ANICTERIC AND ICTERIC HEPATITIS AFTER OPEN-HEART SURGERY

Transcription

1 GASTROENTEROLOGY Copyright C 1970 by The Williams & Wilkins Co. Vol. 58, No. 2 Printed in U.S.A. ANICTERIC AND ICTERIC HEPATITIS AFTER OPEN-HEART SURGERY VINCENT J. PROSKEY, M.D., GEORGE R. MORRISON, M.D., BERNARD P. MCQUILLAN, M.D., AND BRENT M. PARKER, M.D. Departments of Medicine and Preventive Medicine, Washington University School of Medicine, St. Louis, Missouri Fifty patients undergoing open-heart surgery were transfused with an average of 12.9 U of whole blood. During the 6 months following surgery, they were tested every 2 weeks for total bilirubin and transaminase levels in order to detect hepatitis. Between the 5th and 9th postoperative weeks, 2 and 8 % of the patients developed icteric and anicteric hepatitis, respectively, according to the elevated serum transaminase levels. Two of the 4 patients diagnosed as having anicteric hepatitis maintained elevations in serum transaminase levels which persisted without symptoms for up to 2 years. No patient received 'Y-globulin, fibrinogen, or pooled plasma. Compared with other reports dealing with multiple transfusions, the case incidence of post-transfusion hepatitis that we encountered was relatively low. We believe that this is due to the use of blood from volunteers and possibly to the pooled 'Y-globulin content in the multiple transfusions administered to each patient. In patients receiving multiple transfusions, the risk of infectious and serum hepatitis may be appreciable.l This fact has led to attempts to prevent hepatitis in such patients. Earlier claims2 of successful prophylaxis against infectious hepatitis with y-globulin have been followed by reports3 of its modification rather than prevention, i.e., icteric hepatitis being modified to anicteric hepatitis. The ques- Received July 9, Accepted August 5, Address requests for reprints to: Dr. George R. Morrison, Department of Preventive Medicine, Washington University School of Medicine, 4550 Scott A venue, St. Louis, Missouri This work was supported by Grant-in-Aid from the Missouri and St. Louis Heart Associations and by Grant HE from the National Heart Institute, National Institutes of Health, United States Public Health Service. Dr. Proskey's present address is: Division of Cardiology, Barnes Hospital, St. Louis, Missouri The authors wish to thank Doctors Thomas H. Burford, Thomas B. Ferguson, and Charles Roper of the Division of Cardiothoracic Surgery, Washington University School of Medicine, for their cooperation. tion of whether treatment with y-globulin prevents icteric serum hepatitis deserves further investigation. A polarity of opinion orients proponents of prophylactic y-globulin 4 5 (also A. Torii, N. Shoji, and Y. Miyazota, unpublished observations) against opponents,l.6 with some authorities believing in prophylaxis only in special circumstances.3 7 In addition, the efficacy of y-globulin in preventing anicteric serum hepatitis is debatable,! 6 and no prospective studies have been reported. Our initial retrospective observations of 100 patients receiving numerous transfusions during open-heart operations without concomitant y-globulin administration indicated a 3% incidence of icteric posttransfusion hepatitis. This experience suggested that, with careful donor selection, the incidence of icteric hepatitis could be decreased significantly in patients receiving multiple transfusions. However, it has been postulated that the incidence of anicteric hepatitis is increased in such patients. Since hepatic cirrhosis may develop subsequent to anicteric post-transfusion hepatitis, this is an important concern.8 203

2 204 PROSKEY ET AL. Vol. 58, No.2 The present prospective study was undertaken to establish the subsequent risk of developing icteric and anicteric hepatitis during open-heart surgery in patients receiving multiple blood transfusions without y-globulin prophylaxis. It was our hope that such data would shed additional light on the need for y-globulin prophylaxis, a problem worthy of evaluation since the use of y-globulin in all such patients would deplete rapidly available stores. 7 Materials and Methods Fifty patients who received multiple blood transfusions while undergoing open-heart surgery at Barnes Hospital were followed every 2 weeks with selected liver function tests, i.e., total serum bilirubin, serum glutamic oxaloacetic transaminase (SGOT), and serum glutamic pyruvic transaminase (SGPT), during the 6 months following surgery. All were carefully evaluated clinically prior to surgery and had normal liver function tests. They were observed closely t h othe u gpostoperative h period, the majority belllg seen on a regular basis by 1 or all of the authors. There were 19 males (average age, 38.0 years) and 31 females (average age, 41.8 years). Only 2 patients had a history of previous transfusions, but each had received the blood more than 6 months prior to the present study. No patient gave a history of jaundice or exposure to hepatitis or hepatotoxins. At the time of surgery anesthesia was induced with sodium thiopental and was maintained with N20 and halothane. Some patients were supported on bypass by means of a Cooley pump which required priming with lactated Ringer's solution, but most patients were maintained with a Mayo-Gibbon pump TABLE 1. Surgical procedures performed Surgical procedure No. of cases Starr-Edwards prosthesis, aortic.. 9 Starr-Edwards prosthesis, mitral. 11 Starr-Edwards prosthesis, tricuspid... 2 Starr-Edwards prosthesis, aortic and mitral. 2 Tetralogy of Fallot, corrected. 2 Atrial septal defect, secundum Open-mitral commissurotomy Aortic valvulotomy Alvarez prosthesis, tricuspid. Total TABLE 2. Relationship between the units of blood transfused and the incidence of hepatitis No. of patients Blood transfused Incidence of hepatitis U % } } over 25 } 20.0 Total primed with 7 U of heparinized whole blood. (One unit of blood represents approximately 480 ml, the amount from 1 donor.) Additional units of whole blood were administered during the procedure and in the first 2 to 3 days following surgery. The American Red Cross in St. Louis provided all blood for surgery from volunteer donors, nearly all of whom were in the upper half of socioeconomic groupings. Blood for postoperative administration was supplied by the Barnes Hospital Blood Bank from volunteers and in rare instances from professional donors, all of whom had been screened carefully. The operative procedures are tabulated in table 1. Nine operations took place in the. last half of 1965, 29 during 1966, and 12 durlllg The diagnosis of anicteric hepatitis was considered established if, from 2 weeks to 6 months after surgery, both the SGOT and SGPT levels were greater than 80 U (normal values: SGOT, 15 to 45 Bodansky units; SGPT, 5 to 35 Bodan sky units), the total bilirubin did not exceed 2.0 mg per 100 ml, and congestive hepa o e gwas a l y absent. Icteric hepatitis was IlldICated by the presence of jaundice with the total bilirubin level above 2 mg per 100 ml and transaminase levels above 80 U in the absence of congestive hepatomegaly. The tests were performed by many different laboratories, but there seemed to be consistency in reporting and the rare striking variations were rechecked. Liver biopsies were not obtained; y-globulin, pooled plasma, and fibrinogen were not administered. Results There was 1 case of icteric hepatitis and 4 a s of e s anicteric hepatitis during the period of study, incidences of 2 and 8%,

3 February 1970 ANICTERIC AND ICTERIC HEPATITIS respectively. The study was conducted between July 1965 and December Cases of hepatitis appeared only during the 9 months between July 1965 and March Forty-four of the 50 patients were followed for 6 months or longer, 3 for 5 months, 1 for 4 months, and 2 for 3 months. These 50 patients received an average of 12.9 U of whole blood during and immediately after surgery (table 2). A graphic representation of the SGOT levels of the 5 patients who developed hepatitis between 2 weeks and 6 months following surgery is shown in figure 1. In 2 patients the enzyme abnormalities occurred as a single, unsustained elevation. Hampers et al. observed similar brief enzyme rises in hepatitis. 9 Total bilirubin concentration remained less than 1 mg per 100 ml in all 4 anicteric cases. One patient, J. A., had anicteric hepatitis lasting 2 years but never experienced fatigue or anorexia, although he continued his studies at college. Classically, the incubation period of infectious hepatitis is 2 to 6 weeks and that of serum hepatitis is 4 to 23 weeks based on the appearance of jaundice. 1O Because the incubation periods in our patients varied from 5 to 9 weeks (table 3), as determined by enzyme abnormalities rather than by the appearance of jaundice, and since serum transaminase levels become elevated in icteric hepatitis several days before jaundice appears, it seems likely ""'. 500t CJ I<) \ I \.' --' Icteric Patient FIG. 1. Postoperative transaminase levels in the 5 patients contracting hepatitis. 205 TABLE 3. Cases of icteric and anicteric hepatitis Sexa Age Procedure ---- a F, female; M, male. b Only icteric case. c Patient J. A., see text. lncu- bation period Blood trans- fused -- U Fb 53 Open-mitral commissurotomy M 18 Starr-Edwards, aortic Me 21 Starr-Edwards, mitral F 39 Open-mitral commissurotomy F 46 Repair of atrial sepdefect weeks that all of our patients had serum hepatitis. Comment This is the only report of which we are aware that is a prospective study of icteric and anicteric hepaptitis following multiple transfusions of whole blood from volunteer donors without the concomitant administration of y-globulin, fibrinogen, or pooled plasma. The incidence of post-transfusion hepatitis associated with jaundice after multiple transfusions in our earlier retrospective study of 100 cases of open-heart surgery was 3%; in the present prospective study of 50 cases transfused with an average of 12.9 U it was 2%. Other studies to determine the risk of icteric hepatitis among patients transfused with 10 U or more of whole blood are retrospective. They report an incidence of between 5 and 12%1, 11, 12 with a primarily commercial source of blood. On the other hand, Adashek and Adashek3 reported that, when blood of volunteers was used, only 1.9% of their 644 patients receiving an average of 18 U of whole blood developed icteric hepatitis as determined by a retrospective questionnaire. Thus, it would appear that donor source may be of great importance in determining the incidence of icteric hepatitis. The incidence of anicteric hepatitis

4 206 PROSKEY ET AL. Vol. 58, No.2 following multiple transfusions in our prospective study was 8%. In similar prospective studies the incidence of anicteric posttransfusion hepatitis was 189 and 50%.14 The former was a study in which the donors were volunteers. It is possible that our lower incidence of anicteric hepatitis is due to more careful donor selection and more rigid diagnostic criteria for anicteric hepatitis. We recorded an increased incidence of post-transfusion hepatitis as the number of units transfused into a given patient increased (table 2). Although the number of cases developing hepatitis in our series is too small to have statistical significance, other investigators with larger numbers of patients have noted an increase in the incidence of post-transfusion icteric hepatitisll, 12 and anicteric hepatitis9, 14 as the number of units transfused over a short interval increased. In these reports also, a satisfactory statistical evaluation was not possible because of the limited number of cases. Significantly, the report of Allen and Saymanll indicated that the incidence of post-transfusion hepatitis increased until 5 to 8 U of blood had been administered, but was unaltered with larger quantities of transfused blood. The report of Shimizu and Kitamoto14 included enough cases so that it appeared clear that the incidence of post-transfusion anicteric hepatitis increased linearly as the volume of blood was increased up to 5 U (1 U = 500 cc). The risk of hepatitis was not increased further with additional transfused units. Holland et al,12 reported on a large series of patients undergoing open-heart surgery who were transfused with 12 U or more of blood (the average patient was given 25 U, 79% of which was commercial). The patients also were given intramuscularly 10 ml of a 16% solution of y-globulin containing predominantly IgG immediately before surgery and again after 1 month. These authors found an increase in incidence of posttransfusion hepatitis with jaundice as the units transfused were increased from 12 up to 30 or more, and they concluded, unlike Mirick et al.,5 that large doses of y-globulin given as described did not prevent post-transfusion hepatitis. Thus, these reports give no clear picture of whether there is a protective effect of large amounts of blood or of the efficacy of y-globulin. The possibility exists that the difference in the reported results is due to the effect of y-globulin present in the transfused blood on the hepatitis virus on the one hand and on the immune systems of the body on the other. We know of no clinical study specifically designed to evaluate the immune response when y-globulin prophylaxis is employed or when massive blood transfusion with its large pool of y-globulin is administered. Assuming that 3.5 g of y-globulin are contained in each unit of whole blood, then each patient in our study received approximately 40 to 50 g of y-globulin. This amount is far in excess of what usually is given prophylactically. Qualitatively it should offer the same degree of protection as hyperimmune globulin since it represents a large pool. This problem needs further clarification, especially in view of the fact that an unknown percentage of the administered y-globulin is lost in the heart-lung machine and by blood loss. Two valuable methods of reducing the incidence of post-transfusion hepatitis appear to be the use of blood from volunteer donors, preferably from the geographic area of the recipient, and the decrease in the volume of blood transfused. These steps deserve serious consideration since the availability of y-globulin is limited and its efficacy in prophylaxis against serum hepatitis remains unsettled. In our study, anicteric hepatitis again has been demonstrated to occur more commonly than icteric hepatitis and it remains as a possible cause of postnecrotic cirrhosis of unknown etiology, as postulated by Klatskin.8 Our findings do not indicate that, when multiple transfusions are given, icteric hepatitis is modified to anicteric hepatitis. REFERENCES 1. Rubinson, R. M., P. Holland, P. J. Schmidt, and A. G. Morrow Serum hepatitis after open-heart operations. J. Thorac. Cardiovasc. Surg. 50:

5 February 1970 ANICTERIC AND ICTERIC HEPATITIS Stokes, J., Jr., and J. R. Neefe Prevention and attenuation of infectious hepatitis by gamma globulin: preliminary note. J. A. M. A. 127: Krugman, S The clinical use of gamma globulin. New Eng. J. Med. 269: Grossman, E. B., S. G. Stewart, and J. S. Stokes, Jr Post-transfusion hepatitis in battle casualties: and a study of its prophylaxis by means of human immune serum globulin. J. A. M. A. 129: Mirick, G. S., R. Ward, and R. W. Mc Collum Modification of post-transfusion hepatitis by gamma globulin. New Eng. J. M ed. 273: Spellberg, M. A Post-transfusion hepatitis and its possible prophylaxis with gamma globulin (editorial). Amer. J. Gastroent. 46: Senior, J. R Post-transfusion hepatitis (editorial). Gastroenterology 49: Klatskin, G Subacute hepatic necrosis and postnecrotic cirrhosis due to anicteric infections with the hepatitis virus. Amer. J. Med. 25: Hampers, C. L., D. Prager, and J. R. Senior. Post-transfusion anicteric hepatitis. New Eng. J. Med. 271 : Shank, R. E Viral hepatitis. D. M. September. 11. Allen, J. G., and W. A. Sayman Serum hepatitis from transfusions of blood: epidemiologic study. J. A. M. A. 180: Holland, P. V., R. M. Rubinson, A. G. Morrow, and P. J. Schmidt Gamma globulin in the prophylaxis of post-transfusion h e p a t J. i A. t im. s A. 196: Adashek, E. P., and W. H. Adashek Blood transfusion hepatitis in open-heart surgery. Arch. Surg. 87: Shimizu, Y., and O. Kitamoto The incidence of viral hepatitis after blood transfusions. Gastroenterology 44: