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Treatment of Dissecting Aneurysms of the Aorta
Treatment of Dissecting Aneurysms of the Aorta * Roger F. Palmer, M.D., and Myron Wr. Wheat, Jr., M.D.
T
wo years ago we presented our initial clinical experience with the treatment of acute dissecting aneurysms of the thoracic aorta without surgery [ l l , 151. The rush by surgeons and internists alike to use this method of management utilizing agents which decrease the force of myocardial contraction and lower blood pressure was amazing (Table 111.The enthusiasm for an approach other than fenestration or resection is ample testimony to the inadequacy of surgery as a method of managing this disease, at least in the acute phase. Our personal experience has now almost tripled, and we have accumulated 54 cases treated simi1;irly throughout the United States and Canada. Therefore, it seems appropriate at this time to bring our overall experience up to date. T h e purpose of this report is threefold: (1) to review our experience, as it is almost four years since this treatment program was initiated at the University of Florida Hospital; (2) to review the experience with this treatment that has been reported to us; and (3) to discuss our current concepts concerning the use of drugs in the treatment of this disease.
E X P E R I E N C E A T U N I V E R S I T Y OF F L O R I D A First, what has happened to the original 6 successive patients treated successfully? There have been 2 deaths and 1 complication. Four of the original 6 patients are still alive from 31 to 36 months after treatment was begun (Table 2). T h e patient M. H. recently died in our hospital 45 months after his first admission for ;L dissecting aneurysm. Although n o autopsy could be obtained, all of the evidence from the history, physical examination, chest x-ray, and spinal fluid findings indicated that the original aneurysm was stable and that the patient died from an acute, massive intracerebral hemorrhage. T h e other death, in patient P. R., occurred 22 months after the original dissection and was due to rupture of an unrecognized localized saccular aneurysm (Fig. 1). Twenty-two From the Departments of Medicine, Pharmacology, and Surgery, College of Medicine, University of Florida, Gainesville, Fla. *John and Mary R. Markle Scholar in Academic Medicine. Supported in part by Florida Heart Association Grant 66A610. We wish to acknowledge the technical assistance of Mrs. Suzanne Melvin. Presented at the Third Annual Meeting of T h e Society of Thoracic Surgeons, Kansas City, Mo., Jan. 23-25, 1967.
38
THE ANNALS OF THORACIC SURGERY
Drug Therapy of Dissecting Aneurysms TABLE 1. RESULTS IN 54 PATIENTS TREATED WITH DRUGS FOR ACUTE DISSECTING ANEURYSMS, 1965-1967
Source
No. of Pts.
Basis for Diagnosis
University of Florida Jewish Hospital, St. Louis University of Missouri Johns Hopkins Ochsner Clinic Mt. Sinai Hospital, Minneapolis Barnes Hospital, St. Louis T h e Presbyterian Hospital, New York Mt. Sinai Hospital, New York University of Mississippi University of Chicago University of Tennessee, Knoxville Medical College of South Carolina University of North Carolina Toronto General Hospital, Canada Rumel Chest Clinic, Salt Lake City U.S. Naval Hospital, Bethesda, Md. Ohio State University Medical Center, Columbus University of Miami, Florida Total
15 2
13A, 2 C lA, 1 C
Results Failure
Success
1 0
14
__ 2
1A 1A Autopsy 1 c 2
lA, 1 C
0
2
5
5A
0
5
2
2A
1
1
4 1 2
lA, 3C 1A 2A
0 0 0
4 1
2
3
3A
1
2
2 1
2A 1A
0 0
2
1
Autopsy
1
0
1
1A
0
1
6
4A, 2 C
0
6
3
2A, 1 C
0
3
5
49
54
1
A = Aortography; C = clinical criteria.
months after his original dissection, P. R. was readmitted to our hospital because of chest pain and weakness. His chest x-ray (Fig. 2) was interpreted as showing a redissection, but no aortogram was done. Eleven hours later he suddenly expired. Autopsy showed that his original dissection had healed solidly, as shown by the dense connective tissue between the layers of the media of the aortic wall (Fig. lA, B). However, he had developed a localized saccular aneurysm just distal to the left subclavian artery, which in retrospect had been enlarging for about 16 months (see Fig. 2). T h e patient P. R. illustrates two very important points: (1) that these dissecting aneurysms do heal; and (2) that it is mandatory to follow these patients with
PALMER AND \\'HEAT
A
B FIG. 1. ( A ) The localized saccular aneurysm seen at autopsy in patient P . R . (Table 2). (B)Low power photomicrograph of the area in imet in (A).A, aneurysm; HD, healed dissection; M, two layers of aortic wall media separated by dense, mature connective tissue of the healed dissection. periodic chest x-rays to check for localized aneurysm development. Unfortunately, this patient had not had a chest x-ray during the 16 months prior to death, although he had been seen every three months in our clinic. Had he been followed properly, the localized aneurysm could have been diagnosed and treated by resection and replacement, as it should have been. The patient L. W. V. 0. (Table 2) sustained a second dissection of his aorta two years and. nine months after the first. He was managed acutely as before and has made a complete recovery with his blood pressure currently well controlled with reserpine and guanethidine. During the two years since our initial report, our experience has increased to 15 patients. In our 15 consecutive patients there has been only 1 treatment failure. We define a treatment failure as the patient who cannot be controlled acutely by drug therapy alone. In the 1 treatment failure in our 15 cases, the dissection had progressed to involve the carotid, renal, and femoral arteries by the time the patient reached our institution and treatment was begun. The de-
40
THE ANNALS OF THORACIC SURGERY
Drug Therapy of Dissecting Aneurysms
FIG. 2. Chest x-rays of patient P. R. (Table 2), who developed a localized saccitlar aneurysm during an interval of 16 months without a follow-up chest x-ray. ( A ) December, 1963; ( B ) July, 1964; ( C ) October, 1965. cision to attempt drug therapy at this stage in this patient was an error in judgment. Immediate drug therapy prior to such extensive dissection is mandatory if a good result is to be obtained. This particular patient should have been approached surgically at the level of the ascending aorta, as first described by Morris et al. [91. Three of our 14 survivors have had to have elective surgery because of severe aortic valve insufficiency. There are 2 survivors alive and well 18 and 24 months since replacement of their aortic root, aortic valve, and reimplantation of the coronary arteries. The patient with the longest follow-up, B. F. G. (Table 2), is normotensive and living an active, normal life. Figure 3 shows his enlarged heart and pulmonary edema prior to surgery (Fig. 3A) as contrasted to his most recent chest x-ray 5 and 24 months later (Fig. 3B, C ) . We believe there is no indication, at present, to operate to remove the stable distal area of dissection, and obviously operation for fenestration is not needed. Failure of surgery in the third patient was due to a flap of the aortic wall in the aortic arch compromising the perfusion to the brain. This man’s dissection was so extensive that even in retrospect we are not certain that he could have been successfully perfused. T h e replacement of his aortic root was technically successful.
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N, M, 66
2. M. H.
N, F, 63
6. F. C.
"At first admission.
N, M, 36
5. B. F. G .
--
N, M, 52
4. P. R.
3. L. W. V. 0. W, M, 63
N, M, 70
1. E. T.
Patient
Shortness of breath, 1 day Chest pain, 6 hr.
Chest pain, 4 days
Shortness of breath, choking, 1 day Chest pain, 1 day
Chest pain, 1 day
Race, Sex. & Age" Symptomsa
Known
Known
Unknown
Unknown
Known
Known
tension"
U.,nC.r. --1c-=
n
a
Second dissection at 2 yr. 8 mo. managed again with drugs; now 4 mo. later, doing well at age 66 Died, rupture localized saccular aneurysm thoracic aorta; dissection healed at autopsy Aneurysm slightly larger, n o localized sac; working, asymptomatic Aneurysm stable, u p & about at age 66
3 yr.
2 yr. 10 mo. 2 yr. 7 mo.
140/90
-
140180
-
210/ 180
142198
155180 2921140
1 yr. 10 mo.
Aneurysm stable; died, age 70, from massive intracerebra1 hemorrhage
-
3 yr. 9 mo.
Results Aneurysm smaller; alive & well, age 73
Length of Follow-up 3 yr.
(mm. Hg) 95155 2381100 (160/90 after 1 unit whole blood) 240/140
~~
D
U. I.
B. P. Fo11owup (mm. Hg)
TABLE 2. FOLLOW-UP DATA ON ORIGINAL 6 PATIENTS TREATED WITH DRUGS FOR ACUTE DISSECTING ANEURYSMS OF THE AORTA
Drug Therapy of Dissecting Aneurysms
FIG. 3. Chest x-rays of patient B.F.G. ( T a b l e 2) showing the enlarged cardiac silhouette with pulmonary edema secondary to aortic value insuficiency at the t i m e of acute dissection ( A ) and tzuo follow-up chest x-rays five m o n t h s ( B ) and t7u0 years (C) after aortic root replacement.
OVERALL E X P E R I E N C E During this same two-year period since our first report, an additional 39 cases were cared for in at least 18 different and widely separated medical centers throughout the United States and Canada, with an overall success rate of 90%. Of these cases, 80% were proved to be dissecting aneurysms of the thoracic aorta by angiocardiography or autopsy. Adding our own patients, the entire group now totals 54 patients; in this total group there have been only 5 failures for an overall success rate of 92%. We believe this accumulated experience makes several important points. First, this method of management can be used successfully by most physicians practicing in hospitals in all parts of the country. Tables 1 and 2 also emphasize the point that this method of management is highly successful for all forms of dissecting aneurysms, in the range of a 90% successful outcome. All 5 treatment failures in the total group were characterized by very rapid onset of dissection, beginning usually in the ascending aorta and rapidly progressing to involve all vessels down to the external iliac arteries. Operation
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PALMER .4ND WHEAT was attempied in 2 of the cases with no success. Definite hints of the inadequacy of drug therapy in 2 of the patients were manifested by the ineffectiveness of trimethaphan in lowering the blood pressure within four hours after the initiation of therapy. Each of these patients showed dissection of their entire vascular tree including the origins of the renal arteries. Perhaps release of angiotension from ischemic kidneys prevented the desired therapeutic effect in these two patients. Therefore, a t the present time, if a patient with an acute dissecting aneurysm of the aorta does not respond promptly and is not easily maintained within the 100 to 120 mm. Hg systolic blood pressure range within the first four hours following admission, we believe surgical intervention is mandatory. There is no question but that probably 5% to 10% of patients with acute dissecting aneurysms of the aorta develop such a rapid and extensive dissection that a fatal outcome will be the rule. T h e only hope at present for such patients is recognition of the rapid dissection and prompt attempts a t surgical intervention; this occasionally can result in dramatic survival [91.
C U R R E N T MANAGEMENT We have previously outlined the rationale for the use of certain drugs in the treatment of dissecting aneurysms [ l l , 151. T h e argument begins with an analysis of the natural course of the untreated dissecting aneurysm which concludes that 3eath is primarily due to ultimate aortic rupture and hemorrhage rather than to factors associated with the initial intimal tear [71. Therefore, therapy, to be successful, must focus on the prevention of aortic rupture. Dissecting aneurysms, if rupture does not occur, will heal as illustrated by our case P. R. (see Fig. 1B) Spontaneous healing of untreated cases is also widely documented in the literalure [3, 101. T h e forces that further the dissection and produce rupture are undoubtedly related to a complex propagation of impulses and pressures produced by myocardial contraction in the setting of an intricate, nonpassive vascular bed. Such forces are difficult to analyze, but certain observations suggest an important common denominator, eg., the force of myocardial contraction, measured as either dl/dt :fiber length) dpidt (pressure) or calculated as dmvidt (momentum). Previously discussed theoretical reasons suggest that contractility and subsequent cardiac evencs, rather than mean aortic pressure per se, are probably the major determining forces in promoting further dissection. Experimental and clinical observations add further support to this notion. Aortas from diseased as well as normal indiliduals are amazingly resistant to static pressure increases [61. Fluid injected subintimally to pressures of from 320 to 900 mm. Hg are required to produce rupture. EXPERIMENTAL EVIDENCE
Observations in experimentally produced dissecting aneurysms in turkeys suggest that f x t o r s other than blood pressure are operative. Broad Breasted Bronze turkeys under field conditions or when fed a special diet have mortality rates of u p to 60% from rupture of dissecting aneurysms [131. Mortality can be reduced to 10% or less by adding a tiny amount of reserpine (0.1 part per million) to the feed. This amount has little if any effect on blood pressure [121. Hexamec honium, a hypotensive agent, effectively lowered blood pressure in a group of hypertensive patients, yet the mortality from dissecting aneurysms was twentyfold higher than in a control group of hypertensive patients [21. Significantly, it has been shown that hexamethonium increases myocardial contractility while it lowers mean systemic pressure 181. T h e fact that reserpine protects against death from aortic rupture in turkeys without significantly lowering blood prc'ssure implies that it has an effect on the contractile process. Reser-
44
THE ANNALS OF THORACIC SUKGEKY
Drug Therapy of Dissecting Aneurysms TEAR
FL
-t-
FIG. 4. A model aorta as described i n the text. P is a diagrammatic pressure profile on a n arbitrary scale at any time (t) .showing a pressure gradient between the torn intima and the acljnccnt tissue. pine at low doses depletes cardiac catecholamines in most species [51. Reduction of these catecholamines may produce a decrease in myocardial contractility. Reserpine does depress contractility in the isolated rabbit heart [15]. A simple laboratory model directly implicates pulsatile flow as an important factor in the propagation of dissection. Tygon tubing can be made to resemble an aorta by coating the inside of it with rubber cement (Fig. 4). When the cement hardens, a n “intimal tear” can be created by gently separating the layer of hardened cement from the tygon wall with a spatula. Water can then be flowed through the tubing at various rates. As long as the flow is laminar, no extension of the “dissection” takes place. Also, stepwise increases of static pressure to as high as 900 mm. Hg produce no dissection. But when pulsatile flow is initiated, rapid dissection occurs in both directions. T h e explanation seems clear; namely, under the first two conditions, i.e., laminar flow or static pressure, no gradient of pressure exists between the torn intima and the immediately adjacent tissue. Under pulsatile flow conditions, depending upon the sharpness of the pressure curve at any time, a pressure gradient exists between the torn portion and the intact adjacent portion (see Fig. 4). This gradient is the driving force for extending the dissection. T h e relationship between this model and what occurs in naturally occurring aneurysms is obvious. Might one suppose that if pulsatile flow in the aorta were replaced by laminar flow, the process of dissection would be halted? Or, to take the analogy not so far, if the shape of the pressure curve were flattened so that the pressure gradient at any time at the region of dissection were not so great, might not the dissecting process be slowed or even arrested? To establish myocardial events rather than the absolute magnitude of systemic pressures, as the principal cause of mortality, agents which specifically depress contractility with little effect on blood pressure should be tested. Propranolol is such an agent; as is shown in Figures 5 and 6, it depresses contractility in the isolated rabbit heart and in the intact dog heart. MANAGEMENT OF ACUTE EPISODES
Our management of the acute situation has not changed appreciably [15]. Patients are admitted to the intensive care unit, and treatment with trimethaphan, reserpine, and guanethidine is initiated. As the patients stabilize (between the fifth to tenth day of admission), graded ambulation is begun. Discharge is from two to three weeks following admission when the chest x-ray is stable and when the blood pressure has been satisfactorily regulated with reserpine, guanethidine, and, occasionally, propranolol and hydrochlorothiazide. Following discharge, most patients are maintained on guanethidine or reserpine, drugs which have similar catecholamine-depleting effects but which. most importantly, alter the contractile mechanism as discussed above. We believe that reserpine forms the backbone of our long-term therapy, although side effects are bothersome and occasionally prohibit its use. T h e average dose of reserpine
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PALMER AND WHEAT ISOLATED RABBIT HEAR1
5mmlSEC
NmmlSEC
CONTROL
SLOpE-6.0 AMP-2bmm
PROPRANOLOL Wlml 20 MIN
SLOPE-1.7 AMP-14mm
WASHOUT MlMlN
SLOPE-2.5 ~ ~ p - ~ m r n
FZG. 5 . Contractility of the isolated rabbit heart. Therapeutic concentrations of propranoiol depress the slope of the trace ( d l l d t ) and the amplitude of the contraction.
PRL-PROPRANOLOL
PROPRANOLOL
350 P g l K g IV
I
-1
~~~~~
T
WAVE TAKEN AT T
1
wx s LOPE -3.5
-
MYOCARDIAL CONTRACTILIIY
A m m Hg
r
SLOPE-2.3
FEMORAL PRESSURE
- f
20 m i n u t e r
F I G . 6. Contractility and blood pressure as recorded in the pentobarbitalanesthetized dog. A Walton-Brodie strain-gatige sutured t o the left ventricle records isometric contraction. Femoral pressure is recorded with a Statham pressure tranjducer. T h e contractility is depressed by propranolol with only a small eflect or! blood pressure.
46
THE ANNALS OF THORACIC SURGERY
Drug Therapy of Dissecting Aneurysms is from 1 to 5 mg. daily orally as tolerated. Guanethidine is usually given in a dose of 5 to 50 mg. twice a day. Occasionally, a diuretic is added as needed to reduce edema. The object of long-term therapy is aimed at preventing recurrence; thereiore, we attempt to reduce the blood pressure toward levels as near to normal as possible. However, as mentioned previously, prevention of dissecting aneurysms in turkey flocks can be accomplished with amounts of reserpine that do not significantly affect blood pressure, so that reduction of blood pressure is not necessarily a goal of therapy. Therefore, in clinical use, even if blood pressure cannot be lowered with reserpine to levels that we might desire without serious side effects, we continue the drug nevertheless, on the assumption that i t is not blood pressure itself that is important but perhaps something else affected by the drug. COMMENT
There are complications of drug therapy which should be mentioned. Trimethaphan, reserpine, and guanethidine are potent agents, and unless carefully controlled may in themselves be fatal. A frequent complication with trimethaphan is profound hypotension, particularly if careful monitoring of the blood pressure is not performed, and this may result in transient renal failure as occurred in 2 of our cases. Other effects of acute ganglionic blockade, such as ileus, bladder distention, and visual disturbances, must also be watched for. Complications of reserpine include severe sedation and gastric hypersecretion, as first reported by Barrett et al. [I]. We know of 2 cases in which peptic ulcers complicated the picture and necessitated emergency surgery to control the bleeding [4]. Reserpine is known [ l , 131 to produce an increase in the flow of free hydrochloric acid in the stomach of the dog, and presumably it has a similar effect in man. Because of this increased flow of gastric acid, we keep our patients on antacid therapy during the acute phase of treatment with the relatively high dosages of reserpine. During long-term therapy with reserpine, depression with suicidal overtones is an occasional complicating factor. Guanethidine may also produce severe postural hypotension and diarrhea [ 5 ] . The question as to when one should resort to surgery frequently arises. This question should be divided into the acute phase and the chronic phase. During the acute phase, we believe surgery is indicated when there is: (1) failure of the blood pressure to respond satisfactorily within four hours; (2) compromise of a significant branch of the aorta, e.g., the carotid artery, the celiac axis, the renal artery; (3) failure to control progression of the dissection; and (4)uncontrollable acute aortic valve insufficiency. Indications for surgical intervention in the chronic phase are: (1) significant aortic valve insufficiency; (2) development of a saccular aneurysm; and (3) progressive enlargement of the dissecting aneurysm. VOI..
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PALMER AND WHEAT SUMMARY
Almost four years’ experience with nonsurgical management of dissecting aneurysms is reported. Fifteen consecutive cases of dissecting aneurysms have been treated with drugs at the University of Florida, with 1 treatment failure. Four of the original 6 patients presented two years ago [15] are still alive. One patient died of an intracerebral hemorrhage and the other from a ruptured saccular aneurysm. Thirty-nine patients from other hospitals similarly treated have been presented. There were 4 treatment failures in this group, giving an overall success rate of 90%. T h e treatment failures were those who did not respond to the drugs, those whose dissection progressed too far before treatment was begun, and those in whom severe aortic valvular insufficiency demanded immediate surgical intervention. T h e rationale for drug therapy places less emphasis on blood pressure per se and more on the contractile event and the nature of pulsatile flow in large vessels. A model directly implicating pulsatile forces as a cause for continued dissection has been devised and is discussed. REFER ENC27S 1. Barrett, W. E., Plummer, A. J., Earl, A. E., and Kogie, B. Effect of reserpine on gastric: secretion of the dog. J . Pharmacol. 113:3, 1955. 2. Beaven, I). W., and Murphy, E. A. Dissecting aneurysm during methonium therapy. .Brit. Med. J . 1:77, 1956. 3. Conston, A. S. Healed dissecting aneurysm. Arch. Path. (Chicago) 48: 309, 1949. 4. Glenn, W. W. L. Personal communication. 5. Goodmar;, L. S., and Gilman, A. T h e Pharmacological Basis of Thrrapeutics (3d ed.). New York: Macmillan, 1965. 6. Hirst, E. A., Jr., and Johns, V. J., J r . Experimental dissection oE media of aorta by pressure: Its relation to spontaneous dissecting aneurysm. Czrc. Res. 10:897, 1!362. 7. Hirst, E. 4., .Jr., Johns, V. 1.. Jr., and Kime, S. W., Jr. Dissecting aneurysm of the aorta: A review of 505 cases. Medicine (Balt.) 37:217, 1958. 8. Lee, W. (I., and Shideman, F. E. T h e inotropic action of hexamethonium in the heart-lung preparation and isolated papillary muscle. J . Pharmacol. 119:160, 1957. 9. Morris, G . C., Jr., Henly, W. S., and De Bakey, M. E. Correction of acute dissecting aneurysm of aorta with valvular insufficiency. J.A.M.A. 184:63, 1963. 10. Nielson, 7 3 . C. Dissecting aneurysm of the aorta. Acta Med. Scand. 170: 117, 1961. 11. Palmer, F. F., Seelman, R. C., and Wheat, M. W. Pharmacological approach to the therapy of acute dissecting aneurysm of the aorta. Clin. Res. 13:27, 1965. 12. Ringer, F.. K. Aortic Rupture, Plasma Cholesterol, and Arteriosclerosis Following Serpasil Administration to Turkeys. I n T h e Second Confcrenre 012 the Use of Reserpinp in Poultry Production (May 6, 1960, University of Minnesot;,, St. Paul, Minn.). Summit, N.J.: CIBA, 1960. Pp. 32-39.
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THE ANNALS OF THORACIC SURGERY
Drug Therapy of Dissecting Anem-ysms 13. Shapiro, H., and Woodwarcl, E. K. T h e mechanism of action of reserpine on gastric secretion. Fed. Proc. 20:248, 1961. 14. Ringer, R. K. Influence of reserpine on early growth, blood pressure and dissecting aneurysms in turkeys. I n Conference on the Use of Serpasil i n Animal and Poultry Production (May 7 , 1959, Rutgers, T h e State University, New Brunswick, N.J.). Summit, N.J.: CIBA, 1959. Pp. 21-28. 15. Wheat, M. W., Jr., Palmer, R. F., Bartley, T. D., and Seelman, R. C. Treatment of dissecting aneurysms of the aorta without surgery. J. Thorac. Cardiov. Surg. 50:364, 1965.
DISCUSSION’ DR. JOHN H. KENNEDY(Cleveland, Ohio): Dr. Grondin and his co-workers have presented a very interesting paper emphasizing the serious nature of dissecting aneurysms and some of the factors which may influence a successful outcome. I rise to comment briefly on two technical considerations which may also serve as factors influencing survival, particularly in those patients in whom the dissection arises distal to the left subclavian artery. T h e first of these considerations is protection of the brain. T h e reported incidence of vertebral artery asymmetry is as high as 30%. Of these, when asymmetry is present, the left vertebral artery is dominant. For this reason, occlusion of the left subclavian artery, which is often necessary in control of dissection just distal to it, may produce serious cerebral consequences. Therefore, it would seem logical to recommend that either one make provision €or perfusion of the distal left subclavian artery and hypothermia, if one doesn’t know whether vertebral artery asymmetry is present or not on the basis of angiography; or, if time permits (more applicable to the chronic dissection), obtain four-vessel cerebral angiography as a part of the initial diagnostic study in those patients who are being considered for surgical treatment. T h e other point I would like to make is a consideration of the magnitude of surgery. T h a t these patients are ill has already been emphasized. T h e question of repair versus excision, therefore, becomes a consideration. While this is a bad disease, it is not cancer, and therefore ablation of the involved tissue may not really be necessary. Applicable only in those cases in which the dissection arises just distal to the left subclavian artery is the simple expedient of aortorraphy. Shown in Figure D-1 is the opening of the site of dissection. This is applicable only in those patients in whom reentry has not occurred. Evacuation of the dissecting hematoma and closures of the aorta in one layer is carried out. This procedure has been applied in two patients whose dissection proved to be progressive after two weeks and who therefore perhaps would fit into the acute group of Dr. Grondin. I n both patients this procedure was effective in controlling the dissection. One patient subsequently died of the consequences of an atheromatous embolism. DR. ROBERTD. BLOODWELL (Houston, Tex.): I think we must thank Drs. Palmer and Wheat for awakening our interest in reevaluating the management of patients with acute dissecting aneurysms. Dr. Grondin pointed out the heterogeneous group of dissecting aneurysms that we are really considering. Patients with chronic dissecting aneurysms, of course, don’t require drug management to protect them from acute dissection or extension of the process. T h e fact that many present initially in the chronic stage emphasizes the natural history of many *This and the preceding paper, “Dissecting Aneurysms of the Thoracic Aorta: A Review of 52 Cases with Consideration of Factors Influencing Prognosis,” by Claude Grondin et al., page 29, were discussed together.
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PALMER AND WHEAT
A
F I G . D-1. acute dissecting aneurysms. On the other hand, since many in the acute phase may extend unpredictably, we feel that there is a need for some definitive surgical repair of the mechanical problem. The management of acute dissecting aneurysms depends upon, first of all, suspicion that one is present, and then upon determination of the origin and extent of the dissection. This doesn’t always require aortographic study; as was already pointed out in the presentation, the presence of aortic insufficiency often is the factor (hat demands earlier or emergency surgery. Classification of dissecting aneurysms as to origin and extent has been important in tailoring a procedure proper for the aneurysm that is present in a given case. Those originating in the ascending aorta (Type I or Type II), which often, of course, extend into the arch or beyond, are managed differently from those originating in the descending aorta. We are certain that in the latter variety drug therapy may enjoy its best application. Perhaps in time we will be able to employ the technique of drug therapy as an adjunct to the management of certain acute aneurysms. The mechanical problem in dissecting aneurysms of the ascending aorta in which the valve leaflets lose their corn missural suspension and become acutely insufficient requires operation to correci. cardiac failure and to limit the extent of the dissection. I n patients in whom there is aortic insufficiency, which is appreciated by the presence of a new diastolic murmur, or in whom a pericardial friction rub develops while they are being managed acutely, with or without drug therapy to maintain the blood pressure in a reasonable range, we recommend an approach with total cardiopulmonary bypass. One must divide the ascending aorta and resuspend the aortic valve leaflets if there is indeed adequate aortic tissue around the annulus. Replacement of the aortic valve is necessary at times. Then the distal ascending aorta is managed according to what the anatomy demands to restore mural integrity and to limit progression of the dissecting process. During operations upon patients with acute dissections, we have often seen the hemorrha$c appearance of the ascending aorta and bloody pericardial fluid before any rupture of the thin outer wall occurs. I t is difficult to visualize how drug management can alter either these changes or the disruption of most of the aortic wall and provide us with a long-term or even short-term salvage. Certainly pat+ts with this type of mechanical problem can live for a short time, and antihypertensive drugs may be useful as a stopgap in conjunction with operative correction on z more elective basis.
50
T H E ANNALS OF THORACIC SURGERY
Drug Therapy of Dissecting Aneurysms So, in our hands, the problem of managing acute dissecting aneurysms resolves itself into having a high index of suspicion, trying to determine the origin and extent of dissection (often on physical diagnostic grounds alone, without aortography), and then proper timing of an appropriate operation in this heterogeneous group of patients.
DR. GEORGE ROBINSON (Mount Vernon, N.Y.): As I survey my own experience with dissecting aneurysms, it is somewhat discouraging to realize that it would require a successful outcome in the management of the next 325 consecutive patients to achieve a success rate of 92% as reported by Dr. Palmer and Dr. Wheat. I am somewhat consoled by the fact that it will take Dr. Lillehei a longer period of time. The big question is: How do I avoid receiving patients who enter my hospital with their renal and mesenteric vessels sheared? Some are paraplegic, some have other serious neurological injuries, and some have very severe heart disease! What I am questioning really is whether the collected series of Dr. Palmer and Dr. Wheat is truly representative of what is being achieved? I would also like to cite two interesting surgical experiences in two patients with dissecting aneurysms of the ascending aorta. One was repaired locally by suture technique, and the other was repaired with a Teflon tubular graft. Both patients were found to have locally recurrent dissecting aneurysms approximately one to two years after their original repair. Both required reoperation, one because of severe aortic insufficiency and the other because of progressive aortic enlargement. I n the previously grafted case, the Teflon tube had separated from the intima at the distal suture line. Both survived the surgery and are well, but I fear to study them again by aortography, wondering what I would do if I found that I had not cured them the second time around. I wish to thank the discussants for their comments. I certainly DR. GRONDIN: support the view held by Dr. Bloodwell and his group on the urgency that aortic insufficiency presents when it is associated with dissection in the ascending aorta. T h e indication for surgery is clear-cut in this instance.
DR. WHEAT:There are a couple of
oints we would like to make in regard
to the therapy. There may be signii !cant complications of drug therapy.
Trimethaphan, reserpine, and guanethidine are potent agents, and in themselves can be the cause of death unless they are carefully used. A frequent complication with trimethaphan is profound hypotension, particularly if careful monitoring of the blood pressure is not carried out. Transient renal failure can occur, which has happened in two of our cases. Other effects of acute ganglionic blockade such as ileus, bladder distention, and visual disturbances may also occur. Complications of reserpine include severe sedation and gastric hypersecretion. Two cases have been reported to us which necessitated emergency surgery to control the bleeding, and following this both cases were successfully cared for without surgery for their dissecting aneurysms. Reserpine is known to produce an increase in the flow of free hydrochloric acid in the stomach of the dog, and presumably it does the same thing in man. Because of this, during the acute phase when these patients are receiving large amounts of reserpine, we also treat them as one would an acute ulcer in regard to diet. If they go home on significant doses of reserpine (by this I mean 2 to 4 mg. per day), then they should be carried on a bland diet because of increased gastric secretion. I think i t is also important that these patients be kept on the surgical service, because several of the failures that have been reported to us have been patients that have been transferred back to medical services. This is not a form of medical treatment, nor is it a form of conservative treatment. This is radical drug therapy. These patients need to be followed in the compulsive manner that a surgeon fol-
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PALMER AND WHEAT lows his patients, so that one can watch for complicating factors that may have to be dealt with. T h e series may be biased. However, it has been our experience that one of the first things doctors do is tell us about their failures. However, we are not necessarily trying to sell an overall survival rate of 90%, but we do believe that in the majority of cases, if they are caught early, that they can be handled successfully in this manner. I appreciate the comments of Dr. Bloodwell. We certainly agree that acute, unremitting aortic valve insufficiency, as we mentioned, and as was first managed successfully by their group, necessitates acute surgery, and that in all probability had we treat,ed our one failure in this manner, he might have been a success. At least, he would have had a chance. However, on the basis of the information which we have, we believe that this group is no more than 5% to 10% of the cases. As to Dr. Robinson, I think he should not be discouraged, and I think he should keep trying. He has our sympathy. However, if one looks at our series of cases, many of our patients’ ages are 70 years and over. However, the failure which we have had and the ones reported to us are patients, just as Dr. Robinson mentioned, irt whom the renal arteries are sheared off and they dissect from top to bottom, so to speak.
52
T H E ANWALS OF THORACIC SURCYRY
T
wo years ago we presented our initial clinical experience with the treatment of acute dissecting aneurysms of the thoracic aorta without surgery [ l l , 151. The rush by surgeons and internists alike to use this method of management utilizing agents which decrease the force of myocardial contraction and lower blood pressure was amazing (Table 111.The enthusiasm for an approach other than fenestration or resection is ample testimony to the inadequacy of surgery as a method of managing this disease, at least in the acute phase. Our personal experience has now almost tripled, and we have accumulated 54 cases treated simi1;irly throughout the United States and Canada. Therefore, it seems appropriate at this time to bring our overall experience up to date. T h e purpose of this report is threefold: (1) to review our experience, as it is almost four years since this treatment program was initiated at the University of Florida Hospital; (2) to review the experience with this treatment that has been reported to us; and (3) to discuss our current concepts concerning the use of drugs in the treatment of this disease.
E X P E R I E N C E A T U N I V E R S I T Y OF F L O R I D A First, what has happened to the original 6 successive patients treated successfully? There have been 2 deaths and 1 complication. Four of the original 6 patients are still alive from 31 to 36 months after treatment was begun (Table 2). T h e patient M. H. recently died in our hospital 45 months after his first admission for ;L dissecting aneurysm. Although n o autopsy could be obtained, all of the evidence from the history, physical examination, chest x-ray, and spinal fluid findings indicated that the original aneurysm was stable and that the patient died from an acute, massive intracerebral hemorrhage. T h e other death, in patient P. R., occurred 22 months after the original dissection and was due to rupture of an unrecognized localized saccular aneurysm (Fig. 1). Twenty-two From the Departments of Medicine, Pharmacology, and Surgery, College of Medicine, University of Florida, Gainesville, Fla. *John and Mary R. Markle Scholar in Academic Medicine. Supported in part by Florida Heart Association Grant 66A610. We wish to acknowledge the technical assistance of Mrs. Suzanne Melvin. Presented at the Third Annual Meeting of T h e Society of Thoracic Surgeons, Kansas City, Mo., Jan. 23-25, 1967.
38
THE ANNALS OF THORACIC SURGERY
Drug Therapy of Dissecting Aneurysms TABLE 1. RESULTS IN 54 PATIENTS TREATED WITH DRUGS FOR ACUTE DISSECTING ANEURYSMS, 1965-1967
Source
No. of Pts.
Basis for Diagnosis
University of Florida Jewish Hospital, St. Louis University of Missouri Johns Hopkins Ochsner Clinic Mt. Sinai Hospital, Minneapolis Barnes Hospital, St. Louis T h e Presbyterian Hospital, New York Mt. Sinai Hospital, New York University of Mississippi University of Chicago University of Tennessee, Knoxville Medical College of South Carolina University of North Carolina Toronto General Hospital, Canada Rumel Chest Clinic, Salt Lake City U.S. Naval Hospital, Bethesda, Md. Ohio State University Medical Center, Columbus University of Miami, Florida Total
15 2
13A, 2 C lA, 1 C
Results Failure
Success
1 0
14
__ 2
1A 1A Autopsy 1 c 2
lA, 1 C
0
2
5
5A
0
5
2
2A
1
1
4 1 2
lA, 3C 1A 2A
0 0 0
4 1
2
3
3A
1
2
2 1
2A 1A
0 0
2
1
Autopsy
1
0
1
1A
0
1
6
4A, 2 C
0
6
3
2A, 1 C
0
3
5
49
54
1
A = Aortography; C = clinical criteria.
months after his original dissection, P. R. was readmitted to our hospital because of chest pain and weakness. His chest x-ray (Fig. 2) was interpreted as showing a redissection, but no aortogram was done. Eleven hours later he suddenly expired. Autopsy showed that his original dissection had healed solidly, as shown by the dense connective tissue between the layers of the media of the aortic wall (Fig. lA, B). However, he had developed a localized saccular aneurysm just distal to the left subclavian artery, which in retrospect had been enlarging for about 16 months (see Fig. 2). T h e patient P. R. illustrates two very important points: (1) that these dissecting aneurysms do heal; and (2) that it is mandatory to follow these patients with
PALMER AND \\'HEAT
A
B FIG. 1. ( A ) The localized saccular aneurysm seen at autopsy in patient P . R . (Table 2). (B)Low power photomicrograph of the area in imet in (A).A, aneurysm; HD, healed dissection; M, two layers of aortic wall media separated by dense, mature connective tissue of the healed dissection. periodic chest x-rays to check for localized aneurysm development. Unfortunately, this patient had not had a chest x-ray during the 16 months prior to death, although he had been seen every three months in our clinic. Had he been followed properly, the localized aneurysm could have been diagnosed and treated by resection and replacement, as it should have been. The patient L. W. V. 0. (Table 2) sustained a second dissection of his aorta two years and. nine months after the first. He was managed acutely as before and has made a complete recovery with his blood pressure currently well controlled with reserpine and guanethidine. During the two years since our initial report, our experience has increased to 15 patients. In our 15 consecutive patients there has been only 1 treatment failure. We define a treatment failure as the patient who cannot be controlled acutely by drug therapy alone. In the 1 treatment failure in our 15 cases, the dissection had progressed to involve the carotid, renal, and femoral arteries by the time the patient reached our institution and treatment was begun. The de-
40
THE ANNALS OF THORACIC SURGERY
Drug Therapy of Dissecting Aneurysms
FIG. 2. Chest x-rays of patient P. R. (Table 2), who developed a localized saccitlar aneurysm during an interval of 16 months without a follow-up chest x-ray. ( A ) December, 1963; ( B ) July, 1964; ( C ) October, 1965. cision to attempt drug therapy at this stage in this patient was an error in judgment. Immediate drug therapy prior to such extensive dissection is mandatory if a good result is to be obtained. This particular patient should have been approached surgically at the level of the ascending aorta, as first described by Morris et al. [91. Three of our 14 survivors have had to have elective surgery because of severe aortic valve insufficiency. There are 2 survivors alive and well 18 and 24 months since replacement of their aortic root, aortic valve, and reimplantation of the coronary arteries. The patient with the longest follow-up, B. F. G. (Table 2), is normotensive and living an active, normal life. Figure 3 shows his enlarged heart and pulmonary edema prior to surgery (Fig. 3A) as contrasted to his most recent chest x-ray 5 and 24 months later (Fig. 3B, C ) . We believe there is no indication, at present, to operate to remove the stable distal area of dissection, and obviously operation for fenestration is not needed. Failure of surgery in the third patient was due to a flap of the aortic wall in the aortic arch compromising the perfusion to the brain. This man’s dissection was so extensive that even in retrospect we are not certain that he could have been successfully perfused. T h e replacement of his aortic root was technically successful.
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41
N, M, 66
2. M. H.
N, F, 63
6. F. C.
"At first admission.
N, M, 36
5. B. F. G .
--
N, M, 52
4. P. R.
3. L. W. V. 0. W, M, 63
N, M, 70
1. E. T.
Patient
Shortness of breath, 1 day Chest pain, 6 hr.
Chest pain, 4 days
Shortness of breath, choking, 1 day Chest pain, 1 day
Chest pain, 1 day
Race, Sex. & Age" Symptomsa
Known
Known
Unknown
Unknown
Known
Known
tension"
U.,nC.r. --1c-=
n
a
Second dissection at 2 yr. 8 mo. managed again with drugs; now 4 mo. later, doing well at age 66 Died, rupture localized saccular aneurysm thoracic aorta; dissection healed at autopsy Aneurysm slightly larger, n o localized sac; working, asymptomatic Aneurysm stable, u p & about at age 66
3 yr.
2 yr. 10 mo. 2 yr. 7 mo.
140/90
-
140180
-
210/ 180
142198
155180 2921140
1 yr. 10 mo.
Aneurysm stable; died, age 70, from massive intracerebra1 hemorrhage
-
3 yr. 9 mo.
Results Aneurysm smaller; alive & well, age 73
Length of Follow-up 3 yr.
(mm. Hg) 95155 2381100 (160/90 after 1 unit whole blood) 240/140
~~
D
U. I.
B. P. Fo11owup (mm. Hg)
TABLE 2. FOLLOW-UP DATA ON ORIGINAL 6 PATIENTS TREATED WITH DRUGS FOR ACUTE DISSECTING ANEURYSMS OF THE AORTA
Drug Therapy of Dissecting Aneurysms
FIG. 3. Chest x-rays of patient B.F.G. ( T a b l e 2) showing the enlarged cardiac silhouette with pulmonary edema secondary to aortic value insuficiency at the t i m e of acute dissection ( A ) and tzuo follow-up chest x-rays five m o n t h s ( B ) and t7u0 years (C) after aortic root replacement.
OVERALL E X P E R I E N C E During this same two-year period since our first report, an additional 39 cases were cared for in at least 18 different and widely separated medical centers throughout the United States and Canada, with an overall success rate of 90%. Of these cases, 80% were proved to be dissecting aneurysms of the thoracic aorta by angiocardiography or autopsy. Adding our own patients, the entire group now totals 54 patients; in this total group there have been only 5 failures for an overall success rate of 92%. We believe this accumulated experience makes several important points. First, this method of management can be used successfully by most physicians practicing in hospitals in all parts of the country. Tables 1 and 2 also emphasize the point that this method of management is highly successful for all forms of dissecting aneurysms, in the range of a 90% successful outcome. All 5 treatment failures in the total group were characterized by very rapid onset of dissection, beginning usually in the ascending aorta and rapidly progressing to involve all vessels down to the external iliac arteries. Operation
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PALMER .4ND WHEAT was attempied in 2 of the cases with no success. Definite hints of the inadequacy of drug therapy in 2 of the patients were manifested by the ineffectiveness of trimethaphan in lowering the blood pressure within four hours after the initiation of therapy. Each of these patients showed dissection of their entire vascular tree including the origins of the renal arteries. Perhaps release of angiotension from ischemic kidneys prevented the desired therapeutic effect in these two patients. Therefore, a t the present time, if a patient with an acute dissecting aneurysm of the aorta does not respond promptly and is not easily maintained within the 100 to 120 mm. Hg systolic blood pressure range within the first four hours following admission, we believe surgical intervention is mandatory. There is no question but that probably 5% to 10% of patients with acute dissecting aneurysms of the aorta develop such a rapid and extensive dissection that a fatal outcome will be the rule. T h e only hope at present for such patients is recognition of the rapid dissection and prompt attempts a t surgical intervention; this occasionally can result in dramatic survival [91.
C U R R E N T MANAGEMENT We have previously outlined the rationale for the use of certain drugs in the treatment of dissecting aneurysms [ l l , 151. T h e argument begins with an analysis of the natural course of the untreated dissecting aneurysm which concludes that 3eath is primarily due to ultimate aortic rupture and hemorrhage rather than to factors associated with the initial intimal tear [71. Therefore, therapy, to be successful, must focus on the prevention of aortic rupture. Dissecting aneurysms, if rupture does not occur, will heal as illustrated by our case P. R. (see Fig. 1B) Spontaneous healing of untreated cases is also widely documented in the literalure [3, 101. T h e forces that further the dissection and produce rupture are undoubtedly related to a complex propagation of impulses and pressures produced by myocardial contraction in the setting of an intricate, nonpassive vascular bed. Such forces are difficult to analyze, but certain observations suggest an important common denominator, eg., the force of myocardial contraction, measured as either dl/dt :fiber length) dpidt (pressure) or calculated as dmvidt (momentum). Previously discussed theoretical reasons suggest that contractility and subsequent cardiac evencs, rather than mean aortic pressure per se, are probably the major determining forces in promoting further dissection. Experimental and clinical observations add further support to this notion. Aortas from diseased as well as normal indiliduals are amazingly resistant to static pressure increases [61. Fluid injected subintimally to pressures of from 320 to 900 mm. Hg are required to produce rupture. EXPERIMENTAL EVIDENCE
Observations in experimentally produced dissecting aneurysms in turkeys suggest that f x t o r s other than blood pressure are operative. Broad Breasted Bronze turkeys under field conditions or when fed a special diet have mortality rates of u p to 60% from rupture of dissecting aneurysms [131. Mortality can be reduced to 10% or less by adding a tiny amount of reserpine (0.1 part per million) to the feed. This amount has little if any effect on blood pressure [121. Hexamec honium, a hypotensive agent, effectively lowered blood pressure in a group of hypertensive patients, yet the mortality from dissecting aneurysms was twentyfold higher than in a control group of hypertensive patients [21. Significantly, it has been shown that hexamethonium increases myocardial contractility while it lowers mean systemic pressure 181. T h e fact that reserpine protects against death from aortic rupture in turkeys without significantly lowering blood prc'ssure implies that it has an effect on the contractile process. Reser-
44
THE ANNALS OF THORACIC SUKGEKY
Drug Therapy of Dissecting Aneurysms TEAR
FL
-t-
FIG. 4. A model aorta as described i n the text. P is a diagrammatic pressure profile on a n arbitrary scale at any time (t) .showing a pressure gradient between the torn intima and the acljnccnt tissue. pine at low doses depletes cardiac catecholamines in most species [51. Reduction of these catecholamines may produce a decrease in myocardial contractility. Reserpine does depress contractility in the isolated rabbit heart [15]. A simple laboratory model directly implicates pulsatile flow as an important factor in the propagation of dissection. Tygon tubing can be made to resemble an aorta by coating the inside of it with rubber cement (Fig. 4). When the cement hardens, a n “intimal tear” can be created by gently separating the layer of hardened cement from the tygon wall with a spatula. Water can then be flowed through the tubing at various rates. As long as the flow is laminar, no extension of the “dissection” takes place. Also, stepwise increases of static pressure to as high as 900 mm. Hg produce no dissection. But when pulsatile flow is initiated, rapid dissection occurs in both directions. T h e explanation seems clear; namely, under the first two conditions, i.e., laminar flow or static pressure, no gradient of pressure exists between the torn intima and the immediately adjacent tissue. Under pulsatile flow conditions, depending upon the sharpness of the pressure curve at any time, a pressure gradient exists between the torn portion and the intact adjacent portion (see Fig. 4). This gradient is the driving force for extending the dissection. T h e relationship between this model and what occurs in naturally occurring aneurysms is obvious. Might one suppose that if pulsatile flow in the aorta were replaced by laminar flow, the process of dissection would be halted? Or, to take the analogy not so far, if the shape of the pressure curve were flattened so that the pressure gradient at any time at the region of dissection were not so great, might not the dissecting process be slowed or even arrested? To establish myocardial events rather than the absolute magnitude of systemic pressures, as the principal cause of mortality, agents which specifically depress contractility with little effect on blood pressure should be tested. Propranolol is such an agent; as is shown in Figures 5 and 6, it depresses contractility in the isolated rabbit heart and in the intact dog heart. MANAGEMENT OF ACUTE EPISODES
Our management of the acute situation has not changed appreciably [15]. Patients are admitted to the intensive care unit, and treatment with trimethaphan, reserpine, and guanethidine is initiated. As the patients stabilize (between the fifth to tenth day of admission), graded ambulation is begun. Discharge is from two to three weeks following admission when the chest x-ray is stable and when the blood pressure has been satisfactorily regulated with reserpine, guanethidine, and, occasionally, propranolol and hydrochlorothiazide. Following discharge, most patients are maintained on guanethidine or reserpine, drugs which have similar catecholamine-depleting effects but which. most importantly, alter the contractile mechanism as discussed above. We believe that reserpine forms the backbone of our long-term therapy, although side effects are bothersome and occasionally prohibit its use. T h e average dose of reserpine
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PALMER AND WHEAT ISOLATED RABBIT HEAR1
5mmlSEC
NmmlSEC
CONTROL
SLOpE-6.0 AMP-2bmm
PROPRANOLOL Wlml 20 MIN
SLOPE-1.7 AMP-14mm
WASHOUT MlMlN
SLOPE-2.5 ~ ~ p - ~ m r n
FZG. 5 . Contractility of the isolated rabbit heart. Therapeutic concentrations of propranoiol depress the slope of the trace ( d l l d t ) and the amplitude of the contraction.
PRL-PROPRANOLOL
PROPRANOLOL
350 P g l K g IV
I
-1
~~~~~
T
WAVE TAKEN AT T
1
wx s LOPE -3.5
-
MYOCARDIAL CONTRACTILIIY
A m m Hg
r
SLOPE-2.3
FEMORAL PRESSURE
- f
20 m i n u t e r
F I G . 6. Contractility and blood pressure as recorded in the pentobarbitalanesthetized dog. A Walton-Brodie strain-gatige sutured t o the left ventricle records isometric contraction. Femoral pressure is recorded with a Statham pressure tranjducer. T h e contractility is depressed by propranolol with only a small eflect or! blood pressure.
46
THE ANNALS OF THORACIC SURGERY
Drug Therapy of Dissecting Aneurysms is from 1 to 5 mg. daily orally as tolerated. Guanethidine is usually given in a dose of 5 to 50 mg. twice a day. Occasionally, a diuretic is added as needed to reduce edema. The object of long-term therapy is aimed at preventing recurrence; thereiore, we attempt to reduce the blood pressure toward levels as near to normal as possible. However, as mentioned previously, prevention of dissecting aneurysms in turkey flocks can be accomplished with amounts of reserpine that do not significantly affect blood pressure, so that reduction of blood pressure is not necessarily a goal of therapy. Therefore, in clinical use, even if blood pressure cannot be lowered with reserpine to levels that we might desire without serious side effects, we continue the drug nevertheless, on the assumption that i t is not blood pressure itself that is important but perhaps something else affected by the drug. COMMENT
There are complications of drug therapy which should be mentioned. Trimethaphan, reserpine, and guanethidine are potent agents, and unless carefully controlled may in themselves be fatal. A frequent complication with trimethaphan is profound hypotension, particularly if careful monitoring of the blood pressure is not performed, and this may result in transient renal failure as occurred in 2 of our cases. Other effects of acute ganglionic blockade, such as ileus, bladder distention, and visual disturbances, must also be watched for. Complications of reserpine include severe sedation and gastric hypersecretion, as first reported by Barrett et al. [I]. We know of 2 cases in which peptic ulcers complicated the picture and necessitated emergency surgery to control the bleeding [4]. Reserpine is known [ l , 131 to produce an increase in the flow of free hydrochloric acid in the stomach of the dog, and presumably it has a similar effect in man. Because of this increased flow of gastric acid, we keep our patients on antacid therapy during the acute phase of treatment with the relatively high dosages of reserpine. During long-term therapy with reserpine, depression with suicidal overtones is an occasional complicating factor. Guanethidine may also produce severe postural hypotension and diarrhea [ 5 ] . The question as to when one should resort to surgery frequently arises. This question should be divided into the acute phase and the chronic phase. During the acute phase, we believe surgery is indicated when there is: (1) failure of the blood pressure to respond satisfactorily within four hours; (2) compromise of a significant branch of the aorta, e.g., the carotid artery, the celiac axis, the renal artery; (3) failure to control progression of the dissection; and (4)uncontrollable acute aortic valve insufficiency. Indications for surgical intervention in the chronic phase are: (1) significant aortic valve insufficiency; (2) development of a saccular aneurysm; and (3) progressive enlargement of the dissecting aneurysm. VOI..
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47
PALMER AND WHEAT SUMMARY
Almost four years’ experience with nonsurgical management of dissecting aneurysms is reported. Fifteen consecutive cases of dissecting aneurysms have been treated with drugs at the University of Florida, with 1 treatment failure. Four of the original 6 patients presented two years ago [15] are still alive. One patient died of an intracerebral hemorrhage and the other from a ruptured saccular aneurysm. Thirty-nine patients from other hospitals similarly treated have been presented. There were 4 treatment failures in this group, giving an overall success rate of 90%. T h e treatment failures were those who did not respond to the drugs, those whose dissection progressed too far before treatment was begun, and those in whom severe aortic valvular insufficiency demanded immediate surgical intervention. T h e rationale for drug therapy places less emphasis on blood pressure per se and more on the contractile event and the nature of pulsatile flow in large vessels. A model directly implicating pulsatile forces as a cause for continued dissection has been devised and is discussed. REFER ENC27S 1. Barrett, W. E., Plummer, A. J., Earl, A. E., and Kogie, B. Effect of reserpine on gastric: secretion of the dog. J . Pharmacol. 113:3, 1955. 2. Beaven, I). W., and Murphy, E. A. Dissecting aneurysm during methonium therapy. .Brit. Med. J . 1:77, 1956. 3. Conston, A. S. Healed dissecting aneurysm. Arch. Path. (Chicago) 48: 309, 1949. 4. Glenn, W. W. L. Personal communication. 5. Goodmar;, L. S., and Gilman, A. T h e Pharmacological Basis of Thrrapeutics (3d ed.). New York: Macmillan, 1965. 6. Hirst, E. A., Jr., and Johns, V. J., J r . Experimental dissection oE media of aorta by pressure: Its relation to spontaneous dissecting aneurysm. Czrc. Res. 10:897, 1!362. 7. Hirst, E. 4., .Jr., Johns, V. 1.. Jr., and Kime, S. W., Jr. Dissecting aneurysm of the aorta: A review of 505 cases. Medicine (Balt.) 37:217, 1958. 8. Lee, W. (I., and Shideman, F. E. T h e inotropic action of hexamethonium in the heart-lung preparation and isolated papillary muscle. J . Pharmacol. 119:160, 1957. 9. Morris, G . C., Jr., Henly, W. S., and De Bakey, M. E. Correction of acute dissecting aneurysm of aorta with valvular insufficiency. J.A.M.A. 184:63, 1963. 10. Nielson, 7 3 . C. Dissecting aneurysm of the aorta. Acta Med. Scand. 170: 117, 1961. 11. Palmer, F. F., Seelman, R. C., and Wheat, M. W. Pharmacological approach to the therapy of acute dissecting aneurysm of the aorta. Clin. Res. 13:27, 1965. 12. Ringer, F.. K. Aortic Rupture, Plasma Cholesterol, and Arteriosclerosis Following Serpasil Administration to Turkeys. I n T h e Second Confcrenre 012 the Use of Reserpinp in Poultry Production (May 6, 1960, University of Minnesot;,, St. Paul, Minn.). Summit, N.J.: CIBA, 1960. Pp. 32-39.
48
THE ANNALS OF THORACIC SURGERY
Drug Therapy of Dissecting Anem-ysms 13. Shapiro, H., and Woodwarcl, E. K. T h e mechanism of action of reserpine on gastric secretion. Fed. Proc. 20:248, 1961. 14. Ringer, R. K. Influence of reserpine on early growth, blood pressure and dissecting aneurysms in turkeys. I n Conference on the Use of Serpasil i n Animal and Poultry Production (May 7 , 1959, Rutgers, T h e State University, New Brunswick, N.J.). Summit, N.J.: CIBA, 1959. Pp. 21-28. 15. Wheat, M. W., Jr., Palmer, R. F., Bartley, T. D., and Seelman, R. C. Treatment of dissecting aneurysms of the aorta without surgery. J. Thorac. Cardiov. Surg. 50:364, 1965.
DISCUSSION’ DR. JOHN H. KENNEDY(Cleveland, Ohio): Dr. Grondin and his co-workers have presented a very interesting paper emphasizing the serious nature of dissecting aneurysms and some of the factors which may influence a successful outcome. I rise to comment briefly on two technical considerations which may also serve as factors influencing survival, particularly in those patients in whom the dissection arises distal to the left subclavian artery. T h e first of these considerations is protection of the brain. T h e reported incidence of vertebral artery asymmetry is as high as 30%. Of these, when asymmetry is present, the left vertebral artery is dominant. For this reason, occlusion of the left subclavian artery, which is often necessary in control of dissection just distal to it, may produce serious cerebral consequences. Therefore, it would seem logical to recommend that either one make provision €or perfusion of the distal left subclavian artery and hypothermia, if one doesn’t know whether vertebral artery asymmetry is present or not on the basis of angiography; or, if time permits (more applicable to the chronic dissection), obtain four-vessel cerebral angiography as a part of the initial diagnostic study in those patients who are being considered for surgical treatment. T h e other point I would like to make is a consideration of the magnitude of surgery. T h a t these patients are ill has already been emphasized. T h e question of repair versus excision, therefore, becomes a consideration. While this is a bad disease, it is not cancer, and therefore ablation of the involved tissue may not really be necessary. Applicable only in those cases in which the dissection arises just distal to the left subclavian artery is the simple expedient of aortorraphy. Shown in Figure D-1 is the opening of the site of dissection. This is applicable only in those patients in whom reentry has not occurred. Evacuation of the dissecting hematoma and closures of the aorta in one layer is carried out. This procedure has been applied in two patients whose dissection proved to be progressive after two weeks and who therefore perhaps would fit into the acute group of Dr. Grondin. I n both patients this procedure was effective in controlling the dissection. One patient subsequently died of the consequences of an atheromatous embolism. DR. ROBERTD. BLOODWELL (Houston, Tex.): I think we must thank Drs. Palmer and Wheat for awakening our interest in reevaluating the management of patients with acute dissecting aneurysms. Dr. Grondin pointed out the heterogeneous group of dissecting aneurysms that we are really considering. Patients with chronic dissecting aneurysms, of course, don’t require drug management to protect them from acute dissection or extension of the process. T h e fact that many present initially in the chronic stage emphasizes the natural history of many *This and the preceding paper, “Dissecting Aneurysms of the Thoracic Aorta: A Review of 52 Cases with Consideration of Factors Influencing Prognosis,” by Claude Grondin et al., page 29, were discussed together.
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PALMER AND WHEAT
A
F I G . D-1. acute dissecting aneurysms. On the other hand, since many in the acute phase may extend unpredictably, we feel that there is a need for some definitive surgical repair of the mechanical problem. The management of acute dissecting aneurysms depends upon, first of all, suspicion that one is present, and then upon determination of the origin and extent of the dissection. This doesn’t always require aortographic study; as was already pointed out in the presentation, the presence of aortic insufficiency often is the factor (hat demands earlier or emergency surgery. Classification of dissecting aneurysms as to origin and extent has been important in tailoring a procedure proper for the aneurysm that is present in a given case. Those originating in the ascending aorta (Type I or Type II), which often, of course, extend into the arch or beyond, are managed differently from those originating in the descending aorta. We are certain that in the latter variety drug therapy may enjoy its best application. Perhaps in time we will be able to employ the technique of drug therapy as an adjunct to the management of certain acute aneurysms. The mechanical problem in dissecting aneurysms of the ascending aorta in which the valve leaflets lose their corn missural suspension and become acutely insufficient requires operation to correci. cardiac failure and to limit the extent of the dissection. I n patients in whom there is aortic insufficiency, which is appreciated by the presence of a new diastolic murmur, or in whom a pericardial friction rub develops while they are being managed acutely, with or without drug therapy to maintain the blood pressure in a reasonable range, we recommend an approach with total cardiopulmonary bypass. One must divide the ascending aorta and resuspend the aortic valve leaflets if there is indeed adequate aortic tissue around the annulus. Replacement of the aortic valve is necessary at times. Then the distal ascending aorta is managed according to what the anatomy demands to restore mural integrity and to limit progression of the dissecting process. During operations upon patients with acute dissections, we have often seen the hemorrha$c appearance of the ascending aorta and bloody pericardial fluid before any rupture of the thin outer wall occurs. I t is difficult to visualize how drug management can alter either these changes or the disruption of most of the aortic wall and provide us with a long-term or even short-term salvage. Certainly pat+ts with this type of mechanical problem can live for a short time, and antihypertensive drugs may be useful as a stopgap in conjunction with operative correction on z more elective basis.
50
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Drug Therapy of Dissecting Aneurysms So, in our hands, the problem of managing acute dissecting aneurysms resolves itself into having a high index of suspicion, trying to determine the origin and extent of dissection (often on physical diagnostic grounds alone, without aortography), and then proper timing of an appropriate operation in this heterogeneous group of patients.
DR. GEORGE ROBINSON (Mount Vernon, N.Y.): As I survey my own experience with dissecting aneurysms, it is somewhat discouraging to realize that it would require a successful outcome in the management of the next 325 consecutive patients to achieve a success rate of 92% as reported by Dr. Palmer and Dr. Wheat. I am somewhat consoled by the fact that it will take Dr. Lillehei a longer period of time. The big question is: How do I avoid receiving patients who enter my hospital with their renal and mesenteric vessels sheared? Some are paraplegic, some have other serious neurological injuries, and some have very severe heart disease! What I am questioning really is whether the collected series of Dr. Palmer and Dr. Wheat is truly representative of what is being achieved? I would also like to cite two interesting surgical experiences in two patients with dissecting aneurysms of the ascending aorta. One was repaired locally by suture technique, and the other was repaired with a Teflon tubular graft. Both patients were found to have locally recurrent dissecting aneurysms approximately one to two years after their original repair. Both required reoperation, one because of severe aortic insufficiency and the other because of progressive aortic enlargement. I n the previously grafted case, the Teflon tube had separated from the intima at the distal suture line. Both survived the surgery and are well, but I fear to study them again by aortography, wondering what I would do if I found that I had not cured them the second time around. I wish to thank the discussants for their comments. I certainly DR. GRONDIN: support the view held by Dr. Bloodwell and his group on the urgency that aortic insufficiency presents when it is associated with dissection in the ascending aorta. T h e indication for surgery is clear-cut in this instance.
DR. WHEAT:There are a couple of
oints we would like to make in regard
to the therapy. There may be signii !cant complications of drug therapy.
Trimethaphan, reserpine, and guanethidine are potent agents, and in themselves can be the cause of death unless they are carefully used. A frequent complication with trimethaphan is profound hypotension, particularly if careful monitoring of the blood pressure is not carried out. Transient renal failure can occur, which has happened in two of our cases. Other effects of acute ganglionic blockade such as ileus, bladder distention, and visual disturbances may also occur. Complications of reserpine include severe sedation and gastric hypersecretion. Two cases have been reported to us which necessitated emergency surgery to control the bleeding, and following this both cases were successfully cared for without surgery for their dissecting aneurysms. Reserpine is known to produce an increase in the flow of free hydrochloric acid in the stomach of the dog, and presumably it does the same thing in man. Because of this, during the acute phase when these patients are receiving large amounts of reserpine, we also treat them as one would an acute ulcer in regard to diet. If they go home on significant doses of reserpine (by this I mean 2 to 4 mg. per day), then they should be carried on a bland diet because of increased gastric secretion. I think i t is also important that these patients be kept on the surgical service, because several of the failures that have been reported to us have been patients that have been transferred back to medical services. This is not a form of medical treatment, nor is it a form of conservative treatment. This is radical drug therapy. These patients need to be followed in the compulsive manner that a surgeon fol-
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1967
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PALMER AND WHEAT lows his patients, so that one can watch for complicating factors that may have to be dealt with. T h e series may be biased. However, it has been our experience that one of the first things doctors do is tell us about their failures. However, we are not necessarily trying to sell an overall survival rate of 90%, but we do believe that in the majority of cases, if they are caught early, that they can be handled successfully in this manner. I appreciate the comments of Dr. Bloodwell. We certainly agree that acute, unremitting aortic valve insufficiency, as we mentioned, and as was first managed successfully by their group, necessitates acute surgery, and that in all probability had we treat,ed our one failure in this manner, he might have been a success. At least, he would have had a chance. However, on the basis of the information which we have, we believe that this group is no more than 5% to 10% of the cases. As to Dr. Robinson, I think he should not be discouraged, and I think he should keep trying. He has our sympathy. However, if one looks at our series of cases, many of our patients’ ages are 70 years and over. However, the failure which we have had and the ones reported to us are patients, just as Dr. Robinson mentioned, irt whom the renal arteries are sheared off and they dissect from top to bottom, so to speak.
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