Diagnosis and management of complications of prosthetic heart valves

Diagnosis and Management Prosthetic

of

Heart Valves

FRANK E. KLOSTER, MD Portland,

of Complications

Oregon

Complications after heart valve replacement remain a substantial source of morbidity and mortality despite continuing advances in surgical care and prosthetic design. Infectious endocarditis occurs in about 4 percent of patients and may appear early (within 60 days) or late after operation. Endocarditis of early onset is commonly due to staphylococcal, fungal or gram-negative organisms and is fatal in 70 percent or more of cases. Infection of late onset is more often of streptococcal origin and the mortality rate is lower, about 35 percent. With either type, prompt recognition, vigorous and appropriate antimicrobial therapy and early consideration of surgical intervention are crucial. The postperfusion and postpericardiotomy syndromes are relatively common and relatively benign syndromes associated with postoperative fever. Their recognition is important to prevent confusion with endocarditis or sepsis and thus to reassure the patient and physician. Treatment is primarily symptomatic. Intravascular hemolysis occurs with most prosthetic heart valves but is more common with certain prostheses and with paraprosthetic valve regurgitation, with significant hemolytic anemia in 5 to 15 percent. Oral iron replacement therapy is effective in the majority of patients, but occasionally blood transfusion or reoperation for leak around the prosthesis is necessary. Prosthesis dysfunction due to thrombus may be recognized clinically by recurrence of heart failure, syncope, cardiomegaly and altered prosthetic valve sounds or new murmurs. Hemodynamic studies verify the diagnosis, and prompt reoperation is indicated for this potentially lethal problem. Systemic embolization has decreased markedly with the introduction of cloth-covered prostheses and is frequently related to erratic or ineffective anticoagulant therapy. We continue to recommend anticoagulant therapy for all patients with prosthetic heart valves unless there is a major contraindication.

From the Department of Medicine, Division of Cardiology, University of Oregon Medical School, Portland, Ore. This study was supported in part by Program Project Grant HL 06336 from the U. S. Public Health Service. Address for reprints: Frank E. Kloster, MD, Division of Cardiology, University of Oregon Medical School, 3181 S. W. Sam Jackson Park Rd., Portland, Ore. 97201.

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Despite continuing advances in surgical techniques and postoperative care and improvements in prosthetic heart valve design, complications after valve replacement remain a substantial source of morbidity and mortality. Certain problems, such as the postpericardiotomy and postperfusion syndromes, are usually self-limited. Their recognition is of importance primarily to prevent confusion with more serious causes of fever and to reassure the patient and physician. Others, including infectious endocarditis, hemolytic anemia, systemic arterial embolization and obstruction of the prosthesis due to thrombus, are potentially life-threatening problems and must be detected promptly and treated vigorously. This paper reviews the common complications of prosthetic heart valves, including incidence rates, diagnostic features and recommended therapy. Infectious

Infectious

The American Journal of CARDIOLOGY

endocarditis

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Endocarditis

involving prosthetic

heart valves continues

COMPLlCATlONS

to be a relatively common life-threatening complication. The presence of the prosthesis both increases the vulnerability of the patient to endocarditis and makes eradication of the infection difficult. Early experience suggested that infectious prosthetic endocarditis was nearly always fatal.*-4 Recent reports have demonstrated that with appropriate antimicrobial therapy and, when indicated, prompt surgical intervention, survival and apparent cure are possible in a substantial number of patients.5-8

TABLE

PROSTHESES-KLOSTER

I

Findings in Infectious

Prosthetic

Valve Endocarditis Study

Amoury et aI (13 patients) Fever Changing murmur Splenomegaly Systemic embolus Petechiae Clubbing Anemia Leukocytosis Hematuria

Incidence

The reported incidence rate of infectious endocarditis in patients with valve prostheses has ranged from less than 1 to more than 10 percent.5-7,g-16 This wide variation probably reflects in part the duration of observation and availability of patients for followup and the greater incidence of operative contamination in the early years of valve replacement. Recent studies report an overall incidence rate of less than 4 percent divided between early cases (onset of symptoms within 60 days after operation) and late cases (onset after 60 days).5-7J-16 While the exact time periods are somewhat arbitrary, there are characteristic features in endocarditis occurring soon after valve replacement compared with cases of late onset that are helpful in understanding the pathogenesis, in planning therapy and in anticipating the response to treatment.5-7 Early endocarditis: Prosthetic valve endocarditis occurring early after operation is usually due to contamination during the surgical procedure or to obvious infections in noncardiac areas during the immediate postoperative period.2*6,7J1J6 The infecting organisms are Staphylococcus epidermidis or aureus in about half of the cases and fungal or gram-negative bacillary organisms in the others. The same organisms that are identified as causing endocarditis have commonly been cultured from operating room equipment, particularly the pump oxygenator, or from infected intravenous catheters, wound infections and urinary catheters.gJ6 The response to therapy has been poor, and the mortality rate of 87 percent reported from our institution5 and that of 68 percent observed by Dismukes et a1.6 are representative. The dismal outcome may be related to the invasive and resistant organisms involved, direct incorporation of infection into the suture line of the prosthesis and the patient’s decreased resistance to infection in the postoperative period.14 The few survivors have been those with staphylococcus endocarditis; infections with gram-negative organisms and fungi have usually been fatal. Late endocarditis: In contrast, prosthetic valve endocarditis developing late after operation is more similar to classic subacute bacterial endocarditis. A precipitating event unrelated to the original operation can often be identified, including dental procedures, pyogenic skin infections and genitourinary manipulations. The causative organisms are more like those seen in infections of natural valves, with

OF VALVE

Dismu kes et al.6 (38 patients)

100% 85% 61% 31% 15% 8% 54% 31% *

Stein et al.‘4 (17 patients)

100% 65% 61% * 63% 0% 100% 87% 75%

94% 24% 0% 41% 5% * 0% 73% 24%

* Data incomplete.

streptococcus species most common, Staphylococcus epidermidis and aureus less frequent and gram-negative bacillary or fungal organisms infrequent.5-7J1J6 The response to treatment is considerably better than in infection of early onset; mortality rates were 36 percent in the patients described by Slaughter et a1.5 and 42 percent in the series of Dismukes et a1.6 This reduced mortality probably reflects less virulent and more sensitive infecting organisms, greater resistance to infection by the patient and decreased accessibility of the suture line to invasion by the organisms. Diagnosis

Clinical features: The clinical presentation of prosthetic valve endocarditis is also related to the time of onset after operation. Fever is the hallmark of the disease and is present in virtually all patients (Table I).2,6,7J4J7 When endocarditis develops early after operation, fever is persistent throughout the postoperative period and is commonly associated with infections elsewhere in the body, such as a wound infection or pneumonia. Disruption of the suture line around the prosthesis occurs frequently, with development of a regurgitant murmur and severe heart failure; clinical deterioration is often rapid.r6 Infection developing late after insertion of the prosthesis presents as a recurrent or persistent fever, and the clinical course may be insidious and prolonged or acute and rapidly progressive. Patients commonly note fatigue, malaise, lethargy or anorexia, as well as sweating and chills associated with the fever, but sometimes feel quite we11.14 Classic signs of endocarditis such as petechiae, splinter hemorrhages and microscopic hematuria are often absent.2y7,gJ1 The low grade fever and vague systemic symptoms may be mistakenly diagnosed as a “viral infection” or “flu,” and there is commonly a substantial delay between the onset of symptoms and recognition of the infectious endocarditis. During this period, the diag-

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nosis may be further obscured by administration of ineffective doses of antibiotic agents.5*7 The importance of immediately suspecting infectious endocarditis in any patient with a prosthetic valve who has intermittent or persistent fever cannot be overemphasized. A new murmur of valve regurgitation, splenomegaly and systemic embolization are the most common and helpful findings other than fever in clinical recognition of infectious prosthetic endocarditis (Table I). Valve regurgitation is less frequent in endocarditis of late than of early onset and, in general, is less severe. New murmurs of regurgitation usually indicate disruption of the prosthetic suture line but may occur as a result of thrombus on the prosthesis preventing complete opening or closing of the poppet. Impaired poppet seating or extensive disruption of sutures may be demonstrated by fluoroscopy. A helpful radiologic finding, the “double exposure sign,” has been described by Stinson et a1.r8 Abnormal motion of a partially detached valve is shown as a blurred or double image in X-ray film -exposed over a long period of time. Thrombus on the prosthesis may cause stenosis as well as regurgitation, and fatal obstruction has been reported.* It may be apparent clinically as altered prosthetic opening and closing sounds or a diastolic murmur across mitral or tricuspid prostheses. Splenomegaly occurred in about two thirds of the patients described by Amoury et a1.2 and by Dismukes et al6 and has been a relatively common finding in our experience.5 When present in a febrile patient with a valve prosthesis, it is strong evidence of endocarditis. In the early postoperative period splenomegaly and fever are components of the febrile lymphocytic splenomegaly syndrome, which can be differentiated from infectious endocarditis by the presence of abnormal lymphocytes in the peripheral blood.lg Systemic arterial embolization from mycotic or thrombotic material on the prosthesis is relatively common and may be the presenting symptom in infectious prosthetic valve endocarditis.2-14 A systemic embolic episode should always suggest the possible presence of endocarditis particularly in patients with the current cloth-covered prostheses, who rarely experience embolization if they are receiving anticoagulant therapy. Anemia and leukocytosis are frequently present but are difficult to evaluate in the immediate postoperative period because of their common occurrence in the absence of infectious endocarditis. Goodman et a1.20 demonstrated a significantly higher percentage of juvenile neutrophils in patients with infection. In patients with infectious endocarditis of late onset, the presence of anemia or leukocytosis, or both, is helpful ancillary evidence but does not specifically indicate prosthetic involvement.

Blood

cultures-endocarditis

vs. bacteremia:

Multiple blood cultures should be obtained in any patient with a prosthetic valve who has recurrent or persistent fever.5p6 Positive cultures are usually obtained in patients with an infected prosthesis, and

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The American Journal of CARDIOLOGY

the presence of two or more positive blood cultures of the same organism is taken as presumptive evidence of prosthetic valve endocarditis.2,5-7J4 In the series of Amoury and co-workers,2 blood samples were drawn two or three times a day for 3 consecutive days and the organism was generally isolated from the first set of specimens drawn. Five patients required an additional two to seven blood cultures before growth was obtained, and negative cultures were consistently found in patients with endocarditis within the right ventricle. On rare occasions, we have obtained positive cultures by sampling from the pulmonary artery or a systemic artery when venous samples were consistently negative. Infectious endocarditis is unlikely if at least six sterile blood cultures are obtained after incubation in aerobic and anaerobic media for 3 weeks.2 In the usual situation, positive blood cultures are obtained without difficulty, the clinical findings are consistent with infectious endocarditis and treatment can be initiated promptly. Two dilemmas may occur. In the first, positive blood cultures are obtained during the early postoperative period in a patient who has other obvious sources of infection and it must be determined whether septicemia or infectious endocarditis is the cause. To better differentiate the two conditions, Sande et a1.21 studied 24 patients with sustained bacteremia after prosthetic valve implantation, 11 with infectious endocarditis and 13 with bacteremia but without apparent endocarditis. They found that positive blood cultures due to endocarditis developed 25 or more days after operation, involved gram-positive organisms without obvious sources of bacteremia and were accompanied by new or changing heart murmurs. The group without proved valve infection manifested bacteremia with gram-negative bacilli earlier, had obvious potential sources of bacteremia and had no changes in heart murmurs. On the basis of these findings, Sande et al. recommend only short-term antibiotic therapy for patients with gram-negative bacteremia and no valve dysfunction in the early postoperative period. Others5s6p22have pointed out that such criteria are helpful, but in a disease process with the dismal prognosis of infectious endocarditis of early onset a longer and more vigorous course of therapy is to be preferred. A less common dilemma is presented by the patient with a cardiac valve prosthesis who is febrile with clinical findings consistent with infectious endocarditis but in whom positive blood cultures cannot be obtained on repeated attempts. In this case, persistent or recurrent fever and the presence of at least two other criteria for bacterial endocarditis such as a new regurgitant murmur, splenomegaly or peripheral emboli are sufficient for a presumptive diagnosis of prosthetic valve endocarditis and initiation of treatment.5 Treatment Although prosthetic valve endocarditis is not rare, cases appear sporadically and few physicians have

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TABLE II Recommended

Antimicrobial

Therapy

for Prosthetic

Valve Endocarditis Duration

Antibiotic Therapy Organism Streptococcus (susceptible of penicillin

viridans to 0.3 pg/ml G)

Recommended

Alternate

(W

Procaine penicillin G, 1.2 million units every 6 hours intramuscularly or Crystalline penicillin G, 1 million units every 4 hours intravenously

Cephalothin,

Streptococcus viridans or enterococcus (susceptible to >0.3pg/ ml of penicillin G)

Crystalline penicillin daily intravenously

units

Ampicillin,

2 g every 4 hours intravenously plus Gentamycin, 5 mg/kg daily intramuscularly or Vancomycin, 0.5 g every 6 hours intravenously

6

Staphylococcus aureus or epidermidis (susceptible to 0.6 pg/ml of penicillin G)

Crystalline penicillin daily intravenously

G, 20 million

units

Cephalothin, 2 g every 3 to 4 hours intravenously or Vancomycin 1 g every 6 hours intravenously

6*

Staphylococcus aureus or epidermidis (susceptible to >0.6 pg/ml of penicillin G)

Nafcillin or oxacillin, hours intravenously

2-3 g every 3 to 4

None

6*

Gram-negative

Guided by antibiotic susceptibility tests; bactericidal antibiotic agents preferred

None

...

Cephalothin, 2 g every 6 hours intravenously plus Crystalline penicillin G, 20 million units daily intravenously plus Streptomycin, 0.5 g every 12 hours intramuscularly

None

6

Negative

bacilli

blood cultures

* Followed by suppressive therapy Adapted irom Slaughter et aL6

G, 20 million

plus Streptomycin, 0.5 g every 12 hours intramuscularly

with cloxacillin

Vancomycin, intravenously

1 g every 4 hours intravenously or 0.5 g every 6 hours

4

0.25 g every 6 hours orally, for 6 to 12 months.

sufficient experience with the problem to develop standard regimens of therapy. For this reason, the experience during the past 12 years at the University of Oregon Medical School was recently reviewed by Slaughter et a1.,5 and a systematic approach to the therapy of infected prosthetic cardiac valves was proposed. Antibiotic therapy: Antimicrobial agents are selected on the basis of susceptibility of organisms isolated from blood cultures, preferably by the tubedilution technique. Bactericidal drugs that will penetrate vegetations are used whenever possible. Suggested regimens for the common organisms causing prosthetic valve endocarditis are listed in Table II. Intramuscular or intermittent intravenous administration is preferable to attempting continuous intravenous infusion, since the latter may result in erratic dosage due to mechanical problems in maintaining the infusion, drug deterioration during infusion or adsorption to the container. When penicillin is the drug of choice, it should be used even in patients with

a history of penicillin allergy and alternate antibiotic agents should be substituted only if severe hypersensitivity reactions result, since the threat of infectious endocarditis is much greater than the threat from most allergic reactions. The serum bactericidal levels should be determined on the 3rd day after initiation of therapy and intermittently thereafter. Blood specimens are drawn 30 minutes before an antibiotic dose, presumably the low point of blood concentration of the antibiotic agent. The therapeutic aim is for a minimal bactericidal titer of 1.8. Medical therapy is continued for 4 to 6 weeks depending on the clinical findings, the organism involved and laboratory results. Reoperation: Treatment of prosthetic valve endocarditis was successful with antibiotic therapy alone in about 30 percent of the patients in three recent large series516J7 Failure of medical management was indicated by: (1) uncontrolled infection, (2) large or multiple systemic arterial emboli, (3) valve disruption, (4) valve obstruction, or (5) severe or progres-

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sive congestive heart failure, usually resulting from valve disruption or obstruction. In the past, these have been the major causes of death despite vigorous antibiotic therapy. During the last 6 years, there have been increasing reports5,6,8J5-17,2s*24 of surgical intervention when these problems have developed. Results have been encouraging; although mortality rates are still high, these are patients who almost certainly would not survive with continued antibiotic treatment alone. Slaughter et a1.5 reported survival of 5 of 9 patients and Dismukes et a1.,6 survival of 6 of 11 patients who underwent surgery after failure of medical management. 0thers8J5J7~23~24 have had lower survival rates, attributed in part to delay in undertaking reoperation. Failure of medical therapy should be identified promptly and reoperation considered withouh delay, particularly in patients with endocarditis early after operation. Hesitation will commonly lead to progressive cardiac deterioration and increasing morbidity and mortality. antibiotic therapy: Long-term suppressive After successful treatment of prosthetic valve endocarditis, long-term suppressive therapy has been advocated by many and was uniformly recommended at our institution in the past. It was believed necessary because of the continued presence of the prosthetic valve in the heart and uncertainty whether the infection was eradicated or simply suppressed by antibiotic therapy. However, review of our follow-up experience disclosed that patients who were discharged taking orally administered antimicrobial agents commonly were instructed by their private physician to stop treatment. The duration of survival in 12 patients who received no suppressive therapy averaged 44 months compared with 20 months for 7 patients receiving continuous suppressive therapy.5 The effectiveness of long-term suppressive antimicrobial therapy after prosthetic valve endocarditis remains uncertain. We currently recommend limited, extended therapy after staphylococcal infections with cloxacillin, 0.25 g every 6 hours, for 6 to 12 months, because of potential intracellular persistence and abscess formation. Prophylaxis

The importance-of prevention is obvious in a disease as potentially catastrophic and difficult to treat as prosthetic valve endocarditis. Vigorous efforts to avoid contamination of the prosthesis at the time of operation and during subsequent procedures likely to produce bacteremia can result in substantial reductions in the incidence of endocarditis. Perioperative and postoperative: Prophylactic antibiotic coverage during valve replacement and in the early postoperative period is almost universally givenl,‘L5~172023 alth ough there have been no randomized or controlled studies demonstrating a beneficial effect from such therapy. Herr et a1.l reported that after institution of an extensive program of prophylaxis, including administration of methicillin for a minimum of 2 weeks postoperatively, none of 239

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The American Journal of CARDIOLOGY

consecutive patients had staphylococcal endocarditis. Nelson et a1.25 found that a 4.2 percent incidence rate of endocarditis when no prophylactic antibiotic agents were used decreased to 1.2 percent with prophylactic administration of penicillin and streptomycin and was reduced to zero with the addition of methicillin for 1 week postoperatively. Amoury et a1.2 and Stein et a1.14 concluded that there was substantial evidence that prophylactic use of antibiotic agents is effective during the operative and postoperative period. The latter group observed a decrease from 3.7 to 0.2 percent in the incidence rate of fatal bacterial endocarditis. Results of two attempts to provide controlled studies of the benefits of antibiotic prophylaxis have been inconclusive. Goodman et a1.20 initiated a prospective double-blind study comparing the use of placebo, penicillin plus streptomycin, and oxacillin, but terminated the placebo prophylaxis after two patients in that group died from pneumococcal endocarditis. In a recent study by Conte et a1.26 comparing use of a single intraoperative dose of cephalothin and multiple doses through the first 4 postoperative days there was only one episode of endocarditis in 64 patients, thus precluding a decision regarding relative efficacies of the two regimens. Both groups of investigators believed that there was a risk that multiple dose, prolonged antibiotic therapy would predispose patients to other infections caused by resistant organisms. Perioperative antimicrobial prophylaxis is not intended to provide an “umbrella” shield against a wide spectrum of organisms and should be aimed specifically at the organisms causing the majority of early cases of prosthetic endocarditis, Staphylococcus aureus and epidermidis. 2,5~13Selection of drugs for chemoprophylaxis should be determined by the bacterial susceptibility patterns prevalent locally. In our hospitals isolates of Staphylococcus epidermidis currently show a high incidence rate of susceptibility to cephalothin (97 percent), which is our agent of choice.5 Patients receive cephalothin, 1 g intramuscularly the night before and morning of operation, then 1 g intravenously every 6 hours until they are eating, and thereafter cephalexin, 500 mg every 6 hours orally until the skin sutures are removed. Control of potential sources of infection: Efforts to prevent seeding the prosthesis with bacteria during and after operation are as important as antibiotic prophylaxis. Rigid monitoring of operating room technique, including regular cultures from equipment and surgical masks of personnel, helps to identify breaks in sterility or staphylococcal carriers.1T2*6 Nasal and throat culture and preoperative treatment with nasal antibiotic ointment will reduce the risk of staphylococcal infection from the patient’s nasopharynx. Potential sources of infections or bacteremia should be identified and corrected preoperatively, particularly poor dental health and urinary tract or skin infections. Elective operation for valve replacement is postponed in patients with these findings

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TABLE III Recommendations

for Prophylactic

Procedure

Antimicrobial

Therapy

Anticipated Organism

Antimicrobial Coverage

Dental

Streptococcus

viridans

Procaine penicillin G, 600,000 units intramuscularly 1 hour before procedure and daily for 2 more days or Penicillin V, 400,000 units every 6 hours orally for 3 days or Erythromycin, 250 mg every 6 hours orally for 3 days or Clindamycin, 150 mg every 6 hours orally for 3 days

Genitourinary

Streptococcus

fecalis

Procaine penicillin G, 1.2 million units every 8 hours intramuscularly plus Streptomycin, 0.5 g every 12 hours intramuscularly. Begin 1 hour before procedure, continue for 72 hours

Skin surgery

Staphylococcus or epidermidis

Cephalexin, procedure

aureus

500 mg orally 1 hour before then 250 mg every 6 hours

hours Adapted

from Slaughter

for 72

et aL6

until the dental disease or infections have been treated adequately, since the chance of infection appears to be considerably less with an abnormal natural valve than with a prosthesis.g,14J5 Prophylaxis of late endocarditis: Adequate coverage with antibiotic prophylaxis during procedures or illnesses with a potential for bacteremia is imperative for the prevention of late prosthetic valve endocarditis. This is generally recognized for dental and genitourinary procedures, in which a high incidence rate of bacteremia has been demonstrated, but should also include minor skin surgery or any operation through a contaminated field (Table III).6~11 In addition, any infection in a patient with a prosthetic valve should receive prompt and vigorous treatment including appropriate antibiotic coverage. The selection of drugs should be individualized on the basis of the expected bacterial flora or culture material from the patient. Prosthetic valve endocarditis has been reported in patients undergoing procedures despite administration of usually recommended prophylactic antibiotic agents. This emphasizes the importance of treating preexisting dental or genitourinary disease before valve implantation and has prompted suggestions that higher than usual antibiotic dose levels be given for prophylaxis in patients with a prosthesis. Infectious prosthetic valve endocarditis remains a threatening and challenging complication. The importance of prophylactic measures to avoid infection cannot be overemphasized. When endocarditis does develop, the situation is not hopeless, as was commonly accepted in the past. Vigorous, systematic

medical treatment in conjunction with aggressive surgical intervention when indicated can be curative in many patients. Postperfusion

and Postpericardiotomy

Syndromes

Two relatively common and relatively benign syndromes associated with fever have been described after cardiac surgery, the postperfusion and postpericardiotomy syndromes. Their recognition is important because of the justifiable concern that fever in the postoperative period may represent prosthetic valve endocarditis or septicemia. Postperfusion Syndrome The postperfusion syndrome was first described as a triad of fever, splenomegaly and atypical lymphocytosis by Kreel et a1.27 in 1960. Battle and Hewlett?s had previously reported atypical lymphocytes in the blood of patients after open heart surgery in 1958. In the next few years a number of descriptions of the syndrome appeared, indicating that it occurs in 3 to 10 percent of patients undergoing cardiopulmonary bypass.193-"3

Clinical features: The onset occurs 1 to 8 weeks after operation, most commonly in the 3rd or 4th week. Fever usually appears first, followed by splenomegaly in about 1 week and the appearance of atypical lymphocytes after another 1 or 2 weeks.lg Patients are never very ill and commonly feel quite well. The syndrome presents more frequently in younger patients, and hence in those with congenital heart disease. Persons in whom the syndrome develops

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TABLE IV Clinical

Findings in Postperfusion Syndrome

Patients Reference

(no.)

Wheeler et al.zg Seaman and StarrI Perillie and Glenn30 Holswade et aL31 Smitha Reymat+ no. (total group) % (total

group)

6 11 3 14 9 21 64 -

Number of Cases

Onset (days after operation)

Fever

19-48 8-42 20-30 21-49 21-55 14-37 8-55 -

4 11 3 14 7 21 60 94

have always received substantial amounts of fresh blood, usually with cardiopulmonary bypass but occasionally without. The complete triad of findings is present in the majority of patients recognized as having the syndrome (Table IV). Fever occurs in virtually all, usually after the temperature has returned to normal following a febrile period immediately after operation. Characteristically, the temperature is normal or near normal each morning and rises to a late afternoon peak of 100’ to 103O F. lg Splenomegaly is recognized in more than three fourths of patients but is never marked. Atypical lymphocytes with fenestrated, eccentric or indented nuclei, perinuclear pallor and plasmacytoid cytoplasm eventually comprise 3 to 60 percent of the lymphocytes in the peripheral blood.‘g,33 Hepatomegaly is present in about one fourth of the patients with this syndrome, and results of liver function tests, particularly values for serum glutamic oxaloacetic transaminase, lactic dehydrogenase and bromsulfalein retention, are abnormal in about one half.34 Skin rash, pharyngitis and lymphadenopathy seldom occur. In addition to the appearance of atypical lymphocytes in the peripheral blood there is usually a lymphocytosis comprising 40 to 90 percent of leukocytes. The total leukocyte count is characteristically normal, and an absolute neutropenia is common. Anemia is not a characteristic feature of this syndrome.1g>31,34 Multiple blood cultures in many patients with the syndrome have uniformly been negative. Etiology: The similarity of the clinical findings to those of infectious mononucleosis and the presence of atypical “viral” lymphocytes immediately suggested an infectious viral origin for the postperfusion syndrome. Initially a serum-transmitted mononucleosis analogous to homologous serum hepatitis was suspected. 1g*31-33However, the lack of consistently positive heterophil agglutination titers in patients with the syndrome or in their blood donors, as well as the infrequency of common clinical features of mononucleosis such as pharyngitis and lymphadenopathy, made this questionable. In 1966 Kaariainen et a1.34 demonstrated a significant’rise in the titer of comple878

June lS75

The American Journal of CARDIOLOGY

Splenomegaly

Hepatomegaly

6 7 3 12 9 12 49 77

3 3 9 1 4 20 31

Atypical Lymphocytes 6 11 3 6 9 18 53 83

Lymphocytosis 6 11 3 11 9 16 56 8%

Leu kocytosis 1 2 1 3 2 2 11 17

ment-fixing antibodies to the cytomegalovirus in patients with the postperfusion syndrome. A year earlier the same workersa had reported similar increases in cytomegaloviral antibodies in patients with a disease resembling infectious mononucleosis but without pharyngitis, lymphadenopathy or a positive heterophil agglutination test, that is, findings very similar to those of the postperfusion syndrome.35 Subsequently numerous reports36-41 have implicated the cytomegalovirus in the postperfusion syndrome. Although a direct causative role has not been demonstated, the current hypothesis is that the postperfusion syndrome represents a cytomegaloviral infection transmitted in fresh transfused blood. Walsh et a1.42 and Kirsh et a1.43 have recently suggested that the EP virus may also be implicated in some patients. Treatment: The clinical course of the postperfusion syndrome is benign and the findings disappear in roughly the order of their appearance without specific treatment. Fever gradually subsides in 1 to 4 weeks and is rarely associated with malaise, anorexia or toxicity after the first few days. Splenomegaly and atypical lymphocytes may disappear with the fever but commonly persist for several months. Postpericardiotomy

Syndrome

The syndrome of fever and pleuropericarditis after cardiac surgery was first recognized by Janton and Soloff and their co-workers44*45 in the early 1950’s. It was initially called the “postcommissurotomy syndrome” because it appeared to occur only after mitral valve procedures, and was thought to represent reactivation of rheumatic fever. Ito et a1.,46describing the same syndrome after surgery for nonrheumatic heart disease in 1958, found that the only common feature was wide incision of the p.ericardium and suggested the term “postpericardiotomy syndrome.” Since then the syndrome has been reported in a variety of conditions producing pericardial inflammation, including penetrating wounds, blunt chest trauma and myocardial infarction.47-4g Clinical features: Symptoms most commonly appear in the 2nd or 3rd week after operation but may appear as early as 1 week or as late as 5 to 10 months

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COMPLICATIONS

after operation. 44,50-52The incidence rate, as high as 40 percent in early reports,44-46,50,51has recently been considerably lower. 52p53However, this reduction may reflect a shorter postoperative observation period or stricter criteria since Roses et al.53 found a 27 percent incidence rate of unexplained fever in addition to a 6 percent rate of occurrence of the complete syndrome, and Engle et al. 54 have continued to observe a 30 percent incidence rate. There is no apparent predilection based on age, sex or cause of heart disease. Fever and chest pain are the principal symptoms. Fever usually appears first and is low grade, the temperature seldom more than 103“ F5c-52; it may merge with the early postoperative febrile period but is more commonly a secondary fever. Typical pericardial pain occurs: sharp or knifelike, precordial or substernal, aggravated by recumbency and deep breathing and relieved by sitting upright. When pleural involvement also occurs, there may be associated pleuritic pain at the sides of the chest. A pleuropericardial friction rub is probably present in most cases at some time, but is typically fleeting.50-53 Other symptoms such as fatigue, cough, myalgia or arthralgia are infrequent.44,51-54 Laboratory findings are nonspecific and consistent with an inflammatory process. A neutrophilic leukocytosis with 10,000 to 30,000 mm3 white blood cells is present, and the erythrocyte sedimentation rate is elevated. Serum glutamic oxaloacetic transaminase values are normal, but those for lactic dehydrogenase may be elevated and results of the C-reactive protein test are often positive. There is no anemia related to the syndrome, and cultures of blood, throat, sputum and urine are negative. 51 The electrocardiogram shows a changing pattern of S-T segment elevation and T wave inversion characteristic of pericarditis. The cardiac silhouette may be enlarged on the chest X-ray film because of pericardial effusion, and pleural effusions may be visualized. Echocardiography may be useful for documenting the presence of a pericardial effusion and for excluding cardiac dilatation, but cardiac catheterization or angiography for this purpose is seldom necessary. Etiology: The initial episode persisted for less than 2 weeks in half of the patients described by Engle and Ito51 and for less than 1 month in most of the others. Pain subsides and the temperature and white blood count return to normal initially; later, abnormalities in the electrocardiogram and chest X-ray film disappear. Recurrences are not uncommon and may be multiple.44,50,52 There are no longterm sequelae, and neither chronic adhesive nor constrictive pericarditis has been observed.44,50-52 Increasing evidence has accumulated that the syndrome represents an immunologic response to damaged autologous tissue within the pericardium, as suggested initially by Ito et al.46 and Engle and Ito. The production of antibodies to heart tissue has been demonstrated by passive agglutination, indirect immunofluorescence, antiglobulin consumption and tanned red cell hemagglutination techniques in patients with the syndrome.55-5g Recently Engle et al.54

OF VALVE PROSTHESES-KLOSTER

reported a close correlation of heart-reactive antibodies with the clinical syndrome in a prospective double-blind study. However, the precise role of the antibody in the pathogenesis of the syndrome remains undefined.44s54T5s*5g Management: The syndrome is self-limited and treatment is primarily symptomatic. Fever and chest pain will be adequately controlled in most patients with rest and administration of salicylates. Corticosteroids are very effective and control symptoms promptly in those who do not respond to salicylates.44 Antibiotic drugs are not helpful. Pericardiocentesis may be necessary if signs of tamponade develop.51,54 Recognition of the postperfusion and postpericardiotomy syndromes in the febrile postoperative patient is important to avoid prolonged investigation for an unwarranted treatment for bacterial endocarditis.3,4~7*sJ8~26 The postperfusion syndrome can be specifically identified by the peripheral lymphocytosis and atypical lymphocytes and the postpericardiotomy syndrome by the presence of pericardial pain. Differentiation of both syndromes from endocarditis is aided by their less toxic course and the absence of high, spiking fever, anemia, petechiae and However, if there is any peripheral embolization. doubt as to the cause of postoperative fever, blood cultures should be obtained to exclude prosthetic valve endocarditis. Hemolytic

Anemia

Intravascular hemolysis is a well recognized consequence of heart valve replacement and occurs in the majority of patients with a valve prosthesis. Red blood cell survival studies have consistently shown a shortened red cell half-life in patients with artificial valves.60-64 Accelerated erythropoiesis compensates for the increased red cell destruction in many cases, and the only manifestation is laboratory evidence of hemolysis by more sensitive studies. However, Eyster et a1.64 reported below normal hematocrit values in 50 percent of their patients, and Williams et al.65 found hematocrit values of 35 percent or less in one third of patients with a Beall mitral valve prosthesis. Clinically important hemolytic anemia develops in a small number of patients and may become so severe as to require vigorous iron replacement therapy, blood transfusion or consideration of reoperation. The incidence rate of clinically significant anemia has ranged from 5 to 15 percent for different prosthetic valves, with a rate of less than 10 percent for most .63-68 Hemolytic disease has been reported with all of the commonly used prosthetic valves, including StarrEdwards, Magovern, Beall, Cutter-Smeloff and KayShiley prostheses. 60-70 Hemolysis is more common and more severe after aortic valve replacement than after mitral valve replacement, probably because of the greater pressure and velocity of blood flow in the aortic position.61-63 In patients with multiple valve replacement, the incidence of hemolysis is similar to that of aortic valve replacement.

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Pathophysiology

Etiologic factors: Mechanical trauma to red blood cells is the primary cause of hemolytic disease in patients with prosthetic heart valves. The mechanism is thought by most to be turbulence of blood flow through the prosthesis with resulting excessive shearing forces on the red blood ce11s.60,64+s6~71 Factors causing increased turbulence have been associated with a greater incidence or aggravation of hemolysis. The most notable example has been the association of hemolytic anemia with striking paraprosthetic valve regurgitation, presumably due to increased trauma to red cells passing through the small, slit-like defect in the suture line.60~s2~s6-6gPatients with high transvalvular pressure gradients and those with small valve prostheses likely to result in higher pressure gradients have a greater incidence of hemolytic disease.66,67*6g,72 Increased physical activity with a resulting increase in cardiac output and greater blood flow across the prosthesis has also been associated clinically with increased hemolysis, and recent studies have shown laboratory evidence of accelerated hemolysis during periods of acute exercise 64,73,74 The influence of different prosthetic materials on red blood cell destruction and particularly the apparently greater incidence of hemolysis in patients with a cloth-covered prosthesis is less clear. Myhre et a1.72 found a substantially higher level of hemolysis in patients with Starr-Edwards model 2300 aortic valve prostheses than in patients with earlier models and attributed this to the metallic ball and cloth covering of the cage. Others have related increased hemolysis with this prosthesis to unsatisfactory hemodynamics with excessive pressure gradients resulting in more turbulent flow.67,6g Hodam et a1.6g found hemolysis to be only slightly greater in cloth-covered StarrEdwards aortic valve prostheses than in earlier noncloth-covered models with similar gradients. Bonchek and Starr75 recently reviewed an extensive experience with different models of cloth-covered Starr-Edwards prostheses with various prosthetic material components and hemodynamic characteristics. They concluded that hemolysis is greater in the initial cloth-covered prostheses but reduced in the current cloth-covered “track” valve (model 2400) to levels seen with noncloth-covered prostheses, apparently as a result of the texture and type of cloth used. Contributory factors: Several contributory factors may accelerate hemolysis and aggravate the problem of hemolytic anemia. With increased erythropoiesis in response to hemolysis, iron utilization increases and iron deficiency may result. In addition, with intravascular hemolysis and hemoglobin breakdown substantial amounts of iron may be lost in the urine, thus aggravating the problem of iron deficiency 62,63,76,77 Further, iron-poor red cells exhibit increased fragility and are more vulnerable to mechanical trauma.61,62,76,78 Accelerated hematopoiesis requires increased folic acid, and folate deficiency has been de-

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scribed in these patients with consequent inability of the bone marrow to produce red cells as rapidly as they are destroyed. 63@,67 Chronic infection may inhibit erythropoiesis and permit the rate of hemolysis to exceed bone marrow production of red cells. Hemorrhage, sometimes related to anticoagulant therapy, may further increase the need for red cell production beyond bone marrow capacity. Finally, anemia itself may accelerate the rate of hemolysis as a result of both decreased blood viscosity and increased cardiac output, which increase turbulence of flow through the valve prosthesis. Diagnosis

Diagnostic studies may be directed toward one of four goals: demonstration of the presence of anemia, determination of the presence and severity of hemolysis, evaluation of deficiency states secondary to iron loss or accelerated hemotopoiesis, and consideration of factors contributing to increased hemolysis, particularly dysfunction of the prosthesis. The presence or absence of anemia can be established readily by a hematocrit or hemoglobin determination. However, the absence of anemia does not exclude the presence of significant hemolysis, since accelerated hematopoiesis may compensate for increased red cell destruction for a considerable period of time. Clinical anemia and iron or folate deficiency will eventually develop if hemolysis is substantial, and these problems can be more effectively prevented than treated. Red cell survival studies using chromium-51 tagged erythrocytes are the most direct method of quantitating increased red cell destruction, but they are expensive and time-consuming. Walsh et a1.63 and Myhre et a1.7g recently demonstrated an excellent relation between serum lactic dehydrogenase (LDH) levels and red cell survival in patients with hemolytic anemia, thereby providing a simple and sensitive screening test for intravascular hemolysis. Myhre et a1.7g reported LDH levels two and one half times greater than normal values in patients with a red cell half-life of 16 days or less, with exponentially higher LDH values as cell destruction became more severe. They attributed this to higher LDH levels in young erythrocytes, which are proportionately more abundant in severe hemolytic disease. The reticulocyte count is elevated in patients with hemolytic disease and is a nonspecific but fairly accurate indicator of the severity of the problem. Eyster et a1.64 found that the number of schistocytes in the peripheral blood of patients with artificial heart valves also is directly related to the severity of hemolysis. Fragmented cells were more frequent in patients with higher levels of cell destruction and correlated well with reticulocyte counts and LDH levels. Serum haptoglobin: Free hemoglobin resulting from intravascular hemolysis binds rapidly to plasma haptoglobin and the haptoglobin-hemoglobin complex is cleared by the reticuloendothelial system, resulting in decreased serum haptoglobin levels. Walsh et a1.6s and Eyster et a164 found decreased serum hap-

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toglobin levels a good index of intravascular hemolysis and useful as a screening test. Serum haptoglobin is depleted rapidly by brisk hemolysis, and the absence of haptoglobin simply indicates significant hemolysis without being quantitative. The presence of methemalbumin usually indicates brisk hemolysis and is associated with a short red cell survival time.65 Eyster et a1.64 have proposed a hematologic classification of the severity of hemolytic disease in patients with prosthetic valves to be used as a guide in management (Table V). As indicated previously, serum iron and folic acid may be depleted by the accelerated erythropoietic response to hemolytic anemia and should be evaluated in any patient with clinical anemia. In addition, Walsh and co-workers63,76 have found urinary iron determinations useful in estimating iron losses as a guide to therapy. This is usually present as hemosiderin in chronic low grade hemolysis, but may occur as hemoglobin in patients with rapid cell destruction that exceeds the haptoglobin binding capability.64 Valve dysfunction: In any patient with a prosthetic heart valve and hemolytic anemia, the possibility of dysfunction of the prosthesis must be considered. Paraprosthetic valve regurgitation is the most common cause and can often be detected clinically but has been reported without a characteristic regurgitant murmur, particularly in the mitral prosthesis.68 Similarly, the possibility of an excessively high transvalvular pressure gradient may be difficult to evaluate clinically. This problem occurs more frequently with certain models of prostheses, but may develop on an individual basis in some patients as a result of thrombus formation with impairment of poppet motion or compromise of the orifice.64e5*67*72 Hemodynamic and angiographic studies are often necessary to evaluate function of the prosthesis in patients with serious or refractory hemolysis.68 Treatment Medical treatment is effective in the majority of patients with hemolytic disease caused by prosthetic valves, Oral iron therapy is indicated in those with evidence of significant iron loss even in the absence of anemia. Walsh et a1.63 have recommended iron replacement in those whose urinary iron excretion is greater than 4 mg/day, and Eyster et a1.64 suggest iron therapy if hemosiderin is present in the urine. In this way, serious iron depletion and anemia may be prevented. Vigorous oral iron replacement is successful in treating most patients with iron deficiency anemia.76 In a few cases urinary iron loss may exceed the absorptive capacity of the gastrointestinal tract and parenteral iron replacement may be necessary.62s64 Uncommonly, blood transfusion may be necessary to correct refractory anemia, after which oral iron therapy is sufficient to maintain a satisfactory hematocrit level. Whenever anemia is refractory to vigorous iron therapy, the possibility of folate deficiency should be considered and treated if found to be present. Mild limitation of physical activity is probably

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TABLE V

Severity of Hemolysis with Prosthetic Valve Hemolysis Mild Hemosiderinuria Hemoglobinuria Schistocytosis Reticulocytosis Haptoglobins Lactic dehydrogenase

Moderate

Marked Present

Present Absent

Present Absent


.1% >5% Absent >50 units

Adapted from Eyster et aLfi4 < = less than; > = greater than;

Severe

>>l% >>5% Absent >>500 units

>> = much greater

than.

helpful in decreasing intravascular hemolysis.63@,67 The addition of propranolol to restriction of activity has been suggested by Santinga and Kirsh67 in patients with borderline control of anemia. Steroid therapy has usually not been helpfu1.66*67 Reoperation primarily for refractory hemolytic anemia due to leak or dysfunction of the prosthesis is seldom necessary.64p65,67*68,75When corrective surgery has been carried out, it has not consistently been successful in controlling the hemolytic process.66,68 Thrombosis

and Embolism

Thromboembolic complications have been a continuing and distressing problem of prosthetic heart valves. Although many patients experience only transient or mild disability, the incidence of severe or fatal systemic embolization or prosthetic valve dysfunction remains substantial despite anticoagulant therapy and refinements in valve design.1~6g,80-86 The incidence of thromboembolic complications and the evolution of valve design changes directed toward preventing these problems are discussed in detail in an earlier section of this Symposium.75 The diagnosis and management will be discussed in this section. Diagnosis The term thromboembolism has generally been used to include both fibrin deposition or neointimal formation on the prosthesis and subsequent systemic embolization of the material. As a pathogenetic concept this is reasonable since the two processes are intimately related. However, from a diagnostic and therapeutic viewpoint the two are quite different. Detection of thrombus on a prosthesis depends primarily on the presence and demonstration of some degree of prosthetic valve dysfunction due to impaired poppet motion or decreased area of the valve orifice. This can be accomplished with reasonable accuracy by methods outlined later in patients in whom prosthetic valve dysfunction is suspected. More frequently the patient presents after a clinically obvious systemic embolic episode and evaluation is requested to determine if there is residual thrombotic material on the prosthesis. In our experience, studies in this

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situation usually show no evidence of thrombus on the prosthesis or abnormal function, probably because most of the material previously on the valve has embolized. This is particularly pertinent when considering cardiac catheterization studies, with which we have usually been unable to demonstrate hemodynamic abnormalities involving the prosthesis in patients with recent systemic embolization unless there are other clinical findings pointing to prosthesis dysfunction. Auscultation and phonocardiography: Abnormal auscultatory findings are often present in prosthetic valve thrombosis. These should be looked for carefully in patients with symptoms suggesting dysfunction of the prosthesis (recurrence of heart failure and syncope, for example) but may be discovered on routine examination in patients apparently doing well. Common findings include variations in intensity, diminution or loss of prosthetic valve opening sounds due to thrombus on the valve struts, new murmurs of valve regurgitation due to incomplete seating of the poppet or murmurs of mitral or tricuspid stenosis.87T8s The latter can occur as a result of a small prosthesis or as an Austin Flint murmur with aortic regurgitation ” but most commonly indicate a stenotic prosthesis. Similar auscultatory abnormalities may be observed with aortic or mitral ball or disc variance, but these are also potentially lethal complications and cause for further evaluations7JQsi Phonocardiography is helpful in establishing control data for individual patients and in documenting variations in prosthetic valve sounds or murmurs.87,g2,g3 In addition, the timing of opening and closing sounds of normally functioning prostheses has been well described, and alterations in these may be helpful in assessing function.g4,g5 An abnormally late mitral opening sound has been associated with impaired poppet motion due to thrombus, and an unusually early opening sound related to a stenosed mitral orifice.g6-g8 Echocardiography: This is a promising technique for evaluating prosthetic valve function or even directly demonstrating the presence of thrombus noninvasively. Mitral disc prostheses appear to be most suitable for ultrasonic evaluation, and there have been several reports of abnormal disc motion detected by echocardiography with subsequent surgical verification of prosthetic valve dysfunction due to thrombus.gg-102 Variations of abnormal motion have included decreased excursion of the entire disc and incomplete opening of one margin with “cocking.” Detection by echocardiography of mitral ball valve malfunction due to thrombus has also been reported, with delayed ball opening, incomplete opening or sticking and a decreased diastolic opening slope.as~g7 However, variations in physical orientation of the prosthesis hamper comparison of echocardiographic patterns among patients, and serial studies beginning with an early postoperative control study are recommended.ggJ02 Recently, using a multiple-element echocardiographic technique, we were able to demon-

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strate thrombus on the base of a mitral valve prosthesis, which was subsequently verified at operation. Evaluation of aortic valve prostheses is much more limited because of technical difficulties in recording satisfactory echocardiograms.lo2 Cardiac fluoroscopy: This procedure is frequently helpful in demonstrating impaired poppet motion in prostheses with poppets of radiopaque materials. Incomplete opening or sticking of ball valves and “cocking” of discs is dramatically apparent and can be recorded on tine film for later analysis. Unfortunately, these findings are limited to prosthetic valve dysfunction due to thrombus on the struts or extending upward appreciably from the base. Poppet motion may appear normal in patients with severe stenosis of a prosthesis caused by thrombus occluding the valve orifice. cardiac catheterization and angiography: These techniques may be unnecessary when patients have clear clinical evidence of prosthetic valve dysfunction and there are strong supporting data from the studies described. This situation is most likely to occur when the need for reoperation appears urgent, as in obstruction of a tricuspid prosthesis when fluoroscopic studies show that the poppet is barely moving and the patient is severely i11.88 More commonly, the clinical and laboratory findings are less convincing or a comprehensive evaluation is desirable before making therapeutic decisions that may include reoperation. The critical data include the pressure gradient across the prosthesis in question and a simultaneous cardiac output determination to permit calculation of the effective orifice area. Average values and ranges are available for most commonly used prostheses and are helpful guides.lo3-lo7 In patients with regurgitation, careful positioning during angiography may demonstrate that the regurgitant jet is. through the orifice and clearly due to improper seating of the poppet rather than paravalvular due to a leak in the suture line. Actual demonstration of thrombus on the valve as a filling defect on the angiogram has been rare and therefore of no practical help. To emphasize a previous statement, the probability of obtaining hemodynamic or angiographic evidence indicative of thrombus on a prosthesis is greatest in patients with other findings suggesting prosthetic valve dysfunction. The likelihood of demonstrating abnormal findings in patients with a systemic embolus but without clinically apparent valve malfunction is small and we discourage catheterization studies in such cases. Management Reoperation: When significant prosthetic valve dysfunction due to thrombus is present, prompt reoperation is usually necesssary. The urgency of reoperation is obvious in patients in clinical difficulty with heart failure, low cardiac output states, hypotension or arrhythmias. Reoperation in patients without serious symptoms may seem less urgent, but we have observed striking and precipitous deterioration in some instances. This has occurred particularly in

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patients with tricuspid valve obstruction and more recently in patients with Starr-Edwards aortic “track” valves not receiving anticoagulant agents who have manifested orifice occlusion by thrombus.75~88 Hemodynamic abnormalities may be surprisingly severe considering the absent or relatively benign symptoms. In patients with the model 1000 Starr-Edwards aortic valve prosthesis the differential diagnosis between thrombosis and ball variance may not be clear, but this presents no practical problem since both require early reoperation.gl When clinical and laboratory findings are equivocal and, most often, if hemodynamic data are borderline, patients may be observed for a time but must be followed up closely with clear instructions to return promptly if they experience any change in symptoms. Anticoagulant therapy: Management after a sys-

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temic embolic episode is less clear-cut and specific. The adequacy of anticoagulant therapy must be reviewed and necessary changes made, since control frequently has been erratic or ineffective in patients with emboli. Despite the decreased incidence of embolism with cloth-covered prostheses, we continue to recommend anticoagulant therapy for all patients with valve prostheses unless there is a major contraindication; most other centers concur.75,84-86,108 Appropriate evaluation to exclude residual thrombus on the prosthesis should be carried out, although this is usually not productive. Finally, patients with an older model prosthesis who have repeated embolic episodes despite adequate anticoagulant therapy should be considered for reoperation and insertion of one of the newer prostheses which have a markedly smaller incidence of embolization.75~82~84~86

References 1. Herr R, Starr A, McCord CW, et al: Special problems following valve replacement. Ann Thorac Surg 1:403-415, 1965 2. Amoury RA, Bowman FO Jr, Maim JR, et al: Endocarditis associated with intracardiac prosthesis. J Thorac Cardiovasc Surg 5 1~36-40. 1966 3. Cohn LH, Roberts WC, Rockoff SD, et al: Bacterial endocarditis involving prosthetic mitral valves. Circulation 33:209-217, 1966 Roberts WC, Morrow AG: Bacterial endocarditis involving prosthetic mitral valves. Arch Pathol 82: 164- 169, 1966 Slaughter L, Morris JF, Starr A: Prosthetic valvular endocarditis. Circulation 47: 1319-1326, 1973 Dismukes WE, Karchmer AW, Buckley MJ, et al: Prosthetic valve endocarditis. Circulation 48:365-377, 1973 Block PC, DeSanctis RW, Weinberg AN, et al: Prosthetic valve endocarditis. J Thorac Cardiovasc Surg 60:540-548. 1970 8. Okies JE, Viroslav J, Williams TW Jr: Endocarditis after cardiac valvular replacement. Chest 59:198-202, 1971 9. Yeh TJ, Anabtawi IN, Cornett VE, et al: Bacterial endocarditis following open-heart surgery. Ann Thorac Surg 3:29-36, 1967 10. Fraser RS, Rossall RE, Dvorkin J: Bacterial endocarditis occurring after open-heart surgery. Can Med Assoc J 96:15511558, 1967 11. Shafer RB, Hall WH: Bacterial endocarditis following open heart surgery. Am J Cardiol 25602-607, 1970 12. Geracl JE, Dale AJD, McGoon DC: Bacterial endocarditis and endarterltis following cardiac operations. Wls Med J 62:302315, 1963 13. Firor WB: lnfectlon following open-heart surgery, wlth special reference to the role of prophylactic antlblotlcs. J Thorac Cardlovasc Surg 53:371-378, 1967 14. Stetn PD, H&ken DE, Dexter L: The nature and preventlon of prosthetic valve endocardltis. Am Heart J 71:393-407. 1966 15. Killen DA, Collins HA, Koenlg MG, et al: Prosthetic cardiac valves and bacterial endocardltls. Ann Thorac Surg 3:236247, 1970 16. Wefnaleln L, Rubin RH: lnfectlve endocardltls--1973. Prog Cardiovasc Dls 16:239-274, 1973 17. Halrston P, Lee WH Jr: Management of infected prosthetic heart valves. Ann Thorac Surg 9:229-237, 1970 18. Stinson EB, Castellino RA, Shumway NE: Radlologlc signs in endocardltls following prosthetic valve replacement. J Thorac Cardiovasc Surg 56:544-557, 1966 19. Seaman AJ, Starr A: Febrile postcardiotomy lymphocytlc spienomegaly: a new entity. Ann Surg 156:956-960, 1962 20. Goodman JS, Schaffner W, Colllns HA, et al: Infection after cardiovascular surgery. N Engl J Med 278: 117-123, 1968

21. Sande MA, Johnson WD Jr, Hook EW, et al: Sustained bacteremia in patients with prosthetic cardiac valves. N Engl J Med 286:1068-1070, 1972 22. Weinstein L: Infected prosthetic valves: a diagnostic and therapeutic dilemma. N Engl J Med 286:1108-l 109, 1972 23. Walker SR, Shumway NE, Merigan TC: Management of infected cardiac valve prostheses. JAMA 208:531-533. 1969 24. Buckley MJ, Mundth ED, Daggett WM, et al: Surgical management of the complications of sepsis involving the aortic valve, aortic root and ascending aorta. Ann Thorac Surg 12: 391-399, 1971 25. Nelson RM, Jenson CB, Peterson CA, et al: Effective use of prophylactic antibiotics in open-heart surgery. Arch Surg 90: 731-736, 1965 26. Conte JE, Cohen SN, Roe BB, et al: Antibiotic prophylaxis and cardiac surgery. Ann Intern Med 76:943-949, 1972 27. Kreel I, Zaroff LI, Canter JW, et al: A syndrome following total body perfusion. Surg Gynecol Obstet 11:317-32 1, 1960 28. Battle JD Jr, Hewlett JS: Hematologic changes observed after extracorporeal circulation during open-heart operations. Cleve Clin Q 25:112-l 15, 1958 29. Wheeler EO, Turner JD, Scannell JO: Fever, splenomegaly and atypical lymphocytes: a syndrome observed after cardiac surgery utilizing a pump-oxygenator. N Engl J Med 266:454456, 1962 30. Perlllle P, Glenn W: A new post-cardiotomy syndrome. Yale J Biol Med 34:625-628. 1962 31. Holswade OR, Engle MA, Redo SF, et al: Development of viral diseases and a viral disease-like syndrome after extracorporeal clrculatlon. Clrculatlon 27:6 12-8 15, 1963 32. Smith DR: A syndrome resembling infectious mononucleosis after open-heart surgery. Br Med J 1:946-948, 1964 33. Reyman TA: Postperfuslon syndrome. A revlew and report of 21 cases. Am Heart J 72:i 16-123, 1966 34. Kearlainen L, Klemoia E, Paloheimo J: Rise of cytomegalovlrus antibodies In an Infectious-mononucleosis-llke syndrome after transfusion, Br Med J 1:1270-1272, 1968 as a possible 35. Klemoia E, Kaarlalnen L: Cytomegalovirus cause of disease resembling Infectious mononucleosis. Br Med J 2:1099-1102, 1965 36. Lang DJ, Scolnlck EM, Wllierson JT: Assoolatlon of cytomegalovlrus Infection wlth the postperfuslon syndrome. N Engl J Med 278:1147-l 149. 1968 37. Paloheimo JA, Essen von R, Klemola E, et al: Subcllnlcal cytomegalovirus infections and cytomegalovlrus mononucleosis after open heart surgery. Am J Cardiol 22:624-630, 1968 infection and the 38. Lang DJ, Hanshaw JB: Cytomegalovirus postperfusion syndrome. N Engl J Med 280:1145-i 149, 1969

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65.

Foster KM, Jack I: A prospective study of the role of cytomegalovirus in post-transfusion mononucleosis. N Engl J Med 280:1311-1316, 1969 Kanto GL, Johnson BL Jr: Cytomegalovirus infection associated with cardiopulmonary bypass. Arch Intern Med 125:488492, 1970 Kantor GL, Goldberg LS: Cytomegalovirus-induced postperfusion syndrome. Semin Hematol 8:261-266, 1971 Walsh JH, Gerber P, Purcell RH: Viral etiology of the postperfusion syndrome. Am Heart J 80:146, 1970 Kirsh MM, McIntosh K, Kahm DR, et al: Postpericardiotomy syndrome. Ann Thorac Surg 9:158-179. 1970 Janton OH, Glover RP, O’Neill TJE, et al: Results of surgical treatment for mitral stenosis. Circulation 6:321-333, 1952 Soloff LA, Zatuchni J, Janton OH, et al: Reactivation of rheumatic fever following mitral commissurotomy. Circulation 8: 481, 1953 Ito 1, Engle MA, Goldberg HP: Postpericardiotomy syndrome following surgery for nonrheumatic heart disease. Circulation 17:549-556, 1958 Heller R, Rahimtoola SH, Ehsani A, et al: Cardiac complications resulting from penetrating wounds involving the heart. Arch Intern Med 134:491-496, 1974 Tabatznik B, lsaacs JP: Postpericardiotomy syndrome following traumatic hemopericardium. Am J Cardiol 7:83-96. 1961 Dressier W: The postmyocardial-infarction syndrome. Arch Intern Med 103:28-42, 1959 Lisan P, Reale A, Likoff W: The post-mitral commissurotomy syndrome: a four year clinical, pathologic and serologic study, and its relation to restenosis. Ann Intern Med 50:1352-1358, 1959 Engle MA, Ito T: The post-pericardiotomy syndrome. Am J Cardiol 7:73-82. 1961 Uricchlo JF: The post-commissurotomy (postpericardiotomy) syndrome. Am J Cardiol 12:436-438, 1963 Roses DF, Rose MR, Rapaport FT: Febrile responses associated with cardiac surgery. Relationships to the postpericardiotomy syndrome and to altered host immunologic reactivity. J Thorac Cardiovasc Surg 67:251-257, 1974 Engle MA, McCabe JC, Ebert PA, et al: The postpericardiotomy syndrome and anti-heart antibodies. Circulation 49: 401-406, 1974 Gery I, Davies AM, Ehrenfeld EN: Heart-specific auto antibodies. Lancet 1:471-472, 1960 Van der Geld H: Anti-heart antibodies in the postpericardiotomy and the postmyocardial-infarction syndromes. Lancet 2:617-621. 1964 Robinson J, Brigden W: immunological studies in the postcardiotomy syndrome. Br Med J 1:706-709, 1963 Kaplan MH, Frengley JD: Autoimmunity to the heart in cardiac disease. Current concepts of the relation of autoimmunity to rheumatic fever, postcardiotomy and postinfarction syndromes and cardiomyopathies. Am J Cardiol 24:459-473, 1969 Roberts Cl, Lessof MH: Immunological aspects of cardiovascular disorders. In, Progress in Cardiology, II (Vu PN, Goodwin JF, ed). Philadelphia, Lea & Febiger, 1973, p 31-48 Brodeur MTH, Sutherland DW, Koler RD, et al: Red blood cell survival in patients with aortic valvular disease and ball-valve prostheses. Circulation 32:570-581, 1965 Anderson MN, Gabrieli E, Zizzi J: Chronic hemolysis in patients with ball-valve prostheses. J Thorac Cardiovasc Surg 50:501-510, 1965 Brodeur MTH, Koler RD, Starr A, et al: Red cell survival in patients with mitral valvular disease and mitral valve prostheses. Circulation 33: Suppl l:l-140-I-151, 1966 Walsh JR, Starr A, Ritrmann LW: Intravascular hemolysis in patients with prosthetic valves and valvular heart disease. Circulation 39: Suppl l:l-135-I-140, 1969 Eyster E, Rothchild J, Mychajliw 0: Chronic intravascular hemolysis after aortic valve replacement. Long term study comparing different types of ball-valve prostheses. Circulation 44: 657-665, 1971

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89.

35

Williams JC Jr, Vernon CR, Daicoff GR, et al: Hemolysis following mitral valve replacement with the Beall valve prosthesis. J Thorac Cardiovasc Surg 61:393-396, 1971 Rodgers BM, Sabiston DC Jr: Hemolytic anemia following prosthetic valve replacement. Circulation 39:1-155-l-161, 1969 Santinga JT, Kirsh MM: Hemolytic anemia in series 2300 and 2310 Starr-Edwards prosthetic valves. Ann Thorac Surg 14: 539-544. 1972 Kastor JA, Akbarian M, Buckley MJ, et al: Paravalvular leaks and hemolytic anemia following insertion of Starr-Edwards aortic and mitral valves. J Thorac Cardiovasc Surg 56:279-288, 1968 Hodam R, Anderson R, Starr A, et al: Further evaluation of the composite seat cloth-covered aortic prosthesis. Ann Thorac Surg 12:621-638. 1971 Vogel JHK, Paton BC, Overy HR, et al: Abnormal hemodynamic function after disc mitral valve replacement. Circulation 39: Suppl l:l-141-l-148, 1969 Nevaril CG, Lynch EC, Alfrey CP Jr, et al: Erythrocyte damage and destruction induced by shearing stress. J Lab Clin Med 711784, 1968 Myhre E, Dale J, Rasmussen K: Erythrocyte destruction in different types of Starr-Edwards aortic ball valves. Circulation 42:515-520, 1970 Sears DA, Crosby WH: Intravascular hemolysis due to intracardiac prosthetic devices. Diurnal variations related to activity. Am J Med 39:341-354. 1965 Rasmussen K, Anderson A, Myhre E, et al: Hemolysis during acute exercise in patients with aortic ball valve prostheses. Acta Med Stand 188:281-286, 1970 Bonchek LI, Starr A: Ball valve prostheses: a current appraisal of late results. Am J Cardiol 35:843-854, 1975 Walsh JR, Brodeur MTH, Ritzmann LW, et al: Urinary iron excretion in patients with prosthetic heart valves. JAMA 198: 505-510. 1966 Roeser HP, Powell LW: Urinary iron excretion in valvular heart disease and after heart valve replacement. Blood 36:785-792, 1970 Myhre E, Dale J, Rasmussen K: Quantitative aspects of hemolysis in aortic valvular disease and ball valve prosthesis. Acta Med Stand 189:101-104, 1971 Myhre E, Rasmussen K, Anderson A: Serum lactic dehydrogenase activity in patients with prosthetic heart valves: a parameter of intravascular hemolysis. Am Heart J 80:463-468, 1970 Kloster FE, Bristow JD, Griswold HE: Medical problems in mitral and multiple valve replacement. Prog Cardiovasc Dis 7: 504-529. 1965 Herr RH, Starr A, Pierie WR, et al: Aortic valve replacement. A review of six years’ experience with the ball-val;e prosthesis. Ann Thorac Sura 6:199-218, 1968 Hodam R, Starr A, Raible D, et al: Totally cloth-covered prostheses. A review of two years’ clinical experience. Circulation 41: Suppl ll:ll-33-11-38. 1970 Bigelow JC, Herr RH, Wood JA, et al: Multiple valve replacement. Review of five years’ experience. Circulation 38:656663, 1968 Bonchek LI, Anderson RP, Starr A: Mitral valve replacement with cloth-covered composite-seat prostheses. J Thorac Cardiovasc Surg 67:93-109, 1974 Duvolsln GE, Brandenburg RO, McGoon DC: Factors affecting thromboembolism associated with prosthetic heart valves. Circulation 35: Suppl 1:1-70-l-76, 1967 Javler RP, Hlldner FJ, Berry W, et al: Systemic embolism and the Beall mitral valve prosthesis. Ann Thorac Surg 10:20-26. 1970 Hylen JC: Mechanical malfunction and thrombosis of prosthetic heart valves. Am J Cardiol 30:396-404, 1972 Vanderveer JB, Rhyneer GS, Hodam RP, et al: Obstruction of tricuspid ball-valve prostheses. Circulation 43: Suppl 1:1-62-l67, 1971 Schaefler RA, McAnulty JH, Starr A, et al: Diastolic murmurs in the presence of Starr-Edwards mitral prostheses: with emphasis on the genesis of the Austin-Flint murmur. Circulation

COMPLICATIONS

551402~409. 90.

1975

OF

VALVE

PROSTHESES-KLOSTER

100.

Hylen JC, Kloster FE, Herr RH, et al: Phonocardiographic diagnosis of aortic ball variance. Circulation 38:90-102, 1968 9 1. Hylen JC, Kloster FE, Starr A, et al: Aortic ball variance: diagnosis and treatment. Ann Intern Med 72:1-8, 1972 92. Demany MA, Zimmerman HA: Thrombosis of a mitral discvalve prosthesis: diagnostic importance of the absent opening click. Am Heart J 80:816-819, 1970 93. Belenkie I, Carr M, Schlant RC, et al: Malfunction of a CutterSmeloff mitral ball valve prosthesis: diagnosis by phonocardiography and echocardiography. Am Heart J 86:399-403, 1973 94. Hultgren HN, Hubls H: A phonocardiographic study of patients with the Starr-Edwards mitral valve prosthesis. Am Heart J 69:306-319, 1965 95. Bolcouri OW, Bristow JD, Starr A, et al: A phonocardiographic study of patients with multiple Starr-Edwards prosthetic valves. Br Heart J 28531-538, 1966 96. Cralge E, Hutchin P, Sutton R: Impaired function of cloth-covered Starr-Edwards mitral valve prosthesis. Detection by phonocardiography. Circulation 41: 141-148, 1970 97. Pfelffer J, Goldschlager N, Sweatman T, et al: Malfunction of mitral valve prosthesis due to thrombus. Am J Cardiol 29:9599, 1972 98. Wise JR Jr, Webb-Peploe M, Oakley CM: Detection of prosthetic mitral valve obstruction by phonocardiography. Am J Cardiol 28:107-110, 1971 99. Popp RL, Carmichael BM: Cardiac echography in the diagnosis of prosthetic mitral valve malfunction (abstr). Circulation 43: Suppl ll:ll-33, 1971

Oliva PB, Johnson ML, Pomerantz M, et al: Dysfunction of the Beall mitral prosthesis and its detection by cinefluoroscopy and echocardiography. Am J Cardiol 31:393-396. 1973 10 1. Johnson ML, Holmes JH, Paton BC: Echocardiographic determination of mitral disc valve excursion. Circulation 47:12741280, 1973 102. Segal BL, Konecke LL, Kawai N, et al: Echocardiography. Current concepts and clinical application. Am J Med 57:267283, 1974 103. Kloster FE, Farrehi C, Mourdjinis A, et al: Hemodynamic studies in patients with cloth-covered composite-seat Starr-Edwards valve prostheses. J Thorac Cardiovasc Surg 60:879888, 1970 104. Winter TO, Reis RL, Glancy DL, et al: Current status of StarrEdwards cloth-covered prosthetic cardiac valves. Circulation 45:Suppl 1:1-14-l-24, 1972 105. Reid JA, Stevens TW, Sigwart U, et al: Hemodynamic evaluation of the Beall mitral valve prosthesis. Circulation 45: Suppl 1:1-1-l-7, 1972 106. Lepley D Jr, Reuben CF, Flemma RJ, et al: Experience with the Bjork-Shiley prosthetic valve. Circulation 47: Suppl lll:lll51-111-55, 1973 107. Bjork VO, Holmgren A, Olin C, et al: Clinical and hemodynamic results of aortic valve replacement with the Bjork-Shiley tilting disc valve prosthesis. Stand J Thorac Cardiovasc Surg 5: 177-191,197l 108. Friedli B, Aerichide N, Grandin P, et al: Thromboembolic complications of heart valve prostheses. Am Heart J 81:702708, 1971

June 1975

The American Journal of CARDIOLOGY

Volume 35

885