood. M. J., Cobbold, A. F., and Ginsburg, I.: Peripheral vascular effects of noradrenalin, isopropylnoradcenalin and dopamine, Brit. M. Bull. 19:132, 1964. 3. Anderson, R. W.. Ja~nes, P. M.. Bredengerg, C., and Hardaway, R. M.: Phenoxybenzamine in septic shock, Ann. $urg. 165: 341, 1967. 4. Arbulu, A., and Thai, A. P.: The hemodynamic effects of alpha and beta adrenergic blockade, Surgery 60:60. 1966. 5. Aviado, D. M.: Cardiovascular effects o f some commonly used pressor amines, Anesthesiology 20:71, 1959. 6. A~,iado, D. M., and Schmidt, C. E : Effects of sympathomimetic drugs on pulmonary circulation; with special reference to a new pulmonary vasodilator, J, Pharmacol. & Exper. Therap. 120."512, 1957. 6a. Axelrod, J , L : Methylatien reaction in the formation and metabolism of catecholamines and other biogenic amines. Pharmacol. Rev. 1$:95, 1966. 7. Barclay, ]. A., Cooke, W . T . , and Kenney, R. A.:I Observations on the effects of adrenaline on renal function and circulation in iman. AnL J. Physiol. 151:621, 1947. 8. Barcrofl, H., Dornhorst, A. C.,::McClatchey, H, M., and Tanner, R. N,: On blood flow through rhythmically contracting: muscle before an~during release of sympathetic vasoconstrictor tone, J . Physiol. 117:39 I, 1952. 9. Barcroft, H., and Konzett, H.: On the actions of noradrenaline, adrenaline and isopropyl noradrenaline On the arterialblood pressure, heartrate and muscle blood flow in man, I. Physiol,: 110:194, 1949. 10. Barcroft, H . , and! S t Y , I: :::Comparison 0f:i the. actions o f adrenaline and noradrenaline on the:cardtac Output in man, clin:sc. 1o:295;: 195 I; 1i. Barnett, A; L , Blacket, RLB.,: Depoorter,.A..E., :Sanderson, P. H., and Wils0n, i G : M . ' T h e a c t i o n Of noradrenaline in man:and its r e l a t i o n t o pheochromocytoma and hypertension, Clini: Sc. 9:151; 1950, 39

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bladder was removed and a double ]igation in continuity of the common duct was done just distal to the ligated s t u m p of the cystic duct. T h e secondstage operation was done 1 week later. At the second-stage operation, the ligated s e g m e n t of the common duct was resected and the transected ends, the proximal dilated and the distal c o n t r a c t e d , were united by end-to-end anastomosis w i t h o u t a stent support. T h i s e x p e r i m e n t was p l a n n e d to simulate the a n a t o m i c - p a t h o l o g i c findings in the h m n a n following i n a d v e r t e n t ligation of the common duct at the time of cholecystectomy. Of these 13 animals, 6 (46.1~o) died postoperatively of bile peritonitis. T h e r e m a i n i n g 7 (53.9%) were killed ].1-14 weeks postoperatively and none h a d strictures. R e p r e s e n t a t i v e p h o t o g r a p h s o f the anastomosis in 2 dogs at the time of sacrifice are shown in P l a t e V, Figs. S-V. In this e x p e r i m e n t a l study, 47 operations were performed on the 30 animals which comprised the three groups (Table 15). T e n ( 3 3 . 3 ~ ) of the dogs died and in each the cause of death was bile peritonitis secondaD, to leakage from the suture line. T h r e e (15.0%) of the remaining 20 dogs had strictures at the s u t u r e line. However, in the total of 47 operations performed, the operative incidence of stricture was 8.1%. It m a y be argued t h a t the high m o r t a l i ~ rate; (21.2%) from bile peritonitis secondary to leakage at the suture line is justification for the use of a " T " tabe as an i n t e r n a l splint support. However, (1) D r a i n s were not used because of the inability to m a i n t a i n them in situ in the dog. Tiffs would not be a factor in the h u m a n . (2) Bile peritonitis is much m o r e lethal in the dog than in the h u m a n and is reportedly (77) due to the relatively h i g h content of taurocholic acid in tim dog's bile. This is considered m u c h more toxic than the glycocholic acid c o m p o n e n t which is p r e d o m i n a n t in h u m a n bile. It has also been suggested t h a t the greater toxicity of bile peritonitis in the dog is due to the gram-positive anaerobic bacteria n o r m a l l y present, in the dog liver (25). F r e q u e n t l y , i n the animals who died of bile peritonitis, only 10-15 cu. cm. of bile would be found in the peritoneM cavity, I n contrast, a h u m a n m a y survive a bile peritonitis even t h o u g h liters of bile are present (48). T h e operative incidence of stricture formation (8.1%) is believed low w h e n one considers the small diameters of the ducts that were u n i t e d by end-to-end anastomosis.

CLINICAL

STUD

In the 16-year period be.(ween December, 1951 a n d December, 1967, there were 1] patients in w h o m reconstructions of t h e common duct were p e r formed by end-to-end anastomosis w i t h o u t the use of an i n t e r n a l splint support. T h e r e were 7 women a n d 4 m e n whose ages ranged from 32 to 62 years. T h e average a g e was 43 years. In each, i n t e r r u p t e d sutures of 5-0 arterial silk were used, including all layeI's. B o t h a s u m p a n d a P e n r o s e d r a i n were inserted. A p p r o x i m a t e l y 150 cc. of bile passed daily for 2 days t h r o u g h the s u m p drain, which was removed on the 4th day after operation. T h e P e n r o s e d r a i n was removed on the 9th p o s t o p e r a t i v e day. D u r i n g this same period, but beginning in 1954, a comparable but inde47

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j

- -

-

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,,=

.

.

.

=

.

T A B L E 15.--ExPEr:IMENTAL S T U D Y OF R E C O N S T R U C T I O N " THE COMMON B r a e DUCT V(ITIIOUT STENT SUPPORT l ) tJR,vr m x ,

I31L~:

NO.

WElgKS

STR ICTUR F~S

PERT

17 17 13 47

12-14 10-t3 11-14

1" (5.8~/ff~) 2 (11.7%) 0 (0.0~'g)

0 4 6 I0

Group I G r o u p 1I Group I[I TOTAL

OF

3

(6.4/o)

I~,'~ORTAI,ITY

0 ,1 (23.5%) t3 ,',~6...~':,o, 10 (21.25ro)

*"Gravel" ' , " wa,; present in 2 a d d i t i o n a l cas~'.

p e n d e n t s t u d y was being done by L y t l e (54.) of the R o y a l I n f i r m a r y HospitaI in Sheffield, E n g l a n d . In this s t u d y there were 7 patients, of whom 5 were w o m e n and 2 were men. T h e y o u n g e s t was 29 a n d the oldest 69, the average age bet ng ,)3.6. W h e n combined, the two series n u m b e r e d 18 p a t i e n t s in whom a total of '22 end-to-end a n a s t o m o s e s were p e r f o r m e d w i t h o u t a n i n t e r n a l splint sup,. I n 6 t,~.~ ~,,,,..,/o) port ('Fable 1..6) ,~o, p a t i e n t s , the i n j u r y to the c o m m o n duct was recognized a t t h e initial oper ation a n d i m m e d m t e p r i m a r y reconstruction was done. I n 5 (83.3 O-¢ 7 o ) of these 6 t)atient,s, the results h a v e been excellent and they have r e m a i n e d a s y m p t o m a t i c for a :minimum of 9 y e a r s and 10 m o n t h s a n d a m a x i m u m of 16 years. T h e average period-of follow-up is 11 y e a rs a n d 4 m o n t h s . T h e one (16.7 p e r c'ent) failure in the i m m e d i a t e reconstruction g r o u p occurred in a 57-year-old white man. T h r e e year s after the original o p e r a t i o n , a second r e c o n s t r u c t i o n of the c o m m o n bile duct was done by re section of the s t r i c t u r e a n d a r e p e a t : e n d - t o - e n d a n a s t o m o s i s without an i n t e r n a l s p l i n t support. T h i s p a t i e n t is a s y m p t o m a t i c 3 year s and 5 m o n t h s a f t e r the reoperation. I n the r e m a i n i n g 12 (66.6%) p a t i e n t s , all with d e l a y e d reconstructions, had one prea total of 20 o p e r a t i o n s had been performed. F o u r (33.3/(~) " ~" vious o p e r a t i o n a n d 8 (66.6%) h a d two previous operations. T h e r e were 5 (41..6%) failures of the operation; 1 p a t i e n t died and 4 w e r e reoperated on for r e c u r r e n c e of t h e stricture. In the o t h e r 7 (58.3~}g) p a t i e n t s , the results i

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T A B L E 1 6 , R E C O N S T R U C T I O N OF T H E C O S I M O N BILE DUCT WITItOUT THE USE OF AN INTERNAL SPLINT SUI'PORT. CLINICAL STUDY, DECEMBER 1951--DECEMIIEr~ 1967 RESULTS

Own series L y t l e ' s series

No. PTS. 11 7 18"

No. OVER. 1.,1 8 22

F.xcellent Failure 7 3 6 1. 13 4t

P.O. ].)ea/l~ 1 0 1

(5.5%) M a x . F o l l o w - u p - - 1 6 yr. Av. Follow,,Ul>--10 yr, F o l l o w - u p ~> 5 y r , - - 1 5 pts. (83.3%) t e a c h correctf.~l b y a second o p e r a t i o n of s a m e t y p e F a i l u r e ratei U n c o r r e c t c ~ t - - 2 7 . 7 % Correct d--5.aT,, (1 d e a t h ) •* Immc
48

of tile operation have been excellent for follow-up periods t h a t r a n g e from 3 to 16 years. T h e a v e r a g e period of follow-up is 10 y e a r s and 1 month. T h e 4 p a t i e n t s who w e r e failures after the fil~t o p e r a t i o n were r e o p e r a t e d oll a n d each had a second e n d - t o - e n d anastomosis w i t h o u t a splint s u p p o r t . I n 1 p a t i e n t , it was the t h i r d operation a n d in the r e m a i n i n g 3 it was t he f o u r t h r e c o n s t r u c t i o n o p e r a t i o n performed. E a c h of these 4 p a t i e n t s is living a n d well w i t h o u t s y m p t o m s for 8 years a n d 11 montlls, 6 y e a r s a n d 6 m o n t h s , 3 y e a r s a n d 5 m o n t h s , a n d 3 m o n t h s respectively. T h e m ~ t recent p a t i e n t who was r e o p e r a t e d on h a d an e n d - t o - e n d rec o n s t r u c t i o n of the c o m m o n d u c t w i t h o u t a s t e n t s u p p o r t in N o v e m b e r , 1958. T h e anastomosis at t h e time of o p e r a t i o n was not completely satisfactory because ¢ff evident t e n s i o n on the s u t u r e line. A p p r o x i m a t e l y 13 m o n t h s a f t e r operation, a fleeting a t t a c k of chills, fever a n d j a u n d i c e occurred, but did n o t r e c u r d u r i n g the s u c c e e d i n g year, a t t h e end of which time t he patie n t was t e m p o r a r i l y lost to follow-up. In a previous c o m m u n i c a t i o n (55), t h e result: in this p a t i e n t d u r i n g a 2-year period of follow-up was clm~sified as good. T h e p a t i e n t was not s e e n a g a i n u n t i l 7 y e a r s later. At this time, a h i s t o r y of p e r s i s t e n t pain in the right costovertebral angle of 3 weeks' d u r a tion was obtained. ,Jaundice was slight a n d the g e n e r a l condition of t h e p a t i e n t was satisfactory. D u r i n g the 7 years from the time w h e n last seen, a t t a c k s of mild ehi!ls, fever a n d j a u n d i c e o c c u r r e d on the average of one a year. O p e r a t i o n disclosed a s t r i c t u r e at the site of the anastomosis. T h e s t r i c t u r e d s e g m e n t was resected and a second e n d - t o - e n d anastomosis witho u t a n i n t e r n a l splint s u p p o r t was readily a c c o m p l i s h e d w i t h o u t tension, using a single layer of i n t e r r u p t e d s u t u r e s of 5-0 a r t e r i a l silk. T h e one f a i i u r e ~ t h e p a t i e n t who d i e d ~ o c c u r r e d in a 52-year-old w h i t e w o m a n . T w o days after a cholecystectomy, j a u n d i c e occurred a n d per si st ed for th e e n s u i n g 4 months. A t this time, an a t t e m p t at r e c o n s t r u c t i o n of t he c o m m o n duct was unsuccessful. W h e n she was s e e n f o r the first time by us, 8 d a y s later, j a u n d i c e was e x t r e m e a n d a fetor h e p a t i c u s was present. Cholemic toxicity was pronounced, a n d general w e a k n e s s a n d fatigue were severe. A d m i t t e d l y , the p a t i e n t was a poor surgical risk b u t i m m e d i a t e o p e r a t i o n was unavoidable. W h e n the occluded c o m m o n h e p a t i c duct was opened, " w h i t e bile" flowed freely a n d u n d e r m o d e r a t e pressure. It was p l a n n e d originally to l i m i t t h e o p e r a t i o n to the e s t a b l i s h m e n t of a biliary fistula. However, the distal end of t h e c o m m o n duet w as easily a n d quickly i s o l a t e d a n d a p r i m a r y end-toe n d a n a s t o m o s i s w i t h o u t a s p l i n t supI~ort was done. Since the o p e r a t i o n was not u n d u l y prolonged, it was reasoned t h a t this siek p a t i e n t m i g h t benefit m o r e by the e n t r a n c e of t he bile into the i n t e s t i n e t h a n to the outside as a n e x t e r n a l biliary fistula. Six h o u r s postoperatively, golden bile was seen in the L e v i n tube. However, 12 h o u r s a f t e r o p e r a t i o n the p a t i e n t died suddenly. A n a u t o p s y was not performed. I n retrospect, it m a y be j u s t l y a r g u e d t h a t t h e o p e r a t i o n should h a v e been limited to the formation of a n e x t e r n a l biliary fistula because of t h e g r a v i t y of the p a t i e n t ' s illness. I n t h e total of 18 p a t i e n t s ha~dng h a d r e c o n s t r u c t i o n s of the c o m m o n duct by e n d - t o - e n d a n a s t o m o s i s w i t h o u t a s t e n t s u p p o r t , t h e r e were 5 (27.7/~) failures a n d 1.3 (72.3%) succgsses. Of the failures, 1 (5.5%) p a t i e n t died a n d t h e o t h e r 4 (22.2~o) w e r e r e o p e r a t e d on a n d the s a m e o p e r a t i o n was a g a i n p_crformed. I n each, t h e result has proved successful. T h i s is in con49

trast to the experience of Cattell, who listed the failure of a previous end-toend r e p a i r as a contraindication to its repeat performance. T h e corrected failure rate in this combined series for patients having had p r i m a r y reconstructions of the common duct by end-to-end anastomosis w i t h o u t a s t e n t s u p p o r t is 5.5a/g, or 1 failure in 18 patients. T h e lone failure was the p a t i e n t who died the day after operation (see T a b l e 16). T h e exclusion of this deatk as a failure would make the new corrected failure rate 0.0.°-/o, and the corrected success rate 100.0%, with an average follow-up of 1 t years and 4 months..

DISCUSSION

Tile e x p e r i m e n t a l and clinical data presented s u p p o r t well the concept of reconstruction of the common duct by end-to-end anastomosis without an internal splint or stent supporL T h e resulta of i m m e d i a t e p r i m a r y repair of the injured duct, either at the. initial or secondary operation, have been excellent. This is in contrast to the exceedingly poor results reported by L o n g m i r e (52), who routinely used a " T " tube as an internal splint support. T h e o r e t i c a l l y and on the basis o f tradition, better results s h o u l d h a v e been obtained with the use of an indwelling stent. I-towever, Cattell, who ])racticed a n d advocated end-to-end anastomosis with a splint s u p p o r t as the p r i m a r y procedure of choice, was able to report satisfactory results in only 53--58% of the patients so treated (6). This l i m i t a t i o n in satisfactory results assumes g r e a t e r significance w h e n one considers the technical skill and u n p a r a l l e l e d experience of Cattell in the t r e a t m e n t of common duct injuries. Now, more a n d more interest is being e n g e n d e r e d in reconstruction of the common duct by biliary-intestinai decompression because of the evident dissatisfaction with the splinted endto-end anastomoses. In consideration of tlie significanI increase in the percentage of sate. factory. results obtained by end-to-end reconstructions w i t h o u t the use <>f an i n t e r n a l splint support, it is logical to question both the necessity and the reason for the continued u s a g e of indwelling stents. In s u p p o r t of splinting the repaired duct for prolonged periods it is stated (1.2) t h a t they are essentim " . . . to allow cessation of contraction in a nondistended circular anastomosis . . . . " T h e same authors con~pared this practice to the necessity for the long-term use of stents in circular skin grafts in the esophagus. However, this comparison is believed fal][acious on the basis that skin grafts, interposed,in a mucosa-lined tube like the esop!mg~s, are not comparable to a mueosa-to-mucosa a p p r o x i m a t i o n of the common duct. This lack of similarity is f u r t h e r emphasized when one considers the beneficial effect of the gentle dilating action of the pressure o f the bile within the lumen of the common duct t h a t is constantly present. T h e effectiveness of this dilating action of the bile is s u p p o r t e d by the experimental studies of H a r r i d g e (29), who d e m o n s t r a t e d that t h e continuous d r a i n a g e o f bile through a n indwelling " T " tube located completely proximal to the site of an end-toend anastomosis of the common duct: predisposed to the occurrence of a stricture at the suture line. However, when the vertical limb of the " T " 50

t u b e was elanlped a n d bile was p e r m i t t e d to flow c o n t i n u o u s l y across t he a n a s t o m o t i c site, no s t r i c t u r e occurred. Still others (5, 12, 791) s t a t e t h a t t h e a n a s t o m o s i s should be s p l i n t e d for a t le a st a y e a r to p e r m i t the completion of the m a t u r a t i o n a n d c o n t r a c t i o n of th e fibrous tissue s u r r o u n d i n g the anastomosis. Seemingly, this p r a c t i c e would lessen the incidence of s u b s e q u e n t s t r i c t u r e formation w h e n the s t e n t is removed. I t is difficult to justify the a r g u m e n t s for the prolonged m a i n t e n a n c e of i n t e r n a l splints in r e c o n s t r u c t i o n s of t h e c o m m o n d u c t by m u c o s a - t o - m u c o s a u n i o n in view of the universal d i s r e g a r d of i n t e r n a l splints in mucosa-tom u c o s a a n a s t o m o s i s in the g a s t r o i n t e s t i n a l t r a c t a n d t h e i r lim i t ed use in m u c o s a - t o - m u c o s a u r e t e r o u r e t e r a l or u r e t e r o i n t e s t i n a l anastomoses. In the e a rly p h a s e s of the d e v e l o p m e n t of g a s t r o i n t e s t i n a l surgeD', s t e n t s of varioils t y p e s were i n d e e d used. T h e necessity for the long-term m a i n t e n a n c e of a s t e n t as a r o u t i n e in c o m m o n d u c t repairs is u s u a l l y based on the a priori r e a s o n i n g t h a t t h e failure ~o use one would ine~dtabIy r e s u l t in a r e c u r r e n c e of t h e s t r i c t u r e . T h i s reasoning is c o m m o ~ y based on t h e casual observations t h a t w h e n t h e i n t e r n a l splints were a c c i d e n t a l l y e x t r u d e d w i t h i n 7-10 days a f t e r t h e i r insertion, s t r i c t u r e s a l m o s t a l w a y s recurred. T h e s e obse~rvations raise the i m p o r t a n t question: W h y did tl~e tube ext r u d C ) M a n y times t h e r e is no a n s w e r to this question. At o t h e r times it is s t a t e d t h a t the vertical limb of the tube was c a u g h t in the bedcl ot hi ng and c a m e out a c c i d e n t a l l y as t h e p a t i e n t was e i t h e r t u r n i n g or being t u r n e d in bed. One or m o r e of a host of other causes a r e a l s o f r e q u e n t l y i m p u g n e d . A d m i t t e d l y , g e n u i n e accidents which cause a complete d i s p l a c e m e n t of a n i n t e r n a l splint can a n d do occur. However, it is believed t h a t the m o s t c o m m o n cause for this d i s p l a c e m e n t is a d i s r u p t i o n of the anastomosis. T h i s o c c u r r e n c e would p r e c l u d e healing by p r i m a r y i n t e n t i o n a n d r e s u l t in a s t r i c t u r e . I n 2 of the p a t i e n t s in this sttTdy, t h e " T " tube was a c c i d e n t a l l y e x t r u d e d within 10 days. In each, the c~,use of t h e extrusion was a disruption of the s u t u r e line, a n d each had a r e c u r r e n c e of t h e s t r i c t u r e . I n a n y anastomosis, w h e t h e r g a s t r o i n t e s t i n a l , urologic or biliary, t h e r e a r e t h r e e bas~.c t e n e t s t h a t m u s t be a d o p t e d to obtain uniformly successful resul~:~: (1) no teI~i()n on the s u t u r e line, (2) a d e q u a t e bIood supp]y to t he p a r t s a n d (3) a good a n a s t o m o s i s w i t h m u c o s a - t o - m u c o s a apt)osition. If th e s e principh~s prevail, i n t e r n a l splints a r e not essential a n d a r e believed c o n t r a i n d i c a t e d . T h e y a r e considered as u n n e c e s s a r y tissue i r r i t a n t s , part i c u l a r l y wtmn used in a tissue as delicate as t h e common bile duct. T h i s r e a s o n i n g is s u p p o r t e d by the e x p e r i m e n t a l studies by L a r y a n d S chei be (,19) which d e m o n s t r a t e d a n i n c r e a s e in t h e incidence of c o m m o n duct stri ctu res following pro] onged i n t u b a t i on of end- to- end reconstructions. C o r d o n n i e r (10, 11) established the fact t h a t in u r e t e r o i n t e s t i n a l anastomoses by m u c o s a - t o - m u c o s a apposition, i n t e r n a l splints a r e no t required. C o n f i r m a t i o n of this principle was o b t a i n e d by our own studies (56), both e x p e r i m e n t a l a n d clinical, relative to end-to-side u r e t e r o u r e t e r o s t o m y without a n i n t e r n a l s p l i n t s u p p o r t . T h i s s a m e p r i n c i p l e is believed m o s t applicable to e n d - t o - e n d u n i o n s of the i n j u r e d c o m m o n duct. I n s e c o n d a r y r e c o n s t r u c t i o n s of the c o m m o n duct, an u n d u l y long s e a r c h for its distal end is not believed w a r r a n t e d . I n s t e a d , a biliary i n t e s t i n a l de51

,~oml)ression is advised. However, if the lower p o r t i o n of the d u c t is readily available a n d ~ d e q u a t e in l e n g t h and size, tile s u r g e o n has t h e choice, of doing an end-to-end ano-~tomosis or an end-to-side hel)aticcduoden(;stom¥ or a h e p a t i e o j e j u n o s t o m y . T h e p a r t i c u l a r choice selected will d~'l)end on t he individual circumstances. However, regardless of the choice, it is mandatoTT, to Ferform an a c c u r a t e n m c o s a - t o - m u c o s a al)proximation and to haw~ a s t o m a of a d e q u a t e size. If these m a n d a t e s a r e followed, a n indwelling splint s u p p o r t is considered c o n t r a i n d i c a t e d . I n bilia~" i n t e s t i n a l decompression, Cattell (6) favored an entt-t<~-side h e p a t i e o j e j u n o s t o m y a n d proximal e n t e r o e n t e r o s t o m y . O t h e r s {9. 12, 19) h a v e ad~dsed t h a t the a n a s t o m o s i s to the j e j u n u m should be don,~ on t he 1Roux-en-Y principle to p r e v e n t the complication of " a s c e n d i n g cholangitis." It was eml)hasized e a r l i e r in this l)resentatior~, w h e n eomn:on d u c t ston(~s w e r e discussed, t h a t the use of a d e f u n c t i o n e d limb of j e j u n u m is not the basic factor in the preventi(m of cholangitis. In fact, a b e t t e r term would be "'descending cholangitis," sinc~,: it is due to stc~mal obstruction and not due to the reflux of i n t e s t i n a l conte~!ts. C o n f i r m a t i o n of this belief was obtained in th e e x p e r i m e n t a l a n i m a l by anastomosis of the c o m m o n duct to the transverse colon, e i t h e r as a side-to-side anastomosis or as a physi(H()gic end toside a n a s t o m o s i s by ligation of the e(,mmon d u c t e a u d a d to the anastomosis. In h e p a t i c o j e j u n a l anastomoses, th(:, selective use (,f i n t e r n a l splints has been advised (9). T h e i r use is reserved for tlii)se p a t i e n t s in xbh()m t he dia m e t e r of the c o m m o n d u c t is small. However, even then, we have preferrt~d m u e o s a - t o - m u e o s a union w i t h o u t a s t e n t support. T h e i'yt)e of sutur(~ 1)referred is ,.5--0 a r t e r i a l silk, a l t h o u g h equally satisfactory, results .may b(:, o b t a i n e d w i t h similar-size s u t u r e s of chromic p.atgut, whic}~ theoretically is better. I n 1 p a t i e n t , a n avulsion of the l:~al)illa of V a t e r occurred d u r i n g the perf o r m a n e e of a p a r t i a l g a s t r e c t o m y for a d u o d e n a l ulcer. A second corrective o p e r a t i o n for the biliary fistula was a t t e m p t e d w h i c h included a ci~olecyst,)j e j u n o s t o m y a n d tube j e j u n o s t o m y . Wh(m seen for the fi~,,'t t i m e , a b a r i u m eholeeystoeholangiogram, obtained following a b a r i u m meal, showed a norreal b u t n a r r o w c o m m o n d u c t (Fig. 12). At operation, the d i a m e t e r o,¢ the d u c t was less t h a n it a p p e a r e d on the r o e n t g e n o g r a m s . W h e n electi\--ly t r a n s e c t e d , t h e h e p a t i c d u c t was so small t h a t its p r o p e r i d e n t i t y was ~,t first questioned. ' t h e size of its l u m e n p e r m i t t e d the insertion of only 3 s u t u r e s p osteriorly a n d 4 a n t e r i o r l y in the p e r f o r m a n c e of an end-to-side, m u c o s a - t o - m u c o s a h e p a t i c o j e j u n o s t o n l y . D e s p i t e the, n a r r o w d i a m e t e r of th e duct, a n i n t e r n a l splint was not used. A b a r i u m r o e n t g e n o g r a m 4 m o n t h s p o s t o p e r a t i v e l y showed reflux i n t o the h e p a t i c d u e t and ik~ liver radicles (Fig. 13). T h e ductaI s y s t e m wKs not dilated and t h e r e was ease of ingress a n d egress of the barium. F o u r y e a r s a n d 4 m o n t h s a f t e r the o p e r a t i o n the p a t i e n t r e m a i n e d a s y m p t o m a t i e . Accordingly, it i s believed ( h a t w h e n m u c o s a - t o - m u e o s a apposition is obtained, even t h o u g h the duet is small, i n t e r n a l s p l i n t s are n o t required. P o r t a l h y p e r t e n s i o n is a serious a n d f r e q u e n t l y fatal complication of bile d u c t in ju ry. W h e n it occurs, t h e q u e s t i o n n a t u r a l l y arises relative to its reversibility by correction of its c a u s a t i v e factor, n a m e l y , the c o m m o n d u c t stricture. H o w e v e r , t h e r e has been no l a r g e series of cases r e p o r t e d t h a t h a v e been t r e a t e d in this m a n n e r . T h e technical difficulties in the r e p a i r of 52

FI~;. 1.2.~I~ettux barium choleeystocholangiogran~ in patient with avulsion injury of papilla of V a t e r o r i g i n a l l y treate:l by e h o l e c y s t o j e j u n o s t o m y . Arrows i n d i c a t e c o u r s e of n o r m a l b u t narro~

eo[llll~on

dl~le[.

t h e s t r i c t u r e pur.s uan~" to the problem of bleeding a n d the i n c r e a s e d surgical risks imposed have been stressed, b u t tile effect of the r e c o n s t r u c t i o n oi1 the reversibility of the portal h y p e r t e n s i o n has not been clarified. T h e o p p o r t u n i t y to d e t e r m i n e the reversibility of the I)ortal h y p e r t e n s i o n was p r e s e n t e d to us by a 45-year-old white w o m a n who i n c u r r e d a n i n j u r y to the. common duet w h e n a c h o l e c y s t e c t o m y wa.s performed. T h e i n j u r y was recognized i m m e d i a t e l y and r e p a i r e d a t the initial o p e r a t i o n by end-to: end r e c o n s t r u c t i o n over a " T " t u b e support. T h e tube r e m a i n e d in place for 18 m o n t h s , a n d for the e n s u i n g 2 y e a r s i n t e r m i t t e n t a t t a c k s of chills, fever a n d j a u n d i c e oecurred with i n c r e a s i n g f r e q u e n c y a n d severity. T h r e e a n d one half y e a r s after, the i n j u r y , a n a c u t e massive e x s a n g u i n a t i n g hemorr h a g e with shock occurred s e c o n d a r y to bleeding esophageal varices. 53

!

":'"

"

"

" "

'

!

l

-

Fro. 13.~Postol>erative retlux barium clmlangiogranl aftd~ end-to-end hepatic,o iejunov;~omy, I2k~l)ite narrow dimneter of common and hepatic duct.s (Fig. 14), an,.~siomosis without an internal splint support proved satisf:mtory.

At operation, the anatomic findings precluded a planned pormcaval s h u n t a n d it was elected to perform a reconstruction of the common duct. To secure an a d e q u a t e length of the common duct it was necessary to resect a circular cuff of the liver at the porta hepatis. An end-to-end anastomosis was then done w i t h o u t a stent support. However, the tension on the suture line was excessive a n d the anastomosis was dismantled. Next. an end-to-side h e p a t i c o j e j u n o s t o m y was performed. Before completion of the a n t e r i o r l a y e r of the anastomosis, a No. 1.2 F n l b b e r c a t h e t e r was inserted into the l u m e n of the h e p a t i c duet and its bell end was passed into the lumen of the efferent loop of the j e j u n u m a n d brought out t h r o u g h an opening in the a n t e r i o r wall. It was then embedded in a 4-cm.-long serosaI tunnel (Witzel) in the wall of the j e j u n u m before,its final exit to the skin surface. T h e indwelling c a t h e t e r was used for the expressed purpose of obtaining a postoperative cholangiogram to d e t e r m i n e the extent of c o m m u n i c a t i o n between. the biliary radicles w i t h i n the liver and t h e hepatieojejunostomy. This was obtained 10 days after the operation and showed a satisfactory d r a i n a g e of the duet systems w i t h i n the liver (Fig. 14). T h e c a t h e t e r was then removed. T h e s u b s e q u e n t c o u r s e of this patielr~ was satisfactory, and 10 m o n t h s after operation a n esophagogram showed a pronounced decrease in the size of the variees (Fig. 15), N i n e years and 1. m o n t h after the operation the p a t i e n t was asymptomatie. This isolated instance d e m o n s t r a t e s well the possibility of reversal of the portal h y p e r t e n s i o n by correction of its cause, even though some e n l a r g e m e n t of the liver a n d spleen still persists. In such eases, Cole (9) and later Sedgwiek (67) suggested a n d practiced the p e r f o r m a n c e of a p r e l i m i n a r y splenorenal s h u n t as the first-stage pro54

l:'m. ~ 4 . ~ C h o l : m g i o g r a m , 10 days after an end-io-side hetmtieojejunostomy, showing a d ~ quate drainage ol/.the intrahepatic radicle.s.

cedure to the definitive repair of tile common bile duct. In this way, the technical difficulties co~.equent on bleeding secondary to t h e p o r t a l hypertension would be lessened. This reasoning has b e e n justified by continuing experieImes, and this concept is considered of demonstrated clinical value.

Fro. ].5.--Preolmrative (~'e]t) and postoIrerative (.right) roentgenograms to show almost complete disappearance of tim esophageal v a r i e ~ ~0 months after hepatieojejunostomy (Fig. 14).

55

FI(;. 1 6 , ~ I n t r a v e n o u . ~ c h o l a n g i o g r a m 20 m o n t h s after an i , n m e d i a t e e n d - t o - e n d anastomo.~is of the (:oum~on d u c t w i t h o u t a stent suPi×~rt (Fig. 10). T h e two sets of ol)po:~ing ~,rrqws indic a t e the o u t l i n e of t h e r e c o n s t r u c t e d (]uct.

CONCLUSIONS

In r e c o n s t r u c t i o n of the c o m m o n d u c t by e n d - t o - e n d a n a s t o m o s i s , the rationale for the u s e of an internal splint: support: is q u e s t i o n e d . T h e belief t h a t t h e failure to trse a n i n t e r n a l s p l i n t w o u l d i n c r e a s e the i n c i d e n c e of r e c u r r e n t strictures is b a s e d on a priori r e a s o n i n g t h a t is n o t s u b s t a n t i a t e d by scientific fact. P r i m a r y re.constructmn" " of the c o m m o n d u c t by e n d - t o - e n d a n a s t o m o s i s w i t h o u t a n i n t e r n a l s p l i n t s u p p o r t is of p r o v e d m e r i t in b o t h the experim e n t a l a n i m a l a n d in the h u m a n . Its c o n t i n u e d use is r e c o m m e n d e d . REFERENCES Reconstruction of the CommonBile Duel 1. 2. 3. 4. 5.

Allen, A. W . : A m e t h o d or r ~ e s t a b l i s h i n g ~'.ontinuity between t h e bile d u e l s a n d t h e g~stro-in[e::;tina[ t r a c t . Ann. Surg. 121:412, 1945. B a l f o u r , D. C.: T h e tc~chnic of h e p a t i c o d u o d e n o s t o m y , Ann. Surg. 73: 343, ]921. I~artlett, M. K.: C i t e d by E l i o t (22). Cattell, I L I',.: l ] e n ; g n strictures or tile b i l i a r y d u c t s . J . A . M . A . 134:235, ]947. Cattell, IL B . , a m l W a r r e n , K. WI: S u r g e , ' y of the b i l i a r y tract, N e w En:%laml J. Med. 255: 7{~1, 1.05.~.

56

6.

Cattell, It. B., and Braasch, J. W.: P r i m a r y repair of benign striclures of the bile duct, Surg,, Gynec. & Obst. 109:531, 1959. 7. Cattcll, IL B., and Braasch, J. W.: Two stage repairs of benign strictures of the bile duct, Surg., Gynec. & O[)st. 109: 6~}1, 1959. 8. Cole, %V. ft.: Precautions in the treatment of strictures of /he (:ommon duct, Am. Surgeon 20: 234, 1954. 9. Cole, \¥. H.. Ireneus, C., J r . , and Reynoh]s, J. T.: Stricturc~.~ of lhe common bile duct, Ann. Surg. 142: 537, 1955. 10. C<)rdonnier, J . . J . : Ureterosigmoid anastomosis, Surg.. Gynee. & Obst. 88:441, 1949. 11. Cordonnier. J. M., and I.age, W. J.: An evaluation of ureierosigmoi(l anastomosis by mueosa-to-mucosa nm!hod after two and one-half years' experience, J. Urol. 66: 565, 1951. 12. C<~sman, B., and Porler, M. R.: Benign stricture of the bile ducks, Ann. Surg. 152:730, 1960. 13. Deaxer, J. B.: Hepatic drainage, Brit. M. J. 2:821, 1904. 14. Doberauer, G.: Ueber die Careinome ties Ductus Choledochus, Beitr. klin. Clair. 67:472, 1910. 15. Dobrucki: Cited by K e h r (40). 16. l)ownc.~, W. A.: I n j u r y to the c o m m o n bile-duct, Ann. Surg. 67:619, 1918. 17. ] ) o w n s , W. A.: Cited by Douglas (18) and Eliot (23). 18. l )ougl a s , J.: Strictures anti operative i n j u r i ~ of the bile (lucks, Ann. Surg. 84: 392, 1926. 19. l)onaklson, G. A.. Allen, A. W., and Bartlett, M. K.: Postoperative bile-duct strictures. T h e i r etiology and treatment, New E n g l a n d J. Meal. 2r)-l: 50, 1956. 20. l ) o y e n , E.: Quelcluts OpdratiorLu sur le foie et les votes h i l i a i r ~ , Arch. Provinciales Chir. I: 1,I9, 1892. 21. Dreesmann, I-I.: In discu..,~sion of p r ~ e n t e d paper, Zentralbl. Chir. 51: 1244, 1924. 22. Eisendrath, D. N.: Operative i n j u r y of the common and hepatic bile-ducts, Surg., Gynec. & Obst. 31: 1, 1920. 2;1. Eliot, I'2., Jr.: T h e repair and reconstruction of the hepatic and c o m m o n bile duels. Surg., Gynec. & Obst. 26: 81, 1918. 2,t. Eliot, E., Jr,: Benign eicatrieial s t r i c t u r ~ of the bile ducts, Ann. Surg, 104:668, 1936. 25. Elli,~ and I)ragstedt: Cited b y / . i a r r i d g e (29). 2(3. Lrdm~m, S.: Cited by E,"l i, o t ,,,,,),,. ~v',, 27. Gould, A. P.: Citc~l by Walton (75). 28. Grey T u r n e r , G.: I n j u r y to the common bile-duet and the technique of operations on the duels, Proc. Iloy. Soc. Meal. 17: 18, '1923. 29. H a r r i d g e , W. H.: Alterations in C o m m o n Duct Stricture. Surgical Forum, Clin. Cong. Am..Coll. Surg. pp. 411---116, 1952. W. B. Saunders C o m p a n y , Philadell)hia. April. 195,:1. 30. I-lepp, J . , and Couinaud, C.: L'Alx)rd et l'utilisation du canal hepatique gauche dmxs lces reparations de la vote biliaire prineipale, Presse mSd. 64: 947, 1956. 3I. H o m a n s , J.: Cileerationen an den Gallangangen, Miinchen. meal. VVchnschr. 52: 10"37, 1905. 41. K e h r , 14.: Zur Hepaticusdrainage, Zentralbl. Clair. 36:3, 1909. 42. K e h r , tt.: Die Praxis der Gallenwege-Chirurgie in Wort und Bild (Munchen: Lehnaann, 1913), Vol. II, p. 386. 43. K e h r , H . : Cited by Eliot (23). ,/,4. KSrte, W.: Beitrage zur Chirurgie der Gallenwege und der Leber (IIorlin: Hirschwald, 1905), p. 341 (case No. 208). 45. K6rte, W.: Weitre E r f a h r u n g e n uber Operationen an d den Gallenwegen, Arch. klin. Clair. 89: 22, (case No. 9), 1909. 46. Lahey; F.: S t r i c t u r ~ of the c o m m o n and hepatic ducts, Ann. Surg. 105: 765, 1937. 47. Lahey, F. H., and Ryrtek, L. J.: Experience with the operative m a n a g e m e n t of 280 strict u r ~ of the bile ducts with a description of a new method and a complete follow-up s t u d y of the end results in 299 of the c a s ~ , Surg., Gynec. & Obst. 91:25, 1950, 48. Landerer: Cited by Wangensteen (77). 49. I_~ary, B. G., and Scheibe, J. R.: Effect of rubber tubing on the healing of c o m m o n duct anastomoses, Surgery 32: 789, 1952. 50. Longmire, W: P., Jr., and Sanford, M. C.: Intrahepatic cholangiojejunostomy with partim hepatectomy for b i l i a r y obstruction, Surgery 24: 264, 1948. 51. Longmire, W. P., Jr., and Sanford, M. C.: Intrahepatic cholangiojejunostomy for biliary ~:Obstruction~further studies: Report of 4 caste, Ann. Surg. 130:455, 1949. 57

52.

l x m g m i r e . \V. P.. ,Jr.: E a r l y m a n a g e m e n t of i n j u r y lo the e x t r a h e p a t i c biliarv tract, , I . A . M . A . 195:(;23, 1966. ,5:t. l , u n d , F. 13.: Cited by E i s e n d r a l h 122). 54. l,ytle, W. J.: Personal c o m m u n i c a t i o n . N o v e m b e r 19. 1959. 55. Xl a d d e n , J . L,., a n d lk{cCann, \V. ,1.: R e c o n s t n l c t i o n of the c o m m o n bile duct by end-loend a n a s t o m o s i s without the use of an internal splint or stent SUl)lmrt, Surg., Gynec.. & Obst. 112:305, 1961. 56. Ik{adden, ,l. L., T a n , P. Y., and M c C a n n . \V. J.: An e x I ~ r i m e n t a l and clinical s t u d y of cross ureterouretero.~tomy. S u r g . , Gynee. 8: Obst. 124: 483. 1967. 57. M a i n g o t , R.: P o s t o p e r a t i v e stricturL~s of the bile ducts, Ann. R o y . Coll. Surgeons Engl a n d 24:186, 1959. 58. M a y o , W, J.: S o m e r e m a r k s on c ~ n ~ involving o p e r a t i v e loss of c o n t i n u i t y of the comm o n bile duct, Ann. Surg. 42: :~0, 1905. 59. M e n t z e r , S. H.: 13ile peritonitis, Arch. Surg. 29: 227, 1934. 60. M o y n i h a n . B.: A b d o m i n a l O p e r a t i o n s {4th ed.; P h i l a d e l p h i a : W. B. S a u n d e r s C o m p a n y . 1926), Vol. II, pp. 349-351. 61. N o r d m a n n , O.: "Fransjejunale Hepaticus(lrainage. V e r h a n d l . deuL,~ch. G ~ e l l s c h . Clair. 42: 287, 1913. 62. P i - F i g u e r a s , J . , anti Brull, H.: T r a t a m i n e n t o D e Iais Estenosis Postoperatori,'t~ t)el C o n d u c t o Hepatico, An. meal., t~arcelona, Seccion G r u g i a 50: 1, 1964. 63. Riggs, T. F.: E n d - t o - e n d s u t u r e of bile-ducLs, Surg., Gyncc. & Obsl. 22: 660. 1'.)16. 64. I~obson, A. W. M.: T h e surgical t r e a t m e n t of obstruction in the c o m m o n bile-duct by concretions, l ~ m c e t I : 1023, 1902. 65. Rotter: Cited b y E l i o t (23). 66. Schweizer: Cited by E l i o t 124). 67. Sedgwick, C. E., and H u n m . A.: M a n a g e m e n t of bile d u c t stricturc~ with associated l-~n'tal hyperlelasion, S u r g . , Gynec. & Obst. 108: 627, 1959. 68. S m i t h , R.: H e p a t i c o j e j u n o s t o n a y with t r a n s h e p a t i c intubation: A tecAmique for very high stricturt-~ of t h e hepatic duct.s, I3rit. J. Surg. 51: 18(;, 1964. 69. Stettin, 10.: End-to-end s u t u r e of tim hepatic duct, M e d . l~ec. 88: 630, 1915. 70. Stone, I. S.: C o m p l e t e division of c o m m o n d u c t at j t m c t i o n w i t h h e p a t i c and trystic ducts. S u r g . , Gynec, 8,: Obst. 9: 590, 1909. 71. S u l l i v a n , A. G.: Recon-struction of the bile ducts, J . A . M . A . 58:2026, 1912. 72. Voelcker, F.: T r m l s d u o d e n a l e D r a i n a g e d~: Du,:tus h e p a t i c u s b e t l-'lastik th~ 1)uclus hepatico-cholf.~lochus, Beitr. klin. Chir. 72: 581, I911. 73. W a i t e r s , W., anti K e l l y , A. H.: S u r g i c a l t r e a t m e n t of s t r i c t u r e of the c o m m o n and heparle bile ducts; 28-year survey, A . M . A . Arch. Sutg. 66:,117, 1953. 74. ~,Valters, W., N i x o n . d. W., dr., and HodgirLs, T. E.: Stricturc,~s of the c o m m o n bile duct: 5- to 25-ye~tr follow-up of 217 operations, Ann. Surg. ],if): 781, 1959. 75. W a l t o n , A, J.: R e c o n s t r u c t i o n of the c o m m o a bile duct, Surg., Gynee. & Obst. 21:269, 1915. 76. W a l t o n , A. J.: l~ecoru~truction of the c o m m o n bile d u c t , Sttrg., Gynec. & Obst. 79:57, 1944. 77. W a n g e n s t e e n , O. H.: Sterile bile in the peritoneal cavity, Ann. Surg. 84: 691, 1926. 78. \Varren. K . W . , and ]3raasch,: J . ~V.: T h e selection of an o p e r a t i v e for benign s t r i c t u r e of the bile d u e t , S. Clin. Norlla A m e r i c a 44: 717, 1964. 79. W a r r e n , K. W., P o u l a n t z a s , J. K . , and K u n e , G. A.: Use of a Y t u b e splint in *be r e p a i r of biliary stricturt..,s', Surg., Gynec. & Obst. 122: 785, 1966. 80. "Werelius, A.: Accidental surgical injurit~ to the bite ducts. W i t h report of a c~'~e, J . A . M . A . 68: 1545, 1917. 81. Wilson, ,l., and Storer, E. H.: Stricturc~ of tim bile ducts: E t i o l o g y , prevention, a n d m a n a g e m e n t , Arch. Surg. 82: 171, 1961.

CHOLEDOCHODUODENOSTOMY C h o l e d o c h o d u o d e n o s t o m y is an operation that has been popular in E u r o p e for m a n y years but has not gained favor in the U n i t e d States. T h e objections to its performance are considered more theoretical than real. A surgeon of outstanding prominence, w h e n asked to comment on the merits of the operation, stated: "I m e n t i o n it only to condemn it." This s t a t e m e n t was m a d e publicly even though, admittedly; there had been no personal exp.erience with the operation. D o g m a t i c teaching in opposition to c holedochoduodenostomy and unsubstantiated by factual data, is the basis of American surgeons opposition to its use. 58

T h e purl)ose of this p r e s e n t a t i o n is to show by both historical and clinical data t h a t c h o l e d o c h o d u o d e n o s t o m y is an operation of proved merit, a n d to suggest t h a t it be used m o r e f r e q u e n t l y in the c u r a t i v e t r e a t m e n t of benign obstructive lesions in t h e t e r m i n a l portion of the c o m m o n bile duct.

HISTORICAL DATA RiedeI, in 1888, was the first to p e r f o r m c h o l e d c c h o d u o d e n o s t o m y , but it was not reported until 1.892 (29). T h e patient, a 40-year-old woman, was o p e r a t e d on for the first time on J u l y 23, 1888, for abdominal pain a n d jaundice. A c h o l e c y s t e c t o m y was done and recovery ensued. A second o p e r a t i o n was p e r f o r m e d on D e c e m b e r 8, 1888, because of r e c u r r e n t a t t a c k s of abdominal p a i n a n d jaundice. T h e common duct wa.s explored* but a stone was not f~und. B e c a u s e of the possibility of a stone being p r e s e n t in the distal portion of the common duct, a c h o l e d o c h o d u o d e n o s t o m y was performed. T h e p a t i e n t died 9 h ours a f t e r the operation. A u t o p s y showed t h a t the cause of d e a t h was peritonitis s e c o n d a r y to p e r f o r a t i o n and leakage at the site of anastomosis. T h e g a i l b l a d d e r was c o n t r a c t e d and a pea-size soft stone was preset,t in the p a p i l l a r y portion of t h e c,~mmon duct. T h e referenc e to this r e p o r t is commonly and i n c o r r e c t l y given to the publication in 1888 (28). K o e h e r (16.) i n 1890 r e p o r t e d l y considered the p e r f o r m a n c e of a c h o l e d o c h o d u o d e n o s t o m y , but, a f t e r s u t u r i n g the serosa of the d u o d e n u m to the c o m m o n duct. the o p e r a t i o n was a b a n d o n e d . P r i m a r y credit should be given to S p r e n g e l (35) as the first to r e p o r t a n d the first to p e r f o r m successfully a c h o l e d o c h o d u o d e n o s t o m y . T h e p a t i e n t , a 40-year-old woman, was o p e r a t e d on for t h e first time on October 13, 1890. A calculus was pushed from the gallbladder, p r e s u m a b l y into the d u o d e n u m . However, several days a f t e r the o p e r a t i o n t h e r e was rec u r r e n t a bdominal pain in association with jaundice. On J a n u a r y 16, 1891, a second o peration was performed. W h a t a p p e a r e d to be d u o d e n u m at t he first o p e r a t i o n proved to be a h u g e l y dilated c o m m o n d u c t . F u r t h e r m o r e , the stone t h a t was m a n i p u l a t e d a t the first o p e r a t i o n was i m p a c t e d in t h e c y s t i c duct. T h i s stone was trusteed b e t w e e n the fingers e x t e r n a l l y a n d th e cystic d u c t was ligated. A second stone was t h e n p a ! p a t e d in the duct-us choledochus a n d a t t e m p t s to p u s h it t h r o u g h t h e p a p i l l a into the d u o d e n u m were unsuccessful. T h e gallbladder w a s removed a n d the c o m m o n d u c t was opened. T h e c o m m o n d u c t stone was easily r e m o v e d a n d a side-to-side~ t w o - l a y e r a n a s t o m o s i s betw een t h e c o m m o n d u c t and the d u o d e n u m was performed. T h r e e m o n t h s p o s t o p e r a t i v e l y the p a t i e n t was a s y m p t o m a t i c . S p r e n g e l , in giving t h e p r o c e d u r e a n a m e , stated: " . . . so one m u s t , if he is not f r i g h t e n e d by the expression, call this c h c l e d o c h o d u o d e n o s t o m y ? ' However, it r e m a i n e d for S a s s e (32), in 1913, to p o p u l a r i z e the o p e r a t i o n for g e n e r al use. T e n cases were r e p o r t e d a n d t h e indications for the o p e r a t i o n were: (1) t u m o r of p a n c r e a s . 1 p a t i e n t ; (2) stenosis of papilla ~ 3 p a tie nts; (3) c o m m o n d u c t s t o n e s ~ 6 p a t i e n t s . Sasse r e c o m m e n d e d *First common duct exploration. Preceded Thornton, or first choledochotomy. 59

its use routinely in patients with common duct stones to preclude the retention of an "overlooked" or residual stone. Subsequently, there were m a n y excellent reports (I0, 11, o~_,, 27),, all from E u r o p e , concerning choledochoduod-nostomy. In a relatively recent one by P i - F i g u e r a s (26), the operation was performed i n 128 p a t i e n l s a n d in each the sole i n d i c a t i o n for its use was c o m m o n dtrct stones. The first puolication in the United States on the p a r t i c u l a r merits of choledoclioduodenostomy was t h a t of S a n d e r s (31.) in 1946. A side-to-side anastomosis was performed i'n 22 patients. I n 6 of these, the indication for the operation was c o m m o n d u c t obstruction secondary to cancer, either proved or suspected. In the r e n m i n i n g 16 patients, the operation was performed in the t r e a t m e n t of b e n i g n obstructive ductal lesions, I n each of 3 other patients w i t h t r a u m a t i d strictures of the common duct, the union was end-to-side b e t w e e n the hepatic duct a n d the duodenum. In the total of 25 patients, 2 (8:0,%) died, both of whom had benign obstructive lesions. None h a d "ascending" cholangitis. D u r i n g the ensuik~g 21 years, only two other large series have been reported (18, 33) i ~ e A m e r i c a n l i t e r a t u r e p e r t a i n i n g to choledochoduodenostomy. I n each, the logic and feasibilii;y of the ol)eration was confirmed.

CLINICAL

STUDY

D u r i n g the 16-year period between December, 1951, a n d December, 1967, ch6ledochoduodenostomy was performed in 67 patients for the treatmerit of benign obstructive lesions of the terminal portion of the common duct. Biliary,-intestinal reconstructions of the common duct in the treatm e n t of t r a u m a t i c strictures are not included in this study. T h e r e were 29 (4.3.3%) m e n and 88 (56.7%) women. T h e yotmgest was 38 and the oldest 81. T h e average age was 61.1. A p p r o x i m a t e l y 85% of the patients w e r e in the sixth, seventh and eighth decades, the largest p e r c e n t a g e ( 3 7 . 3 ~ ) b e i n g in the seventh decade (Table 17). T h e indications for the operation are listext in Table 18. In about half of the patients a stone or stones in the common duct was the indication

T A B L E 17... CHOL~DOCHODUODENOSTO~r¢ FOR BENIGN LESIONS (67 PATIENTS, 1951--1967) AGE A~-D SEX INffmENCE A~: (YEA~) "]0--39 40-49 50-59

ME,~ 1 5 10

WO.~EN 1 2 7

10 3 0 29 (43.3%)

i5 il 2 38 (56.7.,0)

TOrAh 2 7 17 56

C~:)-69 "9 70-1, 8O-89 TOTAL

•

(~.5%)

25 ]4 2 67 (100.0%)

0 " 7

Y o u n g e s t , 38 yr. ; o l d e s t , 81 yr. ; a v e r a g e age, 61.1 yr. .

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60

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PLATE V G r o u p I I I a n i m a l , sacrificed 14 weeks a f t e r second stage procedure. S, anaso t o m o s i s duct closed: T, a n a s t o m o s i s ..duct: opened. A r r o w indicates healed line of anastomosis. K n o t s of silk s u t u r e are visible at each cut m a r g i n of the anastomotic line. G r o u p I I I a n i m a l sacrificed 13 weeks a f t e r second-stage procedure. /_1, anastomosis opened a n d c o l u m n of clear golden bile m a y be seen. V, a r r o w depicts complete healing w i t h o u t s t r i c t u r e a t site of anastomosis.

6~

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X

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PLATE VII W, choledochoduodenostomy in the h u m a n - - p h o t o g r a p h i c view into the l u m e n of the anastomosis following the completion of t h e i n s e r t i o n of the posterior layer of silk sutures. The adequacy of the lumen is apparent. X, a photograph of the completed second anterior layer of the anastomosis is depicted¢ Its relation to the ligated stump of the cystic duct, just cephalad, is visible. Y, autopsy specimen of the opened anastomosis in an experimental animal (dog) 69 days after a choledochocolostomy. A residual of feces may be seen in the common duct. The lumen of the anastomosis is adequate and the dog was asymptomatic throughout the period of observation. 62

TABLE

1 8 . C H OLEDOC It ODUODENOSTO3,IY FOR B E N I G N L E S I O N S (67 PATIENTS, 1 9 5 1 1967). INDICATIONS F O R O P E R A T I O N No. 34* 16 13 4t

Common duct stones S t e n o s i s of p a p i l l a , a l o n e Chronic pancreatitis, alone M i scel lan eou.-; TOTAl.

P~.a C v..-,,~ 50.7 23.9 19.4 6.0

6-7

i06.0

* P r i m a r y - - < ] 2 ~94.1%). W i t h f i b r o s i s - - 2 1 (65.6,%). ~[hlatcwl commot~ d u c t w i t h j a u n d i c e ; no s t o n e s , fibrosis or p : m c r e a t i t i s t.3). P o l y p in c o m m o n d u c t w i t h stenosis of p a p i l l a a n d j a u n d i c e (1). iJ

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for oI)eration. Over ono~, •~,-,,o of the stones were of the p r i m a r y or stasis t y p e which w e r e associated with fibrosis of the papilla in a p p r o x i m a t e l y 2 of e v e ry 3 patients. T h r e e p a t i e n t s had chills, fever, j a u n d i c e a n d m a r k e d d i l a t a t i o n of the c o m m ( m d u c t w i t h o u t e v i d e n t c a u s e . T h e r e w a s no s t o n e in t h e c o m m o n d u c t , p a n c r e a t i t i s or fibrosis of t h e s p h i n c t e r of Oddi. I n

fact, in 1 patient, the degree of p a t e n c y of the papilla p e r m i t t e d the passage of a size 8 Bfikes dilator. It may be argued that in these 3 patients the basic c a u s e f o r the s y m p t o m s was a stone which h a d blocked the duct but had passed j u s t before the o p e r a t i o n was performed. T h i s can be n e i t h e r proved nor disproved. In a n o t h e r p a t i e n t , a r a r e indication for c h o l e d o c h o d u o d e n o s t o m y was a benign polyp in the c o m m o n d u c t in conjunction with stenosis of the papilla. T h e preoperative diagnosis was c a n c e r of the head of the pancreas. T h e r e were postoperative complications in 11 (16.4%) p a t i e n t s ( T a b l e 19). In 3 (4.4%), w o u n d infections occurred and in the r e m a i n i n g 8 p a t i e n t s the complications were single and distinct. In 1 p a t i e n t , a n e m e r g e n c y r e o p e r a t i o n was n e c e s s a r y 4 h o u r s p o s t o p e r a t i v e l y because of a c u t e h e m o r r h a g i c shock. T h e bleeding ,-,~as from an avulsion of the

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TABLE 1 9 . - - - C H O L E I ) O C H O D U O D E N Ob'l O~ I'/ ( 6 7 P A T I E N T S , 1951-1967). P O S T O P E R A T I W E COMPLICATIONS No. Wound Infection Dehiscence S k i n ne
~:'Susl>ected, not proved. 63

PER CENT

3 1 1

4.4 1.4 1.4

1 1 1

1.4 1.4 1.4

1 1"

1..4 1.4

1 11

1.4 16.4

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T A B L E 20.:-CHOLEDOCHODUODENOSTOMY FOR BENIGN LESIONS (67 PATIENTS). FOLLOW-UP STUDY I -1951-1967. No, PTS. 67

lk~ ORBIDITY AND l k 4 0 R T A L I T Y LOST TO AVAIL. FOLL0W-UP STUDY EXCEL. 9 57 57

P,O, D~THS 1"

(1.4%)

( 13.6 70 )

(85.0%)

( 100.0 ,aZo)

FAIL. 0 (0,0%)

".ASCEND." CHOLANG. 0

(0.0~,o)

* 7 2 - y r . - o l d w o m a n ; 14 (lays p . o . ; p u i m . e m b . - - u n p r o v e ¢ / , S u b s e q u e n t d e a t h s ~ 1 0 (17.5°o) 4 too. to 12 yr. p.o. N o n e r e l a t e d to o p e r a t i o n ,

right ovarian vein at its e n t r a n c e into the inferior vena cava. This occurred d u r i n g the mobili'zation of the d u o d e n u m p r e l i m i n a r y to the choledochoduodenostomy. After s u t u r e ligation of the bleeding site, the convalescence was completely satisfactory. In another p a t i e n t there was a t e m p o r a r y biliary fistula which closed spontaneously. T h e r e was 1 (1.4%) deaH~. The patient, a 72-year-old woman, died s u d d e n l y 14 days after operation, presumably from a p u l m o n a r y embolus (Table 20). An autopsy was riot performea. F o u r years previously this p a t i e n t had had a secondary e x p l o r a t i o n of the common duct p e r f o r m e d for a p r i m a r y stasis stone which w a s r e m o v e d a n d "T" tube d r a i n a g e established. The pro.~ent operation w a s a third exploration of the common duct and again a single primary or stasis stone was removed. Accordingly, a choledochoduodenostomy was p e r f o r m e d which would have been better done following the previous choledochotomy. Fifty-seven (85.0%) p a t i e n t s were available for follow-up study. T h e m i n i m u m follow-up was 1 y e a r and the m a x i m u m 16 years. T h e average was 7 years (Table 21). A p p r o x i m a t e l y 9 of every 10 patients have been followed more than 2 y e a r s and a b o u t 2 of every 3 patients for more t h a n 5 years. T h e r e w e r e no failures of the operation a n d none had an "ascending" cholangitis. (Table 20 a n d 21). i

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T A B L E 21.--CHOLEDOCHODUODENOSTOMYFOR BENIGN LESIONS (67 PATIENTS). FOLLOW-UP STUDY I I - - 1 9 5 1 - 1 9 6 7 ) . DURATION OFFOLLOW'UP LOST TO

No.

P.O.

PTS.

DEATHS 1

67

(1.4%)

"51 (89.4%) pts, M i n . : 1 yr.

FOLLOWUP 9

AVAIL. STUDY" 57*

(13.6%)

(85.0%)

< 2 YR. 6

(10,5%)

> 2 y r . ; 35 (61,4%) pts. Max.: 16 yr.

2--5 YR.

16 (28,0%)

5-10 YR.

19 (33.3%)

> 10 YR.

16 (28.0%)

> 5 yr. Aver.: 7 yr.

T E C H N I C OF OPERATION

The technic used in the performance of choledochoduodenostomy is based on t h a t of FlSrcken (Fig. 18) and is d e p i c t e d in Figure 17. Additional technics of F i n s t e r e r a n d J u r a s z are shown i n F i g u r e 19. A longitudinal incision is usually employed, since the operation is a f r e q u e n t concomitant of exploration of the c o m m o n duct. However, w h e n 64

]?Jc. ].7.--A, the length of the incis'on in the common duct is shown by the broken line. B, C and .D, the opening in the comuaon duct is enlarged with sci~so~ ( B ) a n d explored, first cephalad (C) and thez~ caudad (D), with a " g a l l s t o n e " forceps. E, a I-~ak¢_-,~dilator is next insert~l into t h e c o m m o n ctuct and the finge~ o f the left hand palpate behin~l the mobilized de~scending portion of the duodenunx; palpation is for the presence of a stone. "]'his is frequently indicated by the feel of a grating i m p a r t e d a g a i n s t the steel dilator by a stone. This part. of the expl0rati0n is completed by the passage of tl~e tip of the dilator through the sphincter into the lumen of the duoclenum. A successful n eg o tiatio n is indieatext b y t h e positive "stee.l" sign, which is the visualization of the silvery sheen of the dilator through the anterior wail o f the d u ~ l e n u m . It is absent when the passage is unsuccessful, and the papilla and posterior wall-oLthe d u o d e n u m are invaginated againat the anterior wall. (Continued.)

65

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FI~. 17- (cont.).--F, t h e c o m m o n d u c t is irrigated with copious q u a n t i t i e s of sterile saline, first: c e p h a l a d (dotted outline) and l h e c a u d a d . G, the l o n g i t u d i n a l incision i n the d u o d e n u m is i n d i c a t e d b y t h e b r o k e n line. H . the incision in the d u o d e n u m - i s deel.~.ned t h r o u g h tile s e r o m u s e u l a r l a y e r a n d the blood vt~sels in the sut~mucosa a r e u n d e r s e w n with ligatures of silk (4-0) for hemostasis before incision (broken line) into the l u m e n . I, J a n d /(~ "'.ar~|e" suture.,; of FS-O silk a r e f i ~ t irL,~eried (I) and then the central s u t u r e p o s t e r i o r l y (4). T h e r e m a i n d e r of the posterior l a y e r of i n t e r r u p t e d t h r o u g h - a n d - t h r o u g h sutur~:s Io include all layers are then inserted but not tied ( K ) . (Continued.)

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the duct is widely dilated, a transverse incision has proved n~ost satisfactory. In doing a choledoehoduodenostomy, the most i m p o r t a n t factor to stress for the success of the o p e r a t i o n is t h a t the s t o m a should be a d e q u a t e in size. To obtain an a d e q u a t e stoma, the incision in the duct should be a n,easur¢~t 3 crn. in length. T h e r e s u l t a n t size of the s t o m a is indicated in the photograt)h ( P l a t e VI, Fig. IF) taken d u r i n g the l)erf.ormance of the operation. I n t e r r u p t e d s u t u r e s of 5-0 silk, swedged on a m i n i m u m t r a u m a needle, a r e used for t h e anastomosis a n d include all the l a y e r s of both the duct a n d the d u c d e n u m . One l a y e r of s u t u r e s is u s e d posteriorly and two layers anteriorly. A d r a i n is inserted w h e n choh.,dochoduodenostomy is c o m p l e m e n t a r y to a cholecystectomy. Otherwise. d ~ t i n a g e is not employed. T h e theoretical objection to the use of silk s u t u r e s is t h a t they are n o n a b s o r b a b l e foreign b~dies a n d as such are a nidus for the deposition of p a r t i c u l a t e m a t t e r a n d secondary stone formation. T h e basis for this objection has not been s u b s t a n t i a t e d in clinical 1)raetice, but 5--0 chromic c a t g u t s u t u r e s m a y be used instead of silk.

DISCUSS~ON T h e l)rimary objection of m a n y to tile p e r f o r m a n c e of choledoehoduod e n o s t o m y is t h a t it predisposes the p a t i e n t to a n " a s c e n d i n g " cholangitis from the intestinal tract. For this reason, w h e n e v e r a b i l i a r y - i n t e s t i n a l b y p a s s p r o c e d u r e is r¢~luired, the use of the j e j u n u m is g e n e r a l l y preferred to the d u o d e n u m . T h e j e j u n u m is selected because it l)ermits either an a n a s t o m o s i s on the R o u x - e n - Y principle or a n end-to-side u n i o n with a p r o x i m a l e n t e r o - e n t e r o s t o m y , or B r a u n anast(~mcsis. E a c h of these anastomoses, b u t p a r t i c u l a r l y the R o u x - e n - Y with the use of a d e f u n c t i o n e d limb of j e j u n u m , is p r e s u m a b l y a p r o p h y l a x i s f o r the complication of an " a s c e n d i n g " cholangitis a n d s u b s e q u e n t m u l t i p l e liver abscesses. T h e objection to c h o l e d o c h o d u o d e n o s t o m y because of the potential c o m p l i c a t i o n of a n " a s c e n d i n g " cholangitis is based p r i m a r i l y on faulty a priori r e a s o n i n g r a t h e r t h a n c o n f i r m a t o r y factual d a t a . T h i s complication is the result of a n obstruction of the a n a s t o m o s i s a n d not of the r e g u r g i t a t i o n of the duodenal contents into the biliary tract. W e are in c o m p l e t e a g r e e m e n t with the concept of B e r n h a r d . ( 2 ) t h a t supl)urative c h o l a n g i t i s is not an a s c e n d i n g infection but t r u l y a "descending" infection caused by the obstruction to the e g r e s s of bile from the liver. T h e concept of a "descending" infection caused by obstruction, rathe) t h a n a n a s e e n d m ~ i n f e c t i o n s e c o n d a r y ~ito reflux, is f u r t h e r suggested by the c o m p l i c a t i o n o f "cholangitis" that~occurs following i n j u r y of the c o m m o n d u c t d u r i n g the :~p e r f o r m a n c e Tot a p a r t i a l gastrectomy. U n d e r su~.~ circumstances, t h e biliary t r a c t h a s been normal; yet, as a result of the ductal i n j u r y a n d t h e s u b s e q u e n t obstruction, chillS, fever and jaundice, a "descending" cholangitis occurs. It is f r e q u e n t l y s t a t e d t h a t the reason an "ascending" infection is not m o r e f r e q u e n t l y associated w i t h c h o l e d o e h o d u o d e n o s t o m y is the relative sterility of the d u c d e n u m . T o negate or confirm this reasoning, a n expertg(t

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m e n t a l study was u n d e r t a k e n (1.9). Because of the n a r r o w d i a m e t e r of the common duct: in the dog, the e x p e r i m e n t a l p r e p a r a t i o n required a two-stage procedure. :In the first stage, the distal e n d o f the common duct was occluded with a silk ligature. F o u r to 7 days later, the abdomen was reopened and the dilated obstructed duct was opened and an~stomosed to the " u n p r e p a r e d " transverse colon in a side-to-side union. In 1 dog, the gallbladder, r a t h e r t h a n the common duct, was used for the anastomosis to the colon. In this e x p e r i m e n t a l s t u d y there were 8 dogs available for a follow-up s t u d y t h a t v a r i e d between 28 a n d 32 weeks. :In 7 dogs, including the one with the cholecystocolostomy, the ligature was not removed from the common duct, and in the r e m a i n i n g animal it was. N o n e of the animals has had an "'ascending" cholang.;tis, even though postoperative barium e n e m a studies showed an i m m e d i a t e reflux of the b a r i u m into the gallbladder and biliary radicles (Fig. 20). All a n i m a l s eat a n d behave normally. One dog died 69 days postoperatively i m m e d i a t e l y following the injection of Cholegrafin for r o e n t g e n o g r a p h i c studies. T h e oI~ened anastomotic site is shown in P l a t e VI, Fig. Y. This demonstrates fecal contents within the biliary tract and the absence of stomal obstruction. T h i s animal was completely a s y m p t o m a t i c t h r o u g h o u t the postoperative period. TLe results of this e x p e r i m e n t a l s t u d y s u p p o r t well the thesis, based on clinical observations, t h a t obstruction of the anastomosis and not regurgitation of the i n t e s t i n a l contents (even colon content,s ! ) i s the cause of "descending cholangitis." Of i n t e r e s t in this regard, Robson (30) reported FW,. 20.--B~,rium e n e n m following a side-lo-shie c h o l e d o c h o c o l o s / o m y in tile e x p e r i m e n l a l a n i m a l (dog). T h e rettux b a r i u m cholecystocholangiogr~m~ is r e a d i l y seen. T h e r e was no ~ussociated reflux or " a s c e n d i n g " c h o l a n g i t i s ,l¢~pite lhe fact t h a t the rellux was colon contenks!

71

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FIG. 2 1 . - - A b a r i u m s t u d y Io s h o w t h e e a s e of ref I ux• into t h e b,i l i a r y, trivet of an aSVml)tOmatie ~ p a t i e n t , 15 y e a r s a f t e r l h e p e r f o r m a n c e of a c h o h ~ t o c h o d u o d e n o s l o m y .

a p a t i e n t completely well 3 y e a r s after cholecystoco]ostomy. S i m i l a r l y , Courvoisier (5) and Chavasse (4) also r e p o r t e d successes with the s a m e operation. W h e n postoperative b a r i u m r o e n t g e n o g r a m s are done in patients fo/lowing choledochoduodenostomy, failure to d e m o n s t r a t e rettux of b a r i u m into the biliary tract, regardless of the time since the operation (Fig. 21), is considered ominous, as it m a y prove to be the first evidence of obstruction at the anastomosis. F u r t h e r m o r e , in a R o u x - e n - Y anastomosis, regardless T A B L E 22.,= .,CIIOLEDOCt/ODUODENOSTOS-IY.

FOLLOW-UP STUDY. COI.,LECTED SERIES, 1946--1967 CttOLAN-

AUTI,IOR Sanders* Meier Pinsterer Magary Mallet-Guy Pi-Figueras Izak Capper Valdoni Hurwitz* Own series* TOTAL

No, 25 93 78 133 100 :128 66 125 358 49 67 1222

GITIS 0 0 0 3 1 0 0 0 0 1 0 5 (0.4~)

~'V~ORTALITY I{ATE

'3.0 1.3 8.2 2.2 9.0 3.1 1.5 4.0 1.2 4.2 1.4

* U n i t e d S t a t e s : 141[ (11,5,°,,Io) ; European: 1,081 (88,5~o). i

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of the length of the defunctioned limb of j e j u n u m , if stomal obstruction occurs, chilis, foyer and jaundice ("descending" cholangitis) will ensue. T h e clinical d a t a a c c u m u l a t e d ( T a b l e 22) show t h a t c h o | a n g i t i s as a complication of choledocboduodenostomy i s based p r i m a r i l y on theoretical reasoning r a t h e r t h a n on practical clinical knowledge. In the collected series of e a s e s of c h o l e d o e h o d u o d e n o s t o m y (Table 22), only -5 (0.4%) p a t i e n t s had cholangitis as a complication of the operation. I n one of these patients, t h e a u t h o r s (33) s t a t e d t h a t there was o b s t r u c t i o n of the anastomosis caused b y the failure to establish a s t o m a a d e q u a t e in size. A n o t h e r fr¢~|uently stated objection to c h o l e d o c h o d u o d e n o s t o m y is t h a t the "blind" s e g m e n t of the common duct, b e t w e e n the s i t e of anastomosis and the d u o d e n a l papilla, acts as a n i d u s for the f o r m a t i o n of stasis stones which predispose to s u b s e q u e n t ' complications (Fig. 22). T h i s objection, similar to t h a t of "ascending" cholangitis based on the reflux of d u o d e n a l contents, is n o t considered of practical surgical significance. N o n e of the 67 patients t h a t comprise this s t u d y has h a d a complication r e l a t e d to the "blind" s e g m e n t of c o m m o n duct. Despite the proved merits of choledochoduodenostomy, surgeons in general p r e f e r s p h i n c t e r o t o m y . L a h e y (17) stated t h a t in the p e r f o r m a n c e of a s p h i n c t e r o t o m y the use of a l o n g - a r m e d " T " t u b e w h i c h extended across the t r a n s e c t e d s p h i n c t e r into the d u o d e n u m w a s e s s e n t i a l for the success of the operation. To obtain the best results, it was r e c o n m l e n d e d t h a t the tube r e m a i n in place from 3 to 6 months. However, H o w a r d (38) reported t h a t this practice was associated w i t h a high incidence of seconda r y a n d c o m m o n l y fatal pancreatitis. T h i s m o s t serious of postoperative complications f o r t u n a t e l y has not occurred in a n y of t h e p a t i e n t s in this series following the p e r f o r m a n c e of, a c h o l e d o c h o d u o d e n o s t o m y . 73

I n response to t h e discussion b y L a h e y , S a n d e r s (31) s t a t e d t h a t t h e p e r f o r m a n c e of a s p h i n c t e r o t o m y in p r e f e r e n c e to a c h o ] e d o e h o d u c d e n o s t o m y was m a k i n g a n easy o p e r a t i o n difficult, a n d u n n e c e s s a r i l y predisposed t h e p a t i e n t to m a n y serious c o m p l i c a t i o n s . O n t h e basis of o u r o w n e x p e r i e n c e a n d t h e e x p e r i e n c e of others, w e a r e in c o m p l e t e agreem e n t x~dth the ideas e x p r e s s e d b y S a n d e r s a n d w o u l d like to e m p h a s i z e a g a i n t h a t w e p e r f o r m a s p h i n c t e r o t o m y p r i m a r i l y for t h e r e m o v a l of a comm o n d u c t s t o n e t h a t is i m p a c t e d in the s p h i n c t e r of Oddi. F u r t h e r m o r e , u n d e r such c i r c u m s t a n c e s , a c o m p l e m e n t a r y c h o l e d o c h c d u o d e n o s t o m y also is p e r f o r m e d , I n c o n s i d e r a t i o n of t h e clinical a n d e x p e r i m e n t a l d a t a p r e s e n t e d , c h o l e d o c h o d u o d e n o s t o m y is r e c o m m e n d e d as a n o p e r a t i o n of p r a c t i c a l clinical v a l u e in t h e t r e a t m e n t of b e n i g n o b s t r u c t i v e lesions of the lower p a r t of t h e c o m m o n duet. T h e objections to its use h a v e n o t b e e n s u b s t a n t i a t e d in scientific fact.

CONCLUSIONS C h o l e d o c h o d u o d e n o s t o m y is a logical a n d feasible o p e r a t i o n of p r o v e d c l i n i c a l m e r i t in the t r e a t m e n t of p a t i e n t s w i t h c o m m o n d u c t stones a n d stenosis of t h e s p h i n c t e r of Oddi. W e e m p l o y it a n d - , r e c o m m e n d it. T h e c o m p l i c a t i o n of " a s c e n d i n g " c h o l a n g i t i s is c a u s e d by o b s t r u c t i o n of t h e a n a s t o m o s i s a n d not by the reflux of d u o d e n a l contents. I t is a " d e s c e n d i n g " r a t h e r t h a n a n " a s c e n d i n g " infection. I n t h e e x p e r i m e n t a l a n i m a l (dog), t h e a n a s t o m o s i s of t h e o b s t r u c t e d a n d d i l a t e d c o m m o n d u c t to t h e " u n p r e p a r e d " transw_rse colon m a y be p e r f o r m e d w i t h o u t t h e c o m p l i c a t i o n of " a s c e n d i n g " cholangitis, p r o v i d e d t h e r e is free p a s s a g e of t h e colonic c o n t e n t s t h r o u g h a p a t e n t a n a s t o m o s i s . I n b i l i a r y - i n t e s t i n a l d e c o m p r e s s i o n , t h e use o f a d e f u n c t i o n e d l i m b of j e j u n u m , r e g a r d l e s s of its l e n g t h , is n o t p r o t e c t i v e a g a i n s t " a s c e n d i n g " c h o l a n g i t i s i f the a n a s t o m o s i s is o b s t r u c t e d . T r a n s d u o d e n a l s p h i n c t e r o t o m y or s p h i n c t e r o p l a s t y ( p a p i l l o s t o m y ) is u s e d m a i n l y for t h e r e m o v a l of a s t o n e i m p a c t e d in the s p h i n c t e r of Oddi. REFEIIENCES Choledochod uodenostomy 1. Abbe, R.: The surgery of gall-stone obstruction, Meal. tree. 43: 548, 1893. 2. Bernhard, F.: 0bet moderne Gesiehtspunkte in der chirurgischen Behandlung der Erkrankungen der Leber und tier Gallenwege, Deutsche reed. Wchnschr. 75: 760, 1950. 3. Capper, W. M.: External cho]edochoduodenostomy: An evaluation of 125 cases, Brit. J. Surg. 49: 292, 1961. 4. Cbavm~se,T. F.: Cited by Abbe (1). 5. Courvoisier, L. G.: Cited by Abbe (1). 6. Degenshein, G. A., and Hurwitz, A.: The techniques of side-to-side choledochoduodenosferny, Surgery 6~'972, 1967. 7. Doubilet, H., and Mulholland, J. H.: Eight year study of pancreatitis and sphincterotomy, J,A.M.A. 160: 521, 1956. 8. ]~iseman, B., ]3rown, W.H.; Virabutr, S., and Gottesfeld, S.: Sphincterotomy--Evalua~-ion of physiologic rationale, Areh.:Surg. 79: 294, 1959. 9. ~'i~-~sterer,H.: Die Beduetung der Choledocho-duodenostomia externa ffir die Behandlung des Gallensteinleidens, Arch; kiln. Chit. 156: 417, 1929. 10. Finsterer, H.: Peut-on Recommander la Ch61edochoduod6nostomie pour le Traitement des maladies des voles biliaires? Mere. Acad. Chir. 78: 499, 1952. 74

11.

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