Febrile responses associated with cardiac surgery

Febrile responses associated with cardiac surgery Relationships to the postpericardiotomy syndrome and to altered host immunologic reactivity The etiology of postoperative fevers has been studied in 97 patients after cardiac surgical procedures..Of this group 26 had unexplained fevers higher than I Ol" F. after the first postoperative week, including fevers continuing beyond the first week, and recurrences of fever after an afebrile period. Only 6 (6.2 per cent) of all patients had a postpericardiotomy syndrome as we defined the condition in this study. Other criteria usually applied for the diagnosis of this syndrome appeared to be too unspecific to be of value in this patient population. Patients with a persistent or prolonged febrile course had an increased incidence of atypical lymphocytes in their peripheral blood. This group also received more units of transfused blood during operation. There was no correlation, however, between such cellular activation and the appearance of lymphocytotoxic antibodies. This result suggests that the appearance of atypical lymphocytes reflects a cellular rather than a serologic immune response to massive blood transfusions. Three patients with postpericardiotomy syndromes who had undergone aorto-coronary bypass procedures had a bypass patency rate of 50 per cent, as compared to a patency rate of 78.9 per cent in 8 patients who did not develop this complication.

Daniel F. Roses, M.D., Malcolm R. Rose, M.D., and Felix T. Rapaport, M.D., * New York, N. Y.

Febrile reaction, prolonged or recurrent, after many different types of cardiac surgical procedures are well documented.t-' In association with other signs and symptoms, such reactions have led to the naming of a variety of different syndromes, including the postpericardiotomy syndrome.' The pathogenetic mechanisms suggested for this postoperative febrile phenomenon include reexacerbation of rheumatic fever," inflammatory responses to blood in the pericardial cavity," autoimmune responses to traumatized cardiac tissue,'- 8 and reaction of the From the Department of Surgery, New York University Medical Center, New York, N. Y. 10016. Supported by a Grant from The John A. Hartford Foundation, Inc., the BiIly Rose Foundation, and the Irwin Strasburger Memorial Medical Foundation, Inc. Received for publication July 23, 1973. °Irma T. Hirschi Career Scientist Award.

patient to leukocytes in transfused blood. n The use of massive blood transfusions in cardiac surgical patients, as well as the observation of lymphocytic and febrile responses to leukocytes present in transfused blood," suggests that such reactions may play a role in the febrile course of these patients. The purpose of the present study of 100 patients is twofold: (I) to ascertain the frequency and nature of febrile reactions after cardiac surgery and (2) to determine a possible correlation between such reactions and evidence of host immunization to components of transfused blood. The postpericardiotomy syndrome has been reevaluated on the basis of the clinical and immunologic data collected, with particular regard to its possible significance in patients with aorto-coronary bypass procedures.

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Table I. HL-A phenotypes of lymphocyte donor panel Phenotype Donor

First locus

M.V.

1, 2 1, 3 1, 10 1, 5 2, 10 2, 10 2, x 2, 9 2, 3 2, 11 2, 9 2, W28 2, 12 2, x 2, 3 2, 3 3, 5 3, WI0 3, W19" 3, 12 9, W19' 2, 9 9, W19" 9, W19" 9, W28 WI9", W28 2, W19"

D.M.

J. N. A.M. I. G. B. P. I. A. J.A. A. R. L. S. P. K. S.B. R.E. E. K. P.D. L. M. T.M. B. E. D.M.

A.H. P.M. A. R. M.S. A. B. B. B. M.H. B.G. G.F. J.G. P.O.

Second locus 13, x

7, x 8, WID

W17, x 5, x WlO 12, x 7, W27 7, x 13, x W27, x 8.46 WlO,7c WlO, W15 7, 12 W27, x 12, x W17, x 7c, x W16, x W15, x W15, W18 W17, x 13, x W14, W17 W15, W17

x, x

WID, x x, x

9, W19" 2, 9

W21, W22 W5, x

Methods One hundred consecutive men and women operated upon on the New York University Surgical Service were studied. Three patients died during hospitalization. Of the remaining 97 patients, 44 had aorto-coronary bypass procedures, 38 underwent prosthetic valve replacement or mitral valve commissurotomy, 6 had both aorto-coronary bypass and prosthetic valve replacement, and 9 had miscellaneous procedures. All but 1 patient were placed on cardiac bypass. The pericardium was left open in patients undergoing coronary bypass procedures. After discharge from the hospital, the patients were seen from one to three times monthly. Forty-four patients were studied for at least

3 months, and some patients were studied for as long as 7 months after discharge. Laboratory data obtained during hospitalization included complete blood counts, taken at regular 3 day intervals, serial chest x-ray films, electrocardiograms, and cultures of the blood, urine, sputum, pleural effusions, and of other sites, as indicated by the patient's clinical course. Lymphocytotoxicity reactions. Serum samples were obtained from all patients preoperatively and at 1 and 3 weeks postoperatively, in a search for the presence of lymphocytotoxic antibodies. The sera were tested against a standard reference panel of lymphocytes obtained from 30 normal donors of different HL-A phenotypes covering the currently known HL-A antigen specificities. The technique for serologic testing and criteria for the detection of lymphocytotoxic antibodies have been described in detail elsewhere." The HL-A phenotypes represented in the panel are listed in Table 1. Atypical lymphocytes. Blood samples obtained for complete blood counts were evaluated for the presence of atypical lymphocytes. The presence of more than 10 per cent atypical lymphocytes in the total lymphocyte count was considered to be of significance. Postoperative cardiac catheterization. Eleven of 50 patients who had aorto-coronary bypass procedures underwent catheterization within 5 to 7 months after operation. Catheterizations were performed routinely as part of the postoperative evaluation of these patients.

Results The 97 patients in this report were divided into three groups according to their febrile course: ( 1) subjects who were afebrile after the first postoperative week; (2) patients with prolonged or recurrent fevers greater than 101 F. after the first week, in whom an etiologic factor was identified; and (3) patients with prolonged or recurrent fevers greater than 101 F. after the first postoperative week, in whom no 0

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Febrile responses in cardiac surgery

25 3

Table II. Patterns of febrile responses in 97 postoperative cardiac surgical patients Group I No. of patients No. of patients with leukocytosis after seventh postop. day Mean highest leukocyte count in patients with leukocytosis after seventh postop. day No. of patients with lyrnphocytosis after seventh postop. day No. of patients with atypical lymphocytes after seventh postop. day Mean No. of units transfused whole or packed cells ABO group of patients

Group II

I

Group III

61

10

26

32 (52.5%)

10 (100%)

21 (80.8%)

14,680 ± 2,850

17,410 ± 6,650

14,062 ± 2,570

6 (9.8%)

3 (30%)

2 (7.7%)

15 (24.6%)

5 (50%)

11 (42.3%)

14.3 ± 7.4 24 A (39.3%); 8 B (13.1%); 1 AB (1.6%); 28 0 (46% )

No. of patients with Iymphocytotoxic antibodies 11 (18%) No. of patients with pericardial rubs 25 (41% ) No. of patients treated with steroids 9 (14.8% )

17.3 ± 10.8 3 A (30%); 1 B (10%); 0 AB; 60(60%)

1 (10%) 4 (40% ) (10%)

18.4 ± 13.0 10 A (38.4%); 5 B (19.3%); 1 AB (3.8%); 10 0 (38.5% ) 5 (19.2%) 14 (54% ) 10 (38.5% )

Legend: Group I, Patients afebrile after the seventh postoperative day. Group II, Patients febrile to 101 0 F. after the seventh postoperative day in whom an etiology was determined. Group III, Patients with prolonged or recurrent fever of 101 0 F. after the seventh postoperative day in whom no etiology was determined.

specific etiology could be defined (Table II). Etiologies determined in patients of the second group included sternal wound infections (4 patients), urinary tract infections (2), wound infection of the saphenous vein graft site (l), pneumonia (l), acute cholecystitis ( 1), and cholangitis (1 patient). The three groups were compared by the following criteria: leukocytosis, lymphocytosis, presence of atypical lymphocytes, presence of lymphocytotoxic serum antibodies, number of transfusions received, presence or absence of pericardial friction rubs on ausculation, and frequency of administration of corticosteroids. Group I included 61 patients, Group II included 10, and Group III included 26 patients. Atypical lymphocytes occurred in 11 (42.3 per cent) patients of Group III, as compared to 15 (24.6 per cent) in Group I (p < .01). The mean number of units of blood transfusions was also highest in Group

III, as compared to Group I (p < 0.05). There was no significant difference in ABO blood groups or in the incidence of cytotoxic antibodies in the three groups. Group II patients had the highest incidence of leukocytosis. There was no significant difference in the incidence of pericardial friction rubs in any group, although the types of cardiac procedures performed in each group were comparable (Table III). Transient pericardial rubs were noted in 43 patients (44.3 per cent) within the first postoperative week. Similarly, increased erythrocyte sedimentation rate, leukocytosis, and S-T and T wave changes on postoperative electrocardiograms were common and appeared to be nonspecific in nature. Midsternal chest pain occurred in all patients secondary to the surgical incision, and its similarity to pericardial pain precluded use of this symptom for the evaluation of the postpericardiotomy syn-

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Surgery

Table III. Types of procedures performed in each group No. of patients Coronary bypass procedures Prosthetic valve replacement or mitral commissurotomy Coronary bypass and prosthetic valve replacement Miscellaneous procedures

Group I

Group II

Group III

61 28 (45.9%)

10 4 (40%)

26 12 (46.2% )

26 (42.6%) 1 (1.6%) 6 (9.8%)

2 (20%) 1 (10%) 3 (30%)

10 (38.5%) 4 (15%) 0

Table IV. Clinical data on patients with postopericardiotomy syndrome

Patient

L.B A. P. M.K. B. F.

R. R. S. D.

Atypical Leukocyto- Lymphocytosis after lymphocytes sis after seventh seventh seventh postop. day postop. day postop. day +

+

+ + + +

+ +

drome, even months after surgery. The inaccuracy of evaluating heart size, especially on the portable chest x-ray films, (which are most frequently employed in the early postoperative period) also detracted from the value of this criterion for the assessment of pericardial reactions. Pleural reactions and effusions occurred in more than half of the patients studied. Because the criteria usually applied to the diagnosis of postpericardiotomy syndromes occurred frequently in our patient population, we have limited the term "postpericardiotomy syndrome" in this study. It will refer only to patients with unexplained fevers greater than 101 F., persisting beyond the first postoperative week or recurring after the first postoperative week following an afebrile period, in association with a pericardial friction rub which remained audible after the first postoperative week. After discharge from the hospital, recurrent unexplained fever or a pericardial rub was also accepted as evidence of a postpericardiotomy syndrome. Six patients (6.2 per cent) in the entire group of 97 subjects were therefore considered to have developed a postpericardiotomy syndrome. Their clinical courses are given in Table IV.

Units and group of blood transfused

18 B+ 40+ 5 A+ 16 0+ 12 A+ 10 B-

Cytotoxic antibodies

+ +

Rubs

Steroids

+

+

+ + + +

+ + + +

Eleven patients were recatheterized after coronary bypass procedures. Three of these patients developed a postpericardiotomy syndrome. Comparison of graft patency in these 3 patients with 8 patients who did not develop the syndrome indicates that four of eight grafts (50 per cent) in these 3 patients were patent. In contrast fifteen of nineteen grafts (78.9 per cent) in the remaining 8 patients remained patent (Table V). The 3 patients in whom the criteria for diagnosis of postpericardiotomy syndrome were fulfilled were treated with steroids; only 2 of the 8 patients in the remaining group received steroid therapy.

0

Discussion

Delayed fever and pleuropericardial reactions following mitral commissurotomy were first described in 1952. 12 Since that time, similar syndromes have been described after a variety of cardiac surgical procedures or trauma, i.e., cases in which the pericardium has been incised. Its occurrence after even minor intrusions into the pericardium has led to the term "postpericardiotomy syndrome" to depict the syndrome of signs and symptoms which may be associated with such patients' febrile courses. The syndrome

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has been loosely defined as fever occurring in the second or third postoperative weeks, either continuous, with early postoperative fevers, or recurrent after an afebrile period. It includes manifestations such as sharp substernal or pericardial chest pains exacerbated by respiration; pericardial rubs (in 50 per cent of the cases), evidence of pleural involvement, and a variety of nonspecific findings, such as arthralgia, leukocytosis, elevated erythrocyte sedimentation rate, cardiac enlargement, and electrocardiographic evidence of pericarditis. The incidence of the syndrome has varied from 20 to 30 per cent in previous reports.' The more limited criteria for diagnosis of the postpericardiotomy syndrome used in this study may explain the lower incidence of 6.2 per cent in the present patient population. However, by eliminating the more common postoperative signs and symptoms, it is possible to identify a number of patients with unequivocal evidence of unexplained fever and pericardial reaction. Although the incidence of the postpericardiotomy syndrome was lower in this patient population than in other reports, a high frequency of unexplained febrile courses, either prolonged or recurrent in nature, occurred in 26 (26.9 per cent) patients. A number of different explanations might be offered for this finding. Febrile reactions caused by sensitivity to donor leukocytes and platelets have been documented by Brittingham and Chaplin," among others, in association with the appearance of leukoagglutinins after blood transfusion. More recent studies by Walford and colleagues':' have demonstrated leukocyte antibodies after even one single massive transfusion of living leukocytes at the time of cardiac surgery. An attempt was therefore made to seek the presence of leukocyte antibodies in this patient population and to correlate the existence of such antibodies with the patient's febrile course. Most patients received transfusions of stored and fresh blood during the operation. The sera of 17 of the patients (17.5 per cent) contained cytotoxic antibodies against a panel of lymphocyte donors

Febrile responses in cardiac surgery

255

Table V. Patency rate of coronary bypass grafts 5 to 7 months after surgery

Patient

No. of grafts

No. of grafts patent at recatheterization

Patients considered to have postpericardiotomy syndrome B.p. 2 veins, 1 artery 1 vein, 1 artery M.K. 2 veins, 1 artery 1 artery R. R. 1 vein 2 veins Totals 4 grafts 8 grafts Patency rate 50% Patients not considered to have postpericardiotomy syndrome N. H. 2 veins, 1 artery 2 veins, 1 artery H. G. 1 vein, 1 artery 1 artery W. M. 2 arteries 1 artery W. Z. 3 veins 3 veins P. H. 2 arteries 2 arteries P. G. 3 veins 3 veins* J. M. 1 vein 1 vein G. M. 2 veins, 1 artery 1 vein Totals 15 grafts 19 grafts Patency rate 78.9% 'One graft was partially occluded although still patent.

of known HL-A phenotypes. However, there was no significant correlation between the presence of such antibodies and the occurrence of prolonged or recurrent fevers. Febrile reactions did occur in some patients with anti-HL-A antibodies. Schechter and associates" have demonstrated a fivefold or greater rise in the number of circulating atypical lymphocytes within I week after transfusion of fresh or stored blood. Six of 12 patients studied in their series also developed serum antibodies against lymphocytes. In contrast, such responses did not occur in patients transfused with leukocyte-poor blood. Previous studies have also shown the postoperative appearance of atypical lymphocytes in 5 to 10 per cent of cardiac surgical patients." The occurrence of such atypical lymphocytosis and fever has been noted after arterial graft procedures" as well as in 5 per cent of patients undergoing lung resection for tuberculosis, 18 after exchange transfusions, and after massive transfusions for upper gastrointestinal

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hemorrhages." Suggestions that the appearance of atypical lymphocytes after transfusion might have been a response to viral infection have been weakened by the observation that the blood donors did not demonstrate atypical lymphocytes and had no evidence of viral infection. It is more probable, in the light of present-day knowledge, that such atypical lymphocytes may constitute an in vivo equivalent of the in vitro mixed leukocyte culture. reaction," in response to the infusion of foreign leukocytes into the recipient. Group I patients, those who were afebrile after the first postoperative week, had the lowest incidence of atypical lymphocytes; these was a significantly higher incidence in the febrile patients of Groups II and III which was not correlated with the appearance of antibodies. Thus this alteration in host lymphocyte reactivity may not have been related to responses to serologically detectable antigenic sites; rather, it may have reflected the development of a cellular type of host reactivity to transfused leukocytes. The relatively low incidence of cytotoxic antibodies (17.5 per cent) in this group also suggests that serologically detectable (HL-A) differences in transfused blood may not be a prominent factor in the etiology of febrile reactions in postoperative cardiac surgical patients. In vitro determinations of host lymphocyte reactivity may, however, be of use in further elucidation of this important question. Although the number of patients available for study does not permit a definite conclusion at this time, the somewhat higher rate of graft closure noted in patients with the postpericardiotomy syndrome raises the possibility that prolonged postoperative pericarditis can constitute a hazard in this patient population. This interpretation raises the possibility that the postpericardiotomy syndrome might not be as benign and selflimiting an event as one might suspect in patients who have had aorto-coronary grafting. This is particularly true if stringent criteria for diagnosis of this syndrome are employed. Rather, appearance of the syn-

drome as defined in this report may play a role in conditioning the long-term results of aorto-coronary bypass procedures. We wish to express our gratitude to Drs. Frank C. Spencer, Ephriam Glassman, and Arthur D. Boyd for their invaluable help and advice. Our thanks also go to Mrs. Audrey Raisbeck and Mrs. Bjorg Egelandsdal for their superb technical assistance. REFERENCES

2

3 4 5

6 7 8 9

10 11

12

13

14

Engle, M. A., and Ito, T.: The Postpericardiotomy Syndrome, Am. J. Cardiol. 7: 73, 1961. Wheeler, E. 0., Turner, J. D., and Scannell, J. G.: Fever, Splenomegaly, and Atypical Lymphocytes: A Syndrome Observed After Cardiac Surgery Utilizing a Pump Oxygenator, N. Engl. J. Med. 266: 454, 1962. Anderson, R., and Larsson, 0.: Fever, Splenomegaly and Atypical Lymphocytes After Open Heart Surgery, Lancet 2: 947, 1963. Kirsh, M. M., McIntosh, K., Kahn, D. R., and Sloan, H.: Postpericardiotomy Syndromes, Ann. Thorac. Surg. 9: 158, 1970. Soloff, L. A., Zatuchni, J., Janton, O. H., O'Neill, T. J. E., and Glover, R. P.: Reactivation of Rheumatic Fever Following Mitral Commissurotomy, Circulation 8: 481, 1953. Ehrenhaft, J. L., and Taber, R. E.: Hemopericardium and Constrictive Pericarditis, J. THORAc. SURG. 24: 355, 1952. Robinson, J., and Brigden, W.: Immunological Studies in the Postcardiotomy Syndrome, Br. Med. J. 2: 706, 1963. Van der Geld, H.: Anti-heart antibodies in the Postpericardiotomy and the PostmyocardialInfarction Syndromes, Lancet 2: 617, 1964. Perillie, P. E., and Glenn, W. L.: Fever, Splenomegaly, Lymphocytosis and Eosinophilia: A New Post-cardiotomy Syndrome, Yale J. BioI. Med. 34: 625, 1962. Brittingham, T. E.: Immunologic Studies on Leukocytes, Vox Sang. 2: 242, 1957. Dausset, J., Colombani, J., Legrand, L., Feingold, N., and Rapaport, F. T.: Genetic and Biological Aspects of the HL-A System of Human Histocompatibility, Blood 35: 591, 1970. Janton, O. H., Glover, R. P., O'Neill, T. J. E., Gregory, J. E., and Froio, G. F.: Results of the Surgical Treatment of Mitral Stenosis, Circulation 6: 321, 1952. Brittingham, T. E., and Chaplin, H., JT.: Febrile Transfusion Reactions Caused by Sensitivity to Donor Leukocytes and Platelets, J. A. M. A. 165: 819, 1957. Walford, R. L., Anderson, R. E., and Doyle, P.: Leukocyte Antibodies Following Single

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Massive Transfusion of Living Leukocytes at Cardiac Surgery, Vox Sang. 6: 80, 1961. 15 Schechter, G. P., Soehnlen, F., and McFarland, W.: Lymphocyte Response to Blood Transfusion in Man, N. Eng!. J. Merl. 287: 1169, 1972. 16 Seaman, A. J., and Starr, A.: Febrile Postcardiotomy Lymphocytic Splenomegaly: A New Entity, Ann. Surg. 156: 956, 1962. 17 Gothman, B., and Ohlsson, W. T. L.: Fever With Hematologic Changes Resembling In-

fectious Mononucleosis as a Sequel to Blood Vessel Grafting, Angiology 10: 355, 1959. 18 Bergstrom, I., and Dahlstrom, G.: Fever With a Blood Picture Resembling Infectious Mononucleosis in Operated Tuberculous Cases, Acta Tuberc. Scand. 34: 132, 1957. 19 Tanaka, K. R.: Infectious Mononucleosis Syndromes, Br. Med. J. 2: 122, 1964. 20 Bach, F. H.: The Major Histocompatibility Complex in Transplantation Immunology, Transplant. Proc. 5: 23, 1973.