Correspondence Partial Splenic Embolization for Hypersplenism

To the Editor: We have read with considerable interest the article

by Sangro et all entitled “Partial Splenic Embolization for the Treatment of Hypersplenism in Cirrhosis.” The authors have undoubtedly shown just what was ex- pected- that partial splenic embolization leads to par- tial splenectomy. However, we are perturbed that their excessive emphasis on the technical aspect has given somewhat short shrift to clinical medicine and medical ethics. We wish to make the following points to support our above statement.

First, the authors have ignored the fact that hyper- splenism is usually clinically insignificant’ and there- fore, the whole basis of using drastic measures to treat this condition is tenuous. Surely the authors have tried to weave the story of their technique around a clinical situation of interferon-induced cytopenia in patients with cirrhosis of viral origin. We would like to question the very necessity of such therapy at this late stage when there is little to be gained by eradicating the hepatitis infection; that such patients can benefit from interferon has not been proved so far. Highly question- able on ethical grounds is the inclusion in the study of patients with asymptomatic thrombocytopenia, in whom neither surgery nor interferon therapy could be considered. Mere demonstration of low leukocyte and platelet counts in the absence of symptoms may not warrant any treatment because, although the number of circulating platelets and leukocytes is reduced, their function is often normal.’ Prognosis and long-term sur- vival of such patients are related to the severity of underlying disease rather than to blood cell counts.2

Second, the definition and proof of hypersplenism in the authors’ cases can be questioned. The authors have used the term “hypersplenism” for reduction in one or more cellular elements of blood. However, they neither demonstrated presence of normal or hypercellular bone marrow nor excluded other causes of cytopenias, namely, folate deficiency, drug toxicity, and bone mar- row hypoplasia.

Third, the authors have placed a lot of importance on the withdrawal of interferon because of bone marrow depression. This is not a significant problem in clinical practice. The two main series quoted by the authors

mention that dose reduction in their patients was tempo- rary and that these patients responded to treatment as frequently as those who received scheduled doses of inter- f e r ~ n . ~ , ~ This is contrary to what Sangro et all have men- tioned in reference to these trials. Furthermore, it was shown that after 1 week of partial splenic embolization, aspartate transaminase and alanine transaminase levels decreased significantly. But no suitable explanation has been postulated to explain this improvement.

Finally, the proportion of splenic tissue infarcted was estimated subjectively at the time of embolization. The same could have been assessed more objectively using scintigraphic techniques with radiolabeled red blood cells.

We are reminded of what Will Durant,‘ the famous modern philosopher, had to say about specialists in science, “The specialist puts on blinders in order to shut out from his vision all the world but one little spot, to which he glued his nose. Perspective was lost. Facts replaced understanding; and knowledge, split into a thousand isolated fragments, no longer gener- ated wisdom.” Should we not heed this warning.

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BRIJESH C. SHARMA RAKESH AGGARWAL SUBHASH R. NAIK Department of Gastroenterology Sanjay Gandhi Postgraduate Institute

Lucknow, India of Medical Sciences

REFERENCES

Sangro B, Bilbao I, Herrero I, Corella C, Longo J, Beloqui 0 , Ruiz J, et al. Partial splenic embolization for the treatment of hypersplenism in cirrhosis. HEPATOLOGY 1993; 18:309-314. McCorrnick PA. The spleen, hypersplenism and other relation- ships between liver and spleen. In: McIntyren N, Benhamou JP, Bircher J, Rizzeto M, Rhodes J, eds. Oxford Textbook of Clinical Hepatology. Oxford: University Press 1991:489-493. Causse X, Godinot H, Chevallier M, Chossegros P, Zoulim F, Ov- zan D, Heyrand JP, et al. Comparison of 1 or 3 MU of interferon alpha 2b and placebo in patients with chronic n o d , nonB hepati- tis. Gastroenterology 1991; 101:497-502. Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC, Lindsay K, Payne J, Dienstag JL, et al. A randomized controlled trial of inter- feron alpha 2b alone and after prednisolone withdrawal for treat- ment of chronic hepatitis B. N Engl J Med 1990;323:295-301. Durant W. The story of philosophy. Ed 2. 1993:viii.

Emergency Portacaval Shunt: A Perspective on the Perspective To the Editor:

The editorial by Henderson and Grace’ entitled “A Perspective on Emergency Portacaval Shunt” in the October 1994 issue of HEPATOLOGY raises questions about our randomized controlled trial (RCT)2 that de- mand a response.

The Patient Population. Henderson and Grace stated: “Any center conducting randomized controlled

trials has potential constraint on patient entry dictated by factors such as referral and practice patterns, and patient compliance. These must be clearly defined.”’ Our paper clearly stated: “All patients with liver dis- ease who entered the emergency room at the San Diego Veterans Administration Medical Center because of bleeding esophageal varices (41 patients), or in whom variceal hemorrhage developed during the course of hospitalization (two patients), were included in the

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study.”’ We could not have defined the patient popula- tion more clearly. The study population was not a sub- set of any other study population. Referral bias and practice patterns were not factors in the study because, as is true in most Veterans Administration (VA) hospi- tals, the patients were accustomed to receiving all of their medical care at the San Diego VA Medical Center and were not referred to the study by outside physi- cians. The validity of performing RCTs in VA hospital populations is well recognized. Our study involved “all comers” with bleeding varices in the San Diego VA Medical Center population, which eliminated bias, con- scious or subconscious, and greatly enhanced the objec- tivity of the study. Finally, as we stated on page 870 of our report, the results of our RCT are similar to the results of emergency portacaval shunt (EPCS) obtained in the much larger general population of patients that we have treated during the past 30 years.

Henderson and Grace indicated that Harold Conn3 previously had expressed similar questions about the patient population in our study, and implied that Conn had concerns similar to theirs. In point of fact, Conn raised the same questions rhetorically in 1986 and then indicated that he was quite satisfied with the answers. Conn stated in 1986: “The long-awaited, much needed controlled trial appears to confirm the anecdotal obser- vations. I’m satisfied from personal communication with Orloff that this investigation was well designed and executed, and that the results deserve objective confirmation.” We invite the readers to read Conn’s 1986 commentary on our s t ~ d y . ~

The Study Design. Henderson and Grace stated: “However, a major concern in the study design is the adequacy of medical management,” and they went on to state that our results of balloon tamponade were not as good as “most other series.”l They implied that our medical management might have been deficient be- cause, in contrast to our considerable experience and expertise with EPCS, medical management is “a man- agement method in which the authors have expressed little confidence.”’ These concerns are unwarranted. Our article stated: “A senior faculty gastroenterologist served as a consultant in every case and, along with the gastroenterology fellows under his supervision, had the ultimate authority for treatment of patients in the EMT g r ~ u p . ” ~ The senior faculty gastroenterologist was Professor William G. M. Hardison, a very experienced hepatologist who has never “expressed little confi- dence” in conventional medical management. Further- more, the success rate of medical therapy was not lower than that reported by most investigators. Balloon tam- ponade ultimately controlled bleeding in 53% of our unselected patients during the initial hospitalization for a sufficient length of time to permit preparation for elective shunt. This rate of ultimate success is better than our previously reported experience in 59 patients (initial control, 58%; ultimate control, 22%),4 and simi- lar to the experience of many others that, unlike our study, involved selected patient^.^.^^ In nine series in- volving a total of 524 patients reported in the literature over a period of 28 years, the frequency of ultimate

control of bleeding by balloon tamponade ranged from 22% to 60% and averaged 42%.4-12 It is important to distinguish between the rate of initial control, which generally has been quite high, and the rate of ultimate control, which has been much lower in many series because many patients rebled after the esophageal bal- loon tube was removed.

As we stated in our report, our study, which was planned in 1977 and initiated in 1978, evaluated the type of emergency medical therapy that was most widely used at that time. It did not evaluate endoscopic sclerotherapy, a measure that had not yet received widespread acceptance. Neverless, we believe the re- sults of our study are important for the following rea- sons: (1) Esophageal balloon tamponade and intrave- nous vasopressin are still used throughout the world for the emergency treatment of variceal bleeding. Therefore, the results of our study are relevant to the armamentarium available for the treatment of variceal bleeding today. (2) EPCS is used today for the treat- ment of bleeding from esophageal varices, gastric vari- ces, and portal hypertensive gastropathy. Certainly, our study provides important objective information on the effectiveness of EPCS in treating the bleeding caused by portal hypertension. (3) There is little infor- mation available on the long-term (10-year) results of portacaval shunt. Our study provides such informa- tion.

Impact of Other Therapies. Henderson and Grace re- viewed in detail the general measures of supportive therapy that both groups of patients received and asked the question: “DO these therapies affect out- come?”’ They then answered their own question with the statement: “Certainly they were equivalently ap- plied in the two populations and probably are not major factors in overall survival in this study.’” We certainly agree with their conclusion. In point of fact, all patients received standard supportive therapy that is widely used for patients whose variceal bleeding is treated by either medical or surgical measures. Similar therapy is being given to all patients in our current RCT of endoscopic sclerotherapy versus EPCS, with the en- dorsement of both the National Institutes of Health site visit team that recommended approval of our grant application and the external advisory committee of dis- tinguished clinicians that is monitoring the study.

Other Studies. Our report stated that we undertook a RCT specifically because our previous studies had the shortcoming of being unrandomized. Inclusion of a detailed and lengthy analysis of our previous unran- domized experience with EPCS was not appropriate, nor would the editors have permitted it, but we did point out that the survival rates turned out to be simi- lar in our RCT and our recent unrandomized experi- ence. Nevertheless, in attempting to analyze previous reports of our unrandomized studies, Henderson and Grace incorrectly stated: “In the serial publications re- lated to their overall series, the authors never ade- quately address the changes that led to the dramatic improvement in operative mortality in the late 1970s.”’ Recently, we presented our long-term results of EPCS

HEPATOLOGY Vol. 21, No. 4, 1995 CORRESPONDENCE 1205

in 400 unrandomized patients at the Clinical Congress of the American College of Surgeons, the manuscript of which has been accepted for publication in the March 1995 issue of the Journal of the American College of Surgeons.’“ In that report we described in detail how our treatment strategy changed in the mid- and late 1970s, and the factors responsible for the improved re- sults of EPCS. Briefly, we attributed the improvement in outcome to the following: (1) simplification of the diagnostic work-up by elimination of time-consuming, often invasive, and usually unnecessary studies; (2) re- duction in delays in resuscitation and in the time inter- val from admission to operation; (3) development and refinement of an organized system of preoperative and postoperative care; and (4) intensification of the rigor- ous, lifelong program of follow-up and, particularly, of efforts to obtain dietary protein control and abstinence from alcohol. Henderson and Grace stated further: “It is apparent that other centers have been unable to pro- duce the good results reported by the San Diego group.”’ The facts are that, as far as we know and as we have emphasized repeatedly, no other center has evaluated our approach to emergency treatment of var- iceal bleeding that includes the following: (1) operation within 8 hours; (2) use of a well-defined and consis- tently applied protocol for preoperative, operative, and postoperative care; (3) rigorous, lifelong follow-up; and (4) inclusion of “all comers.” Furthermore, we have learned how to perform the EPCS operation rapidly and with precision. Unfortunately, that is not true of all surgeons who attempt portal-systemic shunts, a phenomenon familiar to Henderson, who expressed concern about technical deficiencies of surgeons doing distal splenorenal shunts in a 1986 edit0ria1.l~’~~ Dur- ing the past 15 years, approximately 85% of the unse- lected patients in whom we have performed EPCS have left the hospital alive. Moreover, the operative mortal- ity rate in 824 patients in whom we performed elective portacaval shunt was only 1.6%.16

Apparent Delay in Publication. Henderson and Grace raised a question “about the apparent delay in publication of the definitive paper on this trial” and speculated “Has the delay in publication of the defini- tive paper been because the authors or their peers have had concerns about the applicability of this study?”’ In point of fact, there has been no “delay” in publication. We reported the early results of our RCT in 1986 at the meeting of the American Gastroenterological Asso- ~ i a t i o n , ’ ~ and the midterm results were reported in 1990 at the annual meeting of the American Associa- tion for the Study of Liver Diseases.” We now have reported important long-term observations, particu- larly with regard to portacaval shunt. A major problem with studies of liver disease and portal hypertension, as with studies of many chronic diseases, is the absence of long-term data on the effectiveness of therapy. With considerable frequency there is a premature rush to publication of early results before adequate follow-up has been accomplished. Examples of this widespread and misleading phenomenon are the many recent re- ports of trans-jugular intrahepatic portosystemic

shunt. We know that Henderson and Grace do not ad- vocate this approach to reporting.

We trust that our response to the questions raised by Henderson and Grace’ will add perspective to their “Perspective on Emergency Portacaval Shunt.”

MARSHALL J. ORLOFF, MD Professor of Surgery Univer-sity of California, San Diego San Diego, CA

RICHARD H. BELL, JR, MD Professor of Surgery University of Washington Seattle, W A

MARK S. ORLOFF, MD Assistant Professor of Surgery University of Rochester Rochester, NY

A. GEESON GREENBURG, MD, PhD Professor of Surgery Brown University Providence, RI

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WILLIAM G. M. HARDISON, MD Professor of Medicine University of California, San Diego Sun Diego, CA

REFERENCES Henderson JM, Grace ND. A perspective on emergency portaca- val shunt. HEPATOLOCY 1994; 20:1090-1091. Orloff MJ, Bell RH, Jr, Orloff MS, Hardison WGM, Greenburg AG. Prospetive randomized trial of emergency portacaval shunt and emergency medical therapy in unselected cirrhotic patients with bleeding varices. HEPATOLOGY 1994; 20:863-872. Conn HO. Emergency portacaval anastomosis (EPCA): the long- awaited trial. HEPATOLOGY 1986;6:1058-1060, Orloff MJ. A comparative study of emergency transesophgeal ligation and nonsurgical treatment of bleeding esophageal vari- ces in unselected patients with cirrhosis. Surgery 1962; 52:103- 125. Reynolds TB, Freedman T, Winsor W. Results of the treatment of bleeding esophageal varices with balloon tamponage. Am J Med Sci 1952;224:500-506, Ludington LG. A study of 158 cases of esophageal varices. Surg Gynecol Obstet 1985; 106:519-526. Read AE, Dawson AM, Kerr DNS, Turner MD, Sherlock S. Bleed- ing oesophageal varices treated by oesophageal compression tube. Br Med J 1960; 1:227-231. Hermann RE, Traul D. Experience with the Sengstaken-Bla- kemore tube for bleeding esophageal varices. Surg Gynecol Obs- tet 1970; 130:879-885. Johansen TS, Baden H. Re-appraisal of the Sengstaken-Blakem- ore balloon tamponade for bleeding esophageal varices, results in 19 patients. Scand J Gastroenterol 1973; 18:181-183. Novis BH, Duys P, Barbezat GO, Clain J, Bank S, Terblanche J. Fiberoptic endoscopy and the use of the Sengstaken tube in acute gastrointestinal hemorrhage in patients with portal hyper- tension and varices. Gut 1976; 17:258-268. Teres J , Anastasio C, Bordas JM, Rimola A, Bru C, Rodes J. Esophageal tamponade for bleeding varices. Controlled trial be- tween the Sengstaken-Blakemore tube and the Linton-Nachlas tube. Gastroenterology 1978; 75:566-569. Chojkier M, Conn HO. Esophageal tamponade in the treatment

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of bleeding varices: a decadal report. Dig Dis Sci 1980;25:267- 272.

13. Orloff MJ, Orloff MS, Orloff SL, Rambotti M, Girard B. Three decades of experience with emergency portacaval shunt for acutely bleeding esophageal varices in 400 unselected patients with cirrhosis of the liver. Presented at the 80th Annual Clinical Congress of the American College of Surgeons, October 13,1994, Chicago IL. J Am Coll Surg 1995; 180:257-272.

14. Henderson JM. Variceal bleeding: which shunt? [Editorial]. Gas- troenterology 1986; 91:1021-1022.

15. Conn HO. Do surgeons led by surgeons operate better than inter- nist-led surgeons? [Correspondence]. Gastroenterology 1987; 92: 841-842.

16. Orloff MJ, Orloff MS. Treatment of portal venous hypertension. In: Wilson SE, Veith FJ, Hobson RW, 11, Williams RA, eds. Vas- cular Surgery: Principles and Practice. Ed 2. New York: McGraw-Hill, 1994:896-932.

17. Orloff MJ, Bell RH, Jr, Greenburg AG. Prospective randomized trial of emergency portacaval shunt and medical therapy in un- selected cirrhotic patients with bleeding varices. Gastroenterol- ogy 1986;90:1754.

18. Orloff MJ, Bell RH, Jr, Hardison WG, Greenburg AG. Random- ized clinical comparison of emergency portacaval shunt versus medical therapy for bleeding varices in cirrhosis. Gastroenterol- ogy 1990; 98:A618.

Reply:

We are pleased that Dr Orloff and his colleagues’ have clarified some of the issues raised in our editorial.’ We are not opposed to the concept that emergent shunt surgery may have a role in the therapy of variceal hem- orrhage. Twenty-nine years ago, Grace et al.3 published a review on the present status of shunts for treatment of portal hypertension in which we noted that “al- though early differences are evident, at the end of 4 years there is no significant difference between the sur-

vival of patients undergoing elective therapeutic shunts and those shunted because their bleeding could not be controlled by conservative means.” We went on to suggest that “this raises the possibility that early (soon after admission) emergency portacaval shunts for the treatment of bleeding esophageal varices may be worth a well-controlled investigation.” Orloff et a14 have now published such a study. The results of their controlled trial are exciting, and we hope they will stim- ulate other investigators to undertake trials using a similar study design.

J. MICHAEL HENDERSON, MD Department of General Surgery The Cleveland Clinic Foundation Cleveland, OH

NORMAN D. GRACE, MD Department of Gastroenterology Faulkner Hospital Boston, MA REFERENCES

1. Orloff MJ, Bell RH, Jr , Orloff MS, Greenburg AG, Hardison WG. Emergency portacaval shunt: a perspective on the perspective [Correspondence]. HEPATOLOGY 1995; 21: 1203-1206.

2. Henderson JM, Grace ND. A perspective on emergency portacaval shunt. HEPATOLOGY 1994; 20:1090-1091.

3. Grace ND, Meunch H, Chalmers TC. The present status of shunts for portal hypertension in cirrhosis. Gastroenterology 1966; 50:

4. Orloff MJ, Bell RH, Jr, Orloff MS, Hardison WGM, Greenburg AG. Prospective randomized trial of emergency portacaval shunt and emergency medical therapy in unselected cirrhotic patients with bleeding varices. HEPATOLOGY 1994; 20:863-872.

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